Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a clinicopathological construct proposed to facilitate studying TDP-43 pathology in older individuals.
Our aim was to describe clinical and cognitive characteristics of LATE-NC without Alzheimer\'s disease neuropathologic change (ADNC) and Lewy body (LB) and to compare this with ADNC and primary age related tauopathy (PART).
In 364 autopsies of the oldest old of The 90+ Study, we identified those with LATE-NC without ADNC and LB. Control groups were participants with ADNC and PART.
Of 31% of participants who had LATE-NC, only 5 (1.4%) had LATE-NC without ADNC and LB, all of whom had tau. These participants had a gradual and progressive cognitive decline. Four (80%) had dementia at death, a rate that was higher than ADNC (50%) and PART (21.7%). Mean duration of cognitive impairment was twice as long in LATE-NC without ADNC and LB (6.2 years) compared to ADNC (2.9 years) and PART (3 years). LATE-NC without ADNC and LB group had a higher prevalence of syncope, depression, and extrapyramidal signs than the ADNC and PART groups.
Despite the high prevalence of LATE-NC, LATE-NC without ADNC and LB was rare in this large oldest-old cohort, highlighting the very high prevalence of multiple pathologic changes in the oldest old. Slowly progressive cognitive decline, ubiquitous memory impairment, history of syncope and depression, and extrapyramidal signs were prominent features among our LATE-NC without ADNC and LB group.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are distinct clinicopathological subtypes of frontotemporal lobar degeneration. They both have atypical parkinsonism, and they usually have distinct clinical features. The most common clinical presentation of PSP is Richardson syndrome, and the most common presentation of CBD is corticobasal syndrome. In this report, we describe a patient with a five-year history of Richardson syndrome and a family history of PSP in her mother and sister. A tau PET scan (18F-APN-1607) revealed low-to-moderate uptake in the substantia nigra, globus pallidus, thalamus and posterior cortical areas, including temporal, parietal and occipital cortices. Neuropathological evaluation revealed widespread neuronal and glial tau pathology in cortical and subcortical structures, including tufted astrocytes in the motor cortex, striatum and midbrain tegmentum. The subthalamic nucleus had mild-to-moderate neuronal loss with globose neurofibrillary tangles, consistent with PSP. On the other hand, there were also astrocytic plaques, a pathological hallmark of CBD, in the neocortex and striatum. To further characterize the mixed pathology, we applied two machine learning-based diagnostic pipelines. These models suggested diagnoses of PSP and CBD depending on the brain region - PSP in the motor cortex and superior frontal gyrus and CBD in caudate nucleus. Western blots of insoluble tau from motor cortex showed a banding pattern consistent with mixed features of PSP and CBD, whereas tau from the superior frontal gyrus showed a pattern consistent with CBD. Real-time quaking-induced conversion (RT-QuIC) using brain homogenates from the motor cortex and superior frontal gyrus showed ThT maxima consistent with PSP, while reaction kinetics were consistent with CBD. There were no pathogenic variants in MAPT with whole genome sequencing. We conclude that this patient had an unclassified tauopathy and features of both PSP and CBD. The different pathologies in specific brain regions suggests caution in diagnosis of tauopathies with limited sampling.

OBJECTIVE: To report a novel tauopathy in a patient with protracted course progressive supranuclear palsy (PC-PSP).
METHODS: This was a clinical follow-up, gene analysis, neuropathologic study.
RESULTS: A 73-year-old man presented with diplopia, slowness, shuffling gait, and falls. Neurologic examination revealed slowed saccades, restricted up-gaze, and mild parkinsonism. Three years after onset, he developed personality changes. Slowly progressive parkinsonism was associated with memory and executive deficits. MRI showed subtle bilateral hippocampal and midbrain tegmentum atrophy and hyperintensity in the brainstem tegmentum and white matter of the medial temporal lobe. The duration of illness was 11 years. There were no pathogenic mutations in 80 genes known to be involved in neurodegeneration, including MAPT (H1/H1 haplotype) and APOE (ε3/ε3 genotype). Neuropathology revealed PSP type pathology together with the pathology described in the novel limbic-predominant neuronal inclusion body 4-repeat tauopathy (LNT) correlating well with the signal alterations seen in MRI.
CONCLUSIONS: Our observation broadens the spectrum of tau pathology associated with PC-PSP and suggests that memory deficit and hippocampal atrophy may be suggestive of non-Alzheimer disease pathology, including LNT. Understanding the diverse range of tau morphologies may help explain phenotypic heterogeneity seen in PSP.

Although the right temporal variant frontotemporal dementia (rtvFTD) is characterised by distinct clinical and radiological features, its underlying histopathology remains elusive. Being considered a right-sided variant of semantic variant primary progressive aphasia (svPPA), TDP-43 type C pathology has been linked to the syndrome, but this has not been studied in detail in large cohorts. In this case report and systematic review, we report the autopsy results of five subjects diagnosed with rtvFTD from our cohort and 44 single rtvFTD subjects from the literature. Macroscopic pathological evaluation of the combined results revealed that rtvFTD demonstrated either a frontotemporal or temporal evolution, even if the degeneration started in the right temporal lobe initially. FTLD-TDP type C was the most common underlying pathology in rtvFTD, however, in 64% of rtvFTD, other underlying pathologies than FTLD-TDP type C were present, such as Tau-MAPT and FTLD-TDP type A and B. Additionally, accompanying motor neuron or corticospinal tract degeneration was observed in 28% of rtvFTD patients. Our results show that in contrast to the general assumption, rtvFTD might not be a pure FTLD-TDP type C disorder, unlike its left temporal counterpart svPPA. Large sample size pathological studies are warranted to understand the diverse pathologies of the right and left temporal variants of frontotemporal dementia.

