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Alzheimer's Disease Reviews: 2007
Webber, K. M., G. Casadesus, et al. (2007). "Gonadotropins: a cohesive gender-based etiology of Alzheimer disease." Mol Cell Endocrinol 260-262: 271-5.
While there is ample experimental evidence supporting the role of estrogen in the pathogenesis of Alzheimer disease, recent inconclusive data regarding hormone replacement therapy (HRT), specifically, the unexpected results of the Women's Health Initiative (WHI) Memory Study has raised serious questions regarding the protective effects of estrogen. Because of this and other inconsistencies in the estrogen hypothesis, we propose that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone, is a major factor in the pathogenesis of Alzheimer disease. Specifically, we suspect that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a primary causative factor for the development of Alzheimer disease. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, Alzheimer disease.
Waldemar, G., B. Dubois, et al. (2007). "Recommendations for the diagnosis and management of Alzheimer's disease and other disorders associated with dementia: EFNS guideline." Eur J Neurol 14(1): e1-26.
The aim of this international guideline on dementia was to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with dementia. It covers major aspects of diagnostic evaluation and treatment, with particular emphasis on the type of patient often referred to the specialist physician. The main focus is Alzheimer's disease, but many of the recommendations apply to dementia disorders in general. The task force working group considered and classified evidence from original research reports, meta-analysis, and systematic reviews, published before January 2006. The evidence was classified and consensus recommendations graded according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. The recommendations for clinical diagnosis, blood tests, neuroimaging, electroencephalography (EEG), cerebrospinal fluid (CSF) analysis, genetic testing, tissue biopsy, disclosure of diagnosis, treatment of Alzheimer's disease, and counselling and support for caregivers were all revised when compared with the previous EFNS guideline. New recommendations were added for the treatment of vascular dementia, Parkinson's disease dementia, and dementia with Lewy bodies, for monitoring treatment, for treatment of behavioural and psychological symptoms in dementia, and for legal issues. The specialist physician plays an important role together with primary care physicians in the multidisciplinary dementia teams, which have been established throughout Europe. This guideline may contribute to the definition of the role of the specialist physician in providing dementia health care.
Vellas, B., S. Andrieu, et al. (2007). "Disease-modifying trials in Alzheimer's disease: a European task force consensus." Lancet Neurol 6(1): 56-62.
After symptomatic treatments, the new target for therapeutic approaches in Alzheimer's disease is the development of disease-modifying drugs. The concept of disease modification in Alzheimer's disease is controversial and the design of these trials raises many questions. Which populations should be studied? For how long? With which principal and secondary endpoints? Are surrogate markers available? Here, we present a European consensus on disease-modifying trials in Alzheimer's disease, agreed under the auspices of the European Alzheimer's Disease Consortium and based on the European perspective of the concept of disease modification, study designs, the role for biomarkers, risk benefit, and pharmacoeconomic issues.
Staessen, J. A., T. Richart, et al. (2007). "Less atherosclerosis and lower blood pressure for a meaningful life perspective with more brain." Hypertension 49(3): 389-400.
Shen, J. and R. J. Kelleher, 3rd (2007). "The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism." Proc Natl Acad Sci U S A 104(2): 403-9.
Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of beta-amyloid (Abeta) peptides, particularly Abeta42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of Abeta have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance Abeta42 production, they typically reduce Abeta40 generation and impair other PS-dependent activities. Third, gamma-secretase inhibitors can enhance the production of Abeta42 while blocking other gamma-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that Abeta42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of gamma-secretase.
Petersen, R. C. (2007). "The current status of mild cognitive impairment--what do we tell our patients?" Nat Clin Pract Neurol 3(2): 60-1.
Pasinetti, G. M., Z. Zhao, et al. (2007). "Caloric intake and Alzheimer's disease. Experimental approaches and therapeutic implications." Interdiscip Top Gerontol 35: 159-75.
