Citations

Abstract Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a complex heterogeneous neurodegenerative disorder for which mechanisms are poorly understood. To explore transcriptional changes underlying FTLD-TDP, we performed RNA-sequencing on 66 genetically unexplained FTLD-TDP patients, 24 FTLD-TDP patients with GRN mutations and 24 control participants. Using principal component analysis, hierarchical clustering, differential expression and coexpression network analyses, we showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that is independent of GRN loss-of-function. After combining both groups, differential expression as compared to the control group and coexpression analyses revealed alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. Deconvolution of the data highlighted strong cellular alterations that were similar in FTLD-TDP-A and GRN mutation carriers with NSF as a potentially important player in both groups. We propose several potentially druggable pathways such as the GABAergic, GDNF and sphingolipid pathways. Our findings underline new disease mechanisms and strongly suggest that affected pathways in GRN mutation carriers extend beyond GRN and contribute to genetically unexplained forms of FTLD-TDP-A.

R47H- TREM2 mutation enhances AKT signaling in human AD microglia and mediates proinflammatory and synaptic toxicity in a tauopathy mouse model.

Abstract Aims Accumulating evidence suggests that patients with frontotemporal lobar degeneration (FTLD) can have pathologic accumulation of multiple proteins, including tau and TDP‐43. This study aimed to determine the frequency and characteristics of concurrent tau pathology in FTLD with TDP‐43 pathology (FTLD‐TDP). Methods The study included 146 autopsy‐confirmed cases of FTLD‐TDP and 55 cases of FTLD‐TDP with motor neuron disease (FTLD‐MND). Sections from the basal forebrain were screened for tau pathology with phosphorylated‐tau immunohistochemistry. For cases with tau pathology on the screening section, additional brain sections were studied to establish a diagnosis. Genetic analysis of C9orf72 , GRN and MAPT was performed on select cases. Results We found 72 cases (36%) with primary age‐related tauopathy (PART), 85 (42%) with ageing‐related tau astrogliopathy (ARTAG), 45 (22%) with argyrophilic grain disease (AGD) and 2 cases (1%) with corticobasal degeneration (CBD). Patients with ARTAG or AGD were significantly older than those without these comorbidities. One of the patients with FTLD‐TDP and CBD had C9orf72 mutation and relatively mild tau pathology, consistent with incidental CBD. Conclusion The coexistence of TDP‐43 and tau pathologies was relatively common, particularly PART and ARTAG. Although rare, patients with FTLD can have multiple neurodegenerative proteinopathies. The absence of TDP‐43‐positive astrocytic plaques may suggest that CBD and FTLD‐TDP were independent disease processes in the two patients with both tau and TDP‐43 pathologies. It remains to be determined if mixed cases represent a unique disease process or two concurrent disease processes in an individual.

AbstractIntroductionWe examined the temporal sequence of the core features in probable dementia with Lewy bodies (DLB).MethodsIn 488 patients with probable DLB, the onset of each core feature and time to diagnosis was determined for men and women, and a pathologic subgroup (n = 209).ResultsREM sleep behavior disorder (RBD) developed before the other core features in men and women. Men were more likely to have RBD and were diagnosed with probable DLB earlier than women. Visual hallucinations developed after the other core features in men, but in women, they appeared earlier and concurrently with fluctuations and parkinsonism. Women were older and more cognitively impaired at first visit, were less likely to have RBD, more likely to be diagnosed with probable DLB later than men, and more likely to have neocortical tangles.DiscussionAn earlier latency to probable DLB was associated with men, RBD, and Lewy body disease without neocortical tangles.

TSC1/hamartin haploinsufficiency increases risk for tauopathy by promoting tau acetylation and accumulation.

ABSTRACTBackgroundProgressive supranuclear palsy (PSP) may present as a speech/language disorder (PSP‐SL).ObjectiveWe assessed pathological correlates of patients with PSP‐SL who retained the suggestive of PSP‐SL (s.o. PSP‐SL) diagnosis versus those who progressed to possible/probable (poss./prob.) PSP.MethodsThirty‐four prospectively recruited patient with s.o. PSP‐SL completed comprehensive speech/language and neurological assessments longitudinally, died, and underwent autopsy.ResultsTwelve patients (35%) evolved to poss./prob PSP, while 22 (65%) remained as s.o. PSP‐SL. Pathological diagnoses differed across the groups (P = 0.025). Patients with s.o. PSP‐SL had four different neuropathologies (corticobasal degeneration [59%], PSP [13%], Pick's disease [14%], and frontotemporal lobar degeneration with TDP‐43 [14%]), while all patients with poss./prob. PSP had a 4R‐tauopathy (PSP [67%] and corticobasal degeneration [33%]). Development of poss./prob. PSP increased the chance of having PSP pathology by 2.38 times.ConclusionsPSP‐SL is associated with heterogenous pathologies. Evolution of PSP‐SL into poss./prob. PSP is more predictive of underlying PSP pathology than s.o. PSP‐SL. © 2021 International Parkinson and Movement Disorder Society

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.