暂无摘要。

We report autopsy results of a female patient who was confirmed pathologically as having corticobasal degeneration (CBD). This patient presented with progressive gait disturbance at the age of 66 years, and subsequently showed parkinsonism with a right-sided predominance and dementia. She was clinically diagnosed as having possible corticobasal syndrome without palatal myoclonus throughout the disease course. An autopsy at 72 years of age revealed that neuronal loss with gliosis was severe in the substantia nigra and the portion from hippocampal cornu ammonis (CA1) region to the parahippocampal gyrus, and mild-to-moderate in the basal ganglia, thalamus, red nucleus, dentate nucleus, and cerebral cortices, predominantly in the frontal lobe. Myelin pallor was observed in the pyramidal tract of the brainstem and central tegmental tract. Neurodegenerative or axonal degenerative findings were observed predominantly on the left side, except for the dentate nucleus, which was more affected on the right side. The inferior olivary nucleus exhibited hypertrophic degeneration predominantly on the left side. The topography of neurodegeneration was likely to correspond to the dentate nucleus and inferior olivary nucleus. Phosphorylated tau-immunoreactive pretangles, neurofibrillary tangles, coiled bodies, and threads were diffusely observed in the whole brain. The distribution of tau deposits was prominent in the deeper affected lesions of the dentate nucleus and inferior olivary nucleus. Inferior olivary hypertrophy is unusual in patients with CBD. It is highly possible that the neurodegeneration of the inferior olivary nucleus followed that of the dentate nucleus in our patient. Moreover, these results indicate not only the severity of neurodegenerative changes, but also that of tau deposition that could be related to the topography of the projections of the dentato-olivary pathway. Tau propagation and subsequent neurodegeneration along the fiber connections may have occurred. Our results support the possibility that progression of CBD lesions can be mediated by tau propagation.

Though distinct pathological entities, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) share multiple biochemical and genetic features suggesting overlapping pathophysiology. We report the case of a patient with an 18-year clinical course consistent with behavioral variant frontotemporal dementia. The neuropathological assessment revealed unclassifiable frontotemporal lobar degeneration with tau-immunoreactive inclusions sharing features of both CBD and PSP. Whole-genome sequencing revealed a unique combination of pleiotropic genetic risk variants associated with both PSP and CBD. These findings support the observation that CBD and PSP share genetic co-expression networks that influence neurodegenerative pathogenesis common to 4R tauopathies.

Anti-IgLON5 disease is a rare neurodegenerative tauopathy that displays heterogeneity in clinical spectrum, disease course, cerebrospinal fluid (CSF) findings, and variable response to immunotherapy. Sleep disorders, bulbar dysfunction, and gait abnormalities are common presenting symptoms, and conventional brain MRI scanning is often unrevealing.
To provide a comprehensive overview of the literature and to assess the frequency of symptoms, MRI findings, and treatment response in patients with IgLON5 autoimmunity in the serum and CSF or restricted to serum.
We examined a 65-year-old woman with bulbar-onset IgLON5 disease with serum-restricted antibodies, and we also performed a systematic review of all confirmed cases reported in the English literature.
We identified 93 patients, included our case. Clinical data were obtained in 58 subjects, in whom the most frequent symptoms were sleep-disordered breathing, dysphagia, parasomnias, dysarthria, limb or gait ataxia, stridor or vocal cord paresis, movement disorders, and postural instability. Distinct MRI alterations were identified in 12.5% of cases, as opposed to unspecific or unremarkable changes in the remaining patients. T2-hyperintense non-enhancing signal alterations involving the hypothalamus and the brainstem tegmentum were observed only in the present case. Inflammatory CSF was found in half of the cases and serum-restricted antibodies in 4 patients. Treatment with immunosuppressant or immunomodulatory drugs led to sustained clinical response in 19/52 patients.
Anti-IgLON5 autoimmunity should be considered in patients with sleep disorders, bulbar syndrome, autonomic involvement, and movement disorders, and high-field brain MRI can be of diagnostic help.

In the past decade, several groups have reported that microRNAs (miRNAs) can participate in the regulation of tau protein at different levels, including its expression, alternative splicing, phosphorylation, and aggregation. These observations are significant, since the abnormal regulation and deposition of tau is associated with nearly 30 neurodegenerative disorders. Interestingly, miRNA profiles go awry in tauopathies such as Alzheimer\'s disease, progressive supranuclear palsy, and frontotemporal dementia. Understanding the role and impact of miRNAs on tau biology could therefore provide important insights into disease risk, diagnostics, and perhaps therapeutics. In this Perspective article, we discuss recent advances in miRNA research related to tau. While proof-of-principle studies hold promise, physiological validation remains limited. To help fill this gap, we describe herein a pure tauopathy mouse model deficient for the miR-132/212 cluster. This miRNA family is strongly downregulated in human tauopathies and shown to regulate tau in vitro and in vivo. No significant differences in survival, motor deficits or body weight were observed in PS19 mice lacking miR-132/212. Age-specific effects were seen on tau expression and phosphorylation but not aggregation. Moreover, various miR-132/212 targets previously implicated in tau modulation were unaffected (GSK-3β, Foxo3a, Mapk1, p300) or, unexpectedly, reduced (Mapk3, Foxo1, p300, Calpain 2) in miR-132/212-deficient PS19 mice. These observations highlight the challenges of miRNA research in living models, and current limitations of transgenic tau mouse models lacking functional miRNA binding sites. Based on these findings, we finally recommend different strategies to better understand the role of miRNAs in tau physiology and pathology.