Tauopathies: 2002

(2002). "PET in Alzheimer's." J Nucl Med 43(5): 36N.

(2002). "Homocysteine may raise Alzheimer's risk. Keep homocysteine levels in check by getting enough folic acid in your diet." Health News 8(4): 4.

(2002). "Seeking security for wandering Alzheimer patients." Johns Hopkins Med Lett Health After 50 14(2): 6-7.

(2002). "[Atypical neuroleptics in dementia. Managing behavioral disorders early and efficiently]." MMW Fortschr Med 144(10): 60-1.

(2002). "Understanding changes in cholinergic function: implications for treating dementia." J Clin Psychiatry 63(3): 259-69.

(2002). "[Geriatric assessment in 3 steps. Often mental decline is not correctly assessed]." MMW Fortschr Med 144(8): 51.

(2002). "[Smoking, drinking and mental laziness. It hastens cognitive cut-down]." MMW Fortschr Med 144(7): 71.

(2002). "Insoluble problem?" Nat Med 8(3): 191.

(2002). "A leisurely approach to averting Alzheimer's." Health News 8(2): 6-7.

(2002). "UCLA PET in Alzheimer's diagnosis gets nation's attention." J Nucl Med 43(2): 20N.

(2002). "[Alzheimer dementia. Intervening as early as possible]." MMW Fortschr Med 144(1-2): 67.

(2002). "Highlights from the annual scientific assembly: managing the stages of Alzheimer's disease--new management options." South Med J 95(1): 102-6.

Abbott, A. (2002). "Neurologists strike gold in drug screen effort." Nature 417(6885): 109.

Abe, T. and H. Tohgi (2002). "[Free radical in Alzheimer's disease]." Nippon Ronen Igakkai Zasshi 39(3): 268-70.

Abel, L. A., F. Unverzagt, et al. (2002). "Effects of stimulus predictability and interstimulus gap on saccades in Alzheimer's disease." Dement Geriatr Cogn Disord 13(4): 235-43.
OBJECTIVES: Studies of saccadic eye movement impairment in Alzheimer's disease (AD) have largely focused on simple reflexive eye movements and the antisaccade task. The effects of manipulating stimulus timing have been little studied. METHODS: Fourteen patients with mild to severe AD and 11 age-matched controls were studied on the antisaccade task, while latencies on simultaneous, gap and predictable tasks were recorded from 11 patients and 11 controls. Dementia severity was assessed with the Mini-Mental State Examination. RESULTS: As a group, patients' latencies were significantly higher and more variable on the simultaneous and gap tasks. Predictable task performance was similar in mean but significantly more variable. Grossly anticipatory responses by patients were common on the predictable, simultaneous and gap tasks. Exclusion of these from subject means revealed that AD patients, when making target-driven saccades, demonstrated a gap effect of similar magnitude to normal subjects. Patients made significantly fewer correct antisaccades and significantly more reflexive errors not followed by a corrective antisaccade than did controls. CONCLUSIONS: The frequent presence of grossly anticipatory saccades may reflect dysfunction of fixation mechanisms possibly involving projections from frontal lobe to superior colliculus. The less frequently seen, marked prolongation of latency may reflect changes in posterior parietal mechanisms mediating reflexive saccade generation. The presence of the gap effect demonstrates a continued ability to benefit from externally controlled stimulus disengagement. Patients' ability to make appropriately timed saccades to targets of known locations was particularly impaired, but the target sequence itself was at least grossly correctly learned. Larger studies may be able to identify clinically distinct populations of AD patients.

Abramova, N. A., D. S. Cassarino, et al. (2002). "Inhibition by R(+) or S(-) pramipexole of caspase activation and cell death induced by methylpyridinium ion or beta amyloid peptide in SH-SY5Y neuroblastoma." J Neurosci Res 67(4): 494-500.
Cell models of neurodegenerative diseases (NDD) can involve expression of mutant nuclear genes associated with Mendelian forms of the diseases or effects of toxins believed to replicate essential disease features. Death produced by exposing neural cells to methylpyridinium ion (MPP(+)) or neurotoxic beta amyloid (BA) peptides is frequently used to study features of the sporadic, most prevalent forms of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. We examined in replicating SH-SY5Y human neuroblastoma cells the release of cytochrome C into cytoplasm, activation of caspases 9 and 3, and loss of calcein retention as markers of the "mitochondrial" pathway of cell death. Exposure to 5 mM MPP(+), which induces apoptotic cell death within 18-24 hr, released cytochrome C within 4 hr, activated caspases 9 and 3, and reduced calcein accumulation. BA 25-35 peptide produced more rapid and greater elevations of caspase 3 activity; no effects were observed with the nontoxic BA 35-25 reverse sequence. The dependence on mitochondrial transition pore (MTP) activity of MPP(+)-induced caspase activations was demonstrated by preincubation with bongkreckic acid, which blocked elevations of caspases 9 and 3. Stereoisomers of pramipexole (PPX), a free radical scavenger and inhibitor of MTP opening, inhibited caspase activation (MPP(+) and BA) and restored calcein accumulation (MPP(+)). Our results demonstrate that MPP(+) and BA can induce cell death through MTP-dependent activation of caspase cascades. PPX stereoisomers interfere with activation of these cell death pathways and may be useful clinically as neuroprotectants in PD and AD and related diseases.

Abrisqueta-Gomez, J., O. F. Bueno, et al. (2002). "Recognition memory for emotional pictures in Alzheimer's patients." Acta Neurol Scand 105(1): 51-4.
OBJECTIVE: The purpose of the present study was to examine whether Alzheimer's Disease (AD) patients can benefit from the emotional content of visual stimuli in a picture recognition test. METHODS: Sixteen patients with AD and 19 normal controls matched for age and years of education, were studied. Sixteen pictures (with varying emotional contents) were presented to each participant. Thirty minutes later, a recognition test was applied with the target-pictures mixed among 34 others of similar content. The subjects were instructed to rate them as pleasant, unpleasant or indifferent. RESULTS: The total of pictures correctly recognized by the AD patients (75.4% of the target-pictures) was smaller than that of the controls (96.4%). Controls recognized more emotional pictures than indifferent pictures. CONCLUSION: Emotional content enhanced recognition of pictures in normal subjects, whereas for the Alzheimer's subjects the emotional significance attached to the pictures was of no benefit to enhance recognition.

Adamec, E., P. Mohan, et al. (2002). "Calpain activation in neurodegenerative diseases: confocal immunofluorescence study with antibodies specifically recognizing the active form of calpain 2." Acta Neuropathol (Berl) 104(1): 92-104.
The calcium-activated protease calpain cleaves a variety of biologically important proteins and serves, therefore, as a key regulator of many cellular functions. Activation of both main isoforms, calpain 1 and calpain 2, was demonstrated previously in Alzheimer's disease. In this report, antibodies specifically recognizing the active form of calpain 2 were used to investigate calpain 2 activation in a broad range of neurodegenerative diseases, utilizing multiple-label confocal immunofluorescence imaging. With rare exceptions, the active form of calpain 2 was found in colocalization with hyperphosphorylated tau protein. Aggregates of mutated huntingtin, alpha-synuclein, or unidentified protein in motor neuron disease type of frontotemporal dementia were always negative. These findings indicate that calpain 2 activation is not a general response to protein aggregation. In tauopathies, more pathological inclusions were labeled for hyperphosphorylated tau than for activated calpain 2. The extent of colocalization varied in both a disease-specific and cell-type specific manner. The active form of calpain 2 was detected in 50-75% of tau neurofibrillary pathology in Alzheimer's disease, Alzheimer neurofibrillary changes and Down's syndrome, as well as in the accompanying Alzheimer-type tau pathology in diffuse Lewy bodies disease, progressive supranuclear palsy, and corticobasal degeneration. For glial cells, only 10-25% of tuft-shaped astrocytes, glial plaques, or coiled bodies contained activated calpain 2. The majority of Pick bodies were negative. The association of calpain 2 activation with hyperphosphorylated tau might be the result of an attempt by the calpain proteolytic system to degrade the tau protein aggregates. Alternatively, calpain 2 could be directly involved in tau hyperphosphorylation by modulating protein kinase activities. Overall, these results provide evidence of the important role of the calpain proteolytic system in the pathogenesis of neurodegenerative diseases with tau neurofibrillary pathology.

Adlard, P. A. and J. C. Vickers (2002). "Morphologically distinct plaque types differentially affect dendritic structure and organisation in the early and late stages of Alzheimer's disease." Acta Neuropathol (Berl) 103(4): 377-83.
We have investigated the effects of the deposition of insoluble beta-amyloid plaques on dendritic morphology within the neocortex. Labelling for beta-amyloid identified three morphologically distinct plaque types present both within the brains of preclinical Alzheimer's disease (AD) and end-stage AD cases. In both preclinical and end-stage AD, the percentage area occupied by diffuse plaques contained a greater density of labelling for microtubule-associated protein-2 (MAP2) relative to the surrounding neuropil (case type, ratio of MAP2 labelling in plaque to MAP2 labelling in surrounding neuropil +/- SEM: preclinical, 1.27+/-0.04; end-stage, 1.32+/-0.05). In contrast, there was a greater density of MAP2-labelled processes surrounding dense-cored plaques compared to that found within the plaque area (preclinical, 0.73+/-0.05; end-stage, 0.62+/-0.07). Fibrillar plaques demonstrated a transition from the early to late stages of AD, with a substantial decrease in the density of MAP2 labelling within the plaque area in end-stage AD cases relative to preclinical AD cases (preclinical, 1.01+/-0.1; end-stage, 0.72+/-0.05). The morphology of dendrites associated with dense-core or fibrillar plaques suggest physical disruption of the neuropil by beta-amyloid plaque formation. These data demonstrate that plaque isoforms differentially affect dendritic morphology in both the early and late stages of AD, with progression to clinical AD associated with evolving dendritic damage localised to fibrillar and dense-core plaques.

Adler, K. A., P. J. Mills, et al. (2002). "Temporal stability of acute stress-induced changes in leukocyte subsets and cellular adhesion molecules in older adults." Brain Behav Immun 16(3): 262-74.
This study investigated the temporal stability of enumerative immune and catecholamine responses to acute psychosocial stress in 67 Alzheimer's caregivers ages 56-82 years (45 women and 22 men) who were required to prepare and deliver two 3-min speeches on three occasions at 2-week and 6-week intervals. All leukocyte subsets and adhesion molecules (CD62L and CD11a) changed significantly from rest to postspeak at each of the three testing sessions (p's <.0005). Responses showed moderate to high temporal stability across baseline and absolute task values (r's =.65-.96). Reliability was predictably lower for both forms of change scores (r's = -.16-.64). The level of temporal stability achieved is comparable to that seen previously in younger adults, indicating that acute psychosocial stress produces reliable changes in circulating leukocytes and cell adhesion molecules in older adults.

Aisen, P. S. (2002). "Evaluation of selective COX-2 inhibitors for the treatment of Alzheimer's disease." J Pain Symptom Manage 23(4 Suppl): S35-40.
Alzheimer's disease (AD) is a worldwide problem that affects 5 million people in the United States alone. Until the approval of tacrine in the mid-1990s, there was no effective therapy for the cognitive symptoms of AD. Although cholinergic therapy provides modest but significant symptomatic relief, the development of effective disease-modifying therapy is essential. It has been demonstrated that a number of inflammatory processes are active in the brain of patients with AD, and therefore it is believed that an anti-inflammatory regimen may offer some degree of neuroprotection. Several studies have indicated that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with delayed onset and/or slowed cognitive decline in AD. Although not currently approved for this condition, recent findings have demonstrated that cyclooxygenase (COX)-2 is of primary importance in the inflammatory response and may have a role in neurodegeneration. Therefore, selective COX-2 inhibitors (coxibs) may have an advantage over traditional NSAIDs as potential therapeutic agents in AD. The Alzheimer's Disease Cooperative Study (ADCS) is conducting an ongoing multicenter, double-blind, placebo-controlled trial to determine whether rofecoxib, a coxib, or naproxen, a nonselective NSAID, will slow the rate of cognitive and clinical decline in AD. This study, along with other clinical studies currently under way, will determine the utility of selective and nonselective COX inhibitors for the prevention and treatment of AD.

Aisen, P. S., J. Schmeidler, et al. (2002). "Randomized pilot study of nimesulide treatment in Alzheimer's disease." Neurology 58(7): 1050-4.
BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAID) may be useful in the treatment of AD. Clinical and laboratory experience with nimesulide, an NSAID with preferential cyclooxygenase-2 inhibition, suggests that it may be a good candidate for AD therapy. METHODS: This pilot study investigated the clinical feasibility of nimesulide treatment in AD. Forty persons with probable AD, most of whom were taking cholinesterase inhibitors, were enrolled in a randomized, controlled, parallel-group trial designed to assess tolerability and short-term cognitive/behavioral effects of nimesulide. In the initial 12-week double-blind phase, participants were treated with nimesulide 100 mg by mouth twice daily or matching placebo; during the second 12-week phase all participants received active drug. Participants who tolerated the drug well and perceived benefit were invited to continue open-label nimesulide treatment. RESULTS: Short-term therapy with nimesulide, compared with placebo, had no significant effect on total assessment scores of measures of cognition, clinical status, activities of daily living, affect, and behavior. Long-term therapy was well tolerated for periods exceeding 2 years. CONCLUSION: These findings support the feasibility of nimesulide therapy in AD; assessment of efficacy will require a larger, long-term treatment study.

