Journal of Neurology最新文献

Discrepancies in results between cerebrospinal fluid (CSF) 14-3-3 protein and prion protein detection using real-time quaking-induced conversion (RT-QuIC) might limit the confidence in ante-mortem clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD). We aimed to evaluate the concordance and diagnostic performance of 14-3-3 protein and RT-QuIC in a real clinical practice cohort, and to analyze neuronal/glial damage biomarkers in sCJD patients based on their diagnostic assay results. A retrospective multicentre study was conducted on 157 suspected sCJD patients from 38 Spanish hospitals in a 4-year period. CSF 14-3-3 protein and RT-QuIC were simultaneously evaluated in a single laboratory. A diagnosis of probable sCJD was established in 63 patients (40.1%), of which 12 (19.0%) were ultimately diagnosed with definite sCJD. Forty-one sCJD patients (65.1%) were positive for both 14-3-3 protein and RT-QuIC, 17 (27.0%) isolated positive for RT-QuIC, and 5 (7.9%) isolated positive for 14-3-3 protein. RT-QuIC demonstrated higher sensitivity (92.1%) and specificity (98.9%) compared to 14-3-3 (73.0% and 62.8%) for the diagnosis of sCJD. Isolated RT-QuIC positivity was associated with longer disease duration (median: 10.5 months, IQR: 8.8-15.7), higher frequency of Met/Val cases (75.0%), lower prevalence of periodic sharp-wave complexes (5.9%), and lower levels of GFAP (3967.4 pg/mL), UCH-L1 (2218.1 pg/mL), and t-Tau (228.8 pg/mL) compared to double-positive and isolated 14-3-3-positive patients. In conclusion, CSF RT-QuIC is a highly specific and sensitive biomarker for ante-mortem sCJD diagnosis and should be considered as the preferred CSF ancillary test. Isolated RT-QuIC positivity indicates a less aggressive biological disease in sCJD patients.

Rituximab (RTX) is a monoclonal antibody targeting the B-cell CD20 surface antigen used as a prophylactic treatment for Aquaporin 4-immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD). However, a consensus regarding dosage and maintenance intervals is lacking, and the effects of regular/irregular use on disease recurrence and prognosis, and the risk factors associated with clinical relapse, remain unclear. Therefore, we investigated the efficacy/safety of regular RTX use in patients with NMOSD, and explored risk factors associated with clinical relapses. Data from 106 patients with NMOSD were retrospectively collected from January 5, 2016, and March 1, 2023. Patients were categorized as regular/irregular RTX use, with the latter defined by two intervals of > 9 months, or a single interval of > 12 months, without B-cell monitoring. Compared to the regular treatment group, irregular treatment group showed significant higher annual recurrence rate (ARR) (p = 0.033), Expanded Disability Status Scale (EDSS) score (p = 0.041), and proportions of severe relapse (p = 0.006). In regular RTX use group, the cumulative relapse risk after RTX treatment was significantly lower (p < 0.001). When only considering relapses occurring more than 1 month after starting RTX treatment, 82.3% (51/62) of AQP4-IgG + NMOSD were relapse-free. Independent risk factors of relapse included serum AQP4-IgG titer ≥ 320 at initial disease onset, and severe demyelinating episodes in the first attack. There were no severe side effects. Regular RTX treatment significantly reduces the ARR, incidence of severe relapse, and disability risk in patients with NMOSD.

Visual hallucinations in individuals following sight loss (Charles Bonnet syndrome; CBS) have been posited to arise because of spontaneous, compensatory, neural activity in the visual cortex following sensory input loss from the eyes-known as deafferentation. However, neurophysiological investigations of CBS remain limited. We performed a multi-modal investigation comparing visual cortical activity in 19 people with eye disease who experience visual hallucinations (CBS) with 18 people with eye disease without hallucinations (ED-Controls; matched for age and visual acuity) utilising functional MRI, EEG, and transcranial magnetic stimulation (TMS). A pattern of altered visual cortical activity in people with CBS was noted across investigations. Reduced BOLD activation in ventral extrastriate and primary visual cortex, and reduced EEG alpha-reactivity in response to visual stimulation was observed in CBS compared to ED-Controls. The CBS group also demonstrated a shift towards lower frequency band oscillations in the EEG, indicative of cortical slowing, with significantly greater occipital theta power compared to ED-controls. Furthermore, a significant association between reduced activation in response to visual stimulation and increased excitability (in the form of reduced TMS phosphene thresholds) was observed in CBS, indicating persistent visual cortical activation consistent with hyperexcitability, which was found to be significantly associated with increased hallucination severity. These results provide converging lines of evidence to support the role of increased visual cortical excitability in the formation of visual hallucinations in some people following sight loss, consistent with the deafferentation hypothesis.

Background: Orthostatic hypotension (OH) is a common symptom of multiple system atrophy (MSA), however, its role in cognitive impairment and the mechanism in these patients remains unclear. This study aims to assess the role of OH on cognitive impairment in MSA patients, as well as to explore the potential association of cerebral autoregulation (CA) and white matter hyperintensities (WMHs) on cognitive impairment.

Methods: This observational study was conducted in three general hospitals in China from January 2018 to October 2023, with patients at one center followed up for 6 months after enrollment. The primary outcomes included cognitive function assessed using the Mini-Mental State Examination (MMSE) and Montreal cognitive assessment (MoCA). Secondary outcomes included the results of the Head-up tilt test, scores for CA and the extent of WMHs.