Alzheimer's disease (AD) is a rapidly growing public health concern with potentially devastating effects. Presently, there are no known cures or effective preventive strategies. While genetic factors are relevant in early-onset cases, they appear to play less of a role in late-onset sporadic AD cases, the most common form of AD. Due to the fact that the disease typically strikes very late in life, delaying symptoms could be as good as a cure for many people. For example, it is now widely accepted that if the onset of the disease could be delayed by even 5 years, the incidence could be cut in half. Both clinical and epidemiological evidence suggests that modification of lifestyle factors such as nutrition may prove crucial to AD management given the mounting experimental evidence suggesting that brain cells are remarkably responsive to "what somebody is doing". Among other nongenetic factors influencing AD, recent studies strongly support the evidence that caloric intake may play a role in the relative risk for AD clinical dementia. Indeed, the effect of diet in AD has been an area of research that has produced promising results, at least experimentally. Most importantly, as mechanistic pathways are defined and their biochemical functions scrutinized, the evidence supporting a direct link between nutrition and AD neuropathology continues to grow. Our work, as well as that of others, has recently resulted in the development of experimental dietary regimens that might promote, attenuate or even reverse features of AD. Most remarkably, while we found that high caloric intake based on saturated fat promotes AD type Beta-amyloidosis, conversely we found that dietary restriction based on reduced carbohydrate intake is able to prevent it. This evidence is very exciting and is, in part, consistent with current epidemiological studies suggesting that obesity and diabetes are associated with a >4-fold increased risk of developing AD. The clarification of the mechanisms through which dietary restriction may beneficially influence AD neuropathology and the eventual discovery of future "mimetics" capable of anti-Beta-amyloidogenic activity will help in the development of "lifestyle therapeutic strategies" in AD and possibly other neurodegenerative disorders.
Parihar, M. S. and G. J. Brewer (2007). "Mitoenergetic failure in Alzheimer disease." Am J Physiol Cell Physiol 292(1): C8-23.
Brain cells are highly energy dependent for maintaining ion homeostasis during high metabolic activity. During active periods, full mitochondrial function is essential to generate ATP from electrons that originate with the oxidation of NADH. Decreasing brain metabolism is a significant cause of cognitive abnormalities of Alzheimer disease (AD), but it remains uncertain whether this is the cause of further pathology or whether synaptic loss results in a lower energy demand. Synapses are the first to show pathological symptoms in AD before the onset of clinical symptoms. Because synaptic function has high energy demands, interruption in mitochondrial energy supply could be the major factor in synaptic failure in AD. A newly discovered age-related decline in neuronal NADH and redox ratio may jeopardize this function. Mitochondrial dehydrogenases and several mutations affecting energy transfer are frequently altered in aging and AD. Thus, with the accumulation of genetic defects in mitochondria at the level of energy transfer, the issue of neuronal susceptibility to damage as a function of age and age-related disease becomes important. In an aging rat neuron model, mitochondria are both chronically depolarized and produce more reactive oxygen species with age. These concepts suggest that multiple treatment targets may be needed to reverse this multifactorial disease. This review summarizes new insights based on the interaction of mitoenergetic failure, glutamate excitotoxicity, and amyloid toxicity in the exacerbation of AD.
Moye, J. and D. C. Marson (2007). "Assessment of decision-making capacity in older adults: an emerging area of practice and research." J Gerontol B Psychol Sci Soc Sci 62(1): P3-P11.
The convergence of the aging of our society, the increase in blended families, and an enormous intergenerational transfer of wealth has greatly expanded the incidence and importance of capacity assessment of older adults. In this article we discuss the emergence of capacity assessment as a distinct field of study. We review research efforts in two domains: medical decision-making capacity and financial capacity. Existing research in these two areas provides a first pass at many key questions related to capacity assessment, but additional studies that replicate, extend, and improve on this research are urgently needed. An agenda for future is detailed that recommends studies of a wide range of capacity constructs, focusing on clinical markers of diminished capacity, methods to improve clinical assessment, and the many intersections of law and clinical practice.
Mazza, M., M. Pomponi, et al. (2007). "Omega-3 fatty acids and antioxidants in neurological and psychiatric diseases: an overview." Prog Neuropsychopharmacol Biol Psychiatry 31(1): 12-26.
