Journal of Neurology, Neurosurgery, and Psychiatry最新文献

Recent revisions of Alzheimer’s Disease (AD) definitions by two leading research groups—the Alzheimer’s Association and the International Working Group—reflect divergent approaches: the former promotes a strictly biological definition, while the latter promotes a clinicalbiological construct. We contend that this emerging controversy is not merely semantic, but scientifically, clinically, and politically significant. Drawing on philosophical tools and situating the current debate within a broader historical context from the reconceptualization of AD in the 1970s onwards, we explore how definitions can serve as transformative instruments, acting as strategic bets that reshape scientific fields and clinical practices. Ultimately, we draw from the AD case study to argue for a critical reflection on the risks and promises of such definitional acts. We also propose a renewed attention to the 'ethics of stipulating' in the field of contemporary biomedical sciences.

Background: Climate change is one of the greatest contemporary challenges to human health, undermining human health through multiple mechanisms. Among relatively understudied mechanisms are those related to individual genomic variation. We aimed to examine this possibility.

Methods: Through a defined, agnostic literature review-based approach, we curated human genetic variants with functionally characterised temperature-dependent effects: we call these 'calortypic variants', some of which are linked to temperature-sensitive disease phenotypes. Next, we examined their occurrence in whole-genome sequenced rare disease cohort and analysed their associated phenotypes. Finally, we performed transcriptomic analysis in astrocyte models to examine the impact of short-term exposure to elevated ambient temperature.

Results: A set of 159 calortypic variants across 65 calortypic genes was identified; most (66.7%) calortypic variants caused temperature-sensitive disease phenotypes, and 44.7% were found in neurological and neurodevelopmental diseases. Calortypic variants were also found in 300/39 834 participants recruited to the Genomics England (GEL) 100 000 Genomes rare disease programme. Temperature-related phenotypes were documented in eight GEL participants; in 6/8 participants (two probands and four of their relatives), calortypic variants had already been identified as the disease-causing variant. Gene expression changes across human astrocyte transcriptomes studied under different temperature exposures prominently featured genes related to extracellular matrix maintenance, inflammation, immune response and energy metabolism, all processes that feature in various neurological diseases.

Conclusions: Genetic variation may generate latent phenotypes that manifest only at elevated ambient temperatures, with some neurological disease groups being highlighted. This is an exploratory study. Identifying more calortypic variants will help uncover the full spectrum of human genetic vulnerability to climate change impacts.

Background: Physical activity has been associated with neuroprotective and immunomodulatory benefits, potentially influencing long-term disability outcomes in multiple sclerosis (MS). However, longitudinal evidence on its role in modifying disease progression remains limited.

Methods: We analysed 3284 individuals with incident relapsing-remitting MS from the Swedish Epidemiologic Investigation of MS. Participants were followed for up to 15 years through the Swedish MS Registry. Physical activity at diagnosis was categorised into low, moderate, moderate-high and high activity. The primary outcomes were time to confirmed disability worsening (CDW) and progression to Expanded Disability Status Scale (EDSS) 3 and 4. Changes in physical activity post diagnosis were analysed in a subsample (n=1724). Cox regression models were used to estimate HRs adjusting for clinical and lifestyle factors.

Results: Higher levels of physical activity at diagnosis were associated with reduced risk of disability progression. Compared with low physical activity, the risk of CDW was reduced for moderate (HR 0.77, 95% CI 0.61 to 0.97), moderate-high (HR 0.71, 95% CI 0.54 to 0.94) and high physical activity (HR 0.64, 95% CI 0.46 to 0.90). Similar trends were observed for reaching EDSS 3 and EDSS 4. Increasing activity post-diagnosis was associated with more favourable outcomes, while physical activity before diagnosis showed no significant association with long-term disability progression.

Conclusions: Our findings suggest that physical activity may beneficially influence disease progression in MS. The observed associations highlight the importance of maintaining regular physical activity for ongoing clinical benefits. Our results support including physical activity promotion as a component of standard MS care to optimise long-term outcomes.