Akatsu, H., M. Takahashi, et al. (2002). "Subtype analysis of neuropathologically diagnosed patients in a Japanese geriatric hospital." J Neurol Sci 196(1-2): 63-9.
Dementia is a social problem in Japan, as it is in other countries. Recently, there has been an increase in the number of patients with Alzheimer-type dementia (ATD) in the population. We analyzed 239 cases of patients autopsied at Fukushimura Hospital over a 10-year period. Clinicopathologically, 66% of these cases (158 cases) presented with dementia symptoms. The predominant form of illness was ATD. We found dementia with Lewy bodies (DLB) to be as frequent as vascular dementia (VD). Although the numbers were small, limbic neurofibrillary tangle dementia (LNTD) and Pick's disease (PiD) followed a clinical course typical of these diseases. On the other hand, senile dementia of the Alzheimer's type (SDAT) and the common form of neocortical type DLB (diffuse Lewy body disease; DLBD) were difficult to distinguish from each other. We attempted to uncover differences between these dementias in terms of how they affect male and female patients. The clinical course of the male patients with the common form of neocortical type DLB was more or less typical, while that of the female patients was not.

Akishita, M. (2002). "[Hormone replacement therapy and the diseases in the elderly]." Nippon Ronen Igakkai Zasshi 39(3): 286-8.

Ala, T. A., L. F. Hughes, et al. (2002). "The Mini-Mental State exam may help in the differentiation of dementia with Lewy bodies and Alzheimer's disease." Int J Geriatr Psychiatry 17(6): 503-9.
OBJECTIVE: Since patients with dementia with Lewy bodies (DLB) tend to have greater impairment of attention and construction and better memory ability on neuropsychological tests than patients with Alzheimer's disease (AD), we determined if the items that measure attention, memory, and construction in the Mini-Mental State Examination (MMSE) help to distinguish DLB from AD early in the course of the dementia. DESIGN: We retrospectively studied the first available MMSE exam for each of our patients with DLB or AD and compared their MMSE subscores for attention, memory, and construction. SETTING: A university dementia brain bank in central Illinois, USA. PATIENTS: All patients with neuropathologically-proven DLB or AD with MMSE scores > or =13. RESULTS: We identified 17 DLB and 27 AD patients for whom we had MMSE exams. The attention and construction subtest scores of the DLB group were worse (p=0.0071 and p=0.0038, respectively) than those of the AD group. The memory subscores of the DLB group were better, although the difference did not reach statistical significance (p=0.22). When a mathematical equation was used to combine the three subscores with equal weighting (Attention-5/3Memory+5.Construction), the scores of the DLB group were worse (p=0.00007). Using this equation, a score less than 5 points was associated with DLB with a sensitivity of 0.82 (95% Confidence Interval (CI)=0.57-0.96) and a specificity of 0.81 (95% CI=0.62-0.94). CONCLUSIONS: Our findings support the work of others regarding the relative neuropsychological impairments of DLB and AD and indicate that the MMSE may be helpful in the differentiation of DLB and AD.

Albers, D. S. and M. F. Beal (2002). "Mitochondrial dysfunction in progressive supranuclear palsy." Neurochem Int 40(6): 559-64.
A progressive impairment of mitochondrial function has been suggested to play a critical role in the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Huntington's disease. Mitochondrial dysfunction can lead to number of deleterious consequences including impaired calcium buffering, generation of free radicals, activation of the mitochondrial permeability transition pore and secondary excitotoxicity. Progressive supranuclear palsy (PSP) is a rare neurological disorder characterized by the appearance of supranuclear gaze palsy and extrapyramidal symptoms [Arch. Neurol. 10 (1964) 333]. Although the etiological basis of PSP is unknown, compelling evidence from spectroscopy studies in PSP patients, biochemical studies in post-mortem PSP brain tissue and PSP cybrids has emerged that supports a contributory role of bio-energetic defects in the pathogenesis of PSP.

Albert, M. S. (2002). "Memory decline: the boundary between aging and age-related disease." Ann Neurol 51(3): 282-4.

Alexander, G. E., K. Chen, et al. (2002). "Longitudinal PET Evaluation of Cerebral Metabolic Decline in Dementia: A Potential Outcome Measure in Alzheimer's Disease Treatment Studies." Am J Psychiatry 159(5): 738-45.
OBJECTIVE: It is well established that regional cerebral metabolic rates for glucose assessed by [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with Alzheimer's disease in the mental resting state (eyes and ears covered) provide a sensitive, in vivo metabolic index of Alzheimer's disease dementia. Few studies, however, have evaluated longitudinal declines in regional cerebral glucose metabolism in patients with dementia caused by Alzheimer's disease. In addition, the available studies have not used recently developed brain mapping algorithms to characterize the progression of Alzheimer's disease throughout the brain, and none considered the statistical power of regional cerebral glucose metabolism in testing the ability of treatments to attenuate the progression of dementia. METHOD: The authors used FDG PET and a brain mapping algorithm to investigate cross-sectional reductions in regional cerebral glucose metabolism, longitudinal decline in regional cerebral glucose metabolism after a 1-year follow-up, and the power of this method to evaluate treatments for Alzheimer's disease in patients with mild to moderate dementia. PET scans were initially acquired in 14 patients with Alzheimer's disease and 34 healthy comparison subjects of similar age and sex. Repeat scans were obtained in the patients 1 year later. Power analyses for voxels showing maximal decline over the 1-year period in regional cerebral glucose metabolism (mg/100 g per minute) were computed to estimate the sample sizes needed to detect a significant treatment response in a 1-year, double-blind, placebo-controlled treatment study. RESULTS: The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. Using maximal glucose metabolism reductions in the left frontal cortex, we estimated that as few as 36 patients per group would be needed to detect a 33% treatment response with one-tailed significance of p</=0.005 and 80% power in a 1-year, double-blind, placebo-controlled treatment study. CONCLUSIONS: These findings indicate that brain metabolism as assessed by FDG PET during mental rest is a sensitive marker of disease progression in Alzheimer's disease over a 1-year period. These findings also support the feasibility of using FDG PET as an outcome measure to test the ability of treatments to attenuate the progression of Alzheimer's disease.

Aliev, G., M. A. Smith, et al. (2002). "The role of oxidative stress in the pathophysiology of cerebrovascular lesions in Alzheimer's disease." Brain Pathol 12(1): 21-35.
Alzheimer's disease (AD) and stroke are two leading causes of age-associated dementia. A rapidly growing body of evidence indicates that increased oxidative stress from reactive oxygen radicals is associated with the aging process and age-related degenerative disorders such as atherosclerosis, ischemia/reperfusion, arthritis, stroke, and neurodegenerative diseases. New evidence has also indicated that vascular lesions are a key factor in the development of AD. This idea is based on a positive correlation between AD and cardiovascular and cerebrovascular diseases such as arterio- and atherosclerosis and ischemia/reperfusion injury. In this review we consider recent evidence supporting the existence of an intimate relationship between oxidative stress and vascular lesions in the pathobiology of AD. We also consider the opportunities for therapeutic interventions based on the molecular pathways involved with these causal relationships.

Allain, H. and D. Bentue-Ferrer (2002). "[Effect of almitrine/raubasine on cerebral metabolism in the elderly]." Presse Med 31(12): 562-4.
Recent neurobiological data has led to renewed interest in oxygen (O2). The discovery of neuroglobin, protein varyingly present in the brain, has been enhanced by the elucidation of the mechanisms through which oxygen intervenes in neuronal metabolism. Almitrine/raubasine activates the metabolism of hypoxic/ischemic neurones by increasing O2 bioavailability. This mechanism supports the effects on behaviour obtained in various animal models and the benefits observed during clinical trials in elderly patients presenting with cognitive defects.

Almeida, O. P., G. K. Hulse, et al. (2002). "Smoking as a risk factor for Alzheimer's disease: contrasting evidence from a systematic review of case-control and cohort studies." Addiction 97(1): 15-28.
AIMS: To investigate the risk of Alzheimer's disease (AD) associated with smoking. DESIGN: Meta-analyses of case-control and cohort studies. Data source: Index Medicus-Medline (1966-April 2000) and PsycINFO (1984-April 2000) databases were systematically consulted for the retrieval of references. This search was supplemented by manual search of relevant references quoted by other studies and reviews. STUDY SELECTION: Irrelevant abstracts and articles were identified by one of the authors. These papers were retrieved and examined by at least two of the authors, who initially assessed them for the relevance of the exposure (smoking), outcome (AD) and study-design (case-control or cohort study). DATA EXTRACTION: Two reviewers rated independently the quality of selected papers. Whenever possible, raw data were extracted and the crude odds ratio (OR) calculated using the Cornfield method. The pooled risk ratios were estimated using a fixed-effects model. FINDINGS: Twenty-one case-control studies reported data on 5323 subjects. The estimated pooled odds ratio (OR) was 0.74 [95% confidence interval (CI) = 0.66-0.84]. In another analysis incorporating ORs adjusted for confounding variables (such as age, sex, schooling and alcohol use), the pooled odds ratio was 0.82 (95% CI = 0.70-0.97). Finally, in a analysis that included only the four case-control studies that used matched design the pooled odds ratio was 0.82 (95% CI = 0.53-1.27). Eight cohort studies reported data on 43 885 people at risk-the overall relative risk (RR) of AD among ever smokers was 1.10 (95% CI = 0.94-1.29). Restricting the analysis to the two cohort studies that described the number of subjects who were smokers at baseline and later developed AD produced a RR of 1.99 (95% CI = 1.33-2.98). CONCLUSIONS: Case-control and cohort studies produce conflicting results as to the direction of the association between smoking and AD. Survival bias and other methodological problems associated with case-control studies may partly explain this difference. Access to information collected by ongoing follow-up studies may contribute to clarify the role of smoking in AD. If new results confirm that smoking is associated with increased risk of AD, then smoking prevention and cessation should become public health priorities in the fight against dementia.

Anderson, S. J., P. E. Barker, et al. (2002). "Cytonectin expression in Alzheimer disease." J Neuropathol Exp Neurol 61(3): 230-6.
Cytonectin is a novel 35,000 molecular weight protein that displays remarkable ion-independent adherence properties. This consigns it to a family of well-known adherence molecules essential for cell communication and the development of 3-dimensional tissue structures. Cytonectin is expressed in a variety of organs and tissues, being evolutionarily conserved from human to avian species. It is hypothesized to serve as a key structural component of the body, and as a "do not attack" signal molecule that prevents tissue destruction by cells of monocyte lineage. This paper describes the properties of cytonectin and its proposed role in normal and disease states. The protein is overexpressed in Alzheimer disease entorhinal cortex as compared to normal age-matched controls. It is also detected in tissues from patients with Down syndrome and leukemia. Its presence in all 3 of these related conditions may prove important to their etiopathogenesis.

Andersson, K., A. Olofsson, et al. (2002). "Only amyloidogenic intermediates of transthyretin induce apoptosis." Biochem Biophys Res Commun 294(2): 309-14.
In diseases like Alzheimer's disease and familial amyloidotic polyneuropathy (FAP) amyloid deposits co-localize with areas of neurodegeneration. FAP is associated with mutations of the plasma protein transthyretin (TTR). We can here show an apoptotic effect of amyloidogenic mutants of TTR on a human neuroblastoma cell line. Toxicity could be blocked by catalase indicating a free oxygen radical dependent mechanism. The toxic effect was dependent on the state of aggregation and unexpectedly mature fibrils from FAP-patients who failed to exert an apoptotic response. Morphological studies revealed a correlation between toxicity and the presence of immature amyloid. Thus, we can show that toxicity is associated with early stages of fibril formation and propose that mature full-length fibrils represent an inert end stage, which might serve as a rescue mechanism.

Anderton, B. H. (2002). "Ageing of the brain." Mech Ageing Dev 123(7): 811-7.
The brains of individuals who are cognitively normal show age-related changes that include an overall reduction in the brain volume and weight and enlargement of the brain ventricles. These changes are partly the result of nerve cell loss but accurate estimates of neuronal loss are notoriously difficult to make. There is loss of synapses and dendritic pruning in the aged brain but in selected areas rather than globally. Neurofibrillary tangles and senile plaques are the neuropathological hallmark of Alzheimer's disease in which they are more abundant and widespread than in the brains of intellectually intact elderly people. Alzheimer's disease has, therefore, been regarded as accelerated brain ageing, however, since there is a strong genetic contribution to developing the disease it implies that it may not be the inevitable, even if frequent, consequence of old age. The interplay between genetic and environmental factors probably determines the degree of pathological brain ageing and whether or not individuals develop dementia.

Andrieu, S., E. Reynish, et al. (2002). "Predictive factors of acute hospitalization in 134 patients with Alzheimer's disease: a one year prospective study." Int J Geriatr Psychiatry 17(5): 422-6.
OBJECTIVE: To evaluate the frequency of and determine predictive factors for acute hospitalization in a prospective study of patients with Alzheimer's disease (AD). DESIGN: A one year prospective study. PARTICIPANTS: 134 patients recruited from the memory clinic in Toulouse University Hospital, with AD diagnosed using the NINCDS-ADRDA criteria. MEASURES: A comprehensive geriatric and neuropsychological assessment was conducted 6 monthly. RESULTS: Among the 134 patients included in this study, at one year follow up, 32 patients had at least one acute hospitalization. Patient-related variables predictive of acute hospitalization in the univariate analysis were: level of education, ADL-bathing, ADL-toileting, ADL-feeding, total ADL score, IADL A scale (daily upkeep), history of falls, and level of behavioural disorder as measured by the Cohen scale. In the multivariate regression model, two variables were associated with acute hospitalization: dependency for ADL-bathing [Odds Ratio (OR) = 5.65, 95% Confidence Intervals (CI): 2.3-14.4] and low level of education. CONCLUSION: The results of this study demonstrate that acute hospitalization is frequent in AD patients resulting in considerable cost implications. Interventions that support patients and their cares to manage their loss of ADL may be a practical approach to reducing the need for acute hospital admissions.