RATIONALE: Omega-3 fatty acids are known to play a role in nervous system activity, cognitive development, memory-related learning, neuroplasticity of nerve membranes, synaptogenesis and synaptic transmission. The brain is considered abnormally sensitive to oxidative damage, and aging is considered one of the most significant risk factors for degenerative neurological disorders. Recently, clinical trials of several neurodegenerative diseases have increasingly targeted the evaluation of the effectiveness of various antioxidants. OBJECTIVES: The effects of omega-3 fatty acids and antioxidants on the anatomic and functional central nervous system development and their possible therapeutical use in some neurological and psychiatric pathologies are evaluated. RESULTS: A number of critical trials have confirmed the benefits of dietary supplementation with omega-3 fatty acids not only in several psychiatric conditions, but also in inflammatory and autoimmune and neurodegenerative diseases. Many evidences indicate that antioxidants are also essential in maintaining a correct neurophysiology. CONCLUSIONS: Omega-3 fatty acids could be useful in the prevention of different pathologies, such as cardiovascular, psychiatric, neurological, dermatological and rheumatological disorders. A number of studies suggest that antioxidants can prevent the oxidation of various macromolecules such as DNA, proteins, and lipids. The ideal use of antioxidants should be a prophylactic and continue treatment before aging.
Madry, H., J. Prudlo, et al. (2007). "Nasu-Hakola disease (PLOSL): report of five cases and review of the literature." Clin Orthop Relat Res 454: 262-9.
The combination of bilateral lytic lesions in the bones of the lower and upper extremities and presenile dementia is characteristic of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, also known as Nasu-Hakola disease. The clinical course of this rare and fatal disorder is characterized by pathologic fractures of these often painful lesions, rapid progression of dementia, and death in the fifth decade of life. The radiographic changes may be confused with cystic angiomatosis, focal metastasizing hemangioendothelioma, or Langerhans' cell histiocytosis. We report five patients to illustrate the clinical presentation, radiographic images, psychiatric abnormalities, and new genetic findings. Three of the patients were siblings. A biopsy is not needed to confirm the diagnosis of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy because of the unique combination of radiographic and neurologic features.
Mack, J. T., D. M. Townsend, et al. (2007). "The ABCA2 transporter: intracellular roles in trafficking and metabolism of LDL-derived cholesterol and sterol-related compounds." Curr Drug Metab 8(1): 47-57.
ATP-binding cassette (ABC) transporters comprise a family of critical membrane bound proteins functioning in the translocation of molecules across cellular membranes. Substrates for transport include lipids, cholesterol and pharmacological agents. Mutations in ABC transporter genes cause a variety of human pathologies and elicit drug resistance phenotypes in cancer cells. ABCA2, the second member the A subfamily to be identified, was highly expressed in ovarian carcinoma cells resistant to the anti-cancer agent, estramustine, and more recently, in human vestibular schwannomas. Cells expressing elevated levels of ABCA2 show resistance to variety of compounds, including estradiol, mitoxantrone and a free radical initiator, 2,2'-azobis-(2-amidinopropane). ABCA2 is expressed in a variety of tissues, with greatest abundance in the central nervous system and macrophages. This transporter, along with other proteins that have a high degree of homology to ABCA2, including ABCA1 and ABCA7, are up-regulated in human macrophages during cholesterol import. Recent studies have shown ABCA2 also plays a role in the trafficking of low-density lipoprotein (LDL)-derived free cholesterol and to be coordinately expressed with sterol-responsive genes. A single nucleotide polymorphism in exon 14 of the ABCA2 gene was shown to be linked to early onset Alzheimer disease (AD) in humans, supporting an earlier study showing ABCA2 expression influences levels of APP and beta-amyloid peptide, the primary component of senile plaques. Studies thus far implicate ABCA2 as a sterol transporter, the deregulation of which may affect a cellular phenotype conducive to the pathogenesis of a variety of human diseases including AD, atherosclerosis and cancer.
