P1‐433: GRAY MATTER DEFICITS IN SYMPTOMATIC AND PRESYMPTOMATIC MAPT MUTATION CARRIERS
Stephanie A. ChuTaru FlaganLize C. JiskootWilliam W. SeeleyJanne M. PapmaJersey DengHoward J. RosenBradley F. BoeveAdam L. BoxerHilary W. HeuerDanielle BrushaberMurray GrossmanGiovanni CoppolaBrad C. DickersonYvette BordelonChristina DheelKelley FaberHoward FeldmanJulie A. FieldsJamie FongTatiana M. ForoudLeah K. ForsbergRalitza H. GavrilovaNupur GhoshalNeill R. Graff‐RadfordGing‐Yuek Robin HsiungEdward D. HueyDavid J. IrwinKejal KantarciDaniel KauferAnna M. KarydasAlex KleinDavid S. KnopmanJohn KornakJoel H. KramerWalter A. KukullMaria I. LapidSamara LaxinetaIrene LitvanIan R. MackenzieMario F. MendezBruce L. MillerChiadi U. OnyikeAlex PantelyatMadeline PotterRosa RademakersErik D. RobersonMaria Carmela TartagliaNadine TattonArthur W. TogaAshley VetorSandra WeıntraubBonnie WongZbigniew K. WszołekJohn C. van SwietenSuzee E. Lee
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Abstract:
MAPT mutations typically cause behavioral variant frontotemporal dementia (bvFTD) with or without parkinsonism. Previous studies have shown that symptomatic MAPT carriers show atrophy in frontotemporal cortex, with mesial temporal lobes predominantly affected (Rohrer et al., 2010; Whitwell et al., 2009). For presymptomatic MAPT carriers, studies have been mixed, with studies showing either no apparent gray matter deficits, or deficits in region of interest parcellations (Dopper et al., 2014; Rohrer et al., 2015). We studied a large cohort of presymptomatic and symptomatic MAPT carriers using a voxelwise approach to further refine neuroanatomical deficits and to examine relationships between gray matter and age. We studied 16 symptomatic MAPT carriers (age 55.3 ± 9.0, 10 female), 45 presymptomatic MAPT carriers (age 39.7 ± 10.5, 24 female), and 109 healthy controls (age 48.8 ± 13.3, 56 female) who had structural brain MRI scans. Symptomatic MAPT carriers included 15 with behavioral variant frontotemporal dementia (bvFTD), among which two had comorbid progressive supranuclear palsy syndrome, and one had Parkinson's disease. One carrier had an amnestic Alzheimer's-like syndrome. Voxel-based morphometry was performed on T1 images using SPM12. We created smoothed gray matter probability maps to generate voxelwise gray matter w-maps, a method of quantifying the difference between an individual carrier's expected and actual gray matter values, to further examine structural deficits (Ossenkoppele et al., 2015). Symptomatic MAPT carriers had bilateral gray matter atrophy in frontal cortex, insula, striatum with mesial temporal atrophy present in all subjects. Presymptomatic MAPT carriers showed an anatomically similar yet milder pattern of gray matter deficits, focused within bilateral hippocampus, amygdala and lateral temporal cortices. Within these regions, deficits emerged in a subset of presymptomatic MAPT carriers as early as their late thirties, while the remaining presymptomatic carriers showed normal gray matter volumes throughout the entire age span studied. Our findings suggest that early mesial temporal gray matter deficits are detectable in a subset of presymptomatic MAPT carriers, and that these same regions were atrophied in all symptomatic MAPT carriers studied. Longitudinal studies will elucidate whether these gray matter deficits represent early neurodegeneration, neurodevelopmental deficits, or both.Pons
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The neuropathological background of parkinsonism includes various neurodegenerative disorders, including Lewy body disease (LBD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). The pathological diagnostic procedure begins by assessing the macroscopic findings to evaluate the degenerative lesions in brains with the naked eye. Usually, degenerative lesions show variable atrophy and brownish discoloration in accordance with disease-specific profiles. These macroscopic appearances support neuropathologists in identifying the relevant regions for microscopic examination. The neuropathological diagnosis of parkinsonism is based on regional distribution and fundamental proteinopathies in neurons and glia cells. LBD and MSA are synucleinopathies, and PSP and CBD are tauopathies. Among them, glial-predominant proteinopathy (MSA, PSP, and CBD) may play a significant role in volume reduction. Therefore, macroscopic inspection provides the appropriate direction for assessment. The disease duration, the severity of lesions, and mixed pathologies make the validation of macroscopic observations more complicated. In this review, we outline the macroscopic diagnostic clues in LBD, MSA, PSP, and CBD that could help with pathological refinement.
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Abstract The mutations on microtubule associated protein tau ( MAPT ) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration, and rarely with amyotrophic lateral sclerosis (ALS). FTD-parkinsonism and FTD-ALS are clinical overlaps included in the spectrum of MAPT mutation’s phenotypes. The mutations on MAPT gene cause the dysfunction of tau protein determining its accumulation in neurofibrillary tangles. Recent data describe frequently the co-occurrence of the aggregation of tau protein and α-synuclein in patients with parkinsonism and Parkinson disease (PD), suggesting an interaction of the two proteins in determining neurodegenerative process. The sporadic description of PD-ALS clinical complex, known as Brait–Fahn–Schwarz disease, supports the hypothesis of common neuropathological pathways between different disorders. Here we report the case of a 54-year-old Italian woman with idiopathic PD later complicated by ALS carrying a novel MAPT variant (Pro494Leu). The variant is characterized by an amino acid substitution and is classified as damaging for MAPT functions. The case supports the hypothesis of tau dysfunction as the basis of multiple neurodegenerative disorders.
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Mutations in the tau gene linked to chromosome 17 cause frontotemporal dementia and parkinsonism (FTDP-17).This study presents 3 Japanese familial cases diagnosed with N279K tau gene mutation, including 1 autopsy-confirmed case.We compared the clinical presentations, cognitive functions, and images between the 3 familial cases diagnosed with N279K mutation.All 3 patients presented symptoms in their early 40s. One patient showed severe cognitive dysfunction and died in his sixth year after onset. The remaining 2 cases presented with parkinsonism-dominant clinical features. Among the 2 cases, 1 presented the characteristic symptoms of progressive supranuclear palsy. The pathological features of the dementia-dominant case showed frontal and temporal lobe-dominant neuronal loss and gliosis. Tau-positive neuronal and glial inclusions were found throughout. Further, tufted astrocytes and globose tangles were present whereas there were no Pick bodies and astrocytic plaques, compatible with pathology-confirmed frontotemporal lobar degeneration (FTLD) -tau subtypes.Patients with FTDP-17 can be classified into the following 2 major groups: dementia and parkinsonism-plus predominant phenotypes. Among our 3 cases, 1 showed dementia predominance whereas the other 2 showed parkinsonism predominance. Mutations in the microtubule-associated protein tau (MAPT) present with several pathological features. Clinically, our case presented a behavioral variant frontotemporal dementia (bvFTD). However, morphologically, the observed glial and neuronal pathology met the criteria for progressive supranuclear palsy (PSP). This study highlights the clinical heterogeneity within and between families with same MAPT mutation. Few pathologically confirmed PSP cases have been reported with mutations in MAPT.
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