Antal, A., S. Keri, et al. (2002). "Corticostriatal circuitry mediates fast-track visual categorization." Brain Res Cogn Brain Res 13(1): 53-9.
Previous studies have shown that briefly presented natural scenes containing non-animals elicited more negative potentials than images with animals even at 150 ms after stimulus onset (dN150). Cognitive models suggest that both feed-forward and feature weighting processes are involved in the rapid categorization of complex natural scenes. Here we examined the possible neuronal substrates of this model. Patients with Alzheimer's disease (AD) exhibited a delayed dN150, but in their case non-animals evoked more negative potentials similarly to the controls (presence of dN150). In contrast, in patients with Parkinson's disease (PD) animal and non-animal stimuli elicited nearly identical early responses (absence of dN150). The results indicate that when cortico-cortical pathways mediating feed-forward mechanisms are impaired (as in the case of AD), dN150 appears later, while in the case of corticostriatal dysfunctions (as in the case of PD) no differential response is present. This supports the hypothesis that corticostriatal circuits mediate perceptual feature weighting and integration in complex situations requiring categorical judgements.

Araria-Goumidi, L., J. C. Lambert, et al. (2002). "Association study of three polymorphisms of TGF-beta1 gene with Alzheimer's disease." J Neurol Neurosurg Psychiatry 73(1): 62-4.
BACKGROUND: There is evidence that inflammatory processes may contribute to the development of Alzheimer's disease through production of cytokines and free radicals that damage neurones. A recent study has shown that transforming growth factor beta1 (TGF-beta1) signalling in astrocytes promotes Abeta production and could play a critical role in the formation of amyloid plaques in the brain. OBJECTIVES: To explore the impact of the -800 and -509 TGF-beta1 promoter polymorphisms and the +25 polymorphism on the risk of occurrence of Alzheimer's disease in a large population of sporadic cases and controls, and on the amyloid beta (Abeta) load in the brains of Alzheimer patients. METHODS: The TGF-beta1 genotypes of the three polymorphisms were determined in 678 sporadic Alzheimer's disease patients and 667 controls. They were also characterised, along with Abeta load, in the brains of 81 necropsy confirmed Alzheimer patients. RESULTS: No significant variations in the distribution of the genotypes and haplotypes were observed between Alzheimer patients and controls, or in the amount of Abeta deposition. CONCLUSIONS: These results do not suggest an influence of genetic variability at the TGF-beta1 gene locus on the occurrence of Alzheimer's disease.

Arnold, G., J. Schwarz, et al. (2002). "Steele-Richardson-Olszewski-syndrome: the relation of dopamine D2 receptor binding and subcortical lesions in MRI." J Neural Transm 109(4): 503-12.
We compared (123)I-iodobenzamide single photon emission computed tomography (IBZM-SPECT) for imaging of striatal dopamine D(2) receptors in vivo, and MRI in 32 patients with the clinical diagnosis of progressive supranuclear palsy (PSP). We found a significant inter-dependence of reduction of specific striatal IBZM binding indicative of striatal degeneration and of the absence of multiple signal hyperintensities in MRI; age had no influence neither on IBZM binding nor on signal hyperintensities. We conclude that the presence of multiple signal hyperintensities should raise doubt on the correct clinical diagnosis.

Arthur, D. and E. D. Levin (2002). "Chronic inhibition of alpha4beta2 nicotinic receptors in the ventral hippocampus of rats: impacts on memory and nicotine response." Psychopharmacology (Berl) 160(2): 140-5.
RATIONALE: Acute and chronic systemic nicotine administration has been shown to cause significant spatial memory improvement. The critical nicotinic receptor subtypes for this effect and their location are still being determined. Nicotinic receptors in the ventral hippocampus have been found to be critically involved in memory. Acute ventral hippocampal infusions of dihydro-beta-erythroidine (DHbetaE), an alpha4beta2 nicotinic receptor antagonist, impaired spatial memory of rats in the radial-arm maze. OBJECTIVES: The current study used chronic ventral hippocampal infusion of DHbetaE as a model of nicotinic receptor loss such as that which occurs in Alzheimer's disease. The therapeutic effect of systemic nicotine treatment in reversing the DHbetaE-induced memory impairment was determined. METHODS: Rats were pretrained to asymptotic levels of performance on the eight-arm radial maze. Then, they were implanted with bilateral infusion cannulae in the ventral hippocampus, through which 0, 33.3, or 100 microg/side/day of DHbetaE was continuously infused for 4 weeks. The rats were retested on the eight-arm maze throughout infusion period and after withdrawal, and the interaction of acute systemic nicotine injections on memory was tested. RESULTS: The higher (100 microg/side/day) but not the lower (33.3 microg/side/day) DHbetaE dose caused a significant spatial memory impairment. Acute systemic nicotine injections (0, 0.1, 0.2, and 0.4 mg/kg, subcutaneous) attenuated the memory impairing effects of 100 microg/side/day of DHbetaE. There was no significant effect on response latency with the chronic DHbetaE infusion. Acute systemic nicotine infusions did significantly speed responding, an effect which was reversed by chronic hippocampal infusions of DHbetaE. After withdrawal there were no significant lasting effects on choice accuracy or response latency. Wet-dog shakes were significantly elevated during chronic hippocampal DHbetaE administration with no effect during the withdrawal period. CONCLUSIONS: These results indicate that chronic inhibition of a subset of nicotinic receptors in the hippocampus results in a significant impairment in the spatial memory choice accuracy. The ability of nicotine to attenuate the impairment supports the development of nicotinic agonist therapy of syndromes, such as Alzheimer's disease, that involve a chronic decrease in the activity of the alpha4beta2 nicotinic receptors and memory impairment.

Arthur, A., R. Matthews, et al. (2002). "Factors associated with antidepressant treatment in residential care: changes between 1990 and 1997." Int J Geriatr Psychiatry 17(1): 54-60.
BACKGROUND: Depression is common among older people living in residential and nursing homes. Detection and treatment of late life depression may be sub-optimal in these settings. AIM: To report the changes in, and factors associated with, antidepressant use among residents in care homes in 1990 and 1997. METHOD: Censuses of those aged 65 years and over in any type of residential care in the county of Leicestershire, UK, on 27 November 1990 and 30 November 1997. Care staff were asked to complete an assessment form for each resident which included a rating of depression and use of antidepressants. RESULTS: The use of antidepressants increased from 11% (484/4415) in 1990 to 18.9% (777/4111) in 1997. Severity of depression as assessed by care staff, gender, younger age, better cognitive functioning, and use of other medications were consistently associated with antidepressant treatment. Antidepressant use was associated with better physical functioning (p = 0.001) in 1990 and frequency of falls in 1997 (p = 0.044). CONCLUSIONS: Increased use of antidepressants appears to be due to the wider range of antidepressant drugs available since 1990. However there is a need for better methods for care staff to detect depression in residents, and for appropriate action to be taken by those responsible for their medical management.

Atack, J. R. and M. B. Schapiro (2002). "Inositol monophosphatase activity in normal, Down syndrome and dementia of the Alzheimer type CSF." Neurobiol Aging 23(3): 389-96.
Inositol monophosphatase (IMPase), a cytoplasmic enzyme that hydrolyses inositol monophosphates to produce inositol is also found in the cerebrospinal fluid (CSF). Since levels of inositol have been previously reported to be elevated in Down syndrome (DS) CSF, IMPase activity was measured in CSF of DS subjects to establish whether altered inositol levels may be related to changes in IMPase activity. In addition, and to better understand the regulation of IMPase expression in the CSF, enzyme activity was measured in normal aging, patients with Alzheimer-type or multi-infarct dementia (DAT and MID, respectively) and in CSF obtained by repeat lumbar puncture or from sequential aliquots of CSF from along the rostro-caudal axis. IMPase activity was relatively constant in CSF obtained from repeated lumbar puncture and there was no significant rostro-caudal gradient of activity in either normal or DS subjects, indicating that the enzyme originates from both brain and spinal cord. Compared to respective age-matched normal subjects, CSF IMPase activity was unaltered in DS, DAT and MID. However, in normal volunteers there was a significant positive correlation between age and CSF IMPase activity. Furthermore, there were significant correlations between CSF IMPase activity and acetylcholinesterase and butyrylcholinesterase activities and total protein, suggesting co-regulation of these parameters within the CSF.

Auer, J., R. Berent, et al. (2002). "Homocysteine and dementia." N Engl J Med 346(25): 2007; discussion 2008.

Augustinack, J. C., J. L. Sanders, et al. (2002). "Colocalization and fluorescence resonance energy transfer between cdk5 and AT8 suggests a close association in pre-neurofibrillary tangles and neurofibrillary tangles." J Neuropathol Exp Neurol 61(6): 557-64.
Cyclin-dependent kinase 5 (cdk5) is a serine/threonine kinase that, when activated, induces neurite outgrowth. Recent in vitro studies have shown that cdk5 phosphorylates tau at serine 199, serine 202, and threonine 205 and that p25, an activator of cdk5, is increased in Alzheimer disease (AD). Since tau is hyperphosphorylated at these sites in neurofibrillary tangles, we examined brain tissue from patients with AD and normal elderly control cases to determine whether cdk5 and these phosphoepitopes colocalize in neurofibrillary tangles. Adjacent temporal lobe sections were double immunostained with a polyclonal anti-cdk5 and monoclonal AT8 (which recognizes phosphorylated serine 199, serine 202, and threonine 205 in tau) antibodies. A subset of AT8 phosphotau-positive neurons was immunoreactive for cdk5 in entorhinal (area 28) and perirhinal (area 35) cortices and CA1 of the hippocampus. We assessed the ratio of cdk5-positive cells to AT8-positive cells and found that there is a higher degree of colocalization in pre-neurofibrillary tangles as opposed to intraneuronal and extraneuronal neurofibrillary tangles. We further examined colocalization using fluorescence resonance energy transfer. This suggests a close, stable intermolecular association between cdk5 and phosphorylated tau, consistent with phosphorylation of tau by cdk5 in AD brain.

Augustinack, J. C., A. Schneider, et al. (2002). "Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease." Acta Neuropathol (Berl) 103(1): 26-35.
Microtubule associated protein tau is abnormally phosphorylated in Alzheimer's disease (AD) and aggregates as paired helical filaments (PHFs) in neurofibrillary tangles (NFTs). We show here that the pattern of tau phosphorylation correlates with the loss of neuronal integrity. Studies using 11 phosphorylation dependent tau antibodies and a panel of AD cases of varying severity were evaluated in terms of three stages of neurofibrillary tangle development: (1) pre-neurofibrillary tangle, (2) intra-, and (3) extra-neuronal neurofibrillary tangles. The pretangle state, in which neurons display nonfibrillar, punctate regions in the cytoplasm, sound dendrites, somas, and nuclei, was observed especially with phospho-tau antibodies TG3 (pT231), pS262, and pT153. Intraneuronal neurofibrillary tangles are homogenously stained with fibrillar tau structures, which were most prominently stained with pT175/181, 12E8 (pS262/pS356), pS422, pS46, pS214 antibodies. Extracellular NFTs, which contain substantial filamentous tau, are most prominently stained with AT8 (pS199/pS202/pT205), AT100 (pT212/pS214), and PHF-1 (pS396/pS404) antibodies, which also stain intracellular NFT. The sequence of early tau phosphorylation suggests that there are events prior to filament formation that are specific to particular phosphorylated tau epitopes, leading to conformational changes and cytopathological alterations.

Averbuch-Heller, L., C. Gordon, et al. (2002). "Small vertical saccades have normal speeds in progressive supranuclear palsy (PSP)." Ann N Y Acad Sci 956: 434-7.

Bacanu, S. A., B. Devlin, et al. (2002). "Linkage analysis of Alzheimer disease with psychosis." Neurology 59(1): 118-20.
Although a portion of risk for late-onset AD (LOAD) is attributable to APOE, the search for other loci is ongoing. The authors hypothesize that psychotic symptoms with LOAD (LOAD+P) identify a potentially more etiologically homogeneous form of AD. Linkage analysis of families with LOAD+P identified one significant and several suggestive novel linkage signals, which bolsters the conjecture of greater etiologic homogeneity.

Ballard, C., J. O'Brien, et al. (2002). "Qualitative performance characteristics differentiate dementia with Lewy bodies and Alzheimer's disease." J Neurol Neurosurg Psychiatry 72(5): 565-6.

Ballard, C., I. Powell, et al. (2002). "Can psychiatric liaison reduce neuroleptic use and reduce health service utilization for dementia patients residing in care facilities." Int J Geriatr Psychiatry 17(2): 140-5.
BACKGROUND: The quality of care and overuse of neuroleptic medication in care environments are major issues in the care of elderly people with dementia. METHOD: The quality of care (Dementia Care Mapping), the severity of Behavioural and Psychological Symptoms (BPSD--Neuropsychiatric Inventory), expressive language skills (Sheffield Acquired Language Disorder scale), service utilization and use of neuroleptic drugs was compared over 9 months between six care facilities receiving a psychiatric liaison service and three facilities receiving the usual clinical support, using a single blind design. RESULTS: There was a significant reduction in neuroleptic usage in the facilities receiving the liaison service (McNemar test p<0.0001), but not amongst those receiving standard clinical support (McNemar test p=0.07). There were also significantly less GP contacts (t=3.9 p=0.0001) for residents in the facilities receiving the liaison service, and a three fold reduction in psychiatric in-patient bed usage (Bed days per person 0.6 vs. 1.5). Residents in care facilities receiving the liaison service experienced significantly less deterioration in expressive language skills (t=2.2 p=0.03), but there were no significant differences in BPSD or wellbeing. CONCLUSION: A resource efficient psychiatric liaison service can reduce neuroleptic drug use and reduce some aspects of health service utilization; but a more extensive intervention is probably required to improve the overall quality of care.

