Baker, Matthew C

AbstractObjectiveTo identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD‐GRN) and chromosome 9 open reading frame 72 (FTLD‐C9ORF72).MethodsWe performed quantitative neuropathologic comparison of 17 FTLD‐C9ORF72 and 15 FTLD‐GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD‐GRN and 13 FTLD‐C9ORF72). Neuropathological analyses were limited to TDP‐43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD‐GRN and 11 FTLD‐C9ORF72). FTLD cases were also compared to age– and sex–matched normal controls. Immunohistochemistry was performed for pTDP‐43, IBA‐1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information.ResultsFTLD‐GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD‐C9ORF72 had greater hippocampal tau pathology and more TDP‐43 neuronal cytoplasmic inclusions. FTLD‐GRN had more neocortical microvacuolation, as well as more IBA‐1–positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD‐GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD‐GRN and FTLD‐C9ORF72 differed from controls.InterpretationOur findings underscore differences in microglial response in FTLD‐C9ORF72 and FTLD‐GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD‐GRN and FTLD‐C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.

Four patients with primary progressive aphasia displayed a greater deficit in understanding words they heard than words they read, and a further deficiency in naming objects orally rather than in writing. All four had frontotemporal lobar degeneration-transactive response DNA binding protein Type A neuropathology, three determined postmortem and one surmised on the basis of granulin gene (GRN) mutation. These features of language impairment are not characteristic of any currently recognized primary progressive aphasia variant. They can be operationalized as manifestations of dysfunction centered on a putative auditory word-form area located in the superior temporal gyrus of the left hemisphere. The small size of our sample makes the conclusions related to underlying pathology and auditory word-form area dysfunction tentative. Nonetheless, a deeper assessment of such patients may clarify the nature of pathways that link modality-specific word-form information to the associations that mediate their recognition as concepts. From a practical point of view, the identification of these features in patients with primary progressive aphasia should help in the design of therapeutic interventions where written communication modalities are promoted to circumvent some of the oral communication deficits.

Abstract Background Cognitive impairment is one of the core features of progressive supranuclear palsy. This study aimed to clarify the profile of cognitive impairment and its underlying pathology in progressive supranuclear palsy. Methods We retrospectively reviewed medical records to evaluate the pattern and severity of cognitive impairment in 121 autopsy‐confirmed progressive supranuclear palsy patients. A subset of 37 patients underwent neuropsychological evaluation as part of their clinical workup. The burden of progressive supranuclear palsy‐related tau pathology (neurofibrillary tangles/pretangles, coiled bodies, tufted astrocytes, and threads) was semiquantitatively scored in 20 vulnerable brain regions. Concurrent pathologies potentially associated with cognitive impairment, such as Alzheimer's‐type pathology, were also assessed. To evaluate possible genetic risk factors for cognitive impairment, genetic analysis for APOE and MAPT was performed. Results Ninety patients (74%) had documented cognitive impairment based on neurologic evaluation. In a subgroup with neuropsychological testing (n = 37), executive functioning was the most severely impaired cognitive domain. A global cognitive impairment index (Spearman's rho, −0.49; P = 0.005) and executive functioning were negatively correlated with total tau burden (Spearman's rho, −0.51; P = 0.003), but not correlated with the Alzheimer's‐type pathology. APOE ɛ4 carriers had more severe amyloid pathology, but total tau burden and a global cognitive impairment index did not differ from APOE ɛ4 noncarriers. Conclusion Cognitive impairment in progressive supranuclear palsy, most notably executive dysfunction, is associated with severity of progressive supranuclear palsy‐related tau pathology. © 2017 International Parkinson and Movement Disorder Society

AbstractMutations in microtubule‐associated protein tau gene (MAPT) cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP‐17). Here, we describe a patient with FTDP‐17 and a novel missense mutation in exon 13 of MAPT, p.E372G. We compare clinicopathologic features of this patient to two previously unreported patients with another exon 13 mutation, p.G389R. The patient with the p.E372G mutation was a 40‐year‐old man with behavioral variant frontotemporal dementia (bvFTD), who subsequently developed agrammatic speech and parkinsonism. One of the FTDP‐17 patients with p.G389R mutation presented at age 24 with agrammatic variant of primary progressive aphasia, and subsequently behavioral dysfunction. The other presented at age 53 with bvFTD, followed by agrammatic speech and corticobasal syndrome. Neuropathologic features of FTDP‐17 due to p.E372G were similar to those of p.G389R, including tau‐immunoreactive Pick body‐like neuronal inclusions and swollen, tapering thread‐like processes in white matter immunoreactive for 3‐repeat and 4‐repeat tau. Biochemical analysis of insoluble tau showed similar isoform compositions in p.E372G and p.G389R. Functional studies of the p.E372G mutation showed marked increase in tau filament formation and its reduced ability to promote microtubule assembly. Together these findings indicate that p.E372G is a pathogenic MAPT mutation that causes FTDP‐17 similar to p.G389R.