Background: The socioeconomic burden of early onset dementia (EOD) defined as disease onset before the age of 65 years, is substantial due to its widespread disabling effects in relatively young individuals. While dementia is widely recognised as a major contributor to mortality among the elderly, only a limited number of studies have assessed survival and factors associated with prognosis specifically in EOD.

Methods: A population-based cohort study, encompassing all incident EOD cases from two defined regions in Finland. The survival and all-cause mortality rates in EOD and its subtypes were evaluated from January 2010 to December 2021. All visits at the dementia outpatient clinics were reviewed and manually re-assessed (n=12 490), resulting in 794 validated EOD cases of Alzheimer's disease (AD), frontotemporal dementia (FTD), alpha-synucleinopathy (α-SYNU) and other EOD spectra. Region-, age- and sex-matched control groups without neurodegenerative diseases were created from nonselective general population data registers (1:10 case to control ratio, 7930 controls in total).

Results: The median survival for EOD was 8.7 years, with the shortest survival in the FTD (6.9 years) and α-SYNU groups (7.0 years), followed by the AD group (9.9 years). Compared with controls, mortality was significantly higher in the total EOD group (HR=6.56, 95% CI=5.56-7.74, p<0.001). Among the dementia subtypes, FTD spectrum patients had the highest all-cause mortality risk compared with controls (HR=13.75, 95% CI=10.25-18.43, p<0.001). Male sex, older age, several comorbidities and lower level of education were associated with increased mortality, but these were not EOD-specific.

Conclusion: EOD diagnosis significantly deteriorates patients' survival, with significant variation between different diagnostic groups and in relation to patients' demographic factors.

Background: Motor and cognitive dysfunctions are common and disabling features in multiple sclerosis (MS) that remain challenging to treat. Here, we aimed to explore the effect of exergames as a stand-alone approach for people with MS and impaired processing speed.

Methods: This was a three-arm, randomised, rater-blinded, sham-controlled trial. People with MS and impaired processing speed were randomised in a 1:1:1 ratio to an 8-week home-based training with exergames (intervention of interest), adaptive Cognitive Training Kit (COGNI-TRAcK) (working memory training as comparator intervention) or sham intervention. A postintervention assessment was scheduled at week 16 postrandomisation. Statistical analyses were conducted to test the hypotheses that exergames were superior to sham intervention and non-inferior to adaptive COGNI-TRAcK on the symbol digit modalities test (SDMT).

Results: We screened 165 people with MS, of whom 102 were randomised (34 per arm). At week 8, both exergames and adaptive COGNI-TRAcK yielded improvements in SDMT, with adjusted mean differences versus sham intervention of 4.3 (95% CI 0.1 to 8.5) and 5.7 (95% CI 1.3 to 10.1) points, respectively. The non-inferiority analysis was inconclusive, as the mean between-arm difference (adaptive COGNI-TRAcK versus exergames) was 1.3 points (90% CI -1.7 to 4.3), crossing the predefined non-inferiority margin of 4 SDMT points. Exergames additionally demonstrated benefits on executive function, dynamic balance, fatigue and reduced work absenteeism. None of these benefits was retained at week 16.

Conclusion: This study provides evidence that home-based exergames are suitable as a standalone approach to improve some specific MS-related cognitive and motor dysfunctions, but there is no evidence about their non-inferiority to working memory training.

Trial registration number: NCT04169750.

Background: The main goal of treatment in relapsing-remitting multiple sclerosis (RRMS) is to reduce the occurrence of relapses. However, little is known about the natural history of relapse recovery.

Methods: We accessed data from DECIDE (n=1841), a phase 3 trial. We investigated factors associated with time to relapse recovery (defined as a return of the Expanded Disability Status Scale (EDSS) score to the pre-relapse level or lower), relapse severity (0.5, 1.0, or >1.0 EDSS score change) and the new concept of 'acute clinical events with stable MRI' (ACES). Variables used were age, sex, disease duration, treatment arm, pre-relapse EDSS, corticosteroid