Lucas Carrasco, R. (2007). "[Quality of life and dementia]." Med Clin (Barc) 128(2): 70-5.
Dementia and Alzheimer disease (AD) are an important public health problem with devastating consequences for the patient and they impose a great burden on the families. However, the concept and emphasis on quality of life (QoL) in dementia and AD has appeared in the last decade. Given that there is not treatment for the disease, the main objective is to preserve the patients' quality of life. QoL is an outcome measure in the assessment of different treatments and health and social interventions. The measurement of QoL allows patients and caregivers to express the impact produced by the treatment and the interventions; also, the measurement of QoL offers to professionals the opportunity to incorporate the value systems of patients and their caregivers in their assessments. The existing specific QoL scales for dementia have been developed mainly in the US and UK. There is a lack of these scales in our culture.
Liu, Q., F. Xie, et al. (2007). "Prevention and treatment of Alzheimer disease and aging: antioxidants." Mini Rev Med Chem 7(2): 171-80.
There is considerable evidence showing that oxidative damage is one of the earliest neuronal and pathological changes of Alzheimer disease and many, if not all, of the etiological and pathological causes of the disease are related, directly or indirectly, to free radical production and oxidative damage. Here we summarize the current body of knowledge suggestive that oxidative damage is, if not the key factor, certainly a major factor in Alzheimer disease. As such, therapeutic modalities encompassing antioxidants may be an effective approach to the treatment of neurodegenerative diseases and delay the aging process.
Krishnan, K. R. (2007). "Concept of disease in geriatric psychiatry." Am J Geriatr Psychiatry 15(1): 1-11.
The concept of disease in geriatric psychiatry has to keep up with the rapid expansion in knowledge about the putative etiology of various diseases of interest. This article reviews the new knowledge that has been acquired about dementia. The proposed classification system has two axes: one for clinical manifestations and the other for etiology. Implementing this nomenclature will allow rapid adaptation of new knowledge for causation while at the same time communicating information on the clinical state. This should improve our ability to incorporate and communicate new knowledge in a dynamic format. In turn, this strategy should improve our ability to discern particular features of a disease and refine our notion of its clinical presentation and lead toward novel and improved treatments for our patients.
Klegeris, A., M. Schulzer, et al. (2007). "Increase in core body temperature of Alzheimer's disease patients as a possible indicator of chronic neuroinflammation: a meta-analysis." Gerontology 53(1): 7-11.
BACKGROUND: Neuroinflammation contributes to the pathogenesis of Alzheimer's disease (AD). Increased pro-inflammatory cytokine levels have been reported in the brain and cerebro-spinal fluid of individuals affected by this neurodegenerative disorder. These same cytokines, including interleukin -1, interleukin-6 and tumor necrosis factor-alpha, are also believed to be involved in thermoregulation. Furthermore, their effects are thought to be mediated through the induction of cyclooxygenases resulting in increased production of inflammatory prostaglandins. Such increases have been observed in AD brains. We hypothesized that these increased levels of inflammatory mediators could lead to an increase in core body temperature in AD patients. OBJECTIVE: To determine whether clinical signs of AD are accompanied by an increase in core body temperature. METHODS: Analysis of the scientific literature identified six studies that used continuous rectal measurements of core body temperature in AD and control patients. Meta-analysis was performed on these published data. RESULTS: Meta-analysis showed that the mean core body temperature in AD patients was significantly increased by 0.10 degrees C when compared to healthy elderly subjects. The two-sided p value was 0.0355, and the 95% confidence interval was 0.0068-0.1950. The severity of AD pathology did not appear to contribute significantly (p = 0.235) to the heterogeneity in the core body temperature among different groups of AD patients. CONCLUSION: The significant increase in core body temperature in AD patients could be a direct consequence of local inflammatory reactions in the brain. Although the changes observed are probably too small to be of any diagnostic value, these observations lend further support to the neuroinflammatory hypothesis of AD pathology.
