Yoshida, H., R. A. Crowther, et al. (2002). "Functional effects of tau gene mutations deltaN296 and N296H." J Neurochem 80(3): 548-51. Mutations in the tau gene cause frontotemporal dementia and parkinsonism linked to chromosome-17 (FTDP-17). Functionally, about half of the known mutations increase the alternative mRNA splicing of exon 10 of the tau gene, resulting in the overproduction of tau isoforms with four microtubule-binding repeats. The other mutations reduce the ability of tau to interact with microtubules, with some mutations also increasing the propensity of tau to assemble into filaments. Here we have examined the functional effects of the recently described tau gene mutations deltaN296 and N296H. Both mutations reduced the ability of tau to promote microtubule assembly, without having a significant effect on tau filament formation. By exon trapping, they increased the splicing of exon 10. DeltaN296 and N296H thus define a class of tau mutations with effects at both the RNA and the protein level. Wada, C. and I. Toyoshima (2002). "[Clinical symptoms and speech disturbance in frontotemporal dementia and parkinsonism linked to chromosome 17 with tau mutation]." No To Shinkei 54(3): 221-33. Verpillat, P., A. Camuzat, et al. (2002). "Association between the extended tau haplotype and frontotemporal dementia." Arch Neurol 59(6): 935-9. BACKGROUND: Recent studies have shown an association between an extended tau haplotype (H1) that covers the entire human tau gene and progressive supranuclear palsy or, more inconsistently, other neurodegenerative disorders, such as corticobasal degeneration, Parkinson disease, Alzheimer disease, and frontotemporal dementia (FTD). In addition, disease-causing mutations in the tau gene on chromosome 17 have been detected in some families with autosomal dominant FTD and parkinsonism. In FTD, the pathological accumulation of the microtubule-associated protein tau suggests that the tau gene may be a genetic risk factor for this disorder. OBJECTIVE: To confirm or refute the association between the H1 haplotype or the H1H1 genotype of the tau gene and FTD. DESIGN: Case-control study. SETTING: Neurology departments of 12 French university hospitals. PARTICIPANTS: One hundred unrelated patients with FTD and 79 controls. METHODS: Tau genotype (contiguous polymorphisms in exons 1, 7, and 13 and in intron 9 used to reconstruct the extended haplotypes H1 and H2). Clinical examination, psychometric testing, laboratory tests, computed tomography and magnetic resonance imaging, single-photon emission computed tomography, and electroencephalography for patients with FTD. RESULTS: The H1H1 genotype was significantly overrepresented in patients with FTD compared with controls (62% vs 46%; P=.01, 1-sided; odds ratio adjusted for age and sex, 1.95). After stratification according to apolipoprotein E (APOE) genotype, we found a significant interaction between APOE and tau genotypes (P=.03). CONCLUSIONS: This study of the largest series of patients with FTD confirms the primary role of tau in FTD and establishes that the H1 haplotype of the tau gene and the E2 allele of APOE interact by an unknown mechanism that increases the risk of FTD. Tsuboi, Y., R. J. Uitti, et al. (2002). "Clinical features and disease haplotypes of individuals with the N279K tau gene mutation: a comparison of the pallidopontonigral degeneration kindred and a French family." Arch Neurol 59(6): 943-50. BACKGROUND: An N279K missense mutation in exon 10 of the tau gene reported in an American family with pallidopontonigral degeneration (PPND family) was recently found in members of a French kindred with dementia and supranuclear palsy. OBJECTIVES: To compare clinical phenotypes of both families and to perform genealogical and molecular genetic studies to determine whether they are derived from a common founder. DESIGN AND METHODS: We performed clinical examinations of affected members of both families and compared clinical phenotypes, existing genealogical family records, and chromosome 17 microsatellite repeat markers in the vicinity of the tau gene. RESULTS: The inheritance pattern is autosomal dominant in the PPND family and appears so in the French family. Average age at onset of clinical symptoms was 43 years in the PPND family and 41 years in the French family. Mean disease duration was 8 years in the PPND family and 6 years in the French family. Parkinsonism, personality changes, and dementia of the frontotemporal type were seen in both kindreds. All affected patients exhibited rapidly progressive parkinsonism characterized by bradykinesia, tremor, postural instability, and rigidity. Some had a transient response to levodopa therapy during the initial stages. Pyramidal signs and eye movement abnormalities, including supranuclear gaze palsy, were common. Results of linkage studies of the tau region in chromosome 17 did not reveal a haplotype common to both kindreds. CONCLUSIONS: Affected members from both families had more clinical similarities than differences. Results of genealogical and molecular genetic studies determined that the families were not related. The N279K mutations found in both families have independent origins. Tang-Wai, D., P. Lewis, et al. (2002). "Familial frontotemporal dementia associated with a novel presenilin-1 mutation." Dement Geriatr Cogn Disord 14(1): 13-21. We report a kindred with three cases of dementia. The proband presented with forgetfulness and personality changes at age 56, followed shortly thereafter by behavioral dyscontrol, hyperphagia, hypersexuality, delusions, illusions, disinhibition and double incontinence. Neuroimaging studies were consistent with frontotemporal dementia (FTD). In one allele, an arginine insertion at codon 352 in the presenilin 1 (PSEN1) gene was identified; no mutation was identified in the amyloid precursor protein or tau genes. We conclude that the clinical features of the Kluver-Bucy syndrome and FTD can be associated with PSEN1 mutations. Furthermore, presenilin analyses may be helpful to characterize kindreds with familial dementing illnesses regardless of the phenotype, particularly if no tau mutation is present. Tanemura, K., M. Murayama, et al. (2002). "Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau." J Neurosci 22(1): 133-41. Formation of neurofibrillary tangles (NFTs) is a common neuropathological feature found in several neurodegenerative diseases, including Alzheimer's disease. We have developed a transgenic (Tg) mouse expressing mutant human tau (V337M), derived from frontotemporal dementia parkinsonism-17. V337M Tg mice revealed tau aggregations in the hippocampus, which fulfills the histological criteria for NFTs in human neurodegenerative diseases. Concurrent with the accumulation of RNA and phosphorylated tau, neurons exhibited morphological characteristics of degenerating neurons, which include a loss of microtubules, accumulation of ribosomes, plasma and nuclear membrane ruffling, and swelling of the Golgi network. Thus, mutant tau induces neuronal degeneration associated with the accumulation of RNA and phosphorylated tau. The functional consequences of this neuronal degeneration was evidenced by the reduction of hippocampal neural activity and behavioral abnormality in Tg mice. Syme, C. D., E. W. Blanch, et al. (2002). "A Raman optical activity study of rheomorphism in caseins, synucleins and tau. New insight into the structure and behaviour of natively unfolded proteins." Eur J Biochem 269(1): 148-56. The casein milk proteins and the brain proteins alpha-synuclein and tau have been described as natively unfolded with random coil structures, which, in the case of alpha-synuclein and tau, have a propensity to form the fibrils found in a number of neurodegenerative diseases. New insight into the structures of these proteins has been provided by a Raman optical activity study, supplemented with differential scanning calorimetry, of bovine beta- and kappa-casein, recombinant human alpha-, beta- and gamma-synuclein, together with the A30P and A53T mutants of alpha-synuclein associated with familial cases of Parkinson's disease, and recombinant human tau 46 together with the tau 46 P301L mutant associated with inherited frontotemporal dementia. The Raman optical activity spectra of all these proteins are very similar, being dominated by a strong positive band centred at approximately 1318 cm(-1) that may be due to the poly(l-proline) II (PPII) helical conformation. There are no Raman optical activity bands characteristic of extended secondary structure, although some unassociated beta strand may be present. Differential scanning calorimetry revealed no thermal transitions for these proteins in the range 15-110 degrees C, suggesting that the structures are loose and noncooperative. As it is extended, flexible, lacks intrachain hydrogen bonds and is hydrated in aqueous solution, PPII helix may impart a rheomorphic (flowing shape) character to the structure of these proteins that could be essential for their native function but which may, in the case of alpha-synuclein and tau, result in a propensity for pathological fibril formation due to particular residue properties. Snowden, J. S., D. Neary, et al. (2002). "Frontotemporal dementia." Br J Psychiatry 180: 140-3. BACKGROUND: Frontotemporal dementia accounts for up to 20% of cases of dementia in the presenium, yet remains poorly recognised. Diagnostic criteria have been devised to aid clinical diagnosis. AIMS: To provide an overview of clinical and pathological characteristics of frontotemporal dementia and its nosological status. METHODS: The review summarises consensus diagnostic criteria for frontotemporal dementia and draws on the authors' clinical experience of 300 frontotemporal dementia cases, and pathological experience of 50 autopsied cases. RESULTS: Frontotemporal dementia is characterised by pronounced changes in affect and personal and social conduct. Some patients also develop motor neuron disease. Mutations in the tau gene account for some but not all familial cases of frontotemporal dementia. CONCLUSIONS: Frontotemporal dementia is a focal form of dementia, which is clinically and pathologically distinct from other dementias. It represents an important model for understanding the functions of the frontotemporal lobes. Sjogren, M., P. Davidsson, et al. (2002). "Decreased CSF-beta-amyloid 42 in Alzheimer's disease and amyotrophic lateral sclerosis may reflect mismetabolism of beta-amyloid induced by disparate mechanisms." Dement Geriatr Cogn Disord 13(2): 112-8. Both tau and beta-amyloid 42 (Abeta42) have been implicated in Alzheimer's disease (AD) and tau alone in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These proteins can be measured in the cerebrospinal fluid (CSF); differences from normal CSF levels may reflect pathophysiological mechanisms. Using ELISAs, we investigated the levels of total CSF-tau (here referred to as tau), phosphorylated CSF-tau (phosphotau), and Abeta42 in patients with AD (n = 19), FTD (n = 14), ALS (n = 11) and Parkinson's disease (PD; n = 15) and in age-matched controls (n = 17). Both CSF-tau and CSF-phosphotau were increased in AD compared with FTD (p < 0.001), ALS (p < 0.001), PD (p < 0.001) and controls (p < 0.001). CSF-Abeta42 was markedly decreased in AD and ALS (both p < 0.001) and slightly decreased in FTD (p < 0.01) and PD (p < 0.05) compared with controls. Using CSF-phosphotau may improve the differentiation of AD from FTD and ALS in clinical praxis. Furthermore, decreased CSF-Abeta42 levels may be common in neurodegenerative disorders possibly reflecting changes in the metabolism of beta-amyloid or axonal degeneration. Short, R. A., N. R. Graff-Radford, et al. (2002). "Differences in tau and apolipoprotein E polymorphism frequencies in sporadic frontotemporal lobar degeneration syndromes." Arch Neurol 59(4): 611-5. BACKGROUND: Frontotemporal lobar degeneration (FTLD) has different clinical phenotypes and is associated with several pathologic findings, most commonly dementia lacking distinctive histology or Pick disease. We know that the tau H1 haplotype is associated with some clinical and histologic phenotypes, for example, progressive supranuclear palsy and corticobasal degeneration. Furthermore, the apolipoprotein epsilon4 allele (APOE epsilon4) may be associated with Pick disease. OBJECTIVE: To determine if different clinical phenotypes of FTLD are associated with different tau haplotype and APOE allele frequencies. PATIENTS AND METHODS: All patients with FTLD with available DNA specimens (n = 63) seen at the Mayo Clinic, Jacksonville, Fla, were retrospectively classified according to the following clinical phenotypes: frontal dementia (FD); progressive, nonfluent aphasia (PA); or fluent, anomic aphasia (AA). DNA specimens were genotyped for APOEallele and tau haplotype frequencies and were compared with cognitively normal patients (n = 338) and patients with Alzheimer disease (AD) (n = 193). RESULTS: Patients with AA had increased APOE epsilon4 frequency (30.4%) compared with patients with FD (14.8%, P=.04) and cognitively normal patients (11.1%, P<.001). Patients with AA also had increased tau H2 haplotype (37.0%) frequency compared with patients with FD (11.1%,P=.002), patients with AD (21.8%, P=.02), and cognitively normal patients (19.8%, P=.004). The increase in tau H2 haplotype frequency (50.0%) is especially pronounced in patients with AA who are APOE epsilon4 positive compared with patients with FD (18.8%, P=.04), patients with AD (24.8%, P=.005), and cognitively normal patients (15.3%, P<.001).APOE epsilon4 and tau H2 haplotype frequencies are not significantly different in patients with FD and PA compared with healthy patients. CONCLUSIONS: Clinical subtypes of FTLD have different tau and APOE genotype frequencies, suggesting these genes may influence the clinical presentation. Further studies should be performed to confirm this finding and to see if the pathologic phenotypes are also associated with different tau and APOE genotype frequencies. Rosso, S. M., E. van Herpen, et al. (2002). "A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick's disease." Ann Neurol 51(3): 373-6. Mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. In this article, we describe a novel missense mutation, S320F, in the tau gene in a family with presenile dementia. To our knowledge, it is the first mutation to be described in exon 11 of tau. The proband died at age 53 years, after a disease duration of 15 years, and autopsy revealed a neuropathological picture similar to Pick's disease. Recombinant tau