Neurology最新文献

Background and objectives: Frontotemporal lobar degeneration (FTLD) can present as a behavioral or language variant (bvFTLD or a primary progressive aphasia [PPA], or as a syndrome with parkinsonism, such as corticobasal syndrome [CBS] or progressive supranuclear palsy [PSP]). The incidence of FTLD varies in epidemiologic studies, reaching 3 per 100,000 person-years. Only few data exist regarding survival times. We evaluated incidence and survival rates in a population-based registry with high coverage in Southern Germany.

Methods: The epidemiologic ALS-FTLD registry Swabia covers a population of 8.4 million inhabitants in south-west Germany. Raw and age-standardized incidence rates, as well as incidence rate ratios (IRR) with 95% CIs were calculated. Median survival time was estimated for different FTLD variants using the Kaplan-Meier method.

Results: Between 2015 and 2022, 515 patients with FTLD (mean age at diagnosis 68.0 ± 9.5 years, 59.8% men) were registered. The median diagnostic delay was 24.8 months. The most common variant was bvFTLD (n = 185, 35.9%; 66.5% men), followed by PPA (n = 147, 28.5%; 51.0% men), PSP (n = 133, 25.8%; 62.9% men), and CBS (n = 22, 4.3%; 50% men). The overall FTLD incidence was 0.77 (95% CI 0.71-0.84), and the age-standardized incidence was 0.76 (95% CI 0.69-0.82) per 100.000 person-years. The age-standardized incidence was higher in men than in women, with an IRR of 1.73 (95% CI 1.44-2.00). In men, incidence increased from the age 50 years, primarily due to bvFTD, whereas in women this rise was primarily due to PSP. The median survival (N = 392) from diagnosis was 53.6 months (95% CI 50.9-62.0) overall, 73.1 months (95% CI 63.6-82.8) for patients with PPA, 42.8 months (95% CI 35.1-64.3) for patients with bvFTD, and 49.5 months (95% CI 39.2-53.7) for patients with PPS/CBS.

Discussion: We observed a raw incidence rate of 0.77, thus considerably lower than in most previous reports. Incidence was substantially higher in men than in women. The prognosis from the time of diagnosis depended highly on the specific FTLD subtype. Our data are based on the large sample size and high capture rate of a central European population-based registry.

Background and objectives: The residual recurrence risk after atrial fibrillation (AF)-related stroke is high despite anticoagulation, thereby necessitating new therapies. The importance of inflammation in AF is increasingly recognized. However, patients with AF-related stroke were excluded from recent trials of anti-inflammatory therapies. It is uncertain whether associations between IL-6/high-sensitivity C-reactive protein (hsCRP) and poststroke recurrence are modified by AF status. In this study, we aimed to analyze the association between IL-6/hsCRP and recurrence according to AF history.

Methods: We leveraged individual participant data from studies identified by systematic review. We analyzed associations between IL-6/hsCRP and recurrent stroke/major adverse cardiovascular events (MACEs) (defined as fatal or nonfatal recurrent stroke or major coronary events) using multivariable Cox regression analyses (conditional logistic regression for 1 study) adjusted for age, sex, index event, cardiovascular risk factors, and medication use, stratified by AF status.

Results: Data from 11 prospective studies with 10,080 patients (2,134 with AF, mean age 70 years, 59.3% male) were included. During 21,080 person-years of follow-up, 1,677 patients had MACEs and 1,342 had recurrent stroke. Inflammatory markers were higher in patients with AF, irrespective of stroke severity and timing of measurement, with elevated levels persisting well beyond the acute phase. hsCRP was associated with recurrent MACEs in patients with AF (adjusted risk ratio [aRR] 1.14, 95% CI 1.04-1.25, per log_e-unit increase) and without AF (aRR 1.08, 1.03-1.13) (P_interaction 0.30). There were similar associations on per-quarter analysis in patients with AF (aRR 1.51, 1.04-2.18) and without AF (aRR 1.32, 1.10-1.59) (Q4 vs Q1). No association was observed between hsCRP and recurrent stroke in either group. For IL-6, there was no evidence of interaction according to AF status for MACEs (P_interaction 0.57) or recurrent stroke (P_interaction 0.82). The aRR per log_e unit for MACE was 1.17 (1.07-1.27) in patients without AF and 1.10 (0.91-1.34) in those with AF. The corresponding aRR for recurrent stroke was 1.15 (1.05-1.25) and 1.12 (0.91-1.37) in patients without and with AF, respectively.

