Jerry Brown

Chromosome 3 linked frontotemporal dementia (FTD-3)

Background: The authors have identified and studied a large kindred in which frontotemporal dementia (FTD) is inherited as an autosomal dominant trait. The trait has been mapped to the pericentromeric region of chromosome 3. Methods: The authors report on the clinical, neuroimaging, neuropsychological, and pathologic features in this unique pedigree collected during 17 years of study. Results: Twenty-two individuals in three generations have been affected; the age at onset varies between 46 and 65 years. The disease presents with a predominantly frontal lobe syndrome but there is also evidence for temporal and dominant parietal lobe dysfunction. Late in the illness individuals develop a florid motor syndrome with pyramidal and extrapyramidal features. Structural imaging reveals generalized cerebral atrophy; H215O-PET scanning in two individuals relatively early and late in the disease shows a striking global reduction in cerebral blood flow affecting all lobes. On macroscopic pathologic examination, there is generalized cerebral atrophy affecting the frontal lobes preferentially. Microscopically, there is neuronal loss and gliosis without specific histopathologic features. Conclusions: FTD-3 shares clinical and pathologic features with other forms of FTD and fulfills international consensus criteria for FTD. There is involvement of the parietal lobes clinically, radiologically, and pathologically in FTD-3 in contrast to some forms of FTD. This more diffuse involvement of the cerebral cortex leads to a distinctive, global pattern of reduced blood flow on PET scanning.

Clinical features of frontotemporal dementia due to the intronic tau 10(+16) mutation

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. MethodsRetrospective 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. ResultsThe 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.

Sequence analysis of tau in familial and sporadic progressive supranuclear palsy

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.

Cognitive impairment in the preclinical stage of dementia in FTD-3 CHMP2B mutation carriers: a longitudinal prospective study

Objective and methods A longitudinal study spanning over 8 years and including 17 asymptomatic individuals with CHMP2B mutations was conducted to assess the earliest neuropsychological changes in autosomal dominant neurodegenerative disease frontotemporal dementia (FTD) linked to chromosome 3 (FTD-3). Subjects were assessed with neuropsychological tests in 2002, 2005 and 2010. Results Cross-sectional analyses showed that the mutation carriers scored lower on tests of psychomotor speed, working memory, executive functions and verbal memory than a control group consisting of not-at-risk family members and spouses. Longitudinal analyses showed a gradual decline in psychomotor speed, working memory capacity and global executive measures in the group of non-demented mutation carriers that was not found in the control group. In contrast, there were no significant group differences in domain scores on memory or visuospatial functions. On an individual level the cognitive changes over time varied considerably. Conclusion Subjects with CHMP2B mutation show cognitive changes dominated by executive dysfunctions, years before they fulfil diagnostic criteria of FTD. However, there is great heterogeneity in the individual cognitive trajectories.

Frontotemporal dementia linked to chromosome 3

A large pedigree with autosomal dominant frontotemporal dementia has been identified. Positional cloning has linked the disease gene to the pericentromeric region of chromosome 3. Clinical, neuropsychological, imaging, pathological and molecular genetic data are presented. The genetic mutation responsible for the disease has not been identified.

CHANGES IN CEREBRAL GLUCOSE METABOLISM IN EARLY SYMPTOMATIC FRONTOTEMPORAL DEMENTIA LINKED TO CHROMOSOME 3 (FTD-3)

Background: Frontotemporal dementia linked to chromosome 3 (FTD-3) is a rare autosomal dominantly inherited neurodegenerative disease first described in a Danish family where it is caused by a truncating mutation in CHMP2B (1). The disease is characterized by insidious and progressive changes in personality, behavior and cognition (2). The CHMP2B protein is a part of the ESCRTIII complex necessary for endosomal trafficking and protein degradation (1,3). The study assesses regional cerebral glucose metabolism in early symptomatic CHMP2B-mutation carriers using 18Fflourodeoxyglucose (FDG) and positron emission tomography (PET). Methods: Three CHMP2B mutation carriers were FDG-PET scanned for 10 minutes on a Siemens Biograph 40 PET/CT scanner, 40 minutes after injection of 200 MBq of FDG. Images were transformed into a standard stereotactic space and compared to a database of healthy age matched subjects (Neurostat (4)). Results: Three early symptomatic mutation carriers all showed abnormal cerebral glucose metabolism. Patient A (58 years, male): Showed moderately reduced activity bilaterally in the inferior parietal and posterior temporal lobes as well as around fissura interhemispherica. Frontal lobes, subcortical structures and cerebellum were unaffected. The pattern resembles an Alzheimer’s profile more than FTD. Patient B (69 years, male): Showed extensive metabolic reductions on frontal, temporal and parietal cortices resembling both FTD and AD. Basal ganglia and cerebellum were unaffected. Patient C (59 years, male): Showed mild to moderate metabolic reductions bilateral in the entire frontal cortex, anterior parts of the temporal and parietal cortex as well as basal ganglia resembling FTD. Conclusions: Decreased cerebral glucose metabolism is present in early symptomatic FTD-3. The pattern of reduced metabolism is very variable ranging from a pattern resembling classical FTD to a more Alzheimer like pattern. Though the genetic background is identical, functional changes differ considerably, presumably due to other genetic and environmental factors. Atypical metabolic patterns do not exclude FTD. References: [1] Nature Genetics 2005;37:806-8. [2] Neurology 2002;59:1585-94. [3] Biochem Soc Trans. 2009;37:208-12. [4] J Nucl Med 1995;36:1238.

Differential Diagnosis and Treatment of Movement Disorders

Differential Diagnosis and Treatment of Movement Disorders . (Book and Video Set). Edited by eduardo tolosa, william c koller, andoscar s gershanik. (£90.00). Published by Heinemann, Oxford, 1998. ISBN 0-7506-9971-X. First impressions count, so it is important for a publisher to choose the right time to send a book to be reviewed. Unfortunately Butterworth Heinemann’s timing for this book was awry. This volume arrived on my desk at the same time as I was struggling to improve a patient’s primary orthostatic tremor in time for her daughter’s wedding in Australia. I was therefore disconcerted when I could find no reference …