Jack, C. R., Jr., M. Marjanska, et al. (2007). "Magnetic resonance imaging of Alzheimer's pathology in the brains of living transgenic mice: a new tool in Alzheimer's disease research." Neuroscientist 13(1): 38-48.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Cardinal pathologic features of AD are amyloid plaques and neurofibrillary tangles, and most in the field believe that the initiating events ultimately leading to clinical AD center on disordered metabolism of amyloid beta protein. Mouse models of AD have been created by inserting one or more human mutations associated with disordered amyloid metabolism and that cause early onset familial AD into the mouse genome. Human-like amyloid plaque formation increases dramatically with age in these transgenic mice. Amyloid reduction in humans is a major therapeutic objective, and AD transgenic mice allow controlled study of this biology. Recent work has shown that amyloid plaques as small as 35 microm can be detected using in vivo magnetic resonance microimaging (MRMI) at high magnetic field (9.4 T). In addition, age-dependent changes in metabolite concentration analogous to those that have been identified in human AD patients can be detected in these transgenic mice using single-voxel (1)H magnetic resonance spectroscopy ((1)H MRS) at high magnetic field. These MR-based techniques provide a new set of tools to the scientific community engaged in studying the biology of AD in transgenic models of the disease. For example, an obvious application is evaluating therapeutic modification of disease progression. Toward the end of this review, the authors include results from a pilot study demonstrating feasibility of using MRMI to detect therapeutic modification of plaque progression in AD transgenic mice.
Holmquist, L., G. Stuchbury, et al. (2007). "Lipoic acid as a novel treatment for Alzheimer's disease and related dementias." Pharmacol Ther 113(1): 154-64.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment - particularly for the early stages of disease - remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring precursor of an essential cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), LA has been shown to have a variety of properties which can interfere with pathogenic principles of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. Via the same mechanisms, downregulation redox-sensitive inflammatory processes is also achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. The reduced form of LA, dihydrolipoic acid (DHLA), is the active compound responsible for most of these beneficial effects. R-alpha-LA can be applied instead of DHLA, as it is reduced by mitochondrial lipoamide dehydrogenase, a part of the PDH complex. In this review, the properties of LA are explored with particular emphasis on how this agent, particularly the R-alpha-enantiomer, may be effective to treat AD and related dementias.
Hirano, A. and R. Wate (2007). "Diagnostic clues and more from photographs." Neuropathology 27(1): 1-9.
During over 50 years of the first author's career in neuropathology at Montefiore Medical Center in New York, we have come across certain interesting neuropathological findings. In this communication, some photographs showing macroscopic, microscopic and electron microscopic significant findings are selected to illustrate usefulness not only for the diagnosis but also for understanding of the nervous system. The six topics presented in this paper are: (i) unattached presynaptic terminals in cerebellar neuroblastoma; (ii) neurofibrillary tangle formation in the nucleus basalis of Meynert ipsilateral to a massive cerebral infarct; (iii) orderly arrangement of tumor cells in leptomeningeal carcinomatosis; (iv) interface between craniopharyngioma and brain tissue; (v) neurofibrillary tangles and Lewy bodies in a single neuron; and (vi) Cu/Zn superoxide dismutase positive Lewy body-like hyaline inclusions in anterior horn cells in familial motor neuron diseases. Analyses of these findings are presented for an educational purpose.
Haass, C. and D. J. Selkoe (2007). "Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide." Nat Rev Mol Cell Biol 8(2): 101-12.
The distinct protein aggregates that are found in Alzheimer's, Parkinson's, Huntington's and prion diseases seem to cause these disorders. Small intermediates - soluble oligomers - in the aggregation process can confer synaptic dysfunction, whereas large, insoluble deposits might function as reservoirs of the bioactive oligomers. These emerging concepts are exemplified by Alzheimer's disease, in which amyloid beta-protein oligomers adversely affect synaptic structure and plasticity. Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.
Gimenez-Llort, L., G. Blazquez, et al. (2007). "Modeling behavioral and neuronal symptoms of Alzheimer's disease in mice: a role for intraneuronal amyloid." Neurosci Biobehav Rev 31(1): 125-47.