protein with the S320F mutation showed a greatly reduced ability to promote microtubule assembly. Rosso, S. M. and J. C. Van Swieten (2002). "New developments in frontotemporal dementia and parkinsonism linked to chromosome 17." Curr Opin Neurol 15(4): 423-8. PURPOSE OF REVIEW: The identification of tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has revealed invaluable information regarding the role of the tau protein in neurodegenerative disease. Over the past year several new mutations have been identified, and experimental studies have provided further insight into the mechanism of neurodegeneration due to tau mutations and possible interactions with amyloid pathology. RECENT FINDINGS: Extensive clinical and pathological variation is seen in patients with different types of mutation, as well as in patients with the same mutation. Mutations may be found in patients with frontotemporal dementia (FTD), parkinsonism, progressive supranuclear palsy and corticobasal degeneration, justifying mutation analysis in familial cases of these disorders. Genetic heterogeneity exists in frontotemporal dementia, because a number of FTDP-17 families have neither tau mutations nor tau pathology. Genetic linkage has been found in familial FTD (chromosome 3), FTD with amyotrophic lateral sclerosis (9q21-q22), and FTD with inclusion body myopathy (9q13.3-p12). Tau deposits may consist of mainly mutated protein, or of mutated and wild-type protein in equal amounts, depending on the mutation. Recent animal studies show that amyloid-beta deposition may accelerate formation of neurofibrillary tangles. SUMMARY: Hopefully, the identification of responsible genetic defects and associated proteins will be helpful in improving our understanding of the role of the tau protein in the common neurodegenerative process of frontotemporal degeneration. Riemenschneider, M., S. Wagenpfeil, et al. (2002). "Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration." Neurology 58(11): 1622-8. BACKGROUND: CSF concentrations of tau and beta-amyloid protein-42 (Abeta42) have been extensively studied in AD. Few data are available concerning CSF levels of both proteins in patients with frontotemporal degeneration (FTD). METHODS: The authors investigated CSF tau and Abeta42 concentrations in 34 patients with FTD, 74 patients with AD, and 40 cognitively healthy control subjects. CSF levels of tau and Abeta42 were measured by ELISA. With use of receiver operating characteristic-derived cutoff points and linear discrimination lines, the diagnostic sensitivity and specificity of both markers were determined. RESULTS: CSF tau concentrations were significantly higher in FTD than in control subjects but were significantly lower than in AD. CSF Abeta42 levels were significantly lower in FTD than in control subjects but were significantly higher than in AD. In subjects with FTD, neither tau nor Abeta42 levels correlated with the severity of dementia. The best discrimination between the diagnostic groups was obtained by simultaneous measurement of tau and Abeta42, yielding a sensitivity of 90% at a specificity of 77% (FTD vs controls) and a sensitivity of 85% at a specificity of 85% (FTD vs AD). CONCLUSIONS: In FTD, CSF levels of tau are elevated and Abeta42 levels are decreased. With use of these markers, subjects with FTD can be distinguished from control subjects and from patients with AD with reasonable accuracy. Pickering-Brown, S. M., A. M. Richardson, et al. (2002). "Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene." Brain 125(Pt 4): 732-51. Genetic screening of 171 patients with frontotemporal lobar degeneration disclosed 14 patients, across nine pedigrees, with mutations in the intron to exon 10 in the tau gene, a region regulating the splicing of exon 10 via a stem loop mechanism. Thirteen of these patients had the +16 splice site mutation and one had the +13 splice site mutation. Affected members of all nine families presented with changes in behaviour and social conduct that were prototypical of frontotemporal dementia (FTD). In all patients with the +16 splice site mutation, the behavioural profile was characterized by disinhibition, restless overactivity, a fatuous affect, puerile behaviour and verbal and motor stereotypies. The single patient with the +13 mutation presented a contrasting picture of apathy and inertia. In addition, all patients had evidence of semantic loss. Pathologically, five of the six patients so far autopsied shared frontotemporal atrophy with involvement of the substantia nigra. The underlying histology was that of microvacuolar-type cortical degeneration with a few swollen cells. Tau pathology was widespread throughout the brain and present in neurones and glial cells, mostly in the frontal and temporal cortical regions. This was in the form of neurofibrillary tangles and amorphous tau deposits (pre-tangles); Pick bodies were not observed. Ultrastructurally, the tau filaments had a twisted, ribbon-like morphology distinct from the paired helical filaments of Alzheimer's disease. One patient died from an unrelated illness whilst in the early clinical stages of FTD. In this patient, cortical microvacuolar and astrocytic changes were absent, though there were scattered neurones and glial cells, immunoreactive to tau, throughout the cortical and subcortical regions. The disease process underlying the neurodegeneration within these inherited forms of FTD may therefore stem directly from early, primary alterations in the function of tau. All eight families with the +16 mutation seem to be part of a common extended pedigree, possibly originating from a founder member residing within the North Wales region of Great Britain. Pastor, P., M. Ezquerra, et al. (2002). "Further extension of the H1 haplotype associated with progressive supranuclear palsy." Mov Disord 17(3): 550-6. The recent finding of disequilibrium among several polymorphisms along the tau gene and the strong association of one of the two haplotypes formed by these polymorphisms (H1) with progressive supranuclear palsy (PSP) suggests that a single allele in or near the tau gene at 17q21 is responsible for increased risk in most of the PSP cases. We sought to determine whether mutations in the tau gene are responsible for the disease in 45 sporadic PSP patients. Furthermore, we analyzed some markers located in the common region of linkage (D17S800-D17S791), associated with some cases of familial frontotemporal dementia (FTDP-17), and the SNPs rs1816 and rs937 close to the tau gene, to determine their possible association with sporadic PSP. We did not find pathogenic mutations in exons 9, 10, 12, or 13 of the tau gene, indicating that tau mutations in both the splice-site region of the exon 10 and in the microtubule-binding region of tau gene are not a cause of PSP in this study group. We found significant overrepresentation of the haplotypes H1, extended up to the promoter of the tau gene (H1P), in PSP patients as compared with controls. In addition, a significant overrepresentation of the D17S810 2/2 and 3/2 genotypes, of the SNP rs1816 A/A, and of the SNP rs937 delG/delG genotypes was detected in PSP, further extending the haplotype described previously. These results are consistent with the hypothesis that a change either in the 5' or in the 3' flanking regions of the tau gene, or even other genes contained in the H1E haplotype, could increase the genetic susceptibility to PSP. Morris, H. R., R. Katzenschlager, et al. (2002). "Sequence analysis of tau in familial and sporadic progressive supranuclear palsy." J Neurol Neurosurg Psychiatry 72(3): 388-90. Progressive supranuclear palsy (PSP) is a tau deposition neurodegenerative disorder which usually occurs in sporadic form and is associated with a common variant of the tau gene. Rare familial forms of PSP have been described. Recently familial frontotemporal dementia linked to chromosome 17 (FTDP-17) has been shown to be due to mutations in tau and there may be a clinical and pathological overlap between PSP and FTDP-17. In this study we have analysed the tau sequence in two small families with PSP, and a number of clinically typical and atypical sporadic cases with pathological confirmation of the diagnosis. The tau mutations described in FTDP-17 were not found in the most clinically diagnosed patients with PSP. This suggests that usually FTDP-17 and PSP, including the rare familial form of PSP, are likely to be separate conditions and that usually PSP and typical PSP-like syndromes are not due to mutations in tau. Lovestone, S., M. Philpot, et al. (2002). "Genetics, molecular biology, neuropathology and phenotype of frontal lobe dementia: a case history." Br J Psychiatry 180: 455-60. BACKGROUND: Mutations in tau have been found in a group of related disorders including the frontal lobe dementias. AIMS: To describe the clinical features and molecular pathology changes in a single case of a patient with frontal lobe dementia. METHOD: A case report was compiled from neuropathological reports and genomic and gene expression analyses. RESULTS: A case with a splice-site mutation resulting in a typical frontotemporal clinical and neuropathological phenotype was found. Gene expression analysis suggests differential expression of isoforms of tau in regions in the brain. CONCLUSIONS; Frontotemporal dementia can result from gene mutations that alter splicing and expression of tau. Lantos, P. L., N. J. Cairns, et al. (2002). "Neuropathologic variation in frontotemporal dementia due to the intronic tau 10(+16) mutation." Neurology 58(8): 1169-75. BACKGROUND: An increasing number of recently described tau mutations show considerable clinical heterogeneity. The assessment of this phenotypic variation is of vital importance in the differential diagnosis of neurodegenerative diseases. OBJECTIVE: To assess the neuropathologic heterogeneity in a comprehensive study of 12 brains with a tau mutation at exon 10(+16) (C-to-T) splice site from 9 families. METHODS: A comprehensive neuropathologic examination has been carried out, using a wide range of tau antibodies. RESULTS: All brains showed frontotemporal atrophy of varying severity and pallor of the pigmented nuclei of the brainstem. The histologic changes were more extensive to include other cortical areas, the deep gray matter, and the white matter. The hallmark histologic lesions were the tau-positive neuronal and glial inclusions. In neurons, these ranged from typical neurofibrillary tangles through well-circumscribed inclusions to diffuse cytoplasmic staining. This tau pathology was complemented by the presence of large, abnormal achromatic neurons, neuronal loss, astrocytosis, and superficial status spongiosus. CONCLUSION: The distribution, type, and severity of these histologic abnormalities varied not only from case to case but also within the same brain. These brains with a common tau mutation raise important differential diagnostic problems: cases in the past might have been misdiagnosed as corticobasal degeneration or even atypical Pick disease, disorders with similar, if not identical, phenotypic manifestations. Kowalska, A., K. Takahashi, et al. (2002). "Microtubule associated protein (tau) gene variability in patients with frontotemporal dementia." Folia Neuropathol 40(1): 1-5. Frontotemporal dementia represents up to 10% of all dementias and is, next to Alzheimer's disease and Lewy body disease, the third most common cause of degenerative dementia. The term "frontotemporal dementia" covers a range of conditions, including Pick's disease, frontal lobe degeneration and dementia associated with motor neurone disease. Neuropathologically FTD is characterised by atrophy of the frontal and temporal lobes of the cerebral cortex, often with additional subcortical changes. Both familial and more frequently sporadic forms of FTD can be recognised. Recently, mutations in the microtubule-associated protein (tau) gene have been found in families with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). The identification of mutations in the tau gene indicates that the protein plays a central role in the process of neurodegeneration. Epidemiology of frontotemporal dementias in Poland remains still unknown. A prevalence of tau mutations among Polish patients has not been established yet. Here, we report results of a mutational analysis of the tau gene among Polish FTD patients. No pathogenic mutation was found in the analysed sample. The study confirmed that the frequency of tau mutations is very low and depends strongly on the clinical criteria used to select patients. Mutations in the tau gene account only for a small number of FTD cases with a clear autosomal dominant pattern of disease inheritance. Therefore there should exist additionalgenetic and non-genetic factors contributing to the pathogenesis of both familial (linked and non-linked to chromosome 17) and sporadic forms of FTD. Kobayashi, T., H. Mori, et al. (2002). "Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17." J Neurol 249(6): 669-75. Association between clinical characteristics and types of the tau gene mutation has been observed in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). P301L mutation seldom causes parkinsonism as a leading symptom; instead it usually causes personality changes with aggressiveness and disinhibition. We experienced two patients of FTDP-17 from separate families (designated as patient 1 from family 1 and patient 2 from family 2). They had P301L mutation in common. However, their phenotypes were distinct from each other. Aggressive behaviors and disinhibition were the main symptoms in patient 1, whereas parkinsonism was the most prominent feature in patient 2. Their genotypes of the tau gene were different at three sites, i. e. in exon 6, in intron segment before exon 10, and in exon 13, though they do not bring amino acid change. Patient 1 had more prevalent C/C, C/C, and rare T/C respectively. Patient 2 had less prevalent T/T, A/A, and more prevalent T/T respectively. These findings suggest two things. Firstly, they do not share a common founder for P301L mutation. Secondly, either of the two less prevalent genotypes observed in patient 2 may be the factor to modify the phenotype of P301L mutation into those unusual clinical features with prominent parkinsonism. Accumulation of information as to phenotype-genotype association will settle this hypothesis. Kertesz, A. and D. G. Munoz (2002). "Frontotemporal dementia." Med Clin North Am 86(3): 501-18, vi. Frontotemporal dementia is a new name for clinical Pick's disease; the eponymic term PiD