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We investigated clinicopathologically the pyramidal signs, including spasticity, hyperreflexia, and Babinski’s sign, and the involvement of the pyramidal tract and primary motor cortex, in seven Japanese autopsy cases of multiple system atrophy (MSA). Pyramidal signs were observed in six (86%) of the seven autopsy cases. Hyperreflexia and Babinski’s sign were each evident in five patients, but spasticity was observed in only one patient. Loss of Betz cells and presence of glial cytoplasmic inclusions in the primary motor cortex were noticed in all seven cases. Astrocytosis in the fifth layer of the primary motor cortex was noticed in five cases, but its presence was not related to the duration of the disease. Involvement of the pyramidal tract in the spinal cord, particularly of the small myelinated fibers, was observed in all seven cases, but no involvement of the pyramidal tract in the midbrain was evident in any of the six cases in which this structure was examined. In MSA, pyramidal signs were shown to be present more frequently than believed before, and the clinicopathological correlation between pyramidal signs and involvement of the pyramidal tract was obvious. Constant involvement of Betz cells in MSA has not been reported. Our clinicopathological findings may also make a contribution to the understanding of the clinicopathological hallmarks of MSA.

An extensive laminar spongiosis was found in the outer part of the dentate gyrus in an 84-year-old patient. An old cavitary infarct in the parahippocampal gyrus disconnected the dentate gyrus from the entorhinal area. This finding prompted us to seek laminar spongiosis in Alzheimer’s disease, where the neuronal loss in the entorhinal cortex might be severe. The dentate gyrus was systematically examined in a series of prospectively assessed cases either intellectually normal or affected by mental impairment of graded severity. Laminar spongiosis was present in the most severely affected patients. The neuritic crown of the senile plaques seen in the laminar band of spongiosis contained only a few tau- and Bodian-positive fibers, a sign that was taken as evidence of “plaque denervation”. By contrast, deposits of Aβ peptide remained abundant but lacked a dense core. These data suggest that dendritic and axonal processes are intermingled in the senile plaque and that the amyloid core is at least partially dependent on the presence of the axonal component.

This report deals with an ultrastructural investigation of the synapses of anterior horn neurons in the lumbar spinal cords of five patients with amyotrophic lateral sclerosis (ALS) who had mild neuronal depletion. Specimens from five age-matched, neurologically normal individuals served as controls. In each instance, the autopsy was performed within 3 h after death. A statistically significant decrease in cell body area, number of synapses and total synaptic length was found in the normal-appearing neurons of the ALS patients. The alterations were more pronounced in neurons with central chromatolysis. However, despite an approximately 20% reduction in the number of synapses, the length of the active synaptic zone of the normal-appearing neurons in the ALS patients was not diminished. This observation may be accounted for by a plasticity to the loss of synapses which maintained the active zone of the remaining synapses to increase synaptic efficiency. It is suggested that when the plasticity of the active zone reaches its limit, the continuing loss of synapses may lead to functional impairment. The capacity of the active synaptic zone to respond to progressive denervation of the anterior horn neurons may preserve motor function or slow the development of motor deficits in the early stage of degeneration of the lower motor neurons.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease mainly affecting upper and lower motoneurons. Several functionally heterogeneous genes have been associated with the familial form of this disorder (fALS), depicting an extremely complex pathogenic landscape. This heterogeneity has limited the identification of an effective therapy, and this bleak prognosis will only improve with a greater understanding of convergent disease mechanisms. Recent evidence from human post-mortem material and diverse model systems has highlighted the synapse as a crucial structure actively involved in disease progression, suggesting that synaptic aberrations might represent a shared pathological feature across the ALS spectrum. To test this hypothesis, we performed the first comprehensive analysis of the synaptic proteome from post-mortem spinal cord and human iPSC-derived motoneurons carrying mutations in the major ALS genes. This integrated approach highlighted perturbations in the molecular machinery controlling vesicle release as a shared pathomechanism in ALS. Mechanistically, phosphoproteomic analysis linked the presynaptic vesicular phenotype to an accumulation of cytotoxic protein aggregates and to the pro-apoptotic activation of the transcription factor c-Jun, providing detailed insights into the shared pathobiochemistry in ALS. Notably, sub-chronic treatment of our iPSC-derived motoneurons with the fatty acid docosahexaenoic acid exerted a neuroprotective effect by efficiently rescuing the alterations revealed by our multidisciplinary approach. Together, this study provides strong evidence for the central and convergent role played by the synaptic microenvironment within the ALS spinal cord and highlights a potential therapeutic target that counteracts degeneration in a heterogeneous cohort of human motoneuron cultures.

