Hiroyuki Sumikura

Distribution of α-synuclein in the spinal cord and dorsal root ganglia in an autopsy cohort of elderly persons.

BackgroundLewy body–related α-synucleinopathy (LBAS, the abnormal accumulation of pathologic α-synuclein) is found in the central and peripheral nervous systems, including the spinal cord, dorsal root ganglia, and sympathetic ganglia, of Parkinson’s disease patients. However, few studies have focused on the distribution of LBAS in the spinal cord, primary sensory neurons, and preganglionic sympathetic nerves.ResultsWe analyzed 265 consecutive subjects with LBAS who underwent autopsy at a general geriatric hospital. LBAS in the spinal cord was significantly associated with that in the lower brainstem regions that are directly connected to the spinal cord (i.e., the medullary reticular formation and locus ceruleus), but it was not associated with the olfactory bulb–amygdala system, which is not directly connected to the spinal cord, suggesting that the lower brainstem is a key structure regarding the spread of LBAS to the spinal cord. In the primary sensory neurons, most subjects with LBAS in the dorsal root ganglia had LBAS in the dorsal root, and all subjects with LBAS in the dorsal root also had LBAS in the dorsal horn, suggesting that LBAS spreads retrogradely from the axonal terminals of the dorsal horn to the somata of the dorsal root ganglia via the dorsal root. In the preganglionic sympathetic nerves, the LBAS in the sympathetic ganglia preceded that in the nucleus of the intermediolateral column of the thoracic cord, suggesting that LBAS spreads retrogradely through the preganglionic sympathetic nerves.ConclusionsLBAS in the spinal cord was associated with the lower regions of the brainstem, but not with the olfactory bulb or amygdala. LBAS may spread centrifugally along the primary sensory neurons, whereas it may spread centripetally along the preganglionic sympathetic nerves.

Lewy body pathology involves the olfactory cells in Parkinson's disease and related disorders

The “dual‐hit” and propagation hypotheses of α‐synuclein suggests that the olfactory cells of the olfactory epithelium are among the earliest sites of involvement in Parkinsons disease (PD). We investigated the olfactory epithelium in consecutive cases that had been registered with a brain bank.

Serine 403-phosphorylated p62/SQSTM1 immunoreactivity in inclusions of neurodegenerative diseases

Protein inclusions in neurodegenerative diseases are associated with p62, which has an important role in autophagic clearance of polyubiquitinated proteins. Selective autophagy is regulated by S403-phosphorylation of p62, and S403-phosphorylated p62 (S403-phos-p62) accumulates in Atg5 conditional knockout (Atg5CKO) mice in which autophagosome formation is impaired. We performed immunohistochemical tests for the presence of S403-phos-p62 in postmortem brain of neurodegenerative disease cases, and found accumulations in amyotrophic lateral sclerosis and Alzheimers disease tissues. In Atg5CKO and HD190QG (Huntingtons disease model) mice, however, we found a postmortem decrease in S403-phos-p62 immunoreactivity, suggesting that post-mortem changes should be considered when interpreting human data.

Homovanillic acid and 5-hydroxyindole acetic acid as biomarkers for dementia with Lewy bodies and coincident Alzheimer’s disease: An autopsy-confirmed study

Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are the two most common causes of dementia. Both pathologies often coexist, and AD patients with concomitant neocortical LB pathology (referred to as the Lewy body variant of AD) generally show faster cognitive decline and accelerated mortality relative to patients with pure AD. Thus, discriminating among patients with DLB, AD, and coincident DLB and AD is important in clinical practice. We examined levels of homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA), tau, phosphorylated tau (p-tau), and beta-amyloid (Aβ) 1–42 in cerebrospinal fluid (CSF) to evaluate their viability as biomarkers to discriminate among different forms of dementia. We obtained a total of 3498 CSF samples from patients admitted to our hospital during the period from 1996 to 2015. Of these patients, we were able to carry out a brain autopsy in 94 cases. Finally, 78 neuropathologically diagnosed cases (10 AD, six DLB, five DLB with AD, five controls without neurological diseases, and 52 cases with other neurological diseases) were studied. CSF levels of HVA and 5-HIAA were consistently decreased in pathologically advanced Lewy body disorder (LBD; Braak LB stages >3) compared with pathologically incipient LBD (Braak LB stages <2). These results suggest that if an individual has LB pathology in the central nervous system, CSF levels of HVA and 5-HIAA may decrease after the onset of clinical symptoms. In addition, CSF levels of HVA and 5-HIAA decreased with LB pathology, and were especially low in cases of DLB and DLB with AD. Furthermore, the combination of HVA, 5-HIAA, and brain specific proteins t-tau, p-tau, and Aβ 1–42 in CSF were useful for discriminating among DLB, DLB with AD, and AD with high diagnostic accuracy.