has been increasingly restricted to the pathologic variant with Pick bodies. This article describes the clinical picture, pathology, and genetic mechanisms of frontal lobe dementia. Frontotemporal dementia is still under-diagnosed and underestimated, partly because the individual components of the complex are considered separately or are considered "heterogeneous," a somewhat misleading adjective used in many descriptions. This article emphasizes the considerable overlap among the different varieties of frontotemporal dementia, as well as the distinctive features of each. Janssen, J. C., E. K. Warrington, et al. (2002). "Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation." Neurology 58(8): 1161-8. OBJECTIVE: To describe the clinical features of nine British families with neuropathologically verified frontotemporal dementia (FTD) due to the intronic tau exon 10(+16) mutation. METHODS: Retrospective chart reviews of family members with FTD belonging to nine tau 10(+16) mutation pedigrees in whom neuropathologic examination had been carried out. APOE genotype was determined for those patients for whom DNA was available. RESULTS: The median age at onset was 50 years (range 37 to 59 years; n = 30). The median age at death was 61 years (range 42 to 72 years; n = 33). The median duration of the disease was 11 years (range 3 to 22 years; n = 25) for those who have died and is 17 years (range 15 to 23 years; n = 3) for those living. The most common presenting symptom was disinhibition (n = 23). A minority presented with frontal dysexecutive symptoms, apathy, impairment of episodic memory, or depression. All of these patients subsequently developed personality and behavioral change. Memory impairment, language deficits, ritualistic behavior, hyperphagia, and hyperorality were frequent symptoms. Parkinsonism, neuroleptic sensitivity, or primitive reflexes were present in half of the patients, where these data were available. The clinical features of ALS were absent. Neuropathologic examination of 12 patients demonstrated the hallmark tau-positive neuronal and glial inclusions. APOE genotype did not account for the considerable variation in age at onset, age at death, duration of disease, or severity of estimated brain atrophy. CONCLUSIONS: All cases fulfilled the clinical criteria for a diagnosis of FTD. Despite similar clinical phenotypes, there was considerable variation in age at onset and duration of disease both between and within families, suggesting the presence of an effect due to other genetic or environmental factors. Jackson, G. R., M. Wiedau-Pazos, et al. (2002). "Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila." Neuron 34(4): 509-19. Pathologic alterations in the microtubule-associated protein tau have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD). Here, we show that tau overexpression, in combination with phosphorylation by the Drosophila glycogen synthase kinase-3 (GSK-3) homolog and wingless pathway component (Shaggy), exacerbated neurodegeneration induced by tau overexpression alone, leading to neurofibrillary pathology in the fly. Furthermore, manipulation of other wingless signaling molecules downstream from shaggy demonstrated that components of the Wnt signaling pathway modulate neurodegeneration induced by tau pathology in vivo but suggested that tau phosphorylation by GSK-3beta differs from canonical Wnt effects on beta-catenin stability and TCF activity. The genetic system we have established provides a powerful reagent for identification of novel modifiers of tau-induced neurodegeneration that may serve as future therapeutic targets. Hayashi, S., Y. Toyoshima, et al. (2002). "Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation." Ann Neurol 51(4): 525-30. We report a case of frontotemporal dementia and parkinsonism linked to chromosome 17 of 5 years' duration in an 81-year-old man whose brother had died at age 86 years with dementia. In this patient, we found frontal and temporal neuronal loss, glial-predominant tau deposits, progressive supranuclear palsy-like straight tubules, accumulation of 4-repeat-predominant Sarkosyl-insoluble tau, and a novel exon 1 (Arg5His) tau gene mutation. This mutation decreased microtubule-promoting capacity and increased fibrillation of tau in vitro. Thus, we consider that the Arg5His mutation is an authentic tau gene abnormality responsible for the patient's tau pathology and late-onset dementia. Forno, L. S., J. W. Langston, et al. (2002). "Ubiquitin-positive neuronal and tau 2-positive glial inclusions in frontotemporal dementia of motor neuron type." Acta Neuropathol (Berl) 103(6): 599-606. Attempts at classification of fronto-temporal dementias have not yet been completely successful. We report ten cases of sporadic fronto-temporal dementia (FTD) with ubiquitin-positive neuronal inclusions in cortex or in motor neurons in brain stem or spinal cord, which may contribute to the classification of FTD. Marked variation in clinical presentation as well as in pathological findings was the rule in all cases. Dementia was a prominent feature. Only one case had clinical features suggestive of motor neuron disease. Three of four younger onset cases displayed an especially severe atrophy of the temporal lobes, the basal ganglia and the substantia nigra. This contrasted with the other seven cases in which the fronto-temporal atrophy and changes in basal ganglia and substantia nigra were variable and sometimes mild. In addition to the presence of ubiquitin-reactive, but tau-and silver impregnation-negative neuronal inclusions, all cases demonstrated tau 2-positive glial inclusions, similar to those recently reported in three motor neuron disease cases with dementia. The glial inclusions were not visible with antibody to tau 1. Reaction with antibody to alpha-synuclein was invariably negative. If the combination of ubiquitin-positive neuronal and tau 2-positive glial inclusions is found to be consistently present in FTD of motor neuron type, this feature will provide a firmer basis for this diagnosis than previously available. Filla, A., G. De Michele, et al. (2002). "Early onset autosomal dominant dementia with ataxia, extrapyramidal features, and epilepsy." Neurology 58(6): 922-8. OBJECTIVE: To perform a clinical and molecular study of a large autosomal dominant family with a complex neurologic syndrome that comprises early-onset dementia, extrapyramidal and cerebellar features, and epilepsy. BACKGROUND: Early-onset forms of dementia often are caused by genetic factors. Mutations of three different genes-amyloid precursor protein (APP), presenilin 1 (PS-1), presenilin 2 (PS-2)-have been found in early-onset autosomal dominant forms of AD, of the human microtubule associated-protein tau gene (MAPT) in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), of the BRI gene in familial British dementia, of the PI12 gene in familial encephalopathy with neuroserpin inclusion bodies. Linkage to chromosome 3 has been found in familial nonspecific dementia (FND) and linkage to chromosome 20 has been found in Huntington disease (HD)-like neurodegenerative disease. Dementia may be a feature of other neurodegenerative diseases such as HD, dentatorubro-pallidoluysian atrophy (DRPLA), diseases caused by mutations of the prion protein gene (PRNP), spinocerebellar ataxias (SCA), and familial parkinsonism. METHODS: A southern Italian family with autosomal dominant dementia-plus was observed. The family includes 57 individuals in 5 generations (14 affected, 7 personally observed). The authors performed linkage analysis to APP, PS-1, PS-2, FTDP-17, BRI, PI12, FND, HD-like, SCA4, SCA5, SCA10, SCA11, SCA13, PARK1, PARK2, PARK3 loci; direct mutation analysis of HD, DRPLA, SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA12, and PRNP genes; and sequencing of the PRNP open reading frame. RESULTS: Linkage to the examined loci was excluded. All of the direct mutation analyses were negative excluding mutations in the examined genes. CONCLUSIONS: This family has a peculiar phenotype and molecular analyses excluded genes known to cause hereditary dementias. Delobel, P., S. Flament, et al. (2002). "Functional characterization of FTDP-17 tau gene mutations through their effects on Xenopus oocyte maturation." J Biol Chem 277(11): 9199-205. tau gene mutations cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Here we have used Xenopus oocyte maturation as an indicator of microtubule function. We show that wild-type four-repeat Tau protein inhibits maturation in a concentration-dependent manner, whereas three-repeat Tau has no effect. Of the seven four-repeat Tau proteins with FTDP-17 mutations tested, five (G272V, DeltaK280, P301L, P301S, and V337M) failed to interfere significantly with oocyte maturation, demonstrating a greatly reduced ability to interact with microtubules. One mutant protein (R406W) almost behaved like wild-type Tau, and one (S305N) inhibited maturation more strongly than wild-type Tau. With the exception of R406W, wild-type Tau and all the mutants studied were similarly phosphorylated during the Xenopus oocyte maturation, and this was independent of their effects on this process. Data obtained with R406W and S305N may be related to charge changes (phosphorylation and basic amino acids). Our results demonstrate variable effects of FTDP-17 mutations on microtubules in an intact cell situation. Those findings establish Xenopus oocyte maturation as a system allowing the study of the functional effects of tau gene mutations in a quantitative manner. D'Souza, I. and G. D. Schellenberg (2002). "tau Exon 10 expression involves a bipartite intron 10 regulatory sequence and weak 5' and 3' splice sites." J Biol Chem 277(29): 26587-99. tau mutations that deregulate alternative exon 10 (E10) splicing cause frontotemporal dementia with parkinsonism chromosome 17-type by several mechanisms. Previously we showed that E10 splicing involved exon splicing enhancer sequences at the 5' and 3' ends of E10, an exon splicing silencer, a weak 5' splice site, and an intron splicing silencer (ISS) within intron 10 (I10). Here, we identify additional regulatory sequences in I10 using both non-neuronal and neuronal cells. The ISS sequence extends from I10 nucleotides 11-18, which is sufficient to inhibit use of a weakened 5' splice site of a heterologous exon. Furthermore, ISS function is location-independent but requires proximity to a weak 5' splice site. Thus, the ISS functions as a linear sequence. A new cis-acting element, the intron splicing modulator (ISM), was identified immediately downstream of the ISS at I10 positions 19-26. The ISM and ISS form a bipartite regulatory element, within which the ISM functions when the ISS is present, mitigating E10 repression by the ISS. Additionally, the 3' splice site of E10 is weak and requires exon splicing enhancer elements for efficient E10 inclusion. Thus far, tau FTDP-17 splicing mutations affect six predicted cis-regulatory sequences. Curcio, S. A., T. Kawarai, et al. (2002). "A large Calabrian kindred segregating frontotemporal dementia." J Neurol 249(7): 911-22. Frontotemporal dementia (FTD) displays significant neuropathological and genetic heterogeneity among and within affected families. An early diagnosis is often difficult because cognitive symptoms are manifest only at a late stage of the disease. We have been studying a large pedigree segregating frontotemporal dementia (FTD) to which belong 34 identified affected persons, 11 of whom were personally examined. The kindred has been genealogically reconstructed; all FTD patients have been linked to the same ancestors who lived in the early 18(th) century (11 generations before the present one). Autosomal dominant transmission was evident. Clinical features were uniform within the kindred and met the Lund-Manchester criteria. Personality changes with absence of insight, lack of empathy and of social awareness manifested up to 5 years before medical advice was sought. Loss of fluency was the earliest neuropsychological sign, in the absence of memory, orientation and praxis deficits, which evolved late, together with hyperorality. Akinesia was observed early, rigidity appeared late, tremor was absent. Two patients showed myoclonus late in their evolution. No ALS signs were observed in this kindred. Mutations of the MAPt gene, coding for the Tau protein, were not detected in affected family members. Linkage studies excluded chromosomes 3 and 9 and gave indeterminate results that were model dependent for chromosome 17. Cuadrado, A., L. F. Garcia-Fernandez, et al. (2002). "Regulation of tau RNA maturation by thyroid hormone is mediated by the neural RNA-binding protein musashi-1." Mol Cell Neurosci 20(2): 198-210. The tau gene encodes a microtubule-associated protein expressed by neuronal and glial cells. Abnormal deposits of Tau protein are characteristic of several neurodegenerative disorders. Additionally, mutations affecting tau pre-mRNA alternative splicing of exon 10 are associated with frontotemporal dementia and Parkinsonism linked to chromosome 17. In rodents, this process is developmentally regulated by thyroid hormone (T3) causing the predominance of exon 10-containing transcripts. Here we demonstrate that musashi-1 (msi-1) gene is induced by T3 during rat brain development and in N2a cells. T3 increases msi-1 mRNA level in an actinomycin D-sensitive, cycloheximide-resistant fashion without affecting its half-life, which suggests a transcriptional effect. Both ectopic Msi-1 expression and T3 treatment increased the proportion of exon 10-containing tau transcripts. Furthermore, antisense msi-1 expression inhibited T3 action. Our results show that msi-1 mediates the posttranscriptional regulation of tau expression by T3. Coleman, L. W., K. B. Digre, et al. (2002). "Autopsy-proven, sporadic pick disease with onset at age 25 years." Arch Neurol 59(5): 856-9. CONTEXT: Pick disease is uncommon and accounts for less than 2% of adult-onset dementias. Reports of Pick disease in young adults have apparently increased in the last decade. OBJECTIVE: To document the presentation and course of a patient with tau-positive Pick disease presenting at an extremely young age. SETTING: A university hospital. PATIENT: A white woman with cognitive impairment that began at age 25 years. She experienced progressive dementia over an 8-year period with radiographic evidence of severe cerebral atrophy of the frontotemporal lobes. Autopsy findings confirmed the diagnosis of Pick disease characterized by tau-positive Pick bodies in the neurons of the fascia