Abstract Purpose We examined the prevalence and risk of clinical symptoms in a large number of Japanese patients with Parkinson's disease (PD) ( n = 1453; 650 males). Methods Events were analyzed ...using Kaplan–Meier survival curves, logistic regression, and Cox proportional-hazards models. Results The mean age (SD) was 67.7 (10.0), age of onset was 58.0 (11.5), and disease duration was 9.7 (6.6) years. The mean modified Hoehn and Yahr stage was 2.8 (1.2). Most patients (88.9%) received levodopa (547.7 (257.6) mg/day). A large proportion (81.3%) received dopamine agonists (136.2 (140.7) mg/day). About 23.4% received pain treatment 6.9 (5.1) years after the onset; females ( p < 0.05) and patients with late-onset PD (≥60 years, p < 0.001) were more likely to be affected. About 44.7% of patients had wearing-off 7.5 (4.7) years after the onset, and it was more common in females ( p < 0.001) and patients with early-onset PD ( p < 0.001). Camptocormia was found in 9.5% of patients 8.1 (6.2) years after the onset, and it was more common in females ( p < 0.05) and patients with late-onset PD ( p < 0.05). About 28.6% of patients developed psychosis 9.0 (5.4) years after the onset, and it was more likely to occur in patients with late-onset PD ( p < 0.001). Late-onset PD and cerebrovascular disease were also associated with increased risk of pneumonia. Conclusions Considering that very few studies have assessed numerous clinical symptoms in the same report, these data provide a useful reference for the clinical course of PD.
A healthy 28-year-old woman presented suddenly with intractable status epilepticus: a focal seizure evolved into a generalized seizure preceded by a high fever. Brain magnetic resonance imaging ...indicated bilateral hyperintensities in the hippocampus on T2-weighted imaging. Electroencephalograms continuously demonstrated diffuse sharp waves and poly-spikes. Comprehensive immunomodulation therapies and anti-epileptic drugs did not lead to any improvements. We therefore diagnosed her with cryptogenic limbic encephalitis and new-onset refractory status epilepticus (NORSE). We detected positive anti-ganglioside antibodies, IgG-GQ1b, GD1a, and GT1b, which were negative at six months after the onset. We emphasize the heterogeneous pathogenesis and intractable conditions of NORSE.
Abstract
Biallelic mutations in PINK1/PRKN cause recessive Parkinson’s disease. Given the established role of PINK1/Parkin in regulating mitochondrial dynamics, we explored mitochondrial DNA ...integrity and inflammation as disease modifiers in carriers of mutations in these genes. Mitochondrial DNA integrity was investigated in a large collection of biallelic (n = 84) and monoallelic (n = 170) carriers of PINK1/PRKN mutations, idiopathic Parkinson’s disease patients (n = 67) and controls (n = 90). In addition, we studied global gene expression and serum cytokine levels in a subset. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mitochondrial DNA variant load (area under the curve = 0.83, CI 0.74–0.93). Biallelic PINK1/PRKN mutation carriers harbour more heteroplasmic mitochondrial DNA variants in blood (P = 0.0006, Z = 3.63) compared to monoallelic mutation carriers. This enrichment was confirmed in induced pluripotent stem cell-derived (controls, n = 3; biallelic PRKN mutation carriers, n = 4) and post-mortem (control, n = 1; biallelic PRKN mutation carrier, n = 1) midbrain neurons. Last, the heteroplasmic mitochondrial DNA variant load correlated with IL6 levels in PINK1/PRKN mutation carriers (r = 0.57, P = 0.0074). PINK1/PRKN mutations predispose individuals to mitochondrial DNA variant accumulation in a dose- and disease-dependent manner.
Trinh et al. report that PINK1/PRKN mutations predispose individuals to mitochondrial DNA (mtDNA) variant accumulation in a dose- and disease-dependent manner. Affected and unaffected PINK1/PRKN monoallelic mutation carriers can be distinguished by heteroplasmic mtDNA variant load.
