Frontotemporal dementias

Frontotemporal dementia with parkinsonism linked to chromosome 17 660... 

Human Genome Variation Society. Alzheimer Disease Frontotemporal Dementia Mutation Database. Available on line at www.molgen.ua.ac.be/ADMutations/. 

McKhann, G. M., Albert, M. S., Grossman, M. et al. Clinical and pathological diagnosis of frontotemporal dementia report of the Work Group on Frontotemporal Dementia and Pick s Disease. Arch. Neurol. 58 1803-1809, 2001. 

Hosier, B. A., Siddique, T., Sapp, P. C. etal. Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. J.A.M.A. 284 1664-1669,2000. 

On the one hand, the biochemical study of the neuro-pathological lesions led to the identification of their main molecular components. On the other hand, the study of rare, familial forms of Alzheimer s disease, frontotemporal dementia and Parkinson s disease led to the identification of gene defects that cause inherited variants of the different diseases. Remarkably, in these cases, the defective genes have been found to encode or increase the expression of the main components of the neuropathological lesions. It has therefore been established that the basis of the familial forms of these diseases is a toxic property conferred by mutations in the proteins that make up the filamentous lesions. A corollary of this insight is that a similar toxic property may also underlie the much more common, sporadic forms of the diseases. 

Lewy bodies, neurofibrillary lesions and Pick bodies are intracellular filamentous inclusions. It is now well established that Lewy bodies are made of the protein a-synuclein and both neurofibrillary lesions and Pick bodies of the microtubule-associated protein tau. Mutations in the a-synuclein gene or an increase in its copy number cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. Mutations in the tau gene cause a familial form of frontotemporal dementia. Here we review the evidence implicating a-synuclein and tau in these inherited and a number of sporadic neurodegenerative diseases. Collectively, a-synucleinopathies and tauopathies account for the vast majority of cases of late-onset neurodegenerative disease (Tables 45-1 and 45-2). 

Frontotemporal dementias occur as familial forms and, more commonly, as sporadic diseases. They are characterized by a remarkably circumscribed atrophy of the frontal and temporal lobes of the cerebral cortex, often with additional, subcortical changes. In 1994, an autosomal-dominantly inherited form of frontotemporal dementia with parkinsonism was linked to chromosome 17q21.2. Subsequently, other forms of frontotemporal dementia were linked to this region, resulting in the denomination frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) for this class of disease. All cases of FTDP-17 have so far shown a filamentous pathology made of hyperphosphorylated tau protein (Fig. 45-7). In 1998, mutations in tau were reported in FTDP-17 patients [29-31]. Since then, more than 30 different mutations have been described in over 80 families with FTDP-17 (Fig. 45-6). 

Frontotemporal dementia involves an early and primary degenerative process of frontal and/or temporal cortex. Several disorders fall under this rubric, such as Pick s disease and the dementia associated with amyotrophic lateral sclerosis (ALS). ALS is a degenerative disease of upper motor neurons that is sometimes accompanied by a frontal lobe dementia (Vercelletto et al. 1999 Abe et al. 1997). ALS has been associated with mutations in the free radical scavenging enzyme superoxide dismutase 1 (Price et al. 1997). Pick s disease is associated histologically with a loss of neurons and cytoplasmic Pick bodies in surviving neurons. 

Frontotemporal dementias are characterized by gross structural changes in the frontal and anterior temporal lobes, metabolic disturbances, and involvement of certain subcortical structures as well (Ishii et al. 1998). Whereas in Alzheimer s disease the early cognitive disturbances are in memory, in frontotemporal dementias the early manifestations are in executive and behavioral function (Pfeffer et al. 1999 Varma et al. 1999). This relative cognitive distinction persists throughout the course of the two disorders (Pachana et al. 1996). Disinhibition and disorganization are common, and psychotic symptoms may be prominent in frontotemporal dementia. 

Ishii K, Sakamoto S, Sasaki M, Kitagaki H, Yamaji S, Hashimoto M, Imamura T, Shimomura T, Hirono N, Mori E. (1998). Cerebral glucose metabolism in patients with frontotemporal dementia. J Nud Med. 39(11) 1875-78. 

Pachana NA, Boone KB, Miiier BL, Cummings JL, Berman N. (1996). Comparison of neuropsychoiogicai functioning in Aizheimer s disease and frontotemporal dementia. J Int Neuropsychol Soc. 2(6) 505-10. 

Varma AR, Snowden JS, Lloyd JJ, Talbot PR, Mann DM, Neary D. (1999). Evaluation of the NINCDS-ADRDA criteria in the differentiation of Alzheimer s disease and frontotemporal dementia. J Neurol Neurosurg Psychiatry. 66(2) 184-88. 

Nilsson CL, Brinkmalm A, Minthon L, Blennow K, Ekman R. 2001. Processing of neuropeptide Y, galanin, and somatostatin in the cerebrospinal fluid of patients with Alzheimer s disease and frontotemporal dementia. Peptides 22 2105. 

Verpillat, P., Camuzat, A., Hannequin, D., et al. (2002) Association between the extended tau haplotype and frontotemporal dementia. Arch. Neurol., 59, 935-839. 

Van Swieten, J.C., Rosso, S.M., van Herpen, E., Kamphorst, W., Ravid, R., Heutink, P. (2004) Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17. Dement. Geriatr. Cogn. Disord., 17, 261-264. 

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