Extracellular vesicles contain filamentous alpha-synuclein and facilitate the propagation of Parkinson's pathology.

Parkinson's disease (PD) is characterized by the pathological deposition of a-synuclein (a-syn) inclusions, known as Lewy bodies/neurites. Emerging evidence suggests that extracellular vesicles (EVs) play a role in facilitating the spreading of Lewy pathology between the peripheral nervous system and the central nervous system. We analyzed serum EVs obtained from patients with PD (n = 142), multiple system atrophy (MSA) (n = 18), progressive supranuclear palsy (PSP) (n = 28), rapid eye movement sleep behavior disorder (n = 31), and controls (n = 105). While we observed a significant reduction in the number of EVs in PD compared to controls (p = 0.006), we also noted a substantial increase in filamentous α-synuclein within EVs in PD compared to controls (p < 0.0001), MSA (0.012), and PSP (p = 0.03). Further analysis unveiled the role of EVs in facilitating the transmission of filamentous α-synuclein between neurons and from peripheral blood to the CNS. These findings highlight the potential utility of serum α-synuclein filaments within EVs as diagnostic markers for synucleinopathies and underscore the significance of EVs in promoting the dissemination of filamentous α-synuclein throughout the entire body.

[Reactivation of latent viruses in Neurology].

After establishing latent infection, some viruses can be reactivated by the alteration of host immunological conditions. First, we reviewed viruses that can cause neuronal damage by reactivation. Then we focused on the herpes simplex virus (HSV). The reactivation leads to neuronal damages through two possible mechanisms; "reactivation of a latent herpes virus" by which viruses can cause direct virus neurotoxicity, and "post-infectious immune inflammatory response" by which a focal reactivation of HSV leads to an inflammatory reaction. The former is radiologically characterized by cortical lesions, the latter is characterized by subcortical white matter lesions. We experienced a female, who underwent the right posterior quadrantectomy and then developed recurrent herpes encephalitis caused by herpes simplex reactivation, which pathologically demonstrated inflammation in the white matter, suggesting a post-infectious immune inflammatory response. The patient was successfully treated with immunosuppressants. The reactivation of the HSV is extremely rare in Japan. Neurologists should recognize this condition because this disorder will increase as epilepsy surgery gains more popularity.

Pathophysiological evaluation of the LRRK2 G2385R risk variant for Parkinson's disease.

Missense variants in leucine-rich repeat kinase 2 (LRRK2) lead to familial and sporadic Parkinson's disease (PD). The pathological features of PD patients with LRRK2 variants differ. Here, we report an autopsy case harboring the LRRK2 G2385R, a risk variant for PD occurring mainly in Asian populations. The patient exhibited levodopa-responsive parkinsonism at the early stage and visual hallucinations at the advanced stage. The pathological study revealed diffuse Lewy bodies with neurofibrillary tangles, amyloid plaques, and mild signs of neuroinflammation. Biochemically, detergent-insoluble phospho-α-synuclein was accumulated in the frontal, temporal, entorhinal cortexes, and putamen, consistent with the pathological observations. Elevated phosphorylation of Rab10, a substrate of LRRK2, was also prominent in various brain regions. In conclusion, G2385R appears to increase LRRK2 kinase activity in the human brain, inducing a deleterious brain environment that causes Lewy body pathology.

Radiation-induced Brain Calcification Leads to L-dopa-resistant Parkinsonism and Cerebellar Ataxia.

We experienced a young patient who presented with progressive parkinsonism and cerebellar ataxia. Brain magnetic resonance imaging revealed progressive brain calcification, expanding from the bilateral basal ganglia to the central pons, caused by a delayed reaction to the radiation therapy that she had received to treat craniopharyngioma 14 years earlier. Heterogeneous clinical symptoms due to radiation-induced brain calcification have been described, but parkinsonism has never been reported. While dopamine transporter-single photon emission computed tomography revealed only slight damage to the dopaminergic striatal pathway, the extension of calcification to the periventricular white matter was likely responsible for her parkinsonism.

