Rest tremor may occur in as many as 30% of essential tremor (ET) patients. It is not clear whether this tremor is a sentinel marker for brainstem Lewy body pathology. Here we report the clinical and ...post-mortem findings of nine ET cases with upper-extremity rest tremor in the absence of other parkinsonian features.
All brains had a complete neuropathological assessment. Tissue sections from the brainstem and basal ganglia were immunostained with α-synuclein antibody.
All cases had longstanding ET (median duration=42 years) with moderate to severe arm tremor. Rest tremor involved both arms in seven (77.8%) cases and one arm in two cases. The rest tremor score was correlated with the total action tremor score (r=0.69, p=0.04). The number of torpedoes was elevated, and Purkinje cells, reduced. Post-mortem changes in the substantia nigra pars compacta (SNc), caudate, putamen and globus pallidum were minimal, and neither Lewy bodies nor Lewy neurites were evident.
In nine ET brains with upper-extremity rest tremor, neither Lewy body-containing neurons nor Lewy neurites were found on α-synuclein immunostained sections, and other pathological changes in the basal ganglia were minimal. These data support the notion that isolated rest tremor in longstanding ET is not the expression of underlying Lewy body pathology in the SNc.
The H1 haplotype of the microtubule-associated protein tau gene (
MAPT
) is associated with an increased risk of Parkinson disease (PD) compared with the H2 haplotype, but its effect on Lewy body ...(LB) formation is unclear. In this study, we compared the
MAPT
haplotype frequency between pathologically confirmed PD patients (
n
= 71) and controls (
n
= 52). We analyzed Braak LB stage, Braak neurofibrillary tangle (NFT) stage, and CERAD amyloid score by haplotype. We further tested the association between
MAPT
haplotype and semi-quantitative counts of LBs, NFTs, and neuritic plaques (NPs) in multiple neocortical regions. Consistent with previous reports, PD cases had an increased likelihood of carrying an H1/H1 genotype compared to controls (OR = 5.72, 95 % CI 1.80–18.21,
p
= 0.003). Braak LB, Braak NFT and CERAD scores did not differ by haplotype. However, H1/H1 carriers had higher LB counts in parietal cortex (
p
= 0.02) and in overall neocortical LBs (
p
= 0.03) compared to non-H1/H1 cases. Our analyses suggest that PD patients homozygous for the H1 haplotype have a higher burden of neocortical LB pathology.
Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria ...define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (n = 12) or Alzheimer's disease neuropathologic change (n = 4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC.
The study of the postmortem changes in essential tremor (ET) is in its infancy, although recent evidence points to a central role of the cerebellum, where Purkinje cell axonal swellings (“torpedoes”) ...are significantly more common in ET than control brains. Yet, all existing studies have been confined to the cerebellar hemispheres, and whether there is a more widely distributed cerebellar problem is presently unknown. Our aims were to address whether: (1) ET cases have greater numbers of torpedoes in the vermis than controls, (2) there a correlation between the extent of vermal torpedo pathology and hemispheric torpedo pathology, and (3) vermal torpedo pathology is correlated with clinical features of the disease. A parasagittal neocerebellar block and a vermal block were harvested from 24 ET and 10 control brains. Paraffin sections (7 μm) were stained with Luxol fast blue/hematoxylin and eosin, and torpedoes were quantified. All torpedo counts were corrected for Purkinje cell layer length. Vermal corrected torpedo count (VermTc) was higher in ET cases than controls (7.1 ± 6.8 median, 4.3 vs. 2.6 ± 2.5 median, 2),
p
= 0.002). The VermTc and the hemispheric corrected torpedo count (HemTc) were correlated with one another (Spearman’s
r
= 0.54,
p
= 0.002). ET cases with neck, voice, and jaw tremors had the highest VermTc (
p
= 0.046). The abundance of torpedoes in the ET brain is not confined to the ponto- or neocerebellum but is more broadly distributed, also involving the spino- or paleocerebellum. These data further confirm the central role of the cerebellum in the underlying pathophysiology of this common neurological disorder.
Background
Multiple system atrophy (MSA) is marked by abnormal inclusions of α‐synuclein in oligodendrogliocytes, and its etiology remains unknown. Variants in the glucocerebrosidase (GBA) gene have ...been associated with the other synucleinopathies, dementia with Lewy bodies, and Parkinson's disease. It is unclear whether glucocerebrosidase variants are associated with MSA. The objective of this study was to analyze the frequency of GBA variants among patients who had autopsy‐proven MSA at a brain bank in New York City.
Methods
GBA was fully sequenced in brain tissues from 17 patients with autopsy‐proven MSA for whom there was extractable DNA at the Columbia University New York Brain Bank from 2002 to 2016. To test whether brains from patients with MSA were enriched for GBA variants, the frequency of GBA variants in the MSA brains was compared with that of variants in all brains from patients with pure Alzheimer's disease (AD) at Columbia University for which GBA genotype was available (n = 82).