The amyloid Abeta-peptide (Abeta) is suspected to play a critical role in the cascade leading to AD as the pathogen that causes neuronal and synaptic dysfunction and, eventually, cell death. Therefore, it has been the subject of a huge number of clinical and basic research studies on this disease. Abeta is typically found aggregated in extracellular amyloid plaques that occur in specific brain regions enriched in nAChRs in Alzheimer's disease (AD) and Down syndrome (DS) brains. Advances in the genetics of its familiar and sporadic forms, together with those in gene transfer technology, have provided valuable animal models that complement the traditional cholinergic approaches, although modeling the neuronal and behavioral deficits of AD in these models has been challenging. More recently, emerging evidence indicates that intraneuronal accumulation of Abeta may also contribute to the cascade of neurodegenerative events and strongly suggest that it is an early, pathological biomarker for the onset of AD and associated cognitive and other behavioral deficits. The present review covers these studies in humans, in in vitro and in transgenic models, also providing more evidence that adult 3xTg-AD mice harboring PS1M146V, APPSwe, tauP301L transgenes, and mimicking many critical hallmarks of AD, show cognitive deficits and other behavioral alterations at ages when overt neuropathology is not yet observed, but when intraneuronal Abeta, synaptic and cholinergic deficits can already be described.
Fadiel, A., K. D. Eichenbaum, et al. (2007). "Modern pathology: protein mis-folding and mis-processing in complex disease." Curr Protein Pept Sci 8(1): 29-37.
Electrostatic and electrochemical properties of bio-molecules, such as proteins, are governed by energy parameters that are, in part dependent on its folding. Disruption of this process can lead to the development of complex, multisystem diseases whose presentation may be organ-dependent. Examples include cystic fibrosis, alpha-1 antitrypsin deficiency, and Alzheimer disease. In addition to explaining exotic pathologic syndromes, an understanding of protein folding mechanisms may facilitate the understanding of less complex diseases and allow the development of novel therapeutic approaches.
Driscoll, I. and S. M. Resnick (2007). "Testosterone and cognition in normal aging and Alzheimer's disease: an update." Curr Alzheimer Res 4(1): 33-45.
There is evidence to suggest that testosterone loss constitutes a risk for cognitive decline and possibly dementia, and that elderly men might benefit from exogenous supplementation of testosterone. Studies in non-human animals repeatedly report neuroexcitatory and neuroprotective properties of testosterone and enhanced memory performance after acute or chronic treatment. Positive effects of testosterone supplementation in older men have been reported in several, but not all, studies and require replication in larger randomized clinical trials before recommendations for clinical practice can be made. The current review summarizes recent studies on the neurobiological connection between testosterone and cognitive function in humans and non-human animals. When appropriate, we use the hippocampus as a model structure given it's involvement in sexually dymorphic spatial ability and sensitivity to both androgens and aging. In addition, a number of potential explanations of the discrepancy between data obtained in humans and non-human animals are discussed.
Ding, Q., E. Dimayuga, et al. (2007). "Oxidative damage, protein synthesis, and protein degradation in Alzheimer's disease." Curr Alzheimer Res 4(1): 73-9.
A large number of studies has firmly established that increases in oxidative damage occurs in Alzheimer's disease (AD). Such studies have demonstrated that increased in oxidative damage selectively occurs within the brain regions involved in regulating cognitive performance. Studies from our laboratory and others have provided experimental evidence that increased levels of oxidative damage occur in subjects with Mild Cognitive Impairment (MCI), which is believed to be one of the earliest stages of AD, and is a condition which is devoid of dementia or the extensive neurofibrillary pathology and neuritic plaque deposition observed in AD. Together, these data support a role for the accrual of oxidative damage potentially serving as an early event that then initiates the development of cognitive disturbances and pathological features observed in AD. Recent studies from our laboratory have demonstrated that a decline in protein synthesis capabilities occurs in the same brain regions which exhibit increased levels of oxidative damage in MCI and AD subjects. The focus of this review is to describe the large number of studies which suggest protein synthesis may be one of the earliest cellular processes disrupted by oxidative damage in AD. Taken together, these findings have important implications for understanding the molecular and cellular basis of AD, understanding the basis for oxidative stress in AD, and may have important implications for studies involving proteomics and proteolysis in AD.