Ballard, C. G. (2002). "Advances in the treatment of Alzheimer's disease: benefits of dual cholinesterase inhibition." Eur Neurol 47(1): 64-70.
Cholinesterase inhibitors have produced the best evidence of clinical efficacy for treating patients with Alzheimer's disease (AD). Many of these drugs selectively inhibit acetylcholinesterase (AChE), but agents that also target butyrylcholinesterase (BuChE) may provide added benefits. As AD progresses, ACh regulation may become increasingly dependent on BuChE and dual inhibitors may provide more sustained efficacy than AChE-selective agents. Dual inhibition may also help to slow the formation of amyloidogenic compounds, providing an important disease-modifying mechanism. Rivastigmine is a dual inhibitor that has demonstrated benefits across the spectrum of AD severity and across the cognitive, functional and behavioural domains of AD. It is a priority for future clinical trials to determine whether agents with dual inhibition properties have greater clinical efficacy.

Barber, R., I. McKeith, et al. (2002). "Volumetric MRI study of the caudate nucleus in patients with dementia with Lewy bodies, Alzheimer's disease, and vascular dementia." J Neurol Neurosurg Psychiatry 72(3): 406-7.
OBJECTIVES: To determine whether parkinsonian symptoms in dementia with Lewy bodies (DLB) are associated with greater atrophy of the caudate nucleus in comparison with patients with Alzheimer's disease (AD) and vascular dementia (VaD). METHODS: T1weighted MR scans were acquired in elderly patients with DLB, AD, VaD, and healthy controls. Normalised volumetric measurements of the caudate nucleus were obtained and parkinsonian symptoms rated using Hoehn and Yahr staging. RESULTS: There were no significant differences in the volume of the caudate nucleus between patients with dementia. However, the left caudate volume was significantly reduced in AD and DLB compared with controls. Parkinsonian symptoms did not correlate with caudate nucleus volume. CONCLUSIONS: Parkinsonian symptoms in DLB may be more closely coupled to neurochemical rather than structural changes in the caudate nucleus, and volumetric MRI analysis of caudate nucleus does not discriminate between patients with DLB, AD, and VaD.

Barra, V., E. Frenoux, et al. (2002). "Automatic volumetric measurement of lateral ventricles on magnetic resonance images with correction of partial volume effects." J Magn Reson Imaging 15(1): 16-22.
PURPOSE: To propose a method for the quantification of lateral ventricle (LV) volumes on a single sequence of 3D magnetic resonance (MR) images. MATERIALS AND METHODS: This algorithm, following a preliminary fuzzy tissue classification step, is based on the development of mathematical morphology processes allowing both the extraction of the LVs and the correction of partial volume effects on their boundaries. The procedure is fast and totally unsupervised. The method is tested on a phantom image, then applied to five patients diagnosed as potentially suffering from Alzheimer's disease, and finally applied on several MR acquisitions to show the genericness of the algorithm. RESULTS AND CONCLUSION: This technique yielded both an accurate estimation of ventricular volumes intra- and intersubject with respect to published data and a relevant management of partial volume effects. Numerous clinical applications are now expected, from the study of schizophrenia to the longitudinal follow-up of Alzheimer's patients.

Bassiony, M. M., A. Warren, et al. (2002). "The relationship between delusions and depression in Alzheimer's disease." Int J Geriatr Psychiatry 17(6): 549-56.
OBJECTIVES: The aim of this investigation was to study the relationship between delusions and depression in Alzheimer's disease (AD). DESIGN: This was a cross-sectional, case control study. SETTING: Neuropsychiatry Service, the Johns Hopkins School of Medicine, USA. PARTICIPANTS: 303 community-residing patients with probable AD according to NINCDS/ADRDA criteria were included in the study. Seventy-five patients with delusions only were compared to a control group of 228 patients who had neither delusions nor hallucinations. Patients with only hallucinations or both delusions and hallucinations were excluded. MEASURES: Patients were assessed clinically for the presence of delusions using the DSM-IV glossary definitions. They were also rated on standardized measures of depression, cognitive impairment, staging of dementia, general medical health, and functional impairment. RESULTS: There was an association between delusions and depression among patients with AD. Before adjustment for other variables, the presence of depression conferred a 1.8-fold (95% confidence intervals (CI) = 1.0-3.1; p = 0.04) higher risk of delusions. After adjustment for multiple other variables, this risk increased further to 6.8-fold (95% CI = 2.1-21.6; p = 0.001). CONCLUSIONS; Delusions in AD are strongly associated with depression after statistical adjustment for all confounding variables, which might distort this association. This finding has implications for our understanding of the etio-pathogenesis and management of delusions and depression in AD.

Bassiony, M. M., A. Warren, et al. (2002). "Isolated hallucinosis in Alzheimer's disease is associated with African-American race." Int J Geriatr Psychiatry 17(3): 205-10.
OBJECTIVES: The aim of this investigation was to study the relationship between isolated hallucinosis and race in Alzheimer's disease. METHODS: This was a cross-sectional, case control study carried out at the Neuropsychiatry Service, outpatient clinic at the Johns Hopkins School of Medicine, USA. The participants were 237 community-residing patients with probable Alzheimer's disease according to NINCDS/ADRDA criteria were included in the study. 9 patients with isolated hallucinosis were compared to a control group of 228 patients who had neither delusions nor hallucinations. Patients with only delusions or both delusions and hallucinations were excluded based on prior research. Patients were assessed clinically for the presence of hallucinations using the DSM-IV glossary definitions. They were also rated on standardized measures of cognitive impairment, depression, functional impairment, and general health. RESULTS: There was a significant association between hallucinations and race in patients with Alzheimer's disease. Before adjustment for other variables, the African-American race conferred a 5.5-fold (95% CI = 1.4-21.6; p = 0.02) increased risk for isolated hallucinosis. After adjustment for multiple other variables, this risk increased further to 27.2-fold (95% CI = 1.6-457.3; p = 0.02). CONCLUSIONS: African-American patients with Alzheimer's disease are more likely to have isolated hallucinations than Caucasian patients even after statistical adjustment for multiple confounding variables, which might distort this association. This finding has implications for our understanding of the etio-pathogenesis of hallucinations in Alzheimer's disease and for meeting health service needs of African-American patients.

Baumeister, R. and L. Ge (2002). "The worm in us - Caenorhabditis elegans as a model of human disease." Trends Biotechnol 20(4): 147-8.

Bayer, A. U., F. Ferrari, et al. (2002). "High occurrence rate of glaucoma among patients with Alzheimer's disease." Eur Neurol 47(3): 165-8.
The purpose of the current study was to reveal the occurrence rate of glaucoma among patients with Alzheimer's disease (AD). All 112 patients of four nursing homes in Upper Bavaria, Germany, who met the diagnostic criteria of probable AD, were incorporated into the study. Visual field defects and/or optic disc cupping compatible with the diagnosis of glaucoma were found in 29 out of 112 patients with AD (25.9%). When compared to a control group (5.2%) and to the prevalence of glaucoma in western countries revealed in a number of glaucoma surveys (2.6-4.7%), patients with AD may have a significantly increased occurrence rate of glaucoma. In addition, ocular hypertension with normal visual fields and normal optic nerve heads was not found in patients with AD. The prevalence of ocular hypertension in the control group was 7.8% and parallels previous surveys. Therefore, we assume that the optic nerve seems to be less resistant to elevated intraocular pressure levels in AD patients.

Bayer, A. U., O. N. Keller, et al. (2002). "Association of glaucoma with neurodegenerative diseases with apoptotic cell death: Alzheimer's disease and Parkinson's disease." Am J Ophthalmol 133(1): 135-7.
PURPOSE: To report a possible association of glaucoma with Parkinson's disease and Alzheimer's disease. METHODS: Retrospective chart review (observational case series). The ophthalmologic charts of 49 patients with Alzheimer's disease and of 38 patients with Parkinson's disease were reviewed to determine the occurrence rate of glaucoma among these patients. RESULTS: Glaucomatous visual field defects or cup-to-disk ratios of 0.8 or greater were recorded in 12 patients with Alzheimer's disease (24.5%) and in 9 patients with Parkinson's disease (23.7%). CONCLUSION: Patients with Alzheimer's disease and Parkinson's disease may have an increased occurrence rate of glaucoma.

Beeri, M. S., P. Werner, et al. (2002). "Economic cost of Alzheimer disease in Israel." Alzheimer Dis Assoc Disord 16(2): 73-80.
The objective of this prospective study was to evaluate the cost of Alzheimer disease (AD) in Israel. Seventy-one AD patients who lived in the community, 50 institutionalized AD patients, both AD groups' respective primary caregivers, and 50 healthy elderly subjects were interviewed. The interviews covered information about the number of caregivers' hours invested in caring for the patient and amount of expenditures such as in house paid help and payments for day care. The annual social cost of caring for a person with AD in Israel was approximately $17,000, whether the patient lived at home or in a nursing home, but the cost components differed in the two groups. For community-dwelling patients, 60% of the cost represented an imputed value of unpaid indirect care compared with 12% for institutionalized patients. Also, in both residences, the private cost was significantly higher than the public cost, i.e., more 75% of the services provided to patients were paid out of pocket. Cost of institutionalization was the major component of the social cost. The cost of the disease increased with functional and cognitive deterioration for the community-dwelling group only. With projected increases in the number of persons at risk for developing AD, the economic impact of the disease on future costs will be significant. Efforts to delay deterioration and, as a result, delay institutionalization seem crucial for cost containment.

Beeri, M. S., P. Werner, et al. (2002). "The cost of behavioral and psychological symptoms of dementia (BPSD) in community dwelling Alzheimer's disease patients." Int J Geriatr Psychiatry 17(5): 403-8.
INTRODUCTION: Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in Alzheimer's disease (AD) patients. They are a source of distress for the caregivers and one of the main reasons for nursing home placement, which is the major component of the cost of Alzheimer's disease. The aim of the present study was to assess the direct and indirect cost related to the care of BPSD within a prospective study examining the overall cost of AD in Israel. METHODS: Seventy-one community dwelling AD patients were interviewed. Interviews covered information about the number of caregivers' hours invested in caring for the patient and amount of expenditure such as in-house paid help and payments for day care. Effort devoted to BPSD was defined as the number of hours spent by primary and secondary caregivers in a typical week dealing with BPSD (managing aggression, pacing, attempts to leave the house under inappropriate circumstances, or comforting a hallucinating, depressed or anxious patient). RESULTS: The annual indirect cost for management of BPSD in an AD patient was approximately 2665 dollars -over 25% of the total annual indirect cost of care ($10 520). The annual direct cost of BPSD of an AD patient was approximately 1450 dollars -over 35% of the total annual direct cost of care (3900 dollars). CONCLUSIONS: Approximately 30% (4115 dollars) of the total annual cost of AD (14420 dollars) is invested in the direct management of BPSD. Given the importance of BPSD as one of the main components of the cost of AD, future cost studies should be designed to measure the cost of specific components of BPSD and verify which are the most costly aspects of the disease. Despite the considerable methodological difficulties in disentangling the costs of the specific symptoms of AD, cost effectiveness studies of different interventions should be conducted in order to determine the optimal intervention with relation to cost.

Beloosesky, Y., H. Salman, et al. (2002). "Cytokine levels and phagocytic activity in patients with Alzheimer's disease." Gerontology 48(3): 128-32.
BACKGROUND: Clinical observations indicate that patients with Alzheimer's disease show a greater susceptibility to infections. One possible explanation is that this predisposition is due to alterations in their immune system. OBJECTIVE: To investigate this assumption, pro- and anti-inflammatory cytokines, as well as the phagocytic activity and superoxide anion generation was examined in aged individuals with and without Alzheimer's disease. METHODS: The production of IL-1beta, IL-2, IL-6, TNFalpha and IL-10 by peripheral blood mononuclear cells from 12 patients with Alzheimer's disease was compared with that of 12 age-matched individuals without any signs of dementia and 12 middle-aged healthy volunteers who served as an additional control. The engulfing capacity of the phagocytic cells was detected by counting cells containing latex beads and the number of particles internalized by each individual cell. RESULTS: The secretion of IL-2 was markedly low in the demented patients, compared with both elderly and middle-aged subjects. IL-1beta and TNFalpha production was similar in the individuals of the 3 groups. The production of IL-6 and IL-10 was significantly lower when compared to that of the middle-aged, but did not differ between the elderly patients with and without dementia. The phagocytic function of both polymorphonuclear cells and monocytes was decreased in individuals of the elderly groups with a low number of engulfed latex particles by each individual polymorphonuclear cell. The production of superoxide anions was increased only by monocytes from the elderly groups. CONCLUSIONS: The results suggest that although the impaired immune function in patients with Alzheimer's disease is related to the aging process, the significant low IL-2 production in these patients may play a role in their increased susceptibility to infections.

