! slow, progressive, permanent loss of neurologic function.
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1 UBC
2 ! slow, progressive, permanent loss of neurologic function.! cause unknown.! sporadic, familial or inherited.! degeneration of specific brain region! clinical syndrome.! pathology: abnormal accumulation of disease specific protein.
3 disease protein deposits anatomy clinical Alzheimer s disease Parkinson s disease ALS!-amyloid (senile plaques) "-synuclein (Lewy bodies) TDP-43 (skeins) cerebral cortex brainstem & basal ganglia spinal cord dementia movement disorder weakness
4 disease protein deposits anatomy clinical Alzheimer s disease Parkinson s disease ALS!-amyloid (senile plaques) "-synuclein (Lewy bodies) TDP-43 (skeins) cerebral cortex brainstem & basal ganglia spinal cord dementia movement disorder weakness
5 disease gene biochemistry protein deposits early-onset fad!app # PS1 # PS2 "!-amyloid " senile plaques late-onset fad #ApoE
6 ! gradual, progressive, permanent, significant change in behaviour, personality and/or language.! memory less affected.! ~10% all dementia.! early onset ~55 years (40-70 years).! 25-50% inherited.! may also have parkinsonism and/or ALS.
7 ! selective atrophy of frontal & temporal lobes
8 frontal lobe (behaviour) temporal lobe (language)! selective atrophy of frontal & temporal lobes
9 Microscopic pathology:! Pick s disease! corticobasal degeneration (CBD)! progressive supranuclear palsy (PSP)! frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U)! FTD with ALS! atypical FTLD-U! neuronal intermediate filament inclusion disease! basophilic inclusion body disease! dementia lacking distinctive histopathology (DLDH)
10 Microscopic pathology: protein! Pick s disease! corticobasal degeneration (CBD) tau! progressive supranuclear palsy (PSP)! frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U)! FTD with ALS! atypical FTLD-U! neuronal intermediate filament inclusion disease! basophilic inclusion body disease! dementia lacking distinctive histopathology (DLDH) gene MAPT?
11 other proteins? genes? FTLD-U FTLD-tau # Pick s # CBD # PSP MAPT
12 Aims:! identify novel FTD genes and proteins.! define earliest clinical changes in FTLD-U disease.! establish clinical/genetic/pathological correlations.! develop animal model of FTLD-U.! find an effective treatment.
13 proband with autopsy proven FTLD-U consent family post mortem tissue blood samples family members! pathology! biochemistry! genetics! cell cultures! biomarkers! clinical studies neurological exam neuropsych testing neuroimaging biomarker studies clinical trials
14 pathology core Mackenzie UBC genetics core Mayo Clinic clinical core Feldman UBC
15 Aims:! identify novel FTD genes and proteins.! define earliest clinical changes in FTLD-U.! develop biomarkers for diagnosis, monitoring disease.! establish clinical/genetic/pathological correlations.! develop animal model of FTLD-U.! find an effective treatment.
16 2006;442: ! first PGRN mutation discovered in a UBC family.! additional PGRN mutations in 5 other UBC families.! PRGN = neuronal growth (survival) factor.! mutations! $ functional PGRN! neurodegeneration.! now 69 mutations in 230 families worldwide.! better diagnosis, genetic counselling, treatment of FTD.! role of PGRN in other neurodegenerative disease (AD)?
17 FTLD-U ALS! TDP-43 is the pathological protein in FTLD-U and ALS.! mutations in TDP-43 gene cause familial and sporadic ALS.! better diagnosis, genetic counselling, treatment of FTD and ALS.
18 ! mutations in FUS gene cause familial ALS.! FUS is also the pathological protein in most tau/tdp-negative FTLD.
19 Microscopic pathology:! Pick s disease! corticobasal degeneration (CBD)! progressive supranuclear palsy (PSP)! frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U)! FTD with ALS! atypical FTLD-U! neuronal intermediate filament inclusion disease! basophilic inclusion body disease! dementia lacking distinctive histopathology (DLDH) protein tau TDP-43 FUS none
20 FTLD- FUS FTLD-TDP #FTLD-U #FTD+ALS FTLD-tau #Pick s #CBD #PSP
21 FUS " FTLD- FUS CHMP2B " GRN VCP TARDBP " FTLD-TDP #FTLD-U #FTD+ALS FTLD-tau #Pick s #CBD #PSP MAPT? chrom 9p
22 L = bvftd R = ALS! autosomal dominant FTD and ALS.! pathology = FTLD-TDP and classical ALS.
23 *! linkage to chromosome 9p (max. 2 pt. LOD 3.01).! combine with other 9p families # candidate region of 3.7 Mb containing 10 genes (5 protein coding).! no mutations, altered splice patterns, altered gene dosage, gene expression.! same locus identified in GWAS of ALS and FTD.
24 ! GGGGCC repeat expansion in intron 1 of C9ORF72 causes familial FTD/ALS linked to 9p.! loss of one alternatively spliced transcript.! nuclear RNA foci in brain and spinal cord.! explains majority of families with combined ALS/FTD.! most common genetic cause of FTD and ALS.
25 FUS " FTLD- FUS CHMP2B " GRN VCP TARDBP " FTLD-TDP #FTLD-U #FTD+ALS FTLD-tau #Pick s #CBD #PSP MAPT " C9ORF72
26
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