TDP-43 proteinopathy, initially associated with ALS and FTD, is also found in 30–60% of Alzheimer’s disease (AD) cases and correlates with worsened cognition and neurodegeneration. A major component of this proteinopathy is depletion of this RNA-binding protein from the nucleus, which compromises repression of non-conserved cryptic exons in neurodegenerative diseases. To test whether nuclear depletion of TDP-43 may contribute to the pathogenesis of AD cases with TDP-43 proteinopathy, we examined the impact of depletion of TDP-43 in populations of neurons vulnerable in AD, and on neurodegeneration in an AD-linked context. Here, we show that some populations of pyramidal neurons that are selectively vulnerable in AD are also vulnerable to TDP-43 depletion in mice, while other forebrain neurons appear spared. Moreover, TDP-43 depletion in forebrain neurons of an AD mouse model exacerbates neurodegeneration, and correlates with increased prefibrillar oligomeric Aβ and decreased Aβ plaque burden. These findings support a role for nuclear depletion of TDP-43 in the pathogenesis of AD and provide strong rationale for developing novel therapeutics to alleviate the depletion of TDP-43 and functional antemortem biomarkers associated with its nuclear loss.

Multiple system atrophy (MSA) is a rapidly progressing fatal synucleinopathy of the aging population characterized by parkinsonism, dysautonomia, and in some cases ataxia. Unlike other synucleinopathies, in this disorder the synaptic protein, α-synuclein (α-syn), predominantly accumulates in oligodendroglial cells (and to some extent in neurons), leading to maturation defects of oligodendrocytes, demyelination, and neurodegeneration. The mechanisms through which α-syn deposits occur in oligodendrocytes and neurons in MSA are not completely clear. While some studies suggest that α-syn might transfer from neurons to glial cells, others propose that α-syn might be aberrantly overexpressed by oligodendroglial cells. A number of in vivo models have been developed, including transgenic mice overexpressing α-syn under oligodendroglial promoters (e.g.: MBP, PLP, and CNP). Other models have been recently developed either by injecting synthetic α-syn fibrils or brain homogenates from patients with MSA into wild-type mice or by using viral vectors expressing α-syn under the MBP promoter in rats and non-human primates. Each of these models reproduces some of the neuropathological and functional aspects of MSA; however, none of them fully replicate the spectrum of MSA. Understanding better the mechanisms of how α-syn accumulates in oligodendrocytes and neurons will help in developing better models that recapitulate various pathogenic aspects of MSA in combination with translatable biomarkers of early stages of the disease that are necessary to devise disease-modifying therapeutics for MSA.

We report the neuropathological evaluation of a 24-year-old autistic woman suffering from a residual state of infantile autism and presenting with self-injury behavior since childhood. Her behavior included head-banging, eye-gouging and self-biting. All intended therapeutic measures remained without effect, including high doses of psychotropic drugs. At autopsy, numerous neurofibrillary tangles were found in the perirhinal and entorhinal cortex where they were frequently grouped in nests or clusters. A few neurofibrillary tangles were also observed in the amygdala and in the prepiriform and orbito-frontal cortex. In the cortex, tangles were located in both layers II and III. There were no neuritic plaques or amyloid deposits. Interestingly, neurofibrillary tangles have been described in brains of individuals who had experienced repeated head injuries such as boxers (dementia pugilistica) and soccer players, suggesting that in our case a similar mechanism induced tangle formation and resulted in the loss of selective neuronal populations.