Citations

Abstract Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions (GCIs). Synucleinopathies can be divided into two major disease entities: Lewy body disease (LBD) and multiple system atrophy (MSA). Common clinical presentations of LBD are Parkinson's disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P). There are currently no disease-modifying therapies for the synucleinopathies, but elucidation of genetics and mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and GCI) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from LBD and MSA are distinct "strains" having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissues. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a review of classification and staging schemes for LBD. We also review evidence supporting the existence of distinct α-synuclein strains in LBD and MSA.

Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Our previous studies have shown that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in AD, and that the SERPINA5 protein binds to tau and co-localizes within neurofibrillary tangles. To determine if genetic variants in the SERPINA5 gene may be contributing to this phenotype, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. We observed one individual with a rare missense variant (rs140138746) in the SERPINA5 gene, resulting in an amino acid change (p.E228Q). We screened a further 1170 neuropathologically diagnosed AD cases and identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.002141 within our AD validation cohort, which was comparable to online genomic databases. Although not significant, SERPINA5 p.E228Q variant carriers were found to be younger at age of onset and age of death than non-carriers. SERPINA5 p.E228Q variant carriers had a longer disease duration than non-carriers, which approached significance. To further elucidate possible neuropathologic contributions of the SERPINA5 p.E228Q variant, we carried out descriptive neuropathologic burden analysis on a variant carrier that was matched to a non-carrier for age, sex, disease duration, Braak tangle stage, TDP-43 positive status, and who possessed an APOE ε4 risk allele. Interestingly, SERPINA5 burden was lower in the SERPINA5 p.E228Q carrier than the non-carrier in 9 corticolimbic brain regions studied, which exaggerated the tau:SERPINA5 immunohistochemical ratio. The SERPINA5 p.E228Q carrier was observed to have more severe neuronal loss in several brain regions compared to the non-carrier. Together, we cautiously interpret these findings to suggest that the SERPINA5 p.E228Q variant may stall tangle maturity and slow AD disease progression, thus prolonging disease duration in these individuals.

Abstract Aims This study aimed to develop a deep learning‐based model for differentiating tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD), based on tau‐immunostained digital slide images. Methods We trained the YOLOv3 object detection algorithm to detect five tau lesion types: neuronal inclusions, neuritic plaques, tufted astrocytes, astrocytic plaques and coiled bodies. We used 2522 digital slide images of CP13‐immunostained slides of the motor cortex from 10 cases each of AD, PSP and CBD for training. Data augmentation was performed to increase the size of the training dataset. We next constructed random forest classifiers using the quantitative burdens of each tau lesion from motor cortex, caudate nucleus and superior frontal gyrus, ascertained from the object detection model. We split 120 cases (32 AD, 36 PSP, 31 CBD and 21 PiD) into training (90 cases) and test (30 cases) sets to train random forest classifiers. Results The resultant random forest classifier achieved an average test score of 0.97, indicating that 29 out of 30 cases were correctly diagnosed. A validation study using hold‐out datasets of CP13‐ and AT8‐stained slides from 50 cases (10 AD, 17 PSP, 13 CBD and 10 PiD) showed >92% (without data augmentation) and >95% (with data augmentation) diagnostic accuracy in both CP13‐ and AT8‐stained slides. Conclusion Our diagnostic model trained with CP13 also works for AT8; therefore, our diagnostic tool can be potentially used by other investigators and may assist medical decision‐making in neuropathological diagnoses of tauopathies.

AbstractBackground and purposePerry disease (or Perry syndrome) is an autosomal dominant neurodegenerative disorder characterized by parkinsonism, neuropsychiatric symptoms, central hypoventilation, weight loss and distinct TDP‐43 pathology. It is caused by mutations of the DCTN1 gene encoding an essential component of axonal transport. The objectives were to provide the current state of knowledge on clinical, pathological and genetic aspects of Perry disease, as well as practical suggestions for the management of the disease.MethodsData on new patients from New Zealand, Poland and Colombia were collected, including autopsy report. Also all of the published papers since the original work by Perry in 1975 were gathered and analyzed.ResultsParkinsonism was symmetrical, progressed rapidly and was poorly responsive to L‐Dopa; nonetheless, a trial with high doses of L‐Dopa is warranted. Depression was severe, associated with suicidal ideations, and benefited from antidepressants and L‐Dopa. Respiratory symptoms were the leading cause of death, and artificial ventilation or a diaphragm pacemaker prolonged survival. Weight loss occurred in most patients and was of multifactorial etiology. Autonomic dysfunction was frequent but underdiagnosed. There was a clinical overlap with other neurodegenerative disorders. An autopsy showed distinctive pallidonigral degeneration with TDP‐43 pathology. Genetic testing provided evidence of a common founder for two families. There was striking phenotypic variability in DCTN1‐related disorders. It is hypothesized that oligogenic or polygenic inheritance is at play.ConclusionsPerry disease and other DCTN1‐related diseases are increasingly diagnosed worldwide. Relatively effective symptomatic treatments are available. Further studies are needed to pave the way toward curative/gene therapy.