Effect of comorbid Parkinson's disease and Parkinson's disease dementia on the course of idiopathic normal pressure hydrocephalus.

OBJECTIVE: The objective of this study was to analyze the effect of concomitant Parkinson's disease (PD) and PD dementia (PD/PDD) on the course of idiopathic normal pressure hydrocephalus (iNPH), especially as related to the outcome of lumboperitoneal shunt (LPS) surgery. METHODS: The authors retrospectively analyzed patients with iNPH without accompanying disorders (iNPH alone [iNPHa]) and iNPH concomitant with PD/PDD (iNPHc+PD/PDD) who had presented to their department between 2010 and 2019. The diagnosis of iNPHc+PD/PDD was established using the diagnostic criteria of the Movement Disorder Society. The effect of LPS surgery on clinical symptoms and striatum volumes was evaluated. RESULTS: Thirty-three patients with iNPHa and 23 patients with iNPHc+PD/PDD were identified. Comorbid PD/PDD significantly worsened clinical outcome as measured by the iNPH grading scale, modified Rankin Scale (mRS), and Hoehn and Yahr (HY) scale. LPS surgery improved the iNPH score including gait disturbance (p < 0.01), cognitive impairment (p = 0.02), and urinary disturbance (p < 0.01) in iNPHa and improved gait disturbance (p = 0.01) and urinary disturbance (p = 0.03) in iNPHc+PD/PDD for 1 year. Comorbid synucleinopathies maintained worse mRS scores and HY stages for 3 years, and LPS surgery extended overall survival (p = 0.003), as well as the period of sustained mRS scores (p = 0.04) and HY stages (p = 0.004) in iNPHc+PD/PDD. Both caudate and putamen volumes were reduced in iNPHa (p < 0.01) compared to those in controls and in patients with iNPHc+PD/PDD compared to those in patients with PD/PDD (p < 0.01), and LPS surgery restored caudate volumes in both groups. CONCLUSIONS: These results revealed that comorbid PD/PDD deteriorates the clinical course of iNPH and that LPS surgery is recommended regardless of this comorbidity.

Hashimoto's encephalopathy with gait disturbance caused by sensory ganglionopathy: A case report and review of the literature.

Hashimoto's encephalopathy (HE) is a steroid-responsive encephalopathy characterized by several neurological symptoms. HE mainly involves the central nervous system; the peripheral nervous system is rarely involved. We treated a previously healthy elderly man showing mild cognitive decline and subacute progressive gait disturbance due to severe sensory deficits, including sensation of touch and deep sensation with elevated anti-NH2 terminal of α-enolase and anti-thyroid antibodies. His sensory disturbance symptoms improved after steroid therapy, suggesting that the neuropathy was related to HE. His disease was characteristic of HE in that his sensory deficits responded well and rapidly to steroid therapy. A nerve conduction study showed reduced sensory nerve action potentials in all limbs, indicating that his neuropathy was not "axonopathy", but "sensory ganglionopathy", which can occur concurrently with autoimmune disorders. Dysautonomia may be the responsible pathomechanism because of the vulnerability of the blood-nerve barrier at the ganglia. Although the pathophysiology of HE has not been clearly elucidated, autoimmune inflammation has been reported in a number of autopsy cases, indicating that sensory ganglionopathy can develop with HE. Therefore, HE should be recognized as one type of "treatable neuropathy".

Relapse of Herpes Simplex Encephalitis by Epilepsy Surgery 35 Years after the First Infection: A Case Report and Literature Review.