dentata. CONCLUSION: Pick disease should be considered in the differential diagnosis of young adults presenting with behavioral symptoms, especially those of frontal impairment. Buerger, K., R. Zinkowski, et al. (2002). "Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231." Arch Neurol 59(8): 1267-72. BACKGROUND: Phosphorylation of tau protein at threonine 231 (using full-length tau, 441 amino acids, for the numbering scheme) (p-tau(231)) occurs specifically in postmortem brain tissue of patients with Alzheimer disease (AD) and can be sensitively detected in cerebrospinal fluid (CSF). OBJECTIVES: To determine to what extent CSF levels of p-tau(231) distinguish patients with AD from control subjects and from patients with other dementias, and to investigate whether p-tau(231) levels are a better diagnostic marker than levels of total tau protein (t-tau) in CSF. DESIGN AND SETTING: Cross-sectional, multicenter, memory clinic-based studies. PARTICIPANTS: One hundred ninety-two patients with a clinical diagnosis of AD, frontotemporal dementia (FTD), vascular dementia, Lewy body dementia, or other neurological disorder and healthy controls. MAIN OUTCOME MEASURES: Levels of CSF tau proteins as measured with enzyme-linked immunosorbent assays. RESULTS: Mean CSF levels of p-tau(231) were significantly elevated in the AD group compared with all other groups. Levels of p-tau(231) did not correlate with dementia severity in AD, and discriminated with a sensitivity of 90.2% and a specificity of 80.0% between AD and all non-AD disorders. Moreover, p-tau(231) levels improved diagnostic accuracy compared with t-tau levels when patients with AD were compared with healthy controls (P =.03) and demented subjects (P<.001), particularly those with FTD (P<.001), but not those with vascular and Lewy body dementias. Sensitivity levels between AD and FTD were raised by p-tau(231) compared with t-tau levels from 57.7% to 90.2% at a specificity level of 92.3% for both markers. CONCLUSION: Increased levels of CSF p-tau(231) may be a useful, clinically applicable biological marker for the differential diagnosis of AD, particularly for distinguishing AD from FTD. Buee, L., M. Hamdane, et al. (2002). "[Tau story: from frontotemporal dementia to other tauopathies]." 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. 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. Adamec, E., J. R. Murrell, et al. (2002). "P301L tauopathy. confocal immunofluorescence study of perinuclear aggregation of the mutated protein." J Neurol Sci 200(1-2): 85-93. The clinical and neuropathological features in the P301L tauopathy have been described in several kindreds. In this study, we present findings in two previously unreported patients, evaluated both genetically, neuropathologically, and with multiparametric confocal immunofluorescence. The patients were female, with age 65 and 75 years old, respectively. Both exhibited clinical symptoms of frontotemporal dementia (FTD). Marked atrophy of the frontal and temporal lobes with moderate atrophy of the remaining cerebral and brain stem structures was present. The substantia nigra was pale. The atrophic neocortical regions exhibited neuronal loss, marked gliosis, status spongiosus, and occasional ballooned neurons. By light microscopy, the most striking findings were argyrophilic perinuclear rings, frequently with an attached small inclusion (mini Pick-like body), especially prominent in dentate granule cells, entorhinal and temporal cortices, and to a lesser extent in CA1. These structures were immunopositive for tau protein (Tau-2, AT-8, PHF-1, MC-1). Numerous astrocytic plaques, tuft-shaped astrocytes, coiled bodies, and dystrophic neurites were also present. Confocal immunofluorescence with a P301L-specific antibody directly demonstrated the presence of the mutated protein in the PHF-1 positive aggregates. The mutated tau protein (4-repeat tau) was detected in the mini Pick-like bodies, indicating an important biochemical difference between these inclusions and classical Pick bodies (3-repeat tau). Additionally, since 4-repeat tau protein is not normally present in dentate granule cells, this result also suggests an abnormality in the mRNA splicing mechanisms. The structural features of the involvement of proteolytic systems in this tauopathy were assessed by immunohistochemistry for the active form of calpain II (C-27) and ubiquitin. Colocalization of PHF-1 positive aggregates with C-27 points to the possible involvement of calpain in tau protein hyperphosphorylation. Absence of immunostaining for ubiquitin indicates possible dysfunction of the ubiquitin-proteasome system in this tauopathy. Zhukareva, V., V. Vogelsberg-Ragaglia, et al. (2001). "Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia." Ann Neurol 49(2): 165-75. Dementia lacking distinctive histopathology (DLDH) or frontotemporal lobe degeneration (FTLD) is the most common neuropathological diagnosis for sporadic frontotemporal dementias (FTDs). The hallmarks of DLDH are neuron loss and gliosis in the absence of any disease-specific brain lesion. Similar brain pathology is also seen in a familial FTD pedigree known as hereditary dysphasic disinhibition dementia 2 (HDDD2). Abnormality in the function or isoform composition of the microtubule binding protein tau is a prominent feature in the brains of many patients with sporadic and hereditary FTDs. Therefore, we studied the tau protein in different brain regions from DLDH and HDDD2 patients. Our results indicate that a selective loss of all six tau isoforms, but not tau mRNA, occurs in these brains compared to normal control and Alzheimer's disease brains. Loss of tau protein was identified by Western blot analysis of protein extracts from DLDH and HDDD2 brains in regions both with and without neuronal degeneration. Functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene identified in familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). Thus, DLDH and HDDD2 are novel tauopathies with a unique mechanism of pathogenesis. The presence of tau mRNA in these brains suggests that the level of tau protein may be controlled posttranscriptionally, at the level of either translation or mRNA stability. Yoshiyama, Y., V. M. Lee, et al. (2001). "Frontotemporal dementia and tauopathy." Curr Neurol Neurosci Rep 1(5): 413-21. The presence of abundant neurofibrillary lesions made of hyperphosphorylated tau proteins is the characteristic neuropathology of a subset of neurodegenerative disorders classified as "tauopathies." The discovery of mutations in the tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) constitutes convincing evidence that tau proteins play a key role in the pathogenesis of neurodegenerative disorders. Moreover, it now is known that the most common form of sporadic frontotemporal dementia (FTD), which is characterized by frontotemporal neuron loss, gliosis, and microvacuolar change, also is a tauopathy caused by a loss of tau protein expression. Thus, these discoveries have begun to change the classification and the neuropathologic diagnosis of FTD and tauopathies, as well as current understanding of the disease mechanisms underlying them. Although transgenic mice expressing wild-type human tau or variants thereof with an FTDP-17 mutation result in tau pathologies and brain degeneration similar to that seen in human tauopathies, the precise mechanisms leading to the onset and progression of neurodegenerative disorders remain incompletely understood. Here, we review current understanding of human neurodegenerative tauopathies and prospects for translative recent insights about these into therapeutic interventions to prevent or ameliorate them. Yang, Y. and H. P. Schmitt (2001). "Frontotemporal dementia: evidence for impairment of ascending serotoninergic but not noradrenergic innervation. Immunocytochemical and quantitative study using a graph method." Acta Neuropathol (Berl) 101(3): 256-70. A graph method was employed to analyze the spatial neuronal patterns of nuclear grays of the pontine tegmentum with ascending aminergic projections to the forebrain in 12 cases of frontotemporal dementia (FTD). The nuclear grays examined were the nucleus centralis superior (NCS), a part of the nucleus raphae dorsalis (NRD), and the locus coeruleus (LC). The results were compared with 30 cases of Alzheimer's disease (AD) and 35 non-demented controls. In addition to the graph evaluations, neuronal cytoplasmic inclusion bodies were stained by silver impregnation and ubiquitin (Ub) and tau immunohistochemistry. The FTD cases showed a significant, 40%, decline in number of neurons in the NCS and NRD, while the LC was spared. The magnitude of neuronal loss matched that of AD where, by contrast, the LC was also severely changed. Amyloid deposition and Alzheimer neurofibrillary tangles occurred in the aminergic nuclei almost exclusively in AD and, to a minor extent, in some aged controls. No cytoplasmic inclusion bodies were found in the aminergic nuclei of the FTD cases. However, 6 cases had Ub-positive but tau-negative neuronal inclusions in the hippocampal dentate fascia and in layer 2 of the prefrontal isocortex, and 3 showed clinical and histological signs of motor neuron disease. Our results suggest that the serotoninergic raphe nuclei with ascending projections to the forebrain, but not the LC, become directly or indirectly involved in frontotemporal dementia both with and without motor neuron disease. Woulfe, J., A. Kertesz, et al. (2001). "Frontotemporal dementia with ubiquitinated cytoplasmic and intranuclear inclusions." Acta Neuropathol (Berl) 102(1): 94-102. Dementia of motor neuron disease type (DMND) is a variety of frontotemporal dementia (FTD) which is pathologically defined by characteristic neuronal ubiquitinated, tau- and synuclein-negative intracytoplasmic inclusions. Many cases with this pathology, however, do not have motor neuron disease. In the present study, we document the presence of ubiquitinated neuronal intranuclear inclusions in a sub-population of cases of neuropathologically verified DMND. Immunohistochemical localization of ubiquitin was performed on sections of post-mortem brain from 12 patients with DMND as well as from cases with other neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and multiple system atrophy. All of the cases of DMND showed ubiquitinated, tau-negative intracytoplasmic inclusions in dentate granule cells and cortical neurons. Of these 12 cases of DMND, 3 also showed neuronal ubiquitinated intranuclear inclusions. In 1 of these cases, CAG repeat expansions in the genes known to harbor these mutations were excluded. Cases with intranuclear inclusions displayed striatal atrophy and reduced brain weight relative to non-inclusion-bearing cases. In addition, patients with intranuclear inclusions tended to have a younger age of onset, a prolonged duration of disease, absence of motor neuron symptoms, and a family history of dementia. Intranuclear inclusions were not identified in the control cases with other neurodegenerative diseases. Ubiquitinated neuronal intranuclear inclusions have not been reported previously in DMND. The presence of ubiquitinated intranuclear inclusions along with striatal atrophy in a subset of cases of DMND may signify the existence of a neuropathologically distinct subset of this unique form of FTD. Wilson, C. M., G. M. Grace, et al. (2001). "Cognitive impairment in sporadic ALS: a pathologic continuum underlying a multisystem disorder." Neurology 57(4): 651-7. BACKGROUND: Traditionally considered a motor neuron-selective disorder, the clinical manifestations of ALS can include a frontotemporal dementia. Although the pathologic substrate of cognitive impairment remains to be defined, the presence of ubiquitin-immunoreactive (Ub+) intraneuronal inclusions in cortical regions has been suggested to constitute a pathologic marker of this process. METHODS: The authors compared the neuropathological features of four cognitively impaired patients with ALS, four cognitively intact patients with ALS, and four neurologically normal patients. The extent and load of Ub+ neuronal inclusions, Ub+ dystrophic neurites, and superficial linear spongiosis (SLS) was determined among a number of cortical, hippocampal, and subcortical regions. RESULTS: Although Ub+, alpha-synuclein-negative, and tau-negative neuronal inclusions were observed in both cognitively impaired and cognitively intact patients with ALS, their density and extent was greater among the former, with the difference greatest in the cingulate gyrus. Ub+ neurites were observed in a similar distribution. Only the presence of SLS, affecting the first and second cortical layers, reliably distinguished between the cognitively impaired and cognitively intact ALS subpopulations. In three of four cognitively impaired patients with ALS, SLS was associated with transcortical microglial activation, in the absence of detectable differences in astrocytosis, density of calbindin or parvalbumin neurons, or optical density of synaptophysin and SNAP-25. CONCLUSIONS: Although intraneuronal Ub+ inclusions and dystrophic neurites are observed in both ALS subpopulations, the presence of cognitive impairment was associated with a greater distribution and load of both neuropathologic features, suggesting a disease continuum. Moreover, cognitive impairment was uniformly associated with superficial linear spongiosis, a pathologic feature common to several forms of frontotemporal dementia. von Bergen, M., S. Barghorn, et al. (2001). "Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure." J Biol Chem 276(51): 48165-74. The microtubule-associated protein tau is a natively unfolded protein in solution, yet it is able to polymerize into the ordered paired helical filaments (PHF) of Alzheimer's disease. In the splice isoforms lacking exon 10, this process is facilitated by the formation of beta-structure around the hexapeptide motif PHF6 ((306)VQIVYK(311)) encoded by exon 11. We have investigated the structural requirements for PHF polymerization in the context of adult tau isoforms containing four repeats (including exon 10). In addition to the PHF6 motif there exists a related PHF6* motif ((275)VQIINK(280)) in the repeat encoded by the alternatively spliced exon 10. We show that this PHF6* motif also promotes aggregation by the formation of beta-structure and that there is a cross-talk between the two hexapeptide motifs during PHF aggregation. We also show that two of the tau mutations found in hereditary frontotemporal dementias, DeltaK280 and P301L, have a much stronger