Dierckx, E., S. Engelborghs, et al. (2007). "Mild cognitive impairment: what's in a name?" Gerontology 53(1): 28-35.
BACKGROUND: Nowadays the term mild cognitive impairment (MCI) is used to fill the gap between cognitive changes associated with normal ageing and those associated with dementia. Despite some agreement in general definitions, MCI is still a heterogeneous clinical syndrome for which no DSM-IV criteria have yet been established. Criteria by Petersen et al. are presently the most applied in clinical practice. Moreover, little attention has been paid to the specific relation between MCI and depression. OBJECTIVE: This review highlights some concerns about the concept of MCI and provides guidelines within the field of neuropsychology to solve them. In a second part, the paper focuses on the specific relationship between depression in the elderly and MCI. RESULTS: We hypothesize that certain test instruments can be used to operationalize the criteria proposed by Petersen et al. Moreover, we suggest that cued recall might be of help to differentiate between progressive and non-progressive MCI. Concerning the specific relation between depression and MCI, we assume that elderly depression with concomitant cognitive problems can be seen as an MCI. CONCLUSION: The proposed adjustments and additions (neuropsychological instruments and the incorporation of depressive symptoms) in the diagnostic flowchart of Petersen may serve as useful tools for clinicians when making a diagnosis of MCI.
Cosman, K. M., L. L. Boyle, et al. (2007). "Memantine in the treatment of mild-to-moderate Alzheimer's disease." Expert Opin Pharmacother 8(2): 203-14.
Memantine is the first and only medication that has been approved by European, US and Canadian regulatory agencies for the treatment of moderate-to-severe Alzheimer's disease (AD). It is an NMDA receptor antagonist that works to prevent excitotoxicity and cell death, which are mediated by the excessive influx of calcium during a sustained release of glutamate. Preclinical studies of memantine reveal that it has the potential to improve memory and learning processes after impairment has occurred, as well as to prevent further neuronal damage. Although memantine has been considered for the treatment of earlier AD, it has not yet been approved for this. Randomized controlled trials of memantine in the treatment of mild-to-moderate AD have demonstrated small treatment effects in measures of cognition, global assessment and behavior favoring the use of memantine. However, the differences between treatment groups were not consistently significant. Two ongoing long-term trials are further investigating the efficacy of memantine in the treatment of mild-to-moderate AD.
Carter, C. J. (2007). "Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis." Neurochem Int 50(1): 12-38.
Polymorphic genes associated with Alzheimer's disease (see ) delineate a clearly defined pathway related to cerebral and peripheral cholesterol and lipoprotein homoeostasis. They include all of the key components of a glia/neurone cholesterol shuttle including cholesterol binding lipoproteins APOA1, APOA4, APOC1, APOC2, APOC3, APOD, APOE and LPA, cholesterol transporters ABCA1, ABCA2, lipoprotein receptors LDLR, LRP1, LRP8 and VLDLR, and the cholesterol metabolising enzymes CYP46A1 and CH25H, whose oxysterol products activate the liver X receptor NR1H2 and are metabolised to esters by SOAT1. LIPA metabolises cholesterol esters, which are transported by the cholesteryl ester transport protein CETP. The transcription factor SREBF1 controls the expression of most enzymes of cholesterol synthesis. APP is involved in this shuttle as it metabolises cholesterol to 7-betahydroxycholesterol, a substrate of SOAT1 and HSD11B1, binds to APOE and is tethered to LRP1 via APPB1, APBB2 and APBB3 at the cytoplasmic domain and via LRPAP1 at the extracellular domain. APP cleavage products are also able to prevent cholesterol binding to APOE. BACE cleaves both APP and LRP1. Gamma-secretase (PSEN1, PSEN2, NCSTN) cleaves LRP1 and LRP8 as well as APP and their degradation products control transcription factor TFCP2, which regulates thymidylate synthase (TS) and GSK3B expression. GSK3B is known to phosphorylate the microtubule protein tau (MAPT). Dysfunction of this cascade, carved