Late relapse of herpes simplex encephalitis (HSE) is defined as the recurrence of HSE more than 3 months after the initial exposure. The postoperative diagnosis of HSE following neurosurgery is complicated because the clinical presentation can mimic other common complications of neurosurgery. Cerebrospinal fluid polymerase chain reactions (CSF-PCR) is the gold standard for the diagnosis of HSE. We describe a case of late HSE relapse after epilepsy surgery in a patient who required a brain biopsy due to repeated negative CSF-PCR results. A 38-year-old woman had a history of HSE from the age of 3 years. She had intractable epilepsy from the age of 20 years and underwent right posterior quadrant disconnection (PQD) at the age of 38 years. Postoperatively, she had a right hemispheric intracerebral hemorrhage (ICH) and her consciousness was gradually worsening. Her consciousness improved after removal of the ICH. However, her consciousness gradually deteriorated again. Fluid-attenuated inversion recovery (FLAIR) revealed bilateral hyperintensity in the frontal lobes, including the white matter. CSF-PCR for herpes simplex virus (HSV) was performed twice, but yielded negative results. We performed a brain biopsy to target FLAIR hyperintensity in the right frontal lobe. PCR of the brain specimen was positive for HSV. Her consciousness improved with acyclovir, methylprednisolone, and cyclophosphamide. To our knowledge, this is a case of HSE induced by epilepsy surgery which had the longest duration until relapse after the initial HSE episode. A brain biopsy can be used to confirm the diagnosis of suspected HSE when CSF-PCR results are negative.

PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan.

This study aimed to evaluate genotype-phenotype correlations of Parkinson's disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

Neuromyelitis optica spectrum disorder after treatment with pembrolizumab.

While immune checkpoint inhibitors (ICIs) have contributed to the development of therapeutic treatments for previously incurable advanced malignancies, they may induce immune-related adverse events (irAEs) in many organs including the CNS [1]. Because immune checkpoint molecules are predominantly expressed on T cells, irAEs are largely not B cell-mediated. Here, we report a patient who was treated with pembrolizumab (a PD-1 monoclonal antibody) for lung adenocarcinoma with brain metastasis, and who developed anti-aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorder (NMOSD). We hypothesized that PD-1 immune checkpoint blockage might induce a B cell-mediated immune response in CNS resulting in this complication, which was further supported by the observation of a transient increase in plasmablasts in their CSF.

Analysis of Clinical Symptoms and Brain MRI of Heat Stroke: 2 Case Reports and a Literature Review.

INTRODUCTION: Heat stroke is defined as high body temperature causing multiple organ failure, psychological change, seizure, and consciousness disturbance, which lead to its high mortality rate. However, the involvement of brain injury is rare, and heat-stroke has only been reported in a few case reports or case series. The purpose of this case study was to evaluate the clinical symptoms and radiological features of heat stroke. METHODS: We reviewed our hospital records and previously published reports to find cases of heat stroke. We excluded those with unknown clinical features or radiological findings. RESULTS: We retrieved 2 cases of heat stroke from our hospital, which presented as extensive lesions on brain imaging that led to disseminated intravascular coagulation and death within a few days. In 21 previously reported cases of heat stroke, similar brain lesions were noted. These were classified as infarction/posterior reversible encephalopathy syndrome (PRES)-like lesions. The patients who developed PRES-like lesions and survived often developed cerebellar sequelae. CONCLUSION: The mechanism of heat stroke is presumed to be multifactorial. Ischemic-like lesions result from hypovolemia and unusual coagulation, whereas PRES-like lesions are caused by direct heat and vasogenic edema due to hypercytokinemia. We need to consider the above mentioned conditions when evaluating heat stroke.

Bilateral thigh compartment syndromes from extended sitting with forward bending.

Alcohol consumption and subsequent sleeping in unusual positions often causes compression neuropathies. In this case, we experienced a unique case of bilateral leg palsy after sleeping in a forward bending position that was photographed by his colleague. We expected that prolonged blockage of the circulation of the femoral arteries resulted in bilateral thigh compartment syndromes (TCSs), leading to sciatic nerve damage. The muscle MRI and needle EMG support this hypothesis. A couple of similar cases have been reported, but the causes of TCS was undetermined due to lack of medical history. This case illustrates that atraumatic compartment syndrome with sciatic nerve palsy can be occurred by prolonged unusual positions.