Benedetti, M. D., A. Salviati, et al. (2002). "Prevalence of dementia and apolipoprotein e genotype distribution in the elderly of buttapietra, verona province, Italy." Neuroepidemiology 21(2): 74-80.
We investigated the prevalence of dementia and the apolipoprotein E (APOE) genotype distribution in the elderly of Buttapietra, a village near Verona, Italy. All residents over the age of 74 (n = 238), including those who were institutionalized, were studied using a direct-contact, single-phase design. The overall prevalence of dementia, clinically defined by DSM-III-R criteria, was 15.8 cases per 100 population, with age-specific figures increasing steeply with advancing age in both sexes. Alzheimer's disease (AD) was the most frequent dementing disorder (43%). APOE genotyping was determined after DNA amplification by restriction isotyping. We found that the epsilon4 allele and the epsilon3/epsilon4 genotype were associated with all types of dementia, although only the association of epsilon3/epsilon4 with AD reached statistical significance (odds ratio 4.5, 95% confidence interval 1.3-16.1). However, as reported in other Mediterranean countries, the frequency of the epsilon4 allele in our population was low (8.9%), suggesting that the population-attributable risk for AD, at least for elderly individuals (> or =75 years), could be small.

Benoit, M., P. M. Koulibaly, et al. (2002). "Brain perfusion in Alzheimer's disease with and without apathy: a SPECT study with statistical parametric mapping analysis." Psychiatry Res 114(2): 103-11.
Alzheimer's disease (AD) is clinically characterized by cognitive symptoms that, in combination with behavioral disturbances, significantly interfere with activities of daily living. These behavioral disorders contribute to the clinical heterogeneity of the disease and probably express different pathophysiological processes. Apathy is one of the most frequent behavioral disorders in AD. The aim of this study was to evaluate brain perfusion of AD patients with and without apathy (as determined by the Neuropsychiatric Inventory) compared with that in healthy elderly subjects. A total of 15 AD patients without apathy (AD/NA; mean age 76.6) and 15 AD patients with apathy (AD/A; mean age 77.6) were studied. Brain perfusion was measured by 99mTc-labeled bicisate (ECD) single-photon emission tomography (ECD SPECT). The images of the two AD subgroups were compared by means of statistical parametric mapping (SPM 99) to corresponding images of 11 healthy elderly control subjects (obtained from the Society of Nuclear Medicine database). Compared with the healthy elderly subjects, the apathy-free AD subgroup had significantly lower perfusion of inferior temporal regions (left fusiform gyrus, left parahippocampal area) and occipital regions (left gyrus lingualis). The apathy subgroup had significantly decreased perfusion of the left anterior cingulate, the right inferior and medial gyrus frontalis, the left orbitofrontal gyrus and the right gyrus lingualis. The differences in the brain areas with reduced perfusion between the apathy-free subjects (mainly the posterior regions) and the apathetic subjects (mainly the anterior regions) indicate that behavioral disorders such as apathy participate in the heterogeneity of brain perfusion in AD.

Berger, A. K., K. Fahlander, et al. (2002). "Negligible effects of depression on verbal and spatial performance in Alzheimer's disease." Dement Geriatr Cogn Disord 13(1): 1-7.
We examined whether a diagnosis of depression affects verbal and visuospatial performance in Alzheimer's disease (AD). Using data from a population-based study, persons with AD and depression (AD/D), AD alone and a control group of normal older adults were compared in two tests of verbal ability (category and letter fluency) and two tests of visuospatial skill (block design and clock drawing). As expected, there were clear AD-related deficits across all cognitive tasks. More importantly, the AD and AD/D groups were indistinguishable on all task variables. The lack of effects of depression was discussed relative to the view that those symptoms of this disease which are especially detrimental to cognitive functioning (e.g. concentration difficulties, lack of interest, loss of energy) may already be present in AD as a result of the neurodegenerative process.

Bigio, E. H., L. S. Hynan, et al. (2002). "Synapse loss is greater in presenile than senile onset Alzheimer disease: implications for the cognitive reserve hypothesis." Neuropathol Appl Neurobiol 28(3): 218-27.
In the past, 'Alzheimer disease' (AD) referred to pathologic AD with clinical onset of dementia in the presenium, while 'senile dementia of the Alzheimer type' (SDAT) referred to senile onset AD. Because AD appears clinically homogeneous regardless of age of onset, the two subtypes in more recent years have not been distinguished. Pathologic differences have been noted, but synapse loss has not previously been compared between the two groups. Hypothesizing that synapse loss would be greater in presenile onset than senile onset AD, we compared synapse loss, as well as Alzheimer pathology in presenile and senile onset AD, using an ELISA method to quantify synaptophysin. Synaptophysin was significantly lower in presenile than senile AD in right frontal and bilateral parietal lobes. Neuritic plaque counts were significantly higher in presenile than senile AD in bilateral frontal and parietal lobes. Semi-quantitative evaluation of neurofibrillary tangles revealed significantly more tangles in bilateral frontal and parietal lobes in presenile than senile AD. Brain weight was significantly lower in presenile than senile AD. The differences in synapse loss and Alzheimer-type pathology in presenile and senile onset AD support the hypothesis that 'cognitive reserve' protects the human brain from neurodegenerative disease.

Bilikiewicz, A., G. Opala, et al. (2002). "An open-label study to evaluate the safety, tolerability and efficacy of rivastigmine in patients with mild to moderate probable Alzheimer's disease in the community setting." Med Sci Monit 8(2): PI9-15.
BACKGROUND: Long-term safety and efficacy of Exelon (rivastigmine) was evaluated in a multi-center open-label study of 62 patients with probable mild to moderate Alzheimer's disease living in community setting. MATERIAL/METHODS: The patients started treatment with 1.5 mg bid (3 mg/day) Exelon and were scheduled to receive doses of 1.5 mg bid Exelon escalating on a biweekly basis. The patients were maintained on the highest tolerated dose within the assigned dose range 1.5-6.0 mg bid (3-12 mg/day) for the rest of the study. Evaluations were scheduled at biweekly intervals for the first 8 weeks and subsequently at study weeks 12, 18 and 26. Effects of Exelon on cognition were evaluated using the mini-mental state examination (MMSE) and selected items of Alzheimer's disease assessment scale (ADAS-cog) and the staging of the disease was measured using the global deterioration scale (GDS). Safety was monitored by physical examinations, vital signs, laboratory tests, ECG recording and by the assessment of adverse events. RESULTS: 55 patients completed the study (89%). Patients treated for 26 weeks showed the mean MMSE, ADAS-cog and GDS scores close to baseline values (p=NS) with no improvement and no deterioration. Exelon was generally well tolerated with 11% of patients withdrawing due to adverse events. The most frequently reported adverse events related to the gastrointestinal tract. CONCLUSIONS: In conclusion, the study data indicate that treatment with Exelon is safe, generally well tolerated and inhibits the progression of cognitive decline in patients with mild to moderate Alzheimer's disease over 26 weeks of treatment.

Birmingham, K. and S. Frantz (2002). "Set back to Alzheimer vaccine studies." Nat Med 8(3): 199-200.

Bishop, G. M., S. R. Robinson, et al. (2002). "Call for Elan to publish Alzheimer's trial details." Nature 416(6882): 677.

Blanchard, B. J., B. R. Stockwell, et al. (2002). "Eliminating membrane depolarization caused by the Alzheimer peptide Abeta(1-42, aggr.)." Biochem Biophys Res Commun 293(4): 1204-8.
A high-throughput screen found compounds that eliminate the dramatic membrane depolarization caused by the aggregated Alzheimer Abeta1-42 peptide, which activates mGluR1 receptors. The library was composed of known biologically active compounds; the cell-based assay measured the changes of membrane potential with a slow-acting voltage-sensitive dye. We found 10 potentially useful compounds, some of which reduce the Abeta-induced membrane depolarization up to 96%. Interestingly, the active compounds include specific tyrosine kinase inhibitors and inhibitors of certain chloride channels. We deduce that mGluR1 receptors, activated by Abeta1-42 or otherwise, can control the membrane potential via downstream activation of certain tyrosine kinases and certain ion channels. Dopaminergic and serotonergic agonists that emerged from the screen presumably compensate for the Abeta-induced membrane depolarization by themselves causing a hyperpolarization. The hit compounds, whose pharmacokinetics are known, show promise for the restoration of cognitive function in the treatment of early and mid-stage Alzheimer's disease.

Block, W., F. Jessen, et al. (2002). "Regional N-acetylaspartate reduction in the hippocampus detected with fast proton magnetic resonance spectroscopic imaging in patients with Alzheimer disease." Arch Neurol 59(5): 828-34.
OBJECTIVE: To detect regional metabolic changes that resemble the expected spatial pattern of neuronal loss in patients with Alzheimer disease (AD). METHODS: Thirty-four patients with AD and 22 healthy control subjects were included in the study. Single-slice fast proton spectroscopic imaging was performed in parallel angulation to the temporal lobes. Proton spectra were selected from the hippocampus, the lateral temporal lobe, and the occipital lobe of both hemispheres to determine metabolite concentration of N-acetylaspartate (NAA), total creatine (tCr), including phosphocreatine and creatine, and choline-containing compounds (Cho). The metabolic ratios of NAA/tCr and Cho/tCr were calculated and compared between patients with AD and healthy volunteers. RESULTS: The NAA/tCr ratios were significantly reduced in the left (F(1,1) = 4.34, P =.04) and right hippocampus (F(1,1) = 9.96, P =.003) in patients with AD. The Cho/tCr ratios remained unchanged in both hippocampi. There was no significant change of either NAA/tCr or Cho/tCr in the lateral temporal and occipital lobes of patients with AD. CONCLUSION: This study provides evidence that fast proton spectroscopic imaging may detect the regional pattern of disturbed neuronal integrity in patients with AD with high spatial resolution in a short acquisition time.

Bokde, A. L., S. J. Teipel, et al. (2002). "A new rapid landmark-based regional MRI segmentation method of the brain." J Neurol Sci 194(1): 35-40.
BACKGROUND: Neurodegenerative and cerebrovascular diseases show a distinct distribution of regional atrophy and subcortical lesions. OBJECTIVE: To develop an easily applicable landmark-based method for segmentation of the brain into the four cerebral lobes from MRI images. METHOD: The segmentation method relies on a combination of anatomical landmarks and geometrical definitions. It is applied on the surface reconstruction of the MRI volume. The internal borders between the lobes are defined on the axial slices of the brain. The reliability of this method was determined from MRI scans of 10 subjects. To illustrate the use of the method, it was applied to MRI scans of an independent group of 10 healthy elderly subjects and 10 patients with vascular dementia to determine the regional distribution of white matter hyperintensities (WMH). RESULTS: The intra-rater relative error (and intra-class correlation coefficient) of the lobe segmentation ranged from 1.6% to 6.9% (from 0.91 to 0.99). The inter-rater relative error (and intra-class correlation coefficient) ranged from 1.4% to 5.2% (from 0.96 to 0.99). Density of WMH was significantly higher in all four lobes in VD patients compared to controls (p<0.05). Within each group, WMH density was significantly higher in frontal and parietal than in temporal and occipital lobes (p<0.05). CONCLUSION: This landmark based method can accommodate age and disease-related changes in brain morphology. It may be particularly useful for the study of neurodegenerative and cerebrovascular disease and for the validation of template-based automated techniques.

Boller, F., M. Verny, et al. (2002). "Clinical features and assessment of severe dementia. A review." Eur J Neurol 9(2): 125-36.
Sound understanding of the dementia syndrome requires adequate acquaintance with its entire spectrum, from the lightest to the most advanced stages. Most studies of dementia deal with light to moderate stages of the condition, while relatively little attention has been paid to its most severe stages. This review presents a clinical description of patients with severe dementia and of the tests currently available to evaluate their cognitive, behavioural, and functional status. Available instruments such as the Hierarchic Dementia Scale or the Severe Impairment Battery now allow quantification of the cognitive and behavioural status of patients with severe dementia. Experience with severe dementia shows that, far from being in a "vegetative state", as is commonly thought, late-stage patients are in fact quite different from one another and in most cases continue to have an interaction with their environment. This ability to better define the characteristics of patients with severe dementia provides the basis for correlations between clinical data and data derived from neuroimaging, neurochemistry, or neuropathology. It also sets the stage for possible therapeutic trials involving these patients.

Boncristiano, S., M. E. Calhoun, et al. (2002). "Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis." J Neurosci 22(8): 3234-43.
Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized by extracellular deposits of amyloid-beta peptide (Abeta) and a severe depletion of the cholinergic system, although the relationship between these two events is poorly understood. In the neocortex, there is a loss of cholinergic fibers and receptors and a decrease of both choline acetyltransferase (ChAT) and acetylcholinesterase enzyme activities. The nucleus basalis of Meynert (NBM), which provides the major cholinergic input to the neocortex, undergoes profound neuron loss in AD. In the present study, we have examined the cholinergic alterations in amyloid precursor protein transgenic mice (APP23), a mouse model of cerebral beta-amyloidosis. In aged APP23 mice, our results reveal modest decreases in cortical cholinergic enzyme activity compared with age-matched wild-type mice. Total cholinergic fiber length was more severely affected, with 29 and 35% decreases in the neocortex of aged APP23 mice compared with age-matched wild-type mice and young transgenic mice, respectively. However, there was no loss of cholinergic basal forebrain neurons in these aged APP23 mice, suggesting that the cortical cholinergic deficit in APP23 mice is locally induced by the deposition of amyloid and is not caused by a loss of cholinergic basal forebrain neurons. To study the impact of cholinergic basal forebrain degeneration on cortical amyloid deposition, we performed unilateral NBM lesions in adult APP23 mice. Three to 8 months after lesioning, a 38% reduction in ChAT activity and significant cholinergic fiber loss were observed in the ipsilateral frontal cortex. There was a 19% decrease in Abeta levels of the ipsilateral compared with contralateral frontal cortex with no change in the ratio of Abeta40 to Abeta42. We conclude that the severe cholinergic deficit in AD is caused by both the loss of cholinergic basal forebrain neurons and locally by cerebral amyloidosis in the neocortex. Moreover, our results suggest that disruption of the basal cholinergic forebrain system does not promote cerebral amyloidosis in APP23 transgenic mice.

