We detected Lewy body pathology in the olfactory epithelium in six of the eight patients with Parkinson's disease and in one patient with incidental Lewy body pathology.

Multiple sclerosis (MS), a putative autoimmune disease of the central nervous system (CNS), commonly presents as relapsing-remitting MS (RRMS), characterized by recurrent episodes of peripheral disabling symptoms resulting from inflammatory CNS damage. Many RRMS patients transition to a chronic disease course with progressive neurological dysfunctions (secondary progressive MS, SPMS), with the progression rate varying between patients and over time. SPMS pathogenesis is now linked to immune-cell–mediated processes, although the mechanisms driving SPMS transition and progression remain elusive, and SPMS lacks biomarkers and effective treatments. We report the crucial involvement of cytotoxic CD4+ T cells expressing Eomes (Eomes+ Th cells) in SPMS pathogenesis—a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation. Few Eomes+ Th cells circulate in RRMS patient peripheral blood (n = 44), primary progressive MS (PPMS) patients (n = 25), or healthy controls (n = 42), but Eomes+ Th cells were significantly increased in SPMS (n = 105, P < 0.0001). Strikingly, lymphocytes isolated from SPMS autopsy brain samples revealed CD4+ T cells infiltrating CNS that coexpressed Eomes and the cytotoxic molecule granzyme B. In particular, the Eomes+ Th cell levels were increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases (P < 0.0001). Moreover, Eomes level acted as a biomarker to predict SPMS patients at risk of disease worsening with over 80% accuracy (ROC-AUC = 0.8276). Overall, our results indicate that granzyme B-expressing Eomes+ T helper cells are involved in the pathogenesis of SPMS, with significant implications for SPMS biomarkers and therapeutic targets.

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Neuronal intranuclear inclusion disease (NIID) exhibits diverse clinical phenotypes caused by the intronic repeat expansion of NOTCH2NLC. 1,2 An acute encephalopathic episode can manifest in some patients with NIID. 3,4 Herein, we report an NIID patient harboring a de novo {(GGA) n (GGC) n } n repeat expansion in NOTCH2NLC, who developed abrupt mitochondrial encephalomyopathy, lactic acidosis, and stroke-like (MELAS)-like episode in the 15-year course clinical diagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). Case report A 31-year-old woman developed slowly progressing muscle weakness and paresthesia in all extremities. Neurologic examination at 33 years of age revealed distal dominant muscle weakness with areflexia and abnormal deep sensations in all extremities without obvious cranial nerve involvement. A nerve-conduction study revealed sensorimotor polyneuropathy in all extremities (table e-1, links.lww.com/NXG/A335). Although clinical and electrophysiologic features met the diagnostic criteria for CIDP, 5 she showed limited response to immunotherapy. At 45 years, she abruptly started experiencing headaches, nausea, and eventually, loss of consciousness. Neurologic examination revealed left conjugate eye deviation, neck stiffness, and left hemiparesis. Blood analysis revealed an elevated blood lactate/pyruvate molar ratio (lactate: 2.1 mmol/L, pyruvate: 0.022 mmol/L, molar ratio: 91, normal range <25.8). Brain MRI showed abnormal hyperintensities in the right hemisphere on diffusion-weighted images (DWIs) (figure, A) and T2weighted images (figure, B), with gadolinium enhancement not corresponding to the vascular distribution. Hyperperfusion on arterial spin labelling (figure, C), dilation of the right cerebral artery (figure, D), and elevated lactate peak on magnetic resonance spectroscopy (MRS) (figure, E) in the involved areas were also identified. She was diagnosed with MELAS and was administered IV levetiracetam, edaravone, and oral taurine. She gradually improved without residual cognitive disturbances. Neither histopathologic studies nor whole mitochondrial genome sequence analysis on muscle biopsy showed any specific findings for mitochondrial disease. At 47 years of age, a follow-up neurologic examination revealed bilateral miosis with sluggish response to light. Brain MRI revealed both gray and white matter hyperintensities on T2-weighted images corresponding to acute encephalopathic lesions (figure, F and G). However, there was no abnormal corticomedullary hyperintensity on DWI. Abdominal skin biopsy performed at 47 years of age and re-examination of the sural nerve sample at 35 years resulted in NIID diagnosis, demonstrating eosinophilic intranuclear inclusions surrounded by a halo and antiubiquitin and p62-immunoreactive intranuclear inclusions in fibroblasts, sweat gland cells (figure, H),

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ErbB4 is the protein implicated in familial amyotrophic lateral sclerosis (ALS), designated as ALS19. ErbB4 is a receptor tyrosine kinase activated by its ligands, neuregulins (NRG), and plays an essential role in the function and viability of motor neurons. Mutations in the ALS19 gene lead to the reduced autophosphorylation capacity of the ErbB4 protein upon stimulation with NRG‐1, suggesting that the disruption of the NRG–ErbB4 pathway causes motor neuron degeneration. We used immunohistochemistry to study ErbB4 in the spinal cord of patients with sporadic ALS (SALS) to test the hypothesis that ErbB4 may be involved in the pathogenesis of SALS. ErbB4 was specifically immunoreactive in the cytoplasm of motor neurons in the anterior horns of the spinal cord. In patients with SALS, some of the motor neurons lost immunoreactivity with ErbB4, with the proportion of motor neurons with a loss of immunoreactivity correlated with the severity of motor neuron loss. The subcellular localization was altered, demonstrating nucleolar or nuclear localization, threads/dots and spheroids. The ectopic glial immunoreactivity was observed, mainly in the oligodendrocytes of the lateral columns and anterior horns. The reduction in the ErbB4 immunoreactivity was significantly correlated with the cytoplasmic mislocalization of transactivation response DNA‐binding protein 43 kDa (TDP‐43) in the motor neurons. No alteration in immunoreactivity was observed in the motor neurons of mice carrying atransgene for mutant form of the superoxide dismutase 1 gene (SOD1). This study provided compelling evidence that ErbB4 is also involved in the pathophysiology of SALS, and that the disruption of the NRG–ErbB4 pathway may underlie the TDP‐43‐dependent motor neuron degeneration in ALS.

SummaryPlatelet aggregability was measured using platelet rich plasma (PRP) collected from 197 clinical cases including 52 healthy volunteers. In 31 patients of acute stage of thrombosis (within 2 weeks from the onset), a significant enhancement of platelet aggregation measured 5 min after an addition of 3 and 10 μM ADP or 0.1 and 1 μg/ml of adrenaline to PRP (p < 0.05, compared to the healthy group). Also a significant enhancement of secondary aggregation induced by adrenaline was observed (p <0.05). The enhancement was especially marked in the response induced by adrenaline. Such an enhancement was not observed in patients in the recovery stage of thrombosis, hypertension, angina pectoris and other miscellaneous diseases. There was no difference in the parameters related to the velocity of aggregation or intensity of primary aggregation between the diseased and the healthy group. In response induced by collagen (bovine achules tendon, 0.3 and 1 mg/ml) any difference in the aggregation curve was not observed between the diseased and the healthy group. Such findings suggest a presence of an enhancement of ADP-release mechanism of platelets in acute thrombosis. Also a significance of adrenaline-induced platelet aggregation was proposed to detect platelet functions for analysis of mechanism of thromboembolic disorders.