Discussion: These data highlight the importance of inflammatory mechanisms in vascular recurrence irrespective of AF, provide rationale for the inclusion of patients with AF in trials of anti-inflammatory therapy, and support a selection approach in future trials based on elevated inflammatory marker levels, rather than stroke etiology alone.

Synaptic vesicle exocytosis and endocytosis are 2 fundamental processes that involve the coordinated and timely activity of many proteins and protein-lipid interactions. Alpha-synuclein (α-Syn) regulates several steps of these processes. Impaired exocytosis and endocytosis are important consequences of Parkinson disease (PD), reflecting both loss of function of normal α-Syn and toxic gain of function of abnormal α-Syn aggregates. Studies in familial forms of PD indicate that abnormal functions of other critical proteins such as leucine repeat rich kinase 2 also impair normal synaptic vesicular trafficking and contribute to synaptic dysfunction and secondary neurodegeneration.

Spinocerebellar ataxia type 27B (SCA27B) is a recently identified autosomal dominant form of late-onset cerebellar ataxia (LOCA) caused by a guanine-adenine-adenine (GAA) > 250 intronic repeat expansion in the fibroblast growth factor 14 (FGF14) gene. Recent studies suggest that SCA27B may account for 10%-60% of undiagnosed patients with LOCA. Age at onset ranges from 40s to 70s, and clinical features include slowly progressive pancerebellar syndrome with prominent gait ataxia and cerebellar oculomotor abnormalities. Positive family history may be absent, particularly given the characteristically late onset of this condition. It is important to note that up to half of the patients with SCA27B report episodic symptoms, including imbalance, vertigo, visual disturbances, or dysarthria, which might initially manifest without clear interictal clinical or radiologic features of cerebellar ataxia. These features can result in the misdiagnosis of SCA27B. We present 2 patients with LOCA. Both patients initially received alternative working diagnoses, which were re-examined several years later only after symptoms and imaging findings progressed. First-line genetic testing for both patients was unrevealing because of the deep intronic location of the causative variant. Ultimately, whole-genome-based testing in one case and targeted FGF14 trinucleotide repeat analysis in the other revealed the diagnosis of SCA27B. These cases highlight SCA27B as a cause of episodic neurologic symptoms in an older adult population. Furthermore, these cases demonstrate the potential pitfalls of panel and exome-based genetic testing, given the important role of pathogenic intronic variants in the spectrum of neurogenetic disorders.

Background and objectives: Smoking has been reported to be inversely associated with Parkinson disease (PD). However, the higher premature mortality among smokers may act as a competing risk, potentially confounding the inverse association. Because smoking behavior is dynamic, the long-term impact of changes among current smokers remains unclear. We investigated the association between longitudinal changes in smoking status and the risks of PD and all-cause mortality using a competing risk framework and an age-based time scale with left truncation.

Methods: This large-scale retrospective cohort study included current smokers aged 40 years or older who participated in all 3 examination periods of the Korean National Health Screening. Based on longitudinal changes from the initial smoking status to 2 subsequent time points, participants were categorized into 4 groups: persistent smokers, recent quitters, sustained quitters, and relapsed smokers. Cumulative incidence functions for PD were estimated, with all-cause mortality as a competing event, and subdistribution hazard ratios (sHRs) with 95% CIs were obtained using Fine-Gray models.

Results: Data were obtained from 410,489 eligible participants (mean age 51.7 ± 9.0 years; 93.5% male). During a median 9.1-year follow-up, persistent smokers exhibited the lowest risk of PD. Both recent quitters and sustained quitters had higher PD risk than persistent smokers (sHR 1.60 [1.41-1.82] and 1.61 [1.42-1.81]), whereas relapsed smokers did not differ from persistent smokers (sHR 1.05 [0.87-1.28]). For all-cause mortality, recent and sustained quitters had 3% and 17% lower risks, respectively, compared with persistent smokers, whereas relapsed smokers showed no significant difference.

Discussion: The observed pattern of PD risk was suggested to be primarily associated with current smoking status rather than cumulative smoking exposure, as relapsed smokers and recent quitters, who had the same number of smoking time points, showed distinctly different risks. Furthermore, 1 time point (∼2 years) of short-term abstinence did not attenuate the protective association. Mortality was lowest in sustained quitters while recent quitters showed a marginal trend toward lower risk, supporting the benefit of early cessation. Interpretation should be cautious because smoking status was assessed at 3 time points, subsequent changes were unknown, and most participants were male.