Progressive supranuclear palsy and Parkinson's disease overlap: A clinicopathological case report

We describe a woman with a 13‐year history of postural instability, vertical gaze palsy and dopa‐responsive parkinsonism ‐ a clinical profile that corresponds to progressive supranuclear palsy (PSP) and Parkinsons disease (PD). The patient died at the age of 82 years. Neuropathological features included neuronal loss and gliosis in the substantia nigra, locus ceruleus, dorsal motor nucleus of the vagus, thoracic intermediolateral nucleus and nucleus basalis of Meynert, in addition to the typical pathology of PSP. Immunohistochemical studies demonstrated that PSP‐tau pathology was localized in the central nervous system, but Lewy body‐related α‐synucleinopathy was extensive in the central and peripheral nervous systems. Although PSP and PD may represent independent processes, this case could provide insight into a common defect in either protein phosphorylation or the proteinase surveillance system that contributes to human aging.

Reduction of Small Fibers of Thoracic Ventral Roots and Neurons of Intermediolateral Nucleus in Parkinson Disease and Dementia with Lewy Bodies

BACKGROUND AND OBJECTIVE Loss of intermediolateral nucleus (IML) neurons is considered to play a major role in orthostatic hypotension (OH) of multiple system atrophy (MSA). In Parkinson disease (PD) and dementia with Lewy bodies (DLB), autonomic phenomena such as OH are common and attributed to dysfunction of sympathetic, parasympathetic, and visceral autonomic neurons. However, apart from MSA, few reports have focused on the neuropathologic aspects in PD and DLB. Here we assessed IML degeneration as well as the fine myelinated fibers (FFs; maximum diameter less than 3 μm) considered to be preganglionic sympathetic nerve fibers derived from IML neurons in PD, DLB, MSA, and age-matched normal controls (NC). METHODS We counted IML neurons and measured the diameter and number of myelinated fibers of the ventral root at the level of the 12th thoracic segment. RESULTS Compared to NC, number of IML neurons and density of FF were significantly reduced in PD (53% and 67%), DLB (47% and 71%) and MSA (27% and 42%). Compared to combined group of PD and DLB without OH (OH-), IML neurons in combined group of PD and DLB with OH (OH+) were significantly reduced (77%). Compared to NC, FF densities in OH-, OH+ were significantly reduced (74% and 59%). The mean ratio of small to large myelinated fibers in OH+ (1.18), but not that in OH-(1.58), was significantly lower than that in NC (3.17). CONCLUSIONS We present neuropathological evidence that IML neurons and FFs in the ventral root are reduced in PD and DLB and that the reduction was more severe in the combined group of OH+ than in OH-.

Autopsy case of severe generalized dystonia and static ataxia with marked cerebellar atrophy

Few reports have focused on the unusual phenotypes in dystonia-ataxia syndrome, and those studies proposed new entities for these phenotypes, such as predominant dystonia with marked cerebellar atrophy (DYTCA) or slowly progressive cerebellar ataxia and cervical dystonia.1,2 We performed pathologic and genetic examinations on a patient presenting a unique dystonia-ataxia phenotype.

Neurologic attack and dynamic perfusion abnormality in neuronal intranuclear inclusion disease

Hyperintensity in the corticomedullary junction on diffusion-weighted imaging is helpful in distinguishing neuronal intranuclear inclusion disease in patients with leukoencephalopathy.

Presence of Citrullinated Histone H3‐Positive Neutrophils in Microscopic Polyangiitis from the Early Phase: An Autopsy Proven Case

A 76‐year‐old man was admitted with general fatigue, weight loss, fever, headache, renal failure, and a high serum level of myeloperoxidase‐antineutrophil cytoplasmic antibody. Biopsy revealed citrullinated histone H3 (citH3)‐positive neutrophils adherent to the temporal artery endothelium. Three days after completing pulse steroid therapy, he suffered from a sudden disturbance of consciousness and died. On autopsy, the kidneys showed the most severe vasculitis with dense infiltration of citH3‐positive neutrophils. The lungs showed intra‐alveolar hemorrhage due to capillaritis. Severe brain hemorrhage was found in the left frontal lobe and putamen with uncal herniation. No vasculitis or thrombi was observed in the brain. The right dura mater was thickened due to fibrosis and inflammation. In conclusion, autopsy revealed systemic vasculitis with infiltration of abundant citH3‐positive neutrophils, suggesting that the neutrophil extracellular trap formation and citH3 might play important roles in the early phases and development of microscopic polyangiitis.