tendency for PHF aggregation which correlates with their high propensity for beta-structure around the hexapeptide motifs. Vanmechelen, E., H. Vanderstichele, et al. (2001). "Cerebrospinal fluid tau and beta-amyloid(1-42) in dementia disorders." Mech Ageing Dev 122(16): 2005-11. The reliability of cerebrospinal fluid (CSF)-tau and CSF-beta-amyloid assays for diagnosis of Alzheimer's disease and other dementing disorders such as frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and Creutzfeldt-Jakob disease (CJD) is reviewed. CSF assessment of the two proteins is useful in early diagnosis of AD and to differentiate it from FTD and DLB. Extremely high CSF-tau levels can discriminate CJD from AD. Tolnay, M. and A. Probst (2001). "Frontotemporal lobar degeneration. An update on clinical, pathological and genetic findings." Gerontology 47(1): 1-8. Frontotemporal lobar degeneration is the second most common form of cortical dementia in the presenium after Alzheimer's disease. Clinically, based on consensus guidelines, three distinct disease entities can be distinguished: frontotemporal dementia, semantic dementia and progressive nonfluent aphasia. Dementia of frontal type and motor neuron disease inclusion dementia are the most frequent neuropathological subtypes of frontotemporal lobar degeneration. By using immunohistochemistry, the latter is characterized by the presence of filamentous ubiquitin-reactive but tau-negative inclusions in nerve cell bodies and neurites. In contrast, Pick's disease and familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) are both characterized by abundant filamentous nerve cell inclusions made up of the microtubule-associated protein tau. The recent discovery of more than 15 different mutations in the tau gene in FTDP-17 brought the tau protein to the centre stage. These findings had a major impact on our understanding of neurodegenerative disorders characterized by tau filamentous inclusions in neurones and/or glial cells which are grouped under the generic term of tauopathies. However, as exciting these new molecular insights are, it would be inappropriate to lump frontotemporal lobar degeneration as tauopathies. Recent neuropathological and genetic data strongly suggest that there is more than one genetic background for frontotemporal lobar degeneration. Tanemura, K., T. Akagi, et al. (2001). "Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau." Neurobiol Dis 8(6): 1036-45. Formation of neurofibrillary tangles (NFTs) is the most common feature in several neurodegenerative diseases, including Alzheimer's disease (AD). Here we report the formation of filamentous tau aggregations having a beta-sheet structure in transgenic mice expressing mutant human tau. These mice contain a tau gene with a mutation of the frontotemporal dementia parkinsonism (FTDP-17) type, in which valine is substituted with methionine residue 337. The aggregation of tau in these transgenic mice satisfies all histological criteria used to identify NFTs common to human neurodegenerative diseases. These mice, therefore, provide a preclinical model for the testing of therapeutic drugs for the treatment of neurodegenerative disorders that exhibit NFTs. Steinbart, E. J., C. O. Smith, et al. (2001). "Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia." Arch Neurol 58(11): 1828-31. BACKGROUND: DNA testing of persons at risk for hereditary, degenerative neurologic diseases is relatively new. Only anecdotal reports of such testing in familial Alzheimer disease (FAD) exist, and little is know about the personal and social impact of such testing. METHODS: In a descriptive, observational study, individuals at 50% risk for autosomal dominant, early-onset FAD or frontotemporal dementia with parkinsonism linked to chromosome 17 underwent DNA testing for the genetic mutations previously identified in affected family members. Individuals were followed up for (1/2) to 3 years and were interviewed regarding attitudes toward the testing process and the impact of the results. RESULTS: Twenty-one (8.4%) of 251 persons at risk for FAD or frontotemporal dementia requested genetic testing. The most common reasons for requesting testing were concern about early symptoms of dementia, financial or family planning, and relief from anxiety. Twelve individuals had positive DNA test results, and 6 of these had early symptoms of dementia; 8 had negative results; and 1 has not yet received results. Of 14 asymptomatic individuals completing testing, 13 believed the testing was beneficial. Two persons reported moderate anxiety and 1 reported moderate depression. As expected, persons with negative test results had happier experiences overall, but even they had to deal with ongoing anxiety and depression. Thus far, there have been no psychiatric hospitalizations, suicide attempts, or denials of insurance. CONCLUSIONS: Genetic testing in early-onset FAD and frontotemporal dementia can be completed successfully. Most individuals demonstrate effective coping skills and find the testing to be beneficial, but long-term effects remain unknown. Spillantini, M. G. and M. Goedert (2001). "Tau gene mutations and tau pathology in frontotemporal dementia and parkinsonism linked to chromosome 17." Adv Exp Med Biol 487: 21-37. Sjogren, M., P. Davidsson, et al. (2001). "Both total and phosphorylated tau are increased in Alzheimer's disease." J Neurol Neurosurg Psychiatry 70(5): 624-30. BACKROUND: Pathological tau protein concentrations in CSF are found in both Alzheimer's disease (AD) and frontotemporal dementia (FTD), but studies on brain tissue have suggested that the tau pathology in AD differs from that in FTD and that the difference may be related to the degree of phosphorylation. As CSF tau protein is increased after stroke, tau may also be implicated in the pathophysiology of vascular dementia, of which subcortical arteriosclerotic encephalopathy (SAE) is a putative subtype. OBJECTIVES: To investigate the nature of tau protein in CSF and the involvement of total CSF tau and phosphorylated CSF tau (phosphotau) in various types of dementia. METHODS: Using ELISAs for total tau and tau phosphorylated at Thr181 (phosphotau), the CSF concentrations of total tau and phosphotau were determined in patients with probable and possible AD (n=41 and 19, respectively), FTD (n=18), SAE (n=17), and Parkinson's disease (PD; n=15) and in age matched controls (n=17). All the antibodies stained the lower molecular weight bands, whereas only the antibodies that recognise phosphorylated tau stained the higher molecular bands. RESULTS: Both CSF tau and CSF phosphotau were increased in probable AD compared with FTD (p<0.001), SAE (p<0.001), PD (p<0.001), and controls (p<0.001). CSF phosphotau was increased in possible AD compared with FTD (p<0.001) and SAE (p<0.001). CSF tau and CSF phosphotau were positively correlated in all the groups. Molecular weight forms of tau ranging from 25 kDa to 80 kDa were found in the CSF CONCLUSION: Both phosphorylated and unphosphorylated tau isoforms were present in the CSF, and tau protein appeared in both truncated and full length forms. The results suggest that the CSF concentrations of tau and phosphotau are increased in about two thirds of patients with probable AD and in half of those with possible AD but are normal in FTD, SAE, and PD compared with normal aging. Values in the normal range do not exclude AD. Sjogren, M., P. Davidsson, et al. (2001). "The cerebrospinal fluid levels of tau, growth-associated protein-43 and soluble amyloid precursor protein correlate in Alzheimer's disease, reflecting a common pathophysiological process." Dement Geriatr Cogn Disord 12(4): 257-64. Cerebrospinal fluid (CSF) levels of tau (total tau), growth-associated protein-43 (GAP-43), soluble amyloid precursor protein (sAPP; i.e. total sAPP), and beta-amyloid(42) (Abeta(42)) were studied in patients with frontotemporal dementia (FTD; n = 14), Alzheimer's disease (AD; n = 47) and vascular dementia (VAD; n = 16), and in age-matched controls (n = 12). CSF-tau was increased in AD compared to controls and FTD (p < 0.001 for both). CSF-GAP-43 was increased in AD compared to controls (p < 0.05), and both CSF-GAP-43 and CSF-sAPP were increased in AD compared to FTD (p < 0.01). Positive and highly significant correlations were found between CSF-tau and CSF-GAP-43 in all groups and between CSF-tau, CSF-GAP-43 and CSF-sAPP in AD. The correlations found may reflect a common pathophysiologic process such as axonal degeneration. Sjogren, M. and A. Wallin (2001). "Pathophysiological aspects of frontotemporal dementia--emphasis on cytoskeleton proteins and autoimmunity." Mech Ageing Dev 122(16): 1923-35. The aim of this study was to investigate two putative pathophysiological aspects of the common neurodegenerative disorder frontotemporal dementia (FTD). To this end, cerebrospinal fluid (CSF) levels of tau (total tau) and the light subtype of the neurofilament proteins (NFL) were studied in patients with FTD (n=16) and in age-matched controls (n=16). In addition, serum was analysed for IgG and IgM antibodies to the most common gangliosides and sulfatide in FTD patients (n=13) and in age-matched controls (n=20). The CSF-NFL levels were increased in FTD (1606+/-1151 pg/ml, mean+/-S.D.; P<0.001) compared with controls (308+/-203 pg/ml), whereas the CSF-tau levels were normal. In serum, autoantibody IgG-GA1 was significantly increased in FTD (P<0.05) compared with controls. No correlations were found between the effect parameters and demographic variables in any group. The results of this study suggest that cytoskeleton proteins other than tau are also involved in the pathophysiology of FTD and that autoimmunity may be part of the pathophysiological processes in FTD, as it is believed to be in Alzheimer's disease. Shafiq, M., L. Nee, et al. (2001). "Frontotemporal dementia: report of a familial case." Neurology 56(11 Suppl 4): S31-4. The authors describe a 49-year-old woman (R.K.) who presented with one year of progressive frontal lobe dysfunction, including signs of expressive aphasia. Signs of parkinsonism were absent until late in the clinical course. Neuropsychologic testing and neuroimaging studies are described. The patient died at age 55, after 7 years of symptoms. Family history was remarkable for a mother who died at the age of 45, after experiencing 7 years of progressive aphasia. R.K.'s brain showed asymmetric frontotemporal atrophy, which was more severe on the left side. Histopathologic analysis was remarkable for numerous tau-positive neurons with some classic-appearing Pick bodies and many ballooned neurons. Tau-positive glial cells were also present. The authors suggest that the abnormal tau aggregates are related to the symptoms experienced by affected members of this family. Russ, C., S. Lovestone, et al. (2001). "The extended haplotype of the microtubule associated protein tau gene is not associated with Pick's disease." Neurosci Lett 299(1-2): 156-8. Pick's disease (PiD) is a rare neurodegenerative condition and is a member of a heterogeneous group of disorders known as tauopathies, so-called because of the predominantly neuronal aberrant tau accumulations found in these diseases. The tauopathy, familial frontotemporal dementia (FTD), is caused by mutations in the tau gene. Moreover, progressive supranuclear palsy (PSP) is associated with the tau H1 haplotype. In certain familial forms of FTD and in PSP the microtubule-binding four repeat tau isoform principally accumulates in neuropathological lesions. However, in PiD three repeat tau accumulations are found. We therefore investigated whether either the tau H1 or H2 haplotype was associated with PiD. Our results indicate a slight increase in H2H2 frequency in Pick's cases which is not statistically significant. Rossor, M. N. (2001). "Pick's disease: a clinical overview." Neurology 56(11 Suppl 4): S3-5. What is to be understood by the term Pick's disease? Is this a clinical syndrome(s) of frontotemporal lobar atrophy, or a more specific clinicopathological concept of frontotemporal lobar atrophy with Pick bodies and/or Pick cells on neuropathology? The author discusses these concepts in an historical context as an introduction to this symposium. Rosso, S. M., W. Kamphorst, et al. (2001). "Familial frontotemporal dementia with ubiquitin-positive inclusions is linked to chromosome 17q21-22." Brain 124(Pt 10): 1948-57. Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that is associated with mutations in the tau gene and with the pathological accumulation of hyperphosphorylated tau protein in affected brain cells in about a quarter of cases. However, most FTD families have no demonstrable tau mutations. Here we describe the clinical and neuropathological features of a large family with hereditary FTD. Genetic analysis showed strong evidence for linkage to chromosome 17q21-22 (maximum lod score 3.46, theta = 0 for marker D17S950), but mutations in the tau gene were not found. Clinical symptoms, neuropsychological deficits and neuroimaging findings of affected family members were similar to sporadic and tau-related FTD. The mean age at onset was 61.2 years, with loss of initiative and decreased spontaneous speech as the most prominent presenting symptoms. Pathological examination of the brains of two affected family members showed non-specific neuronal degeneration with dense cytoplasmic ubiquitin-positive inclusions in neurones of the second layer of the frontotemporal cortex and dentate gyrus of the hippocampus. In a number of neurones these inclusions appeared to be located inside the nucleus, although due to the small number of these inclusions this localization could not be confirmed by electron microscopy. The inclusions were not stained by tau, alpha-synuclein or polyglutamine antibodies. Biochemical analysis of soluble tau did not reveal abnormalities in tau isoform distribution and analysis of mRNA showed the presence of both three- and four-repeat transcripts. This is the first report of ubiquitin-positive, tau-negative inclusions in an FTD family with significant linkage to chromosome 17q21-22. Further characterization of the ubiquitin-positive inclusions may clarify the neurodegenerative pathways involved in this subtype of FTD. Reed, L. A., Z. K. Wszolek, et al. (2001). "Phenotypic correlations in FTDP-17." Neurobiol Aging 22(1): 89-107. Frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17) are hereditary tauopathies affecting at least 50 known kindred worldwide. Most kindred present with severe behavioral or psychiatric manifestations progressing to dementia, while some kindred first manifest a parkinsonian-plus syndrome. Nine missense mutations, one deletion mutation, and two transition mutations not altering the encoded amino acid, have been described in or near the microtubule-binding domains within exons 9, 10, 12, and 13. In addition, five different intronic mutations have been reported in the 5' splice-site of the alternatively spliced exon 10. Missense mutations affecting constitutively expressed exons affect all six major tau isoforms and result in neurofibrillary tangles similar to those present in secondary tauopathies, such as Alzheimer's disease. In contrast, mutations that affect the alternatively spliced exon 10 or its 5' splice regulatory region alter the ratio of the tau isoforms incorporated into the tangles and result in filamentous inclusions resembling those seen in the primary tauopathies, such as progressive supranuclear palsy, corticobasal degeneration, and Pick's disease.The severity and heterogeneity of the clinicomorphologic phenotype may, in part, reflect the diversity in the primary molecular mechanisms of disease in FTDP-17. Poorkaj, P., M. Grossman, et al. (2001). "Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia." Arch Neurol 58(3): 383-7. BACKGROUND: Mutations in the tau gene have been reported in families with frontotemporal dementia (FTD) linked to chromosome 17. It remains uncertain how commonly such mutations are found in patients with FTD or non-Alzheimer dementia with or without a positive family history. OBJECTIVE: To determine the frequency of tau mutations in patients with non-Alzheimer dementia. PATIENTS AND METHODS: One hundred one patients with non-Alzheimer, nonvascular dementia, most thought to have FTD. Of these, 57 had a positive family history of dementia. Neuropathologic findings were available in 32. The tau gene was sequenced for all exons including flanking intronic DNA, portions of the 3' and 5' untranslated regions, and at least 146 base pairs in the intron following exon 10. RESULTS: Overall, the frequency of the tau mutations was low, being 5.9% (6/101) in the entire group. No mutations were found in the 44 sporadic cases. However, 6 (10.5%) of the 57 familial cases and 4 (33%) of the 12 familial cases with tau pathologic findings had mutations in the tau gene. The most common mutation was P301L. CONCLUSIONS: We conclude that tau mutations are uncommon in a neurology referral population with non-Alzheimer dementia, even in those with a clinical diagnosis of FTD. However, a positive family history and/or tau pathologic findings increase the likelihood of a tau mutation. There must be other genetic and nongenetic causes of FTD and non-Alzheimer dementia, similar to the etiologic heterogeneity present in Alzheimer disease. Poorkaj, P., A. Kas, et al. (2001). "A genomic sequence analysis of the mouse and human microtubule-associated protein tau." Mamm Genome 12(9): 700-12. Microtubule associated protein tau (MAPT) encodes the microtubule associated protein tau, the primary component of neurofibrillary tangles found in Alzheimer's disease and other neurodegenerative disorders. Mutations in the coding and intronic sequences of MAPT cause autosomal dominant frontotemporal dementia (FTDP-17). MAPT is also a candidate gene for progressive supranuclear palsy and hereditary dysphagic dementia. A human PAC (201 kb) and a mouse BAC (161 kb) containing the entire MAPT and Mtapt genes, respectively, were identified and sequenced. Comparative DNA sequence analysis revealed over 100 conserved non-repeat potential cis-acting regulatory sequences in or close to MAPT. Those islands with greater than 67% nucleotide identity range in size from 20 to greater than 1700 nucleotides. Over 90 single nucleotide polymorphisms were identified in MAPT that are candidate susceptibility alleles for neurodegenerative disease. The 5' and 3' flanking genes for MAPT are the corticotrophin-releasing factor receptor (CRFR) gene and KIAA1267, a gene of unknown function expressed in brain. Poorkaj, P., D. Tsuang, et al. (2001). "TAU as a susceptibility gene for amyotropic lateral sclerosis-parkinsonism dementia complex of Guam." Arch Neurol 58(11): 1871-8. BACKGROUND: A Guam variant of amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia complex (PDC-G) are found in the Chamorro people of Guam. Both disorders have overlapping neuropathologic findings, with neurofibrillary tangles in spinal cord and brain. The cause of ALS-G-PDC-G is unknown, although inheritance and environment appear important. Because neurofibrillary tangles containing tau protein are present in ALS-G-PDC-G, and because mutations in the tau gene (TAU) cause autosomal dominant frontotemporal dementia, TAU was examined as a candidate gene for ALS-G-PDC-G. METHODS: TAU was evaluated by DNA sequence analysis in subjects with ALS-G-PDC-G, by linkage analysis of TAU polymorphisms in an extended pedigree from the village of Umatac, and by evaluation of linkage disequilibrium with polymorphic markers flanking and within TAU. RESULTS: Linkage disequilibrium between ALS-G-PDC-G and the TAU polymorphism CA3662 was observed. For this 2-allele system, PDC and ALS cases were significantly less likely than Guamanian controls to have the 1 allele (4.9% and 2% vs 11.5%, respectively; Fisher exact P =.007). DNA sequence analysis of TAU coding regions did not demonstrate a mutation responsible for ALS-G-PDC-G. Analysis of TAU genotypes in an extended pedigree of subjects from Umatac showed obligate recombinants between TAU and ALS-G-PDC-G. Linkage analysis of the Umatac pedigree indicates that TAU is not the major gene for ALS-G-PDC-G. CONCLUSIONS: The genetic association between ALS-G-PDC-G implicates TAU in the genetic susceptibility to ALS-G-PDC-G. TAU may be a modifying gene increasing risk for ALS-G-PDC-G in the presence of another, as yet, unidentified gene. Pastor, P., E. Pastor, et al. (2001). "Familial atypical progressive supranuclear palsy associated with homozigosity for the delN296 mutation in the tau gene." Ann Neurol 49(2): 263-7. Heterozygous missense and splice-site mutations in the tau gene have been previously identified in familial frontotemporal dementia with autosomal dominant inheritance. Here we report a Spanish kindred in which two brothers born from a third-degree consanguineous marriage were both affected with atypical progressive supranuclear palsy. A homozygous deletion at codon 296 (delN296) was identified in one of the affected siblings. Among the heterozygous carriers, two members with probable Parkinson's disease were identified, but none of heterozygotes developed atypical parkinsonism. The delN296 mutation lies in the sequence corresponding to the second tubulin-binding repeat of tau protein and affects one asparagine residue absolutely conserved in other species. This finding indicates that homozygous mutations in the tau gene may also cause hereditary tauopathies. Pal, P. K., Z. K. Wszolek, et al. (2001). "Positron emission tomography in pallido-ponto-nigral degeneration (PPND) family (frontotemporal dementia with parkinsonism linked to chromosome 17 and point mutation in tau gene)." 7(2): 81-88. Pallido-ponto-nigral degeneration (PPND) is a rapidly progressive disorder characterized by frontotemporal dementia with parkinsonism unresponsive to levodopa therapy. In this study, we have further characterized the regional abnormalities of cerebral function using PET with 6-[18F]fluoro-L-dopa (FD), [11C] raclopride (RAC), and 2-deoxy-2-fluoro-[18F]-D-glucose (FDG). FD and RAC scans were performed in 3 patients-2 new patients and a previously reported asymptomatic at-risk individual who became symptomatic 2years after the first FD scan. Cerebral glucose metabolism was studied by FDG in 2 other patients. In keeping with previous reports, there was a severe reduction of FD uptake, which affected both caudate and putamen to a similar degree in all 3 patients. RAC scans showed normal to elevated striatal D2-receptor binding in all patients. Cerebral glucose metabolism was globally reduced (>2 SD below control mean) in one patient, with maximal involvement of frontal regions, and to a lesser degree in the other patient. Our study showed severe presynaptic dopaminergic dysfunction with intact striatal D2 receptors in PPND patients, implying that the dopa unresponsiveness is probably a result of pathology downstream to the striatum. The pattern of presynaptic dysfunction contrasts with that seen in idiopathic parkinsonism, where the putamen is affected more than the caudate nucleus. The pattern of glucose hypometabolism correlates well with the presence of frontotemporal dementia. Neumann, M., W. Schulz-Schaeffer, et al. (2001). "Pick's disease associated with the novel Tau gene mutation K369I." Ann Neurol 50(4): 503-13. Exonic and intronic mutations in Tau cause neurodegenerative syndromes characterized by frontotemporal dementia and filamentous tau protein deposits. We describe a K369I missense mutation in exon 12 of Tau in a patient with a pathology typical of sporadic Pick's disease. The proband presented with severe personality changes, followed by loss of cognitive function. Detailed postmortem examination of the brain showed atrophy, which was most pronounced in the temporal lobes; and numerous tau-immunoreactive Pick bodies and Pick cells in the neocortex and the hippocampal formation, as well as in subcortical brain regions. Their appearance and staining characteristics were indistinguishable from those of sporadic Pick's disease. However, immunoblot analysis of sarkosyl-insoluble tau showed three major bands of 60, 64, and 68 kDa, consistent with the presence of 3- and 4-repeat tau isoforms, as in Alzheimer's disease. Isolated tau filaments were irregularly twisted ribbons, with a small number of Alzheimer-type paired helical filaments. In the presence of heparin, tau proteins with the K369I mutation formed short, slender filaments. Biochemically, recombinant tau proteins with the K369I mutation showed reduced ability to promote microtubule assembly, suggesting that this may be the primary effect of the mutation by providing a pool of aberrant tau for filament assembly. Taken together, results indicate that the K369I mutation in Tau can cause a dementing disease with a neuropathology like that of Pick's disease. Nagiec, E. W., K. E. Sampson, et al. (2001). "Mutated tau binds less avidly to microtubules than wildtype tau in living cells." J Neurosci Res 63(3): 268-75. Some forms of genetically inherited dementia, including frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), are caused by mutations in tau. We have examined several mutations in the microtubule-binding portion of tau for their effect on microtubule binding, cellular distribution and cytoskeletal structure in mammalian cells. Using constructs coding for mutant (P301L and V337M) and wildtype human tau fused to a green fluorescent protein analog (EGFP) we followed the disposition of tau in live cells after transient transfection using confocal microscopy. Most of the tau protein localized to structures that resembled microtubules or microtubule bundles and co-localized with tubulin. At 3 days post-transfection mutant tau proteins showed a higher abundance of free tau in the cytoplasm than did wildtype tau. Cells expressing the P301L mutation showed proportionally more cytoplasmic localization of tau. Confirming these results, fractionated cells with mutant tau had a higher percentage of tau in the cytoplasmic compartment as compared to the cytoskeletal compartment. Cells with wildtype tau had most tau in the cytoskeletal fraction. Because the mutations (V337M, P301L) are associated with genetic tauopathies, these results suggest that a factor in disease etiology of genetic tauopathies and other dementias with altered tau is a greater abundance of tau in the cytoplasm due to decreased binding to microtubules. This increased cytoplasmic presence may be a significant factor in promoting tau aggregation. Morris, H. R., M. N. Khan, et al. (2001). "The genetic and pathological classification of familial frontotemporal dementia." Arch Neurol 58(11): 1813-6. BACKGROUND: Frontotemporal dementia (FTD) is an important cause of neurodegenerative dementia, particularly in younger patients. TAU has been identified as the gene responsible for FTD linked to chromosome 17, but it is likely that there is pathological and genetic heterogeneity among families with FTD. OBJECTIVE: To explore the genetic and pathological basis of familial FTD. DESIGN: Clinical case series with genetic analysis of each family, and pathological confirmation of diagnosis where possible. SETTING: Specialist dementia research group, particularly recruiting patients with young-onset dementia. PATIENTS: Twenty-two families with an index member with FTD, meeting Lund-Manchester criteria, and a family history of other affected members with dementia were ascertained. RESULTS: Half of the families had mutations in the TAU gene (TAU exon 10 +14, +16, and P301S), and pathological diagnoses were available in 17 of 22 families. Three main pathological diagnoses were made: FTD with neuronal and glial tau deposition, FTD with ubiquitin inclusions, and FTD with neuronal loss and spongiosis but without intracellular inclusions. No cases of familial Pick disease were identified. With the use of the pathological diagnoses, each family with FTD with neuronal and glial tau deposition had a TAU mutation, whereas TAU mutations were not identified in families in the other 2 diagnostic groups. CONCLUSIONS: This study illustrates the value of TAU sequencing in FTD and suggests that around one half of individuals with familial FTD have TAU mutations and dementia with tau pathological findings. Furthermore, these data suggest that there are at least 2 additional genes to be identified among families with autosomal dominant FTD. Miyasaka, T., M. Morishima-Kawashima, et al. (2001). "Molecular analysis of mutant and wild-type tau deposited in the brain affected by the FTDP-17 R406W mutation." Am J Pathol 158(2): 373-9. Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a familial neurological disorder, characterized genetically by autosomal dominant inheritance, clinically by behavioral abnormalities and parkinsonism, and neuropathologically by tauopathy. Linkage analyses of affected families have led to identification of several exonic and intronic mutations in the tau gene. In this study, we analyzed molecular species of tau in the soluble and insoluble fractions of brain affected by the FTDP-17 R406W mutation. Protein chemical analysis and Western blotting using site-specific antibodies indicated that almost equal amounts of wild-type and mutant tau were present in the Sarkosyl-insoluble fraction of the R406W brain. Consistent with this, wild-type and mutant tau colocalized in neurofibrillary tangles in the frontal cortex and hippocampus of the R406W brain. In contrast to soluble R406W tau, which was less phosphorylated than soluble wild-type tau, the Sarkosyl-insoluble mutant tau was highly phosphorylated as well as the insoluble wild-type tau. Miyasaka, T., M. Morishima-Kawashima, et al. (2001). "Selective deposition of mutant tau in the FTDP-17 brain affected by the P301L mutation." J Neuropathol Exp Neurol 60(9): 872-84. Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a familial neurological disorder exhibiting autosomal dominant inheritance. Linkage analyses have led to the identification of many exonic and intronic mutations in the tau gene in affected families. Because FTDP- 17 causes extensive neuronal loss and intracellular tau deposits in affected regions, investigation of this disease should provide an important insight into the significance of tau deposits leading to neurodegeneration. Using site-specific antibodies that distinguish between wild-type and mutant tau, we have analyzed the proportions of wild-type and mutant tau in the soluble and insoluble fractions of the P301L brain. Western blotting showed that mutant tau was selectively deposited in the Sarkosyl-insoluble fraction. Consistent with this, immunocytochemistry showed that intraneuronal tau deposits consisted exclusively of mutant tau. In one case in which abundant senile plaques occurred, in addition to mutant tau, small amounts of wild-type tau were also deposited. On the other hand, the protein levels of mutant tau in the soluble fraction were selectively decreased despite no detectable decrease in the levels of mutant tau mRNA. Miyamoto, K., A. Ikemoto, et al. (2001). "A case of frontotemporal dementia and parkinsonism of early onset with progressive supranuclear palsy-like features." Clin Neuropathol 20(1): 8-12. We report a patient with frontotemporal degeneration and parkinsonism with mental retardation. The patient was a 54-year-old man who had parkinsonism that resembled progressive supranuclear palsy, frontotemporal degeneration and myoclonus. His family included many affected members. Neuropathologically, there was degeneration of the frontal and temporal cortices, the basal ganglia, the brainstem and the cerebellum. Microscopically, neuronal loss was severe in the frontal and temporal cortex, the globus pallidus, substantia nigra, red nucleus and dentate nucleus. Fibrillary changes were found in neurons and glia that were immunostained for tau. Although we could not define the genetic abnormalities, we thought that this case might have involved frontotemporal dementia and parkinsonism linked to chromosome 17. Miyamoto, K., A. Kowalska, et al. (2001). "Familial frontotemporal dementia and parkinsonism with a novel mutation at an intron 10+11-splice site in the tau gene." Ann Neurol 50(1): 117-20. We report a case of familial frontotemporal dementia and parkinsonism characterized by early onset with mental retardation. The patient died at the age of 54; neuronal loss was severe in the frontal and temporal cortices, globus pallidus, substantia nigra, red nucleus and dentate nucleus. Anti-tau-positive fibrillary changes were observed in neurons and glia in these regions. Although the patient had 2 novel point mutations of the tau gene, P301P (CCG to CCA) and an intron 10+11-splice site (T to C), exon trapping analysis indicated that the latter was pathogenic. Michotte, A., S. Goldman, et al. (2001). "Frontotemporal dementia: a clinical-pathological study." Acta Neurol Belg 101(4): 224-9. We report a 44-year-old female patient without any familial history of dementia presenting with increasing disturbances in behaviour and language followed by a progressive cognitive deterioration. Neuropsychological evaluation revealed a significant impairment on frontal lobe tests. A brain PET scan disclosed a severe frontal hypometabolism. The tentative diagnosis of frontotemporal dementia was made. Her condition rapidly worsened and she died 2 years after the beginning of her disease. Gross examination of the brain showed a selective symmetrical atrophy of both frontal and anterior part of the temporal lobes. Microscopical examination revealed severe neuronal loss in the frontal and anterior temporal cortex associated with gliosis and microvascular spongiosis in the superficial cortical layers in the absence of any specific neuronal or glial inclusions. These neuropathological findings were consistent with the diagnosis of dementia lacking distinctive histology. We discuss the nosology of the frontotemporal dementias, the diagnostic value of PET scan, the recent genetical developments which strongly support the pathogenic role of tau and we emphasize the importance of immunohistochemical examination for a definite neuropathological diagnosis. McRae, C. A., G. Diem, et al. (2001). "Interest in genetic testing in pallido-ponto-nigral degeneration (PPND): a family with frontotemporal dementia with Parkinsonism linked to chromosome 17." Eur J Neurol 8(2): 179-83. The specific mutation on the tau gene responsible for a neurodegenerative disease known as pallido-ponto-nigral degeneration (PPND) was recently located. PPND family members are at risk for an autosomal dominant form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). This study investigated whether individuals in this family would consider presymptomatic genetic testing. Surveys were sent to 66 at-risk individuals in the family; replies were received from 20 (30%). Family members were asked if they would consider having testing now or in the future, and to indicate their reasons for and against proceeding with testing. Fifty per cent (n=10) of those who were at risk and who responded indicated they would consider testing now, and 55% (n=11) would think about it in the future. The most frequently cited reasons to proceed with testing were to 'collaborate with research' (70%) and to 'know if my children are at risk' (45%). The most frequently cited reason not to pursue testing was 'I can enjoy my life more fully by not knowing' (50%). Results suggest that interest in determining whether they will manifest PPND is generally low among at-risk members of this family, despite wide support and participation in other research studies. Manna, D. M. and S. Pickering-Brown (2001). "The status of "Pick's Disease" and other tauopathies within the frontotemporal dementias." Neurobiol Aging 22(1): 109-11. Mack, T. G., R. Dayanandan, et al. (2001). "Tau proteins with frontotemporal dementia-17 mutations have both altered expression levels and phosphorylation profiles in differentiated neuroblastoma cells." Neuroscience 108(4): 701-12. The inherited form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) has been attributed to mutations in the tau gene. Pathologically, affected FTDP-17 brains share tau aggregates with other tauopathies, the most common being Alzheimer's disease. FTDP-17 mutations may therefore affect tau function leading to tau aggregation and cell loss. Interaction of tau with microtubules is thought to be regulated by phosphorylation. Investigating FTDP-17 mutations transiently expressed as enhanced green fluorescent protein (EGFP)-tagged proteins for the first time in differentiated neuronal cells, we found that two out of three missense mutations showed surprisingly decreased phosphorylation at the pathologically relevant S202/T205 site, mutant EGFP-tau being completely dephosphorylated in most cells. Moreover, phosphorylation at the S396/S404 site was moderately decreased for all mutant isoforms. Although microtubule integrity was not affected, with all mutants tested we demonstrated an increase in cellular tau protein level, some of which is microtubule-bound. Further enhancing this EGFP-tau accumulation by inhibition of tau degradation resulted in the previously less phosphorylated mutant EGFP-tau becoming highly phosphorylated.We conclude that the missense tau mutations primarily result in an excess of neuronal tau, which may interfere with important cellular functions such as axonal transport. Ludolph, A. C., A. Sperfeld, et al. (2001). "[Tauopathies--a new class of neurodegenerative diseases]." Nervenarzt 72(2): 78-85. Recently it was shown by several research groups that mutations in the gene encoding for the tau protein associated with microtubuli on chromosome 17 caused a distinct form of dementia named frontotemporal dementia and parkinsonism (FTDP-17). This disease includes familial asymmetrical frontal and, in the further course, frontotemporal dementia, parkinsonism, which is often initially sensitive to levodopa, signs of upper motor neuron degeneration, and, less commonly, amyotrophy. Tau is an intracellular protein of the cytoskeleton, which is responsible for the arrangement and stabilization of microtubuli. The discovery of mutations in the tau gene causing a distinct neurodegenerative disease in humans has firmly established the importance of the tau gene for neurodegenerative processes, not only in tauopathies but also in other degenerative disorders with tau pathology, such as corticobasal degeneration, supranuclear progressive paralysis, amyotropic lateral sclerosis, parkinsonism-dementia complex of Guam, and Alzheimer's disease. Our experience with patients suffering from PTDP-17 shows that its phenotype varies more than was described in the first consensus conferences. In the future, it will be important to designate the diagnostic gold standard not by clinical description, but etiologic classification. Lim, F., F. Hernandez, et al. (2001). "FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain." Mol Cell Neurosci 18(6): 702-14. The tauopathies, which include Alzheimer's disease (AD) and frontotemporal dementias, are a group of neurodegenerative disorders characterized by filamentous Tau aggregates. That Tau dysfunction can cause neurodegeneration is indicated by pathogenic tau mutations in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). To investigate how Tau alterations provoke neurodegeneration we generated transgenic mice expressing human Tau with four tubulin-binding repeats (increased by FTDP-17 splice donor mutations) and three FTDP-17 missense mutations: G272V, P301L, and R406W. Ultrastructural analysis of mutant Tau-positive neurons revealed a pretangle appearance, with filaments of Tau and increased numbers of lysosomes displaying aberrant morphology similar to those found in AD. Lysosomal alterations were confirmed by activity analysis of the marker acid phosphatase, which was increased in both transgenic mice and transfected neuroblastoma cells. Our results show that Tau modifications can provoke lysosomal aberrations and suggest that this may be a cause of neurodegeneration in tauopathies. Lev, N. and E. Melamed (2001). "Heredity in Parkinson's disease: new findings." Isr Med Assoc J 3(6): 435-8. Multiple factors have been hypothesized over the last century to be causative or contributory for Parkinson's disease. Hereditary factors have recently emerged as a major focus of Parkinson's disease research. Until recently most of the research on the etiology of Parkinson's disease concentrated on environmental factors, and the possibility that genetic factors contribute significantly to the pathogenesis of Parkinson's disease has been neglected. However, it has become increasingly apparent that even in sporadic cases, the disease most likely reflects a combination of genetic susceptibility and an unknown environmental insult. Moreover, the identification of genes and proteins that may cause hereditary parkinsonism substantially contributes to our ability to understand the pathogenesis of Parkinson's disease and may help in the early identification of the disease and its treatment. The discovery of alpha-synuclein mutations in families with autosomal dominant Parkinson's disease sheds light on its role in sporadic Parkinson's disease. It seems that this protein tends to aggregate when the cellular milieu is altered [14-16]. The question as to the exact changes that cause its deposition remains open. One of the major possibilities is oxidative stress [16]. The role of these aggregates in neuronal cell death is also still unclear. Transgenic mice expressing wild-type human alpha-synuclein developed progressive accumulation of alpha-synuclein and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus and the substantia nigra. These alterations were associated with loss of dopaminergic terminals and motor impairments [24]. This finding suggests that accumulation of alpha-synuclein may play a causal role in sporadic Parkinson's disease as well. The parkin protein seems to be a crucial survival factor for nigral neurons [15]. The parkin protein is related to the ubiquitin pathway, which is important in the elimination of damaged proteins. Ubiquitin-mediated degradation of proteins plays a central role in the control of numerous processes, including signal transduction, receptor and transcriptional regulations, programmed cell death, and breakdown of abnormal proteins that may interfere with normal cell functions. Further studies on the function of Parkin protein and its relation to the ubiquitin pathway could elucidate at least one of the molecular mechanisms of nigral neuronal death. A mutation in the ubiquitin carboxy-teminal hydrolase L1 gene also implies the importance of the ubiquitin pathway in Parkinson's disease. Abnormal tau protein was found to be the cause of familial frontotemporal dementia and parkinsonism. It tends to form filamentous structures, which may lead to neuronal death. Elucidation of the molecular mechanism of neuronal death in this disease may contribute to our understanding of sporadic diseases with tau accumulation, such as corticobasal degeneration, progressive supranuclear palsy, Pick's disease, Alzheimer's disease and possibly also the pathogenesis of Parkinson's disease. Other genetic loci have been identified by linkage analysis of patients with familial parkinsonism. These loci conceal other genes and proteins that may be pivotal factors in the pathogenesis of Parkinson's disease. The discovery of genetic mutations in patients with parkinsonism may offer us new insights into the understanding of the pathways leading to neuronal death and development of Parkinson's disease. It may also help in the early