Results: The 132 MSA patients included 72 men (54.54%) with a mean age of 61.16 (7.80) years. Among them, 80 patients (60.61%) had orthostatic hypotension, and 48 patients (36.36%) had cognitive impairment. OH plays an important role in cognitive impairment in MSA patients (OR = 0.328,95% CI 0.135-0.797, P = 0.014). Cognitive impairment was associated with impaired CA (OR = 0.088,95% CI 0.012-0.657, P = 0.018) and severe WMHs (OR = 0.030,95% CI 0.002-0.423, P = 0.009), particularly in the presence of OH.

Conclusion: OH is associated with cognitive impairment in MSA patients, and cognitive decline is linked to impaired CA and increased WMHs. Future studies are needed to explore the mechanisms underlying cognitive impairment in MSA patients.

Background: Cognitive dysfunction is increasingly recognized in multiple system atrophy (MSA). Locus coeruleus (LC) integrity is associated with cognitive performance both in healthy controls (HC) and neurodegenerative conditions such as Parkinson's disease (PD). Furthermore, cortical glucose hypometabolism is associated with impaired cognitive performance in MSA. However, knowledge about LC sub-regional degeneration and its association with cognitive dysfunction and cortical glucose metabolism is lacking.

Objective: To investigate LC sub-regional involvement and its association with cognitive impairment and brain metabolism in MSA.

Methods: Eleven MSA, eighteen PD, and eighteen HC participants were included in the study. Neuromelanin-sensitive MRI was used to determine rostral, middle and caudal LC neuromelanin signals. Brain glucose metabolism was investigated with [¹⁸F]Fluorodeoxyglucose PET (FDG-PET). The Montreal Cognitive Assessment (MoCA) was used as a measure of global cognition.

Results: Middle LC neuromelanin signal was significantly reduced in MSA [t(43) = 3.70, corrected-p = 0.004] and PD [t(43) = 2.63, corrected-p = 0.041] compared to HC, while caudal LC was only reduced in MSA [t(43) = 2.82, corrected-p = 0.030]. In MSA, decreased rostral LC neuromelanin was associated with lower MoCA scores (ρ = 0.760, p = 0.006) which, in turn, were associated with lower frontal cortex glucose metabolism. An association between rostral LC neuromelanin signal and frontal cortex glucose metabolism was found in exploratory analyses.

Conclusion: Loss of LC neuromelanin signal was found in MSA, the middle and caudal parts being targeted. Rostral LC neuromelanin signal loss was associated with both frontal cortex hypometabolism and lower MoCA scores. This pathophysiological link should be further investigated as the noradrenergic system transmission is amenable to pharmacological manipulation.

Background: Inherited peripheral neuropathies (IPNs) encompass a wide range of disorders affecting the peripheral nervous system, often with complex genetic causes and frequent underdiagnosis. The variants in the superoxide dismutase 1 (SOD1) gene, primarily linked to amyotrophic lateral sclerosis (ALS), have also been associated with peripheral neuropathy. The recent approval of Tofersen, targeting SOD1-related ALS, highlights the importance of precise genetic diagnosis. This study explores the clinical and genetic profiles of SOD1-related IPNs (SOD1-IPN) in a nationwide Japanese IPN cohort.

Methods: Clinical and genetic data were assessed from 1483 Japanese patients with IPN, with a focus on those harboring SOD1 pathogenic variants. The clinical evaluations included age of onset, gender, muscle weakness patterns, sensory disturbances, reflex responses, and electrophysiological findings.

Results: Seventeen patients with SOD1 pathogenic variants were identified, reinforcing SOD1's role in IPN. The average onset age was 47, with a slight male predominance. Distal muscle weakness was noted in 9 of 13 patients, and asymmetric muscle weakness and atrophy in 10 of 14 cases. Mild sensory disturbances were observed in eight patients, with some showing hyperreflexia and abnormal reflexes. Electrophysiology predominantly indicated a length-dependent, motor-dominant axonal neuropathy.

Conclusion: This study reveals the clinical variability and likely underdiagnosis of SOD1-IPN, supporting the integration of SOD1 screening in IPN genetic testing, especially for patients with asymmetric, length-dependent axonal neuropathy evident in clinical and electrophysiological assessments.

Accelerometry enables passive, continuous, high-frequency monitoring under free-living conditions. For individuals with isolated REM sleep behavior disorder (iRBD), a potential prodromal phase of Parkinson's disease (PD) and dementia with Lewy bodies, accelerometry has been primarily applied to aid diagnosis and to assess phenoconversion risk. To extend this knowledge, we cross-sectionally combined clinical assessments focusing on non-motor symptoms with accelerometry-derived features of physical activity (PA), sleep, and circadian rhythm of N = 68 individuals with iRBD (age: 69.48 ± 6.01 years, self-reported RBD symptom duration: 9.46 ± 6.21 years, 85 % male). Accelerometry-assessed PA was associated with more stable circadian rhythms. Additionally, higher PA and more stable circadian rhythms were linked to a lower burden of overall non-motor symptoms, depressive symptoms, and fatigue with small to moderate effect sizes. Furthermore, including accelerometry-derived features improved the prediction of individual clinical scores, particularly for cognitive performance. Our findings contribute to the growing body of evidence highlighting the complex interplay between PA, sleep, circadian rhythm, and non-motor symptoms in α-synucleinopathies. Future research should focus on longitudinal studies to monitor changes in clinical outcomes and digital biomarkers over time to enhance our understanding of symptom progression and corresponding lifestyle changes in prodromal and manifest α-synucleinopathies.