Bondolfi, L., M. Calhoun, et al. (2002). "Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice." J Neurosci 22(2): 515-22.
APP23 transgenic mice express mutant human amyloid precursor protein and develop amyloid plaques predominantly in neocortex and hippocampus progressively with age, similar to Alzheimer's disease. We have previously reported neuron loss in the hippocampal CA1 region of 14- to 18-month-old APP23 mice. In contrast, no neuron loss was found in neocortex. In the present study we have reinvestigated neocortical neuron numbers in adult and aged APP23 mice. Surprisingly, results revealed that 8-month-old APP23 mice have 13 and 14% more neocortical neurons compared with 8-month-old wild-type and 27-month-old APP23 mice, respectively. In 27-month-old APP23 mice we found an inverse correlation between amyloid load and neuron number. These results suggest that APP23 mice have more neurons until they develop amyloid plaques but then lose neurons in the process of cerebral amyloidogenesis. Supporting this notion, we found more neurons with a necrotic-apoptotic phenotype in the neocortex of 24-month-old APP23 mice compared with age-matched wild-type mice. Stimulated by recent reports that demonstrated neurogenesis after targeted neuron death in the mouse neocortex, we have also examined neurogenesis in APP23 mice. Strikingly, we found a fourfold to sixfold increase in newly produced cells in 24-month-old APP23 mice compared with both age-matched wild-type mice and young APP23 transgenic mice. However, subsequent cellular phenotyping revealed that none of the newly generated cells in neocortex had a neuronal phenotype. The majority were microglial and to a lesser extent astroglial cells. We conclude that cerebral amyloidosis in APP23 mice causes a modest neuron loss in neocortex and induces marked gliogenesis.

Bonetta, L. (2002). "Potential neurological value of statins increases." Nat Med 8(6): 541.

Borchelt, D. R., M. K. Lee, et al. (2002). "Accumulation of proteolytic fragments of mutant presenilin 1 and accelerated amyloid deposition are co-regulated in transgenic mice." Neurobiol Aging 23(2): 171-7.
The activities of presenilin 1 (PS1) and 2 modulate the proteolytic processing of amyloid precursor proteins to produce Abeta1-42, and mutations in these proteins are associated with an accelerated rate of Abeta deposition. PS1 and PS2 themselves are subject to a highly-regulated endoproteolytic cleavage to generate stable 27 kDa N-terminal and 17 kDa C-terminal fragments. Here, we examined the relationship between the regulated cleavage of PS1 and the acceleration of Abeta deposition in transgenic mice that co-express Mo/Hu APPswe and varied levels mutant PS1 (A246E variant). The steady-state levels of the N- and C-terminal fragments of mutant PS1 in mice expressing low levels of mRNA were similar to that of mice expressing high levels of mRNA. Only mice expressing high levels of transgene mRNA accumulated uncleaved full-length protein. In mice co-expressing low levels of PS1A246E mRNA with Mo/Hu APPswe the age of appearance of Abeta deposits was similar to that of mice co-expressing expressing Mo/Hu APPswe with very high levels of mutant PS1. Our findings demonstrate that the levels of accumulated human PS1 N- and C-terminal fragments do not increase in proportion to the level of transgene mRNA and that similarly, the magnitude by which mutant PS1 accelerates the deposition of beta-amyloid is not proportional to the level of transgene expression.

Borghi, R., L. Giliberto, et al. (2002). "Increase of cdk5 is related to neurofibrillary pathology in progressive supranuclear palsy." Neurology 58(4): 589-92.
BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by a pure neurofibrillary tau pathology involving mainly basal ganglia and brainstem nuclei. In addition to a haplotype of the tau gene potentially favoring tau aggregation, lipoperoxidation has been shown to be associated with PSP tau pathology. OBJECTIVE: To analyze cdk5/p35 complex, a kinase that regulates neurite outgrowth, as a potential cellular mechanism underlying tau phosphorylation in brain tissues from PSP and control cases and comparatively in cerebral cortex from subjects with AD. METHODS: Cdk5/p35 protein levels and distribution were evaluated by immunoblotting and immunocytochemistry in brain regions from seven PSP, six AD, and seven control cases, with similar postmortem intervals. RESULTS: Total cdk5 protein levels were significantly increased by more than threefold in PSP tissue and were augmented in PSP neurons, codistributed with tau immunoreactivity. P35, the regulatory subunit of cdk5, was degraded by postmortem proteolysis to the same extent in PSP, AD, and control tissues. CONCLUSIONS: The proteolysis in vivo of p35, the regulatory subunit of the kinase, is not ascertainable because it is masked by its postmortem degradation. The study, however, indicates that in PSP, the alteration of cdk5 is different from that described in AD and suggests that the absence of amyloid beta protein deposition may account for the different pathways responsible for the same kinase activation.

Borroni, B., F. Colciaghi, et al. (2002). "ApoE genotype influences the biological effect of donepezil on APP metabolism in Alzheimer disease: evidence from a peripheral model." Eur Neuropsychopharmacol 12(3): 195-200.
Three major amyloid precursor protein (APP) forms with apparent molecular weight ranging from 106 to 130 kDa are present in human platelets. Alzheimer disease (AD) is associated with a decreased APP forms ratio (APPr) between the three major forms. A total of 25 mild to moderate AD patients were investigated. Platelet APPr was studied before and after 30 days of acetylcholinesterase-inhibitor treatment (donepezil, 5 mg daily). Patients were grouped into non-epsilon4 carriers and epsilon4 carriers according to apolipoprotein E (ApoE) genotype. At baseline, all patients showed low APPr levels and no significant difference was found between the two ApoE subgroups. After treatment, although a marked improvement in APPr was observed in most patients, non-epsilon4 carriers displayed a higher increase compared to epsilon4 carriers (P<0.0001). The present study provides evidence that donepezil influences APP metabolism in platelets, and suggests that ApoE genotype might be an important modulating factor for drug responsiveness in AD.

Bosetti, F., F. Brizzi, et al. (2002). "Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease." Neurobiol Aging 23(3): 371-6.
Evidence suggests that mitochondrial dysfunction is prominent in Alzheimer's disease (AD). A failure of one or more of the mitochondrial electron transport chain enzymes or of F(1)F(0)-ATPase (ATP synthase) could compromise brain energy stores, generate damaging reactive oxygen species (ROS), and lead to neuronal death. In the present study, cytochrome c oxidase (COX) and F(1)F(0)-ATPase activities of isolated mitochondria from platelets and postmortem motor cortex and hippocampus from AD patients and age-matched control subjects were assayed. Compared with controls, COX activity was decreased significantly in platelets (-30%, P < 0.01, n = 20) and hippocampus (-35 to -40%, P < 0.05, n = 6), but not in motor cortex from the AD patients. In contrast, in AD platelets and brain tissues, F(1)F(0)-ATP hydrolysis activity was not significantly changed. Moreover, the ATP synthesis rate was similar in mitochondria of platelets from AD patients and controls. These results demonstrate that COX but not F(1)F(0)-ATPase is a mitochondrial target in AD, in both a brain association area and in platelets. A reduced COX activity may make the tissue vulnerable to excitotoxicity or reduced oxygen availability.

Bottino, C. M., I. A. Carvalho, et al. (2002). "[Cognitive rehabilitation in Alzheimer's disease patients: multidisciplinary team report]." Arq Neuropsiquiatr 60(1): 70-9.
OBJECTIVE: This study aims to show preliminary results of the 'combined treatment' (acetylcholinesterase inhibitor + cognitive training) on a group of mild Alzheimer's disease (AD) patients, followed-up for 7 months. METHODS: Six mild AD patients, diagnosed according to ICD-10 and NINCDS-ADRDA criteria, were included on a open trial with Rivastigmine, 6-12 mg/day, for 2 months, followed by a weekly cognitive rehabilitation group, for 5 months. Caregivers were submitted to a weekly group of counseling and support for 5 months. RESULTS: Stabilization or mild improvement of patients' cognitive and activities of daily living deficits were found, besides reduction of patients and caregivers' depressive and anxiety levels. CONCLUSION: The 'combined treatment' can help on the stabilization or result on a mild improvement of AD patients' cognitive and functional deficits. Support and counseling interventions can reduce the levels of caregivers' psychiatric symptoms.

Boutajangout, A., K. Leroy, et al. (2002). "Increased tau phosphorylation but absence of formation of neurofibrillary tangles in mice double transgenic for human tau and Alzheimer mutant (M146L) presenilin-1." Neurosci Lett 318(1): 29-33.
Neurofibrillary tangles, composed of tau proteins, are a key lesion observed in sporadic forms of Alzheimer's disease and in familial forms associated with mutations of presenilin-1 (PS1). We have generated a double transgenic mouse line expressing a human tau isoform and a mutated form of PS1 (M146L) in neurons. Increased expression of the PS1 holoprotein was observed in the tau/PS1 transgenic mice and the proteolytic fragments of PS1 did not appear to be modified. A somatodendritic accumulation of the transgenic tau and an increase in tau phosphorylation were observed in both tau- and tau/PS1 transgenic mice. Neurofibrillary tangles were not observed in animals analyzed up to 17 months. Immunoprecipitation of tau from brain homogenates demonstrated its binding with active glycogen synthase kinase-3beta in control, tau- and tau/PS1 transgenic lines. These results suggest that overexpression of this Alzheimer mutant PS1 in vivo is not by itself sufficient to induce the formation of neurofibrillary tangles, even in neurons co-expressing and accumulating a human tau isoform.

Bozikas, V. P., E. Kovari, et al. (2002). "Neurofibrillary tangles in elderly patients with late onset schizophrenia." Neurosci Lett 324(2): 109-12.
The objective of the present study was to examine whether neurofibrillary tangles densities are increased in elderly patients with late-onset schizophrenia (LOS). A neuropathological examination was performed in 32 consecutive autopsy brain specimens of ten patients with early-onset schizophrenia (EOS; onset of symptoms before the age of 40 years), eight patients with LOS (onset of symptoms after the age of 40 years) and 14 age-matched controls with no known neuropsychiatric disorder. Neurofibrillary tangle densities observed in the CA1 field of the hippocampus, the enthorhinal cortex, and the inferior temporal cortex in patients with LOS, EOS, and controls were not significantly different. All patients with EOS or LOS had Braak stages of III or less, which may correspond to normal aging. Thus, patients with schizophrenia, regardless of the age of onset of their symptoms, are no more prone to the development of Alzheimer's disease than the general population.

Bozzali, M., A. Falini, et al. (2002). "White matter damage in Alzheimer's disease assessed in vivo using diffusion tensor magnetic resonance imaging." J Neurol Neurosurg Psychiatry 72(6): 742-6.
OBJECTIVE: To investigate the extent and the nature of white matter tissue damage of patients with Alzheimer's disease using diffusion tensor magnetic resonance imaging (DT-MRI). BACKGROUND: Although Alzheimer's disease pathology mainly affects cortical grey matter, previous pathological and MRI studies showed that also the brain white matter of patients is damaged. However, the nature of Alzheimer's disease associated white matter damage is still unclear. METHODS: Conventional and DT-MRI scans were obtained from 16 patients with Alzheimer's disease and 10 sex and age matched healthy volunteers. The mean diffusivity (D), fractional anisotropy (FA), and inter-voxel coherence (C) of several white matter regions were measured. RESULTS: D was higher and FA lower in the corpus callosum, as well as in the white matter of the frontal, temporal, and parietal lobes from patients with Alzheimer's disease than in the corresponding regions from healthy controls. D and FA of the white matter of the occipital lobe and internal capsule were not different between patients and controls. C values were also not different between patients and controls for any of the regions studied. Strong correlations were found between the mini mental state examination score and the average overall white matter D (r=0.92, p<0.001) and FA (r=0.78; p<0.001). CONCLUSIONS: White matter changes in patients with Alzheimer's disease are likely to be secondary to wallerian degeneration of fibre tracts due to neuronal loss in cortical associative areas.

Brendza, R. P., K. R. Bales, et al. (2002). "Role of apoE/Abeta interactions in Alzheimer's disease: insights from transgenic mouse models." Mol Psychiatry 7(2): 132-5.

Briani, C., S. Ruggero, et al. (2002). "Combined analysis of CSF betaA42 peptide and tau protein and serum antibodies to glycosaminoglycans in Alzheimer's disease: preliminary data." J Neural Transm 109(3): 393-8.
Neuropathological hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles, containing betaA(42) peptide and tau protein, respectively. Amyloid plaques contain also glycosaminoglycans (GAGs). Whereas cerebrospinal fluid (CSF) levels of betaA(42) peptide and tau protein have been demonstrated as potential markers of Alzheimer's disease (AD), no data are available for GAGs. We determined (Elisa) tau and betaA(42) CSF levels, as well as serum antibodies to GAGs in 9 AD patients, and the values were analyzed in relation to age and severity of the disease. Beta-A42 and tau CSF levels were significantly reduced and increased, respectively, in AD patients when compared to controls, but they did not correlate with the severity of the disease. Despite their role in amyloidogenesis, we did not find evidence for the use of GAGs as diagnostic marker of AD.