Autosomal recessive juvenile parkinsonism (ARJP) is a distinct clinical and genetic entity characterized by highly selective neuronal death in the substantia nigra (SN) and locus coeruleus neurons ...without Lewy body formation. The mechanism of neuronal death of ARJP is still unknown. Our study demonstrated that iron staining was more intense in ARJP than in both controls and sporadic Parkinson's disease (PD), and there were differences in the pattern of distribution of iron staining between ARJP and PD. In addition neurites of SN in ARJP showed intense iron staining. Thus, we postulate that oxidative stress may play an important role in the neurodegeneration that occurs in ARJP.
In Parkinson disease (PD), α-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this ...phenomenon is unclear. Here, we show the physiological association of Sept4 with α-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human α-synucleinA53T (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PD model, insoluble deposits of Ser129-phosphorylated α-synucleinA53T are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects α-synuclein against self-aggregation and Ser129 phosphorylation. Taken together, these data show that Sept4 may be involved in PD as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance α-synuclein neurotoxicity.
A 44-year-old woman presented with a large-cell neuroendocrine carcinoma and uterine endometrioid carcinoma with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. Following the diagnosis of ...uterine cancer, the patient suddenly developed psychosis with abnormal behaviors, delusions, irritability, and forgetfulness. The cerebrospinal fluid tested positive for anti-NMDAR antibodies (encoding the NR1 subunit). The patient was diagnosed with paraneoplastic limbic encephalitis due to uterine cancer. Histology of multiple abdominal metastatic samples revealed a neuroendocrine tumor. Her consciousness improved temporarily after tumor resection and comprehensive immunomodulatory therapy. On day 104 after admission, the patient died of multiple organ failure. The autopsy revealed a perivascular infiltration of inflammatory cells in the amygdala and NMDAR-positive cells in the primary uterine cancer. Our findings demonstrated that neuroendocrine tumors can induce anti-NMDAR encephalitis, which is consistent with three previous reports. A comprehensive treatment with resection of the carcinoma, immunoglobulins, and plasma exchange can induce a partial improvement of the symptoms.
•A case of a neuroendocrine tumor and endometrioid carcinoma of the uterus.•Subsequently, she developed anti-N-methyl-d-aspartate receptor encephalitis.•Immunohistochemistry confirmed that the patient's uterine cancer expressed NMDAR1.•The comprehensive treatments resulted in temporary improvements in consciousness.•Anti-NMDAR encephalitis is associated with neuroendocrine tumors.
The present report documents a patient harboring an alpha-synuclein p.A53T variant from a family presenting with autosomal dominant inheritance, including four patients clinically diagnosed with ...Parkinson's disease (PD) and two with dementia. The alpha-synuclein p.A53T variant is linked to young- or middle-aged onset parkinsonism and cognitive decline. Our patient had a different haplotype from that of a patient with a p.A53T variant from an Italian family. The proband presented at 42 years of age with progressive parkinsonism and good response to levodopa in the early stages of the disease. At 46 years of age, he developed delusions and cognitive decline. Brain magnetic resonance imaging showed bilateral atrophic changes in the hippocampus and temporal lobes. He died of pneumonia at the age of 52 years. Neuropathological examination revealed severe neuronal loss in the substantia nigra, locus coeruleus, and dorsal nucleus of the vagus nerve, as well as widespread Lewy pathology including Lewy bodies and neurites, corresponding to Braak stage 6, and diffuse neocortical-type PD. There was mild appearance of tau pathology and glial cytoplasmic inclusion, in the absence of TDP-43 pathology. Alpha-synuclein p.A53T characteristically cause the Lewy body pathology and the symptoms, that resembled those of the reported patients with p.A53T.
•We describe a case of patient with an alpha-synuclein p.A53T mutation.•Widespread cortical Lewy bodies and diffuse neocortical-type PD were noted.•Mild tau pathology and the absence of TDP-43 pathology were also noted.
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