Nuclear accumulation of CHMP7 leads to multiple cellular pathologies that can be mitigated via CHMP7 ASOs in familial and sporadic ALS iPSNs.

TAR DNA binding protein‐43 (TDP‐43)‐immunoreactive neuronal cytoplasmic inclusions (NCIs), characteristically associated with frontotemporal lobar degenerations (FTLD‐U and FTLD‐MND), have been found in the hippocampal dentate granule cells of about 20% of cases with advanced Alzheimer disease (AD). The extent and distribution of TDP‐43 pathology in brain regions other than hippocampus in AD is not known, especially in AD cases without hippocampal NCIs. Sections of hippocampus, amygdala, neocortex, and medulla from patients with clinical dementia and pathologic features of AD were analyzed for the presence of TDP‐43‐immunoreactive NCIs. 22 cases of advanced AD (Braak Stage V‐VI) without hippocampal NCIs and 23 cases of advanced AD with hippocampal NCIs were included. 6 hippocampal‐negative cases (27%) had TDP‐43 positive NCIs in the amygdala. All 23 cases of hippocampal‐positive cases had numerous TDP‐43 NCIs in the amygdala, with decreasing density of NCIs in the other brain regions. In summary, TDP‐43 immunoreactive NCIs are found predominantly in the medial temporal structures in advanced AD, and the amygdala appears to be the area most vulnerable.

Objective: To determine if subcortical, brainstem and cerebellar lesion pattern characteristics of the different types of tau‐negative frontotemporal lobar degeneration (FTLD) would be similar to neocortical and hippocampal patterns [Type 1 has neuronal cytoplasmic inclusions (NCI) and dystrophic neurites (DN), type 2 mainly DN, and type 3 mainly NCI (Mackenzie et al., 2006)]. Design/Methods: We analyzed 40 cases of tau‐negative FTLD from Mayo Clinic, Florida. For each case, 12 standardized sections covering 16 different brain regions or nuclei were sampled including neocortex, hippocampus, subcortical grey, brainstem and cerebellum. TDP‐43 immunohistochemistry was performed and abnormal immunoreactivity semiquantitated. Results: Thirty‐six cases were classified into one of the three types. For subcortical grey and brainstem regions, we did not see predominance of DN in type 2, and the density of NCI and DN were similar in type 3. Type 2 cases had significantly more NCI in basal ganglia compared to the other types (p<0.05). We found a trend that fine DN in hippocampal CA1 region was more frequent in type 1 compared to type 2 and 3 (p=0.07). A novel finding was that NCI were Pick body‐like in type 2 but granular‐like in type 3. Conclusion: This study extends the patterns of pathology previously described in the three variants of tau‐negative FTLD and shows how subcortical areas are affected by TDP‐43.

TAR DNA‐binding protein of 43 kDa (TDP‐43) is a nuclear protein involved in transcriptional repression and alternative splicing. It has been shown to be a component of ubiquitin‐positive, tau‐ and á‐synuclein‐negative inclusions in neuronal soma and nuclei as well as neurites of frontotemporal lobar degeneration (FTLD‐U) and in motor neurons of amyotrophic lateral sclerosis (ALS). Recently, it has been co‐localized with Lewy bodies in Lewy body disease (LBD). In this study we use immunogold electron microscopy to study the ultrastructural features of TDP‐43‐labeled structures. The results showed that in all FTLD‐U, ALS and LBD, TDP‐43 was localized to filaments coated with granular material. Both coated and uncoated regions of the filaments were labeled. In FTLD‐U a subset of neurites filled with densely packed filaments were also labeled. The filaments have a diameter of 10–17 nm. Neurofilament and glial filaments were not labeled by TDP‐43. The data suggests that TDP‐43 is a constituent protein in filamentous inclusions in neurodegenerative diseases. Supported by NIH grant AG17216.

Objective: To determine whether all cases of tau‐negative frontotemporal lobar degeneration (FTLD) show abnormal TDP‐43 immunoreactivity. Design/methods: The neuropathological database at Mayo Clinic, Florida, was queried to identify all cases of tau‐negative FTLD. Forty cases were identified that underwent analysis with TDP‐43 immunohistochemistry. Cases without abnormal TDP‐43 immunoreactivity were further analyzed with H&E, PAS and silver stains, and with immunohistochemistry for phosphorylated tau, alpha‐synuclein, ubiquitin, neurofilament, alpha‐internexin and p62. Results: Of the 40 cases, 3 did not show abnormal TDP‐43 immunoreactivity. Cases 1 and 3 had clinical features of behavioral variant FTD while case 2 had features of the corticobasal syndrome. Case 3 had a positive family history. Case 1 had a pathological diagnosis of dementia lacking distinctive histology (DLDH) and case 2 basophilic inclusion body disease. Case 3 had ubiquitin‐positive but TDP‐43 negative neuronal inclusions and dystrophic neurites. Conclusion: Not all cases of tau‐negative FTLD have abnormal TDP‐43 immunoreactivity; basophilic inclusion body disease and DLDH are rare examples that do not. Given the positive family history and histological findings in case 3, there likely exists a yet to be identified gene and protein associated with tau negative FTLD.