Bronge, L., N. Bogdanovic, et al. (2002). "Postmortem MRI and histopathology of white matter changes in Alzheimer brains. A quantitative, comparative study." Dement Geriatr Cogn Disord 13(4): 205-12.
To evaluate whether magnetic resonance imaging (MRI) of white matter changes in Alzheimer's disease either under- or overestimates the findings on neuropathology. Postmortem MRI and neuropathological examination were performed on 6 brains from elderly individuals with a postmortem diagnosis of AD. Using a specially designed brain slicer, the brains were cut corresponding to the MRI images, and stained by Luxol Fast Blue. Quantitative analysis of white matter changes on MRI and neuropathology was performed using stereological principles. Measures from MRI and pathology were highly correlated (r(2) = 0.71). However, pathology showed significantly more extensive changes than did MRI in all cases, with a mean of 54% larger areas. The lesions not identified with MRI represented, however, only minor changes with lower intensity of myelin staining and with an accentuation of the distance between fibres but with preserved axonal network and glial cell density.

Brown, P. (2002). "Drug therapy in human and experimental transmissible spongiform encephalopathy." Neurology 58(12): 1720-5.
During the past 30 years, over 60 different chemical compounds have been used to treat experimental animals infected with transmissible spongiform encephalopathies (TSE), including a wide variety of anti-infectious agents, immunomodulating drugs, and chemicals interacting with the lympho-reticular system. Some compounds achieved a prolongation of the incubation period, but this effect decreased or disappeared when they were administered at or near the onset of symptomatic disease. Recent in vitro and tissue culture studies support earlier speculation about the importance of a chemical structure containing both water-soluble and lipid-soluble components, evidently as a means of interaction with the misfolded membrane-bound 'prion' protein. A number of compounds shown to eliminate the protein (or infectivity) in TSE-infected tissue cultures are the subject of ongoing studies in animals, and are under consideration for human drug trials. As with other recalcitrant infections, combinations of drugs with different modes of action are likely to be necessary for any effective therapy. Also, very recent work in developing antibodies that can neutralize in vitro infection (and, in conjunction with genetic engineering, in vivo infection) has renewed interest in the strategies of both active and passive immunization.

Brown, V. M., A. Ossadtchi, et al. (2002). "High-throughput imaging of brain gene expression." Genome Res 12(2): 244-54.
Voxelation is a new method for acquisition of three dimensional (3D) gene expression patterns in the brain. It employs high-throughput analysis of spatially registered voxels (cubes) to produce multiple volumetric maps of gene expression analogous to the images reconstructed in biomedical imaging systems. Using microarrays, 24 voxel images of coronal hemisections at the level of the hippocampus of both the normal human brain and Alzheimer's disease brain were acquired for 2000 genes. The analysis revealed a common network of coregulated genes, and allowed identification of putative control regions. In addition, singular value decomposition (SVD), a mathematical method used to provide economical explanations of complex data sets, produced images that distinguished between brain structures, including cortex, caudate, and hippocampus. The results suggest that voxelation will be a useful approach for understanding how the genome constructs the brain.

Bucciantini, M., E. Giannoni, et al. (2002). "Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases." Nature 416(6880): 507-11.
A range of human degenerative conditions, including Alzheimer's disease, light-chain amyloidosis and the spongiform encephalopathies, is associated with the deposition in tissue of proteinaceous aggregates known as amyloid fibrils or plaques. It has been shown previously that fibrillar aggregates that are closely similar to those associated with clinical amyloidoses can be formed in vitro from proteins not connected with these diseases, including the SH3 domain from bovine phosphatidyl-inositol-3'-kinase and the amino-terminal domain of the Escherichia coli HypF protein. Here we show that species formed early in the aggregation of these non-disease-associated proteins can be inherently highly cytotoxic. This finding provides added evidence that avoidance of protein aggregation is crucial for the preservation of biological function and suggests common features in the origins of this family of protein deposition diseases.

Bucks, R. S., L. Byrne, et al. (2002). "Interventions in Alzheimer's disease." Int J Geriatr Psychiatry 17(5): 492-3.

Buckwalter, J. G., V. C. Crooks, et al. (2002). "A preliminary psychometric analysis of a computer-assisted administration of the Telephone Interview of Cognitive Status-modified." J Clin Exp Neuropsychol 24(2): 168-75.
Most screening tests of cognitive functioning require face to face administration by trained examiners. This limits their utility in epidemiology and in primary care settings. Further, existing screening tests have not been developed using established psychometric principles. We adapted the Telephone Interview of Cognitive Status-modified (TICSm) for administration as a computer-assisted telephone interview (CATI). We screened 3,681 elderly women with the CATI version of the TICSm, using lay staff as part of a longitudinal study. A preliminary analysis of the psychometric properties of the TICSm indicated good internal consistency. Test-retest reliability is needed to confirm reliability. Further work remains to adequately judge the validity of the TICSm including comparisons with well-standardized tests and assessment of its predictive properties in identifying dementia. However, the CATI version of the TICSm appears to have potential as a cost-effective means of testing cognitive performance.

Buee, L., M. Hamdane, et al. (2002). "[In Process Citation]." J Soc Biol 196(1): 103-8.
Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, the recent discovery of tau gene mutations in fronto-temporal dementia with parkinsonism linked to chromosome 17 has reinforced the direct role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies. Conversely, recent data in myotonic dystrophy has demonstrated that indirect effect (CTG repeat expansion) leading to variations in tau alternative splicing also produce neurofibrillary degeneration.

Buee-Scherrer, V. and M. Goedert (2002). "Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells." FEBS Lett 515(1-3): 151-4.
Tau is a microtubule-associated protein that is abnormally hyperphosphorylated in the filamentous lesions that define a number of neurodegenerative diseases collectively referred to as tauopathies. We previously showed that stress-activated protein (SAP) kinases phosphorylate tau protein at many of the hyperphosphorylated sites in vitro. Here we have developed a system to study the effects of five SAP kinases (SAPK1c/JNK1, SAPK2a/p38alpha, SAPK2b/p38beta, SAPK3/p38gamma and SAPK4/p38delta) on tau phosphorylation in intact cells. All kinases phosphorylated tau, albeit at different efficiencies. Tau was a good substrate for SAPK3/p38gamma and SAPK4/p38delta, a reasonable substrate for SAPK2b/p38beta and a relatively poor substrate for SAPK2a/p38alpha and SAPK1c/JNK1. These findings indicate that the aberrant activation of SAP kinases, especially SAPK3/p38gamma and SAPK4/p38delta, could play an important role in the abnormal hyperphosphorylation of tau that is an invariant feature of the tauopathies.

Bullock, R. (2002). "The clinical benefits of rivastigmine may reflect its dual inhibitory mode of action: an hypothesis." Int J Clin Pract 56(3): 206-14.
Recent health technology assessments have given us the go-ahead to use cholinesterase inhibitors, which, in combination with community services, are currently the most appropriate treatment for patients with Alzheimer's disease (AD). Initial research focused upon acetylcholinesterase (AChE)-selective agents, but it is now thought that dual inhibitors of AChE and butyrylcholinesterase (BuChE) may provide more sustained efficacy over the course of AD and may help to slow disease progression. Rivastigmine is a potent inhibitor of AChE and BuChE and has demonstrated broad benefits across the severity of AD and across the cognitive, functional and behavioural domains of AD. In addition, rivastigmine has shown cognitive and behavioural benefits in patients with dementia with the Lewy body variant of AD. These benefits may reflect the inhibition of both AChE and BuChE, as demonstrated by significant correlations between cognitive improvements and cholinesterase inhibition in rivastigmine-treated patients with AD. Rivastigmine shows a clear dose-response relationship, and physicians should aim to maintain patients on doses of 6 mg/day or higher, to a maximum of 12 mg/day. As with all cholinesterase inhibitors, rapid forced dose escalation may increase the incidence of typical cholinergic side-effects, resulting in lower maintenance doses. In a chronic disease such as AD, there is time to implement slow dose escalation and higher final maintenance doses. If used appropriately, the benefits of rivastigmine seen in clinical practice may prove to be even greater than those reported in clinical trials.

Bullock, R. and C. Connolly (2002). "Switching cholinesterase inhibitor therapy in Alzheimer's disease--donepezil to rivastigmine, is it worth it?" Int J Geriatr Psychiatry 17(3): 288-9.

Bullock, R. (2002). "New drugs for Alzheimer's disease and other dementias." Br J Psychiatry 180: 135-9.
BACKGROUND: Alzheimer's disease management involves symptomatic drug treatments passed by the National Institute for Clinical Excellence. Disease modification is now the goal. AIMS: To review current and developmental drugs for Alzheimer's disease, their usage, and the clinical context of known facts and proposed specific models. METHOD: A brief evidence-based review was made, using literature where available, or evidence from consensus groups where it was absent. RESULTS: There is good evidence to support the use of cholinesterase inhibitors, and perhaps vitamin E. Oestrogen and anti-inflammatory agents show possibility, but there is not enough evidence to support routine use. CONCLUSIONS: Symptomatic treatments exist for Alzheimer's disease. Observational studies and increasing knowledge of brain biology are leading towards further treatment options. Old age psychiatrists have valuable treatments they now have to learn to use.

Burgener, S. and P. Twigg (2002). "Relationships among caregiver factors and quality of life in care recipients with irreversible dementia." Alzheimer Dis Assoc Disord 16(2): 88-102.
Using Lawton's (1983) model of quality of life (QoL) in older adults as a guiding framework, the central purpose of this ongoing longitudinal, prospective study is to examine predictors of QoL outcomes in persons with irreversible dementia as they move through the disease stages. From an initial sample of 96 caregiver/care recipient pairs, 73 (N = 146) pairs remain at the 18-month data collection point. Changes in care recipient outcomes from baseline to the 18-month assessment include significant declines in mental status, productive behaviors, and functional ability, with a statistically significant improvement in depression. Controlling for 12-month mental ability, caregiver factors at 12 months predicting care recipient QoL outcomes at 18 months include psychologic well being predicted by the quality of the relationship with the caregiver and activity participation. Depression was predicted by activity participation as well. Care recipient functional ability was predicted by activity participation and caregiver role stress (disruption to routines and social functioning). Two of the three aspects of care recipient productive behaviors were predicted by caregiver factors, with quality of the relationship predicting problem solving and caregiver role stress (negative attitudes toward care recipient) and total social contacts predicting care recipient social behaviors in the expected direction. Lawton's QoL model was supported by this analysis, with a total explained variance of 32% for three (psychologic well being, productive behaviors, functional ability) of the five (physical impairment and perceived personal control not included) components of care recipient QoL outcomes.

Burggren, A. C., G. W. Small, et al. (2002). "Specificity of brain activation patterns in people at genetic risk for Alzheimer disease." Am J Geriatr Psychiatry 10(1): 44-51.
Previous studies with positron-emission tomography (PET) and functional magnetic resonance imaging (fMRI) have indicated differences in neural metabolism and activity between carriers of the APOE epsilon4 allele and those who are not at risk for Alzheimer disease (AD). Persons without dementia carrying the epsilon4 allele showed greater magnitude and extent of brain activation than noncarriers in regions required for memory, suggesting they performed additional cognitive work to accomplish the same task. To determine whether the fMRI differences were specific to a memory task or generalizable to any difficult cognitive task, the authors performed fMRI and compared images from 25 subjects with and without the APOE epsilon4 allele. In the most difficult conditions, all subjects showed increased MR signal in the prefrontal cortex, indicating increased cognitive effort. However, the two genetic groups showed no differences in activation patterns even at the most difficult task level, suggesting that additional cognitive effort in persons at genetic risk for AD is specific to episodic encoding and is not merely a reflection of task difficulty.

Burns, A., E. J. Byrne, et al. (2002). "Alzheimer's disease." Lancet 360(9327): 163-5.

Busciglio, J., A. Pelsman, et al. (2002). "Altered metabolism of the amyloid beta precursor protein is associated with mitochondrial dysfunction in Down's syndrome." Neuron 33(5): 677-88.
Most Down's syndrome (DS) patients develop Alzheimer's disease (AD) neuropathology. Astrocyte and neuronal cultures derived from fetal DS brain show alterations in the processing of amyloid beta precursor protein (AbetaPP), including increased levels of AbetaPP and C99, reduced levels of secreted AbetaPP (AbetaPPs) and C83, and intracellular accumulation of insoluble Abeta42. This pattern of AbetaPP processing is recapitulated in normal astrocytes by inhibition of mitochondrial metabolism, consistent with impaired mitochondrial function in DS astrocytes. Intracellular Abeta42 and reduced AbetaPPs are also detected in DS and AD brains. The survival of DS neurons is markedly increased by recombinant or astrocyte-produced AbetaPPs, suggesting that AbetaPPs may be a neuronal survival factor. Thus, mitochondrial dysfunction in DS may lead to intracellular deposition of Abeta42, reduced levels of AbetaPPs, and a chronic state of increased neuronal vulnerability.

Bush, A. I. and R. E. Tanzi (2002). "The galvanization of beta-amyloid in Alzheimer's disease." Proc Natl Acad Sci U S A 99(11): 7317-9.