Results
Of 17 MSA brains, 4 carried GBA variants (23.5%), including 1 that was homozygous for N370S and 1 each that carried heterozygous N370S, T369M, and R496H variants. Among the comparator brains with pure AD, 3 of 82 (3.7%) carried GBA variants (P = 0.0127; Fisher exact test), including 1 each with an N370S homozygous variant, an R496H heterozygous variant, and a T369M heterozygous variant.
Conclusion
A higher frequency of GBA variants was observed among brains from patients who had pathologically diagnosed MSA compared with the frequency of variants in brains from patients who had AD. The results indicate a need for further investigation into the role of glucocerebrosidase and lysosomal dysfunction in the etiology of MSA.
Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia. In addition to grey matter pathology, white matter changes are now recognized as an important ...pathological feature in the emergence of the disease. Despite growing recognition of the importance of white matter abnormalities in the pathogenesis of AD, the causes of white matter degeneration are still unknown. While multiple studies propose Wallerian-like degeneration as the source of white matter change, others suggest that primary white matter pathology may be due, at least in part, to other mechanisms, including local effects of toxic Aβ peptides. In the current study, we investigated levels of soluble amyloid-beta (Aβ) in white matter of AD patients (n=12) compared with controls (n=10). Fresh frozen white matter samples were obtained from anterior (Brodmann area 9) and posterior (Brodmann area 1, 2 and 3) areas of post-mortem AD and control brains. ELISA was used to examine levels of soluble Aβ -42 and Aβ -40. Total cortical neuritic plaque severity rating was derived from individual ratings in the following areas of cortex: mid-frontal, superior temporal, pre-central, inferior parietal, hippocampus (CA1), subiculum, entorhinal cortex, transentorhinal cortex, inferior temporal, amygdala and basal forebrain. Compared with controls, AD samples had higher white matter levels of both soluble Aβ -42 and Aβ -40. While no regional white matter differences were found in Aβ -40, Aβ -42 levels were higher in anterior regions than in posterior regions across both groups. After statistically controlling for total cortical neuritic plaque severity, differences in both soluble Aβ -42 and Aβ -40 between the groups remained, suggesting that white matter Aβ peptides accumulate independent of overall grey matter fibrillar amyloid pathology and are not simply a reflection of overall amyloid burden. These results shed light on one potential mechanism through which white matter degeneration may occur in AD. Given that white matter degeneration may be an early marker of disease, preceding grey matter atrophy, understanding the mechanisms and risk factors that may lead to white matter loss could help to identify those at high risk and to intervene earlier in the pathogenic process.
ABSTRACT
Background
The pathological hallmark in MSA is oligodendrocytic glial cytoplasmic inclusions (GCIs) containing α‐synuclein, in addition to neuronal loss and astrogliosis especially involving ...the striatonigral and olivopontocerebellar systems. Rarely, TAR DNA‐binding protein of 43 kDa (TDP‐43), a component of ubiquitinated inclusions observed mainly in amyotrophic lateral sclerosis and frontotemporal lobar degeneration has been demonstrated in cases of MSA and, more recently, was shown to colocalize with α‐synuclein pathology in GCIs in 2 patients.
Methods
A 66‐year‐old woman presented with a syndrome characterized by spasticity, dysautonomia, bulbar dysfunction, and parkinsonism. Symptoms progressed until her death at age 74. Neuropathological evaluation was performed at the New York Brain Bank at Columbia University.
Results
On gross examination, there was striking severe volume loss of the left striatum compared to mild involvement of the right striatum. Microscopically, neuronal loss and gliosis of the putamen and globus pallidus were severe on the left side, in contrast to mild involvement on the right side. Immunohistochemistry for α‐synuclein revealed widespread GCIs. The sections subjected to TDP‐43 antibodies showed a few GCIs with definite nucleocytoplasmic translocation of the labeling within the lenticular nucleus and within the paracentral cortex.
Conclusions
This report adds to the evidence that TDP‐43 and α‐synuclein colocalize in GCIs. Whether this coexistence contributes to the pathogenesis of a subset of MSA patients or is an age‐related process is not known. More cases with these peculiar pathological hallmarks might help determine whether TDP‐43 contributes to neurodegeneration in a subset of patients with MSA.
The objective of this study is to describe the neuropathologic findings in three
LRRK2
G2019S carriers with Parkinson's disease (PD). We cross-referenced a list of 956 PD individuals that had been ...previously genotyped in clinical studies at Columbia University, with 282 subjects with a parkinsonian syndrome who came to autopsy in our brain bank since 1991. We found three autopsies of G2019S mutation carriers. Pathological analyses of the samples were blind to the genetic findings. We retrospectively reviewed the clinical records of the three patients. All three had a clinical and pathological diagnosis of PD. Cognitive impairment was a late feature in two out of three patients. Cortical involvement varied significantly: one had diffuse Lewy body (LB) pathology, tau inclusions, and amyloid pathology consistent with advanced Alzheimer's disease; one had diffuse cortical LB; and one had only brainstem predominant LB pathology. Cognitive impairment may be a long-term complication in G2019S mutation carriers. However, the extent of cortical involvement is variable. Larger longitudinal follow-up of
LRRK2
G2019S mutation carriers is required to assess for risk factors for cortical involvement and dementia.
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