identification of susceptible people to this disease and possibly in developing new treatment strategies. Lee, V. M., M. Goedert, et al. (2001). "Neurodegenerative tauopathies." Annu Rev Neurosci 24: 1121-59. The defining neuropathological characteristics of Alzheimer's disease are abundant filamentous tau lesions and deposits of fibrillar amyloid beta peptides. Prominent filamentous tau inclusions and brain degeneration in the absence of beta-amyloid deposits are also hallmarks of neurodegenerative tauopathies exemplified by sporadic corticobasal degeneration, progressive supranuclear palsy, and Pick's disease, as well as by hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Because multiple tau gene mutations are pathogenic for FTDP-17 and tau polymorphisms appear to be genetic risk factors for sporadic progressive supranuclear palsy and corticobasal degeneration, tau abnormalities are linked directly to the etiology and pathogenesis of neurodegenerative disease. Indeed, emerging data support the hypothesis that different tau gene mutations are pathogenic because they impair tau functions, promote tau fibrillization, or perturb tau gene splicing, thereby leading to formation of biochemically and structurally distinct aggregates of tau. Nonetheless, different members of the same kindred often exhibit diverse FTDP-17 syndromes, which suggests that additional genetic or epigenetic factors influence the phenotypic manifestations of neurodegenerative tauopathies. Although these and other hypothetical mechanisms of neurodegenerative tauopathies remain to be tested and validated, transgenic models are increasingly available for this purpose, and they will accelerate discovery of more effective therapies for neurodegenerative tauopathies and related disorders, including Alzheimer's disease. Kowalska, A., T. Asada, et al. (2001). "Genetic analysis in patients with familial and sporadic frontotemporal dementia: two tau mutations in only familial cases and no association with apolipoprotein epsilon4." Dement Geriatr Cogn Disord 12(6): 387-92. We screened for tau gene mutations among 24 Japanese (6 familial and 18 sporadic cases) and 4 Polish patients with frontotemporal dementia (FTD) using PCR-SSCP analysis followed by DNA sequencing. We identified 2 missense mutations in exon 10: N279K and P301L in 2 Japanese patients with familial FTD. Additionally 3 DNA polymorphisms: 2 known (3' exon 3 + 9, A --> G and exon 7, codon 176, G --> A) and 1 new (exon 8, codon 185, T --> C) were identified in 1 Polish patient. Tau mutations were not found in subjects with a negative family history suggesting that tau mutations do not account for most sporadic cases of FTD. We also found no association of apolipoprotein E4 allele with FTD. Knopman, D. S. (2001). "An overview of common non-Alzheimer dementias." Clin Geriatr Med 17(2): 281-301. Approximately 20% to 40% of dementia is caused by diseases other than Alzheimer's disease. This article reviews the major categories of non-Alzheimer dementia, including dementia associated with cerebrovascular disease, dementia associated with extrapyramidal features, and the frontotemporal dementias. Dementia associated with cerebrovascular disease is a heterogeneous condition the importance of which is often misunderstood. Dementia with Lewy bodies, the most common of the dementias associated with extrapyramidal disease, is becoming better recognized for its unique management issues. At least some of the frontotemporal dementias, which in this article encompass the progressive aphasias, have mutations in the tau gene that account for some of the phenotypic variations. Kalbfuss, B., S. A. Mabon, et al. (2001). "Correction of alternative splicing of tau in frontotemporal dementia and parkinsonism linked to chromosome 17." J Biol Chem 276(46): 42986-93. Mutations in the human tau gene cause frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17). One of the major disease mechanisms in FTDP-17 is the increased inclusion of tau exon 10 during pre-mRNA splicing. Here we show that modified oligonucleotides directed against the tau exon 10 splice junctions suppress inclusion of tau exon 10. The effect is mediated by the formation of a stable pre-mRNA-oligonucleotide hybrid, which blocks access of the splicing machinery to the pre-mRNA. Correction of tau splicing occurs in a tau minigene system and in endogenous tau RNA in neuronal pheochromocytoma cells and is specific to exon 10 of the tau gene. Antisense oligonucleotide-mediated exclusion of exon 10 has a physiological effect by increasing the ratio of protein lacking the microtubule-binding domain encoded by exon 10. As a consequence, the microtubule cytoskeleton becomes destabilized and cell morphology is altered. Our results demonstrate that alternative splicing defects of tau as found in FTDP-17 patients can be corrected by application of antisense oligonucleotides. These findings provide a tool to study specific tau isoforms in vivo and might lead to a novel therapeutic strategy for FTDP-17. Jauss, M., K. Herholz, et al. (2001). "Frontotemporal dementia: clinical, neuroimaging, and molecular biological findings in 6 patients." Eur Arch Psychiatry Clin Neurosci 251(5): 225-31. Establishing the diagnosis in patients with clinical signs and symptoms suggesting primary degenerative disease with marked frontal lobe involvement is difficult. Neuroimaging methods, in particular positron emission tomography (PET) with the tracer 18fluoro-2-deoxyglucose (FDG) and cerebrospinal fluid (CSF) examination of beta-amyloid and tau-protein levels may give additional information. We report five patients with clinical and radiological features of degenerative dementia with predominantly frontal involvement and one patient with primary progressive aphasia Diagnostic work-up included computed tomography (CT), magnetic resonance imaging (MRI), PET and tau-protein and beta-amyloid level determination in CSF. While neuropsychological performance varied among patients, CT and MRI demonstrated persistently frontal lobe involvement. PET revealed corresponding changes with frontal hypometabolism, but in addition, four patients (among them two with no corresponding temporal changes in CT or MRI) showed a decreased glucose uptake in the temporal cortices. CSF samples from five patients revealed elevated beta-amyloid 1-42 and tau levels in three and two patients, respectively. Reduced beta-amyloid 1-40 was found in two patients. We conclude that occurrence of clinical symptoms of frontotemporal dementia is accompanied by frontal hypometabolism regardless of additional clinical findings. The value of determination of beta-amyloid and tau protein levels remains to be determined. Iseki, E., T. Matsumura, et al. (2001). "Familial frontotemporal dementia and parkinsonism with a novel N296H mutation in exon 10 of the tau gene and a widespread tau accumulation in the glial cells." Acta Neuropathol (Berl) 102(3): 285-92. We report a 62-year-old Japanese man with familial frontotemporal dementia and a novel missense mutation (N296H) in exon 10 of the tau gene. The patient presented with frontal signs followed by temporal signs and parkinsonism. The brain showed localized frontotemporal lobe atrophy including the precentral gyrus and discoloration of the substantia nigra, and revealed severe neuronal loss with proliferation of tau-positive protoplasmic astroglia in the affected cerebral cortex, tau-positive coiled bodies and threads in the subcortical white matter, and tau-positive pretangle neurons in the subcortical and brain stem nuclei. There were no tau-positive neurofibrillary tangles, Pick bodies, tuft-shaped astrocytes or astrocytic plaques in the cerebral cortex. Immunoelectron microscopically, phosphorylated tau accumulated in both neurons and glial cells in different modalities, such as glial filaments in protoplasmic astroglia, straight tubules in coiled bodies, and free ribosomes in pretangle neurons. These findings suggest that tau proteins are not always assembled in abnormal filaments such as twisted ribbons, paired helical filaments and straight tubules in neurons and glial cells, which have been shown in previous cases with frontotemporal dementia and parkinsonism linked to chromosome 17. Immunoblotting of sarkosyl-insoluble tau exhibited accumulation of four-repeat tau isoforms in the brain. The N296H mutation may interfere with the ability of mutated tau to bind with microtubules and lead to tau aggregation. Further study is necessary to determine whether this mutation can account for the characteristic tau pathology of this case. Ingelson, M., S. F. Fabre, et al. (2001). "Increased risk for frontotemporal dementia through interaction between tau polymorphisms and apolipoprotein E epsilon4." Neuroreport 12(5): 905-9. The tau gene has an important role in frontotemporal dementia (FTD) as pathogenic mutations have been found in hereditary forms of the disease. Furthermore, a certain extended tau haplotype has been shown to increase the risk for progressive supranuclear palsy, corticobasal degeneration, Parkinson's disease and, in interaction with the apolipoprotein E (apoE) epsilon4 allele, Alzheimer's disease. By microsatellite analysis we investigated an intronic tau polymorphism, in linkage disequilibrium with the extended tau haplotype, in FTD patients (n = 36) and healthy controls (n = 39). No association between any of the tau alleles/genotypes and FTD was seen, but certain tau alleles and apoE epsilon4 interactively increased the risk of FTD (p = 0.006). We thus propose that this extended tau haplotype in combination with apoE epsilon4 is a genetic risk factor for FTD. Hutton, M. (2001). "Missense and splice site mutations in tau associated with FTDP-17: multiple pathogenic mechanisms." Neurology 56(11 Suppl 4): S21-5. Recent identification of mutations in the gene encoding the microtubule-associated protein tau in the inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has demonstrated that tau dysfunction can lead to neurodegeneration. At least nine missense mutations and one deletion mutation (DeltaK280) have been identified in exons 9 through 13 that encode the microtubule-binding domains of tau. In addition, five mutations have been found close to the 5' splice site of exon 10. The FTDP-17 missense and splice site mutations have multiple effects on the biology and function of tau. It is likely that these varied pathogenic mechanisms explain the wide range of clinical and neuropathologic features observed in the FTDP-17 tauopathies. Hutton, M., J. Lewis, et al. (2001). "Analysis of tauopathies with transgenic mice." Trends Mol Med 7(10): 467-70. Intraneuronal filamentous inclusions composed of the microtubule-associated protein tau are a feature of several neurodegenerative diseases (including Alzheimer's disease) known as tauopathies. A pivotal finding was the identification in 1998 of mutations in tau associated with frontotemporal dementia with parkinsonism linked to chromosome 17. This demonstrated that tau dysfunction is sufficient to cause neurodegeneration, and indicated that tau is likely to play a crucial role in the pathogenesis of other tauopathies. However, the mechanism by which tau filamentous lesions form and their role in neurodegeneration remains uncertain. Recent progress in the development of transgenic mouse models of human tauopathy is allowing these questions to be addressed. Hodges, J. R. and B. Miller (2001). "The classification, genetics and neuropathology of frontotemporal dementia. Introduction to the special topic papers: Part I." Neurocase 7(1): 31-5. Interest in the neuropsychology and neuropsychiatry of frontotemporal dementia (FTD) has escalated in the past decade, as evidenced by the accompanying 10 special topic papers from research groups in the UK, France, North America and Australia addressing a wide range of theoretical and clinical issues. The first part of this review deals with the confusing terminologies that have been used in the area and argues for the retention of the term FTD as the general clinical label, with further subcategorization into the three principal clinical syndromes seen at presentation: frontal variant FTD (often called dementia of frontal type), semantic dementia and progressive non-fluent aphasia. Each of these syndromes has a characteristic profile of presenting clinical features, but may be accompanied by any one of five types of non-Alzheimer pathological change. There have also been significant advances in the genetics of FTD with the identification of tau gene mutations on chromosome 17 in some familial cases. The remarkable story of the discovery of these, the tau gene mutations, is briefly described. Part II of this review (Hodges and Miller, 2001) sets the special issue papers within the context of advances in the neuropsychology of frontal variant FTD and semantic dementia. Ho, L., Z. Xiang, et al. (2001). "Gene expression profiling of the tau mutant (P301L) transgenic mouse brain." Neurosci Lett 310(1): 1-4. To provide a global analysis of the influence of Tau neuropathology at molecular level, we used cDNA arrays representing 8832 genes to determine the mRNA expression profile in transgenic mice expressing the most common frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) Tau mutation (P301L) (Nat. Genet. (2000) 402). Genes whose expression is associated with development of neurofibrillary tangles and neuron loss in P301L mice with motor and behavioral deficits were identified. The data suggest that a major mechanism underlying P301LTau neurodegeneration primarily involved altered expression of genes contributing to inhibition of apoptosis and intracellular transport. We propose that the expression of mutated P301L may lead to select altered expression of genes which may cause neurodegeneration in FTDP-17. Henderson, J. M., W. P. Gai, et al. (2001). "Parkinson's disease with late Pick's dementia." Mov Disord 16(2): 311-9. We report a case in which typical clinical features of idiopathic Parkinson's disease existed for seven years prior to the development of significant behavioral and cognitive changes and severe dementia. The patient presented with right-sided resting tremor, bradykinesia, and rigidity, which were highly responsive to levodopa. Serial neuropsychological evaluation revealed no evidence of dementia until late in the disease. The patient deteriorated rapidly eight years into the disease, requiring full care. She died 16 years after symptom onset and post-mortem neuropathological analysis revealed Lewy body Parkinson's disease and Pick