Buxbaum, J. D., E. I. Cullen, et al. (2002). "Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients." Front Biosci 7: a50-9.
Epidemiological studies demonstrate that hypercholesterolemia is a risk factor for Alzheimer's disease (AD). As the generation and accumulation of the beta-amyloid peptide (Abeta) in the brain appears to be significant for the initiation and progression of AD, it is possible that cholesterol levels regulate Abeta formation and/or clearance. To test the effects of altering cholesterol on Abeta formation, we incubated cells with or without lovastatin acid, the active metabolite of the HMG-CoA reductase inhibitor lovastatin, and measured the fraction of Abeta formed from its precursor under each condition. We observed that treatment with lovastatin acid led to a profound decrease in the levels of Abeta formed. This effect was observed at concentrations of 0.05-5 microM, ranges where this compound is effective at inhibiting HMG-CoA reductase. To examine the effects of lovastatin on Abeta in vivo, human subjects who had elevated low-density lipoprotein cholesterol were treated during a double-blind, randomized study with 10-60-mg once-daily doses of a controlled-release formulation of lovastatin, or matching placebo. Serum Abeta concentrations were measured before and after up to 3 months of treatment. Mean and median changes from baseline in serum Abeta concentrations showed a significant (p < 0.0348), dose-dependent decrease. Differences between the 40- and 60-mg dose groups and placebo were statistically significant (Dunnett's p< 0.05). Our results suggest a mechanism by which hypercholesterolemia may increase risk for AD and indicate that lovastatin reduces Abeta formation and may thereby be effective in delaying the onset and/or slowing the progression of AD.

Byne, W., M. S. Buchsbaum, et al. (2002). "Postmortem assessment of thalamic nuclear volumes in subjects with schizophrenia." Am J Psychiatry 159(1): 59-65.
OBJECTIVE: The authors assessed schizophrenia-associated changes in volume and neuronal number in the mediodorsal nucleus and the pulvinar regions of the thalamus. METHOD: Right-hemisphere thalami obtained at autopsy from 14 schizophrenic and eight comparison subjects were examined. Computer-assisted morphometric techniques were used to determine volumes for the mediodorsal nucleus, pulvinar, and the anterior and centromedian nuclei as well as the parvocellular, magnocellular, and caudodorsal subdivisions of the mediodorsal nucleus. Neurons in the mediodorsal nucleus and pulvinar were counted and measured by using a stereology-based sampling strategy. RESULTS: Four schizophrenic and three comparison subjects had Alzheimer's type pathology, leaving 10 schizophrenic and five comparison subjects without other documented neuropathological changes. In analyses that included either the full cohort or only the subjects without Alzheimer's type pathology, volumes of the mediodorsal nucleus and pulvinar, but not the anterior or centromedian nuclei, were significantly smaller in the schizophrenic subjects. For the schizophrenic subjects, neuronal number in the mediodorsal nucleus, parvocellular subdivision, and pulvinar was significantly lower, and neuronal size in the mediodorsal nucleus, caudodorsal subdivision, and pulvinar was significantly smaller. CONCLUSIONS: Schizophrenia is associated with volume and neuronal changes in the mediodorsal nucleus and pulvinar, the major association nuclei of the thalamus, whereas total thalamic volume and the volumes of anterior and centromedian nuclei were not significantly altered.

Calingasan, N. Y., H. A. Erdely, et al. (2002). "Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury." Neurobiol Aging 23(1): 31-9.
Chronic neuroinflammatory processes including glial activation may play a role in the pathogenesis of Alzheimer's disease (AD). The immune and inflammatory mediator CD40 ligand (CD40L) can augment the activation of cultured microglia by amyloid beta-protein (Abeta) and promote neuron death. We investigated whether CD40L is increased in AD and in animal models of AD and neuroinflammation. In the frontal cortex of elderly, non-AD controls, CD40L immunoreactivity was found in the glial limiting membrane, astrocytes, and vascular profiles in gray and white matter. In AD, intense CD40L immunoreactivity occurred in hypertrophied astrocytes throughout the frontal cortex. The majority of CD40L-immunoreactive astrocytes in the gray matter occurred within, or at the periphery of, Abeta(1-42)-immunoreactive plaques. A semiquantitative analysis revealed a three-fold elevation in the number of CD40L-immunoreactive astrocytes in AD compared to controls. The cortex and hippocampus from 6 and 12 month-old amyloid precursor protein/presenilin 1 transgenic mice exhibited numerous neuritic plaques and CD40L-positive astrocytes, which were not detected in non-transgenic controls. In adult rats, little or no CD40L staining occurred in astrocytes of the intact brain, whereas intrastriatal excitotoxic or stab wound lesions produced a strong CD40L immunoreactivity that was more segregated than glial fibrillary acidic protein. These findings indicate that astrocytes are the predominant source of CD40L in brain, and are consistent with the proposed role of CD40L-mediated neurotoxic inflammation in AD.

Callahan, L. M., W. A. Vaules, et al. (2002). "Progressive reduction of synaptophysin message in single neurons in Alzheimer disease." J Neuropathol Exp Neurol 61(5): 384-95.
The data presented here examine 2 hypotheses: 1) that viable but vulnerable single neurons remaining in the Alzheimer brain lose synaptic markers, and 2) that the extent of this loss is related to the disease state of these single neurons when disease state is defined by immunoreactivity. We used double immunohistochemistry (IHC) to define neurofibrillary tangle (NFT) and phosphorylation status of tau at selected defined epitopes. This double IHC was combined with quantitative in situ hybridization for message for the synaptic marker, synaptophysin, in 1,127 single hippocampal CA1 pyramidal neurons from 15 Alzheimer disease (AD) and 4 control cases. We found that there is a graded, progressive, decrease of synaptophysin message expressed by single neurons related to immunohistochemical markers of tau status, and that neurons in similar immunohistochemically defined classes show similar losses of synaptophysin message regardless of whether they were sampled from clinical control brains or advanced AD. The resulting conclusions are consistent with a suggestion that differences among clinically defined AD and control status are defined by the numbers of neurons in various disease states.

Cannata, A. P., M. Alberoni, et al. (2002). "Frontal impairment in subcortical ischemic vascular dementia in comparison to Alzheimer's disease." Dement Geriatr Cogn Disord 13(2): 101-11.
We compared the performance of patients with Alzheimer's disease to that of patients with subcortical vascular dementia (s-IVD) in a set of tasks assessing categorization abilities, sustained and selective attention, and set-shifting and set-maintaining skills. Only the measures of naming and categorization abilities on the Test of Classification and Recall of Pictures (TCRP) proved useful in differentiating AD from s-IVD patients. s-IVD patients showed worse performance than AD on the TCRP categorization measures, while both AD and s-IVD patients were equally impaired in other tasks assessing executive functions (EF). With respect to the naming task, s-IVD patients made significantly more perseverative and unrelated errors than AD patients. Moreover, in the s-IVD group, we found a strong correlation between categorization ability and an attentional test score (Attentional Matrices), while no such correlation emerged in the AD group. These results suggest a dissociated impairment of EF in the 2 dementia groups. In our view, the lack of inhibition and the inability to manipulate complex information are responsible for a greater executive dysfunction in s-IVD patients in comparison with AD patients. The capacity to build up strategies appears more preserved in AD patients, whose impaired performance in executive tasks seems to be related to an impairment of attentional shifting and working memory.

Cantuti-Castelvetri, I., C. E. Keller-McGandy, et al. (2002). "Expression and activity of antioxidants in the brain in progressive supranuclear palsy." Brain Res 930(1-2): 170-81.
Recent evidence implicates oxidative stress in the pathophysiology of progressive supranuclear palsy (PSP). Thus, we undertook a study of the activity and localization of two essential antioxidant systems (superoxide dismutase [SOD] enzymes and total glutathione) in the human post-mortem PSP and control brain. Marked increases in SOD1 (Cu/ZnSOD) activity and glutathione levels were measured within most PSP brain regions examined, whereas, only the subthalamic nucleus exhibited a significant increase (+68%) in SOD2 (MnSOD) activity. Two additional cases with mild pathological abnormalities were studied. The first (case A) may represent an example of an asymptomatic PSP case, while the second (case B) had mild pathological abnormalities consistent with typical PSP. In case A, only the STN had elevated levels of SOD activity, in the absence of an increase in tissue glutathione content. In case B, SOD activities and tissue glutathione content were elevated in several regions. Immunolocalization of the SOD1 and SOD2 proteins in paraffin-embedded tissue sections revealed a marked increase in the density of SOD immunopositive profiles (particularly glia) in the typical PSP brain, particularly within the white matter. Together, our data argues strongly in favor of the involvement of oxidative stress in the etiology and progression of PSP, and suggests that deficit in SOD or glutathione metabolism are not causative.

Caparros-Lefebvre, D., N. Sergeant, et al. (2002). "Guadeloupean parkinsonism: a cluster of progressive supranuclear palsy-like tauopathy." Brain 125(Pt 4): 801-11.
An unusually high frequency of atypical Parkinson syndrome has been delineated over the last 5 years in the French West Indies. Postural instability with early falls, prominent frontal lobe dysfunction and pseudo-bulbar palsy were common and three-quarters of the patients were L-dopa unresponsive. One-third of all patients seen had probable progressive supranuclear palsy (PSP). This new focus of atypical parkinsonism is reminiscent of the one described in Guam and may be linked to exposure to tropical plants containing mitochondrial complex I inhibitors (quinolines, acetogenins, rotenoids). Two hundred and twenty consecutive patients with Parkinson's syndrome seen by the neurology service at Pointe a Pitre, Guadeloupe University Hospital were studied. Currently accepted operational clinical criteria for Parkinson's syndromes were applied. The pathological findings of three patients who came to autopsy are reported. Fifty-eight patients had probable PSP, 96 had undetermined parkinsonism and 50 had Parkinson's disease, 15 had amyotrophic lateral sclerosis with parkinsonism and one had probable multiple system atrophy. All three PSP patients in whom post-mortem study was performed had early postural instability, gaze palsy and parkinsonian symptoms, followed by a frontolimbic dementia and corticobulbar signs. Neuropathological examination showed an accumulation of tau proteins, predominating in the midbrain. There was an exceptionally large accumulation of neuropil threads in Case 1. Biochemical studies detected a major doublet of pathological tau at 64 and 69 kDa in brain tissue homogenates. All cases were homozygous for the H1 tau haplotype, but no mutation of the tau gene was observed. Clinical, neuropathological and biochemical features were compatible with the diagnosis of PSP, although some unusual pathological features were noted in Case 1. A cluster of cases presenting with atypical parkinsonism is reported. Guadeloupean parkinsonism may prove to be a tauopathy identical or closely related to PSP.

Carlson, M. C., J. T. Tschanz, et al. (2002). "H2 histamine receptor blockade in the treatment of Alzheimer disease: a randomized, double-blind, placebo-controlled trial of nizatidine." Alzheimer Dis Assoc Disord 16(1): 24-30.
OBJECTIVES: To evaluate the efficacy of nizatidine, a histamine H2-blocking drug, in delaying the progression of cognitive impairment in older adults with Alzheimer disease (AD). DESIGN: A one-year, randomized, double-blind, placebo-controlled trial. PARTICIPANTS: Fifty-one older men and women aged 67 to 96 years with AD were recruited from the Cache County Study on Memory in Aging. METHODS: Patients were stratified by age and by the presence of one or more epsilon 4 alleles at the APOE locus, then randomized to receive nizatidine 75 mg (Axid ARTM, Whitehall Robins) or a matching placebo tablet twice daily. Cognitive outcomes were assessed at baseline, six, and twelve months after enrollment using tests from the CERAD battery and additional measures of visuospatial memory, verbal memory, and verbal fluency. RESULTS: Subjects showed significant declines in language, fluency, and praxis but most measures of memory had already "bottomed out." Intention-to-treat and compliance-based analyses showed no effect of nizatidine on any of the cognitive outcome measures over the one-year study interval. CONCLUSIONS: These results do not support claims for the efficacy of nizatidine in over-the-counter dosages as a means of preventing symptom progression in AD.

Casal, C., J. Serratosa, et al. (2002). "Relationship between beta-AP peptide aggregation and microglial activation." Brain Res 928(1-2): 76-84.
We compared the relationship between the state of aggregation of two peptides (beta-AP 25-35 and beta-AP 1-42) and microglial activation. After 7 days at 37 degrees C beta-AP 25-35 was in an amorphous state and did not activate microglial cells. In the same conditions, aggregated beta-AP 1-42 activated these cells and caused changes in microglial ramification, increasing the proliferation index and inducing tumor necrosis factor alpha (TNF alpha) release. Neither peptide induced a release of nitric oxide (NO). As the toxicity of beta-AP peptides in cell culture is associated with the formation of amyloid fibrils, we also examined the toxicity of both peptides in microglial cell cultures and in PC 12 cell cultures. The results suggest that the two beta-AP fragments studied have similar neurotoxic effects but different pro-inflammatory activities.

Castro, C. M., S. Wilcox, et al. (2002). "An exercise program for women who are caring for relatives with dementia." Psychosom Med 64(3): 458-68.
OBJECTIVE: This study describes factors related to retention and adherence to an exercise program for women caregivers. METHODS: One hundred sedentary women (average age = 62 years) caring for relatives with dementia were randomly assigned to an exercise program or an attention control (nutrition education) condition. Participants in the exercise condition received 12 months of home-based exercise counseling to achieve at least four exercise sessions per week, for at least 30 minutes per session. Adherence was tracked through monthly exercise logs, validated in a subsample by ambulatory heart rate and motion monitors. Participants also completed a psychosocial questionnaire battery at baseline and 12 months after randomization. RESULTS: Participants achieved a 12-month average exercise adherence rate of 74% (ie, three exercise sessions per week) with an average of 35 minutes per session. At 12 months, the exercise condition demonstrated increased knowledge of the benefits of exercise and increased motivational readiness for exercise compared with t