out by genes implicated in Alzheimer's disease, may play a major role in its pathology. Many other genes associated with Alzheimer's disease affect cholesterol or lipoprotein function and/or have also been implicated in atherosclerosis, a feature of Alzheimer's disease, and this duality may well explain the close links between vascular and cerebral pathology in Alzheimer's disease. The definition of many of these genes as risk factors is highly contested. However, when polymorphic susceptibility genes belong to the same signaling pathway, the risk associated with multigenic disease is better related to the integrated effects of multiple polymorphisms of genes within the same pathway than to variants in any single gene [Wu, X., Gu, J., Grossman, H.B., Amos, C.I., Etzel, C., Huang, M., Zhang, Q., Millikan, R.E., Lerner, S., Dinney, C.P., Spitz, M.R., 2006. Bladder cancer predisposition: a multigenic approach to DNA-repair and cell-cycle-control genes. Am. J. Hum. Genet. 78, 464-479.]. Thus, the fact that Alzheimer's disease susceptibility genes converge on a clearly defined signaling network has important implications for genetic association studies.
Brewer, G. J. (2007). "Iron and copper toxicity in diseases of aging, particularly atherosclerosis and Alzheimer's disease." Exp Biol Med (Maywood) 232(2): 323-35.
In this review, we point out that natural selection does not act to lessen human diseases after the reproductive and caregiving period and that normal levels of iron and copper that may be healthy during the reproductive years appear to be contributing to diseases of aging and possibly the aging process itself. It is clear that oxidant damage contributes to many of the diseases of aging, such as atherosclerosis, Alzheimer's disease, Parkinson's diseases, diabetes, diseases of inflammation, diseases of fibrosis, diseases of autoimmunity, and so on. It is equally clear that both iron and copper can contribute to excess production of damaging reactive oxygen species through Fenton chemistry. Here, we examine the evidence that "normal" levels of iron and copper contribute to various diseases of aging.
Bertram, L., M. Hsiao, et al. (2007). "The LDLR locus in Alzheimer's disease: a family-based study and meta-analysis of case-control data." Neurobiol Aging 28(1): 18 e1-4.
Genetic linkage studies suggest the presence of an Alzheimer's disease (AD) risk gene on chromosome 19, acting independently of apolipoprotein E (apoE), a known AD risk factor on 19q13. The low density lipoprotein receptor (LDLR) is an interesting candidate because it maps within the linked interval, and is intimately involved in cholesterol homeostasis and the function of apoE. We tested three previously reported single nucleotide polymorphisms (SNPs) within LDLR in a large sample of discordant sibships from multiplex AD families, and failed to find evidence for genetic association with disease risk. In addition, we performed meta-analyses for SNP rs5925 on published data from five independent case control samples, but did not detect any significant summary odds ratios. Based on our data, it seems unlikely that these genetic variants in LDLR make a significant contribution to AD risk in the general population.
Alkon, D. L., M. K. Sun, et al. (2007). "PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease." Trends Pharmacol Sci 28(2): 51-60.
There is strong evidence that protein kinase C (PKC) isozyme signaling pathways are causally involved in associative memory storage. Other observations have indicated that PKC signaling pathways regulate important molecular events in the neurodegenerative pathophysiology of Alzheimer's disease (AD), which is a progressive dementia that is characterized by loss of recent memory. This parallel involvement of PKC signaling in both memory and neurodegeneration indicates a common basis for the origins of both the symptoms and the pathology of AD. Here, we discuss this conceptual framework as a basis for an autopsy-validated peripheral biomarker--and for AD drug design targeting drugs (bryostatin and bryologs) that activate PKC isozymes--that has already demonstrated significant promise for treating both AD neurodegeneration and its symptomatic memory loss.
(2007). "Drugs for cognitive loss and dementia." Treat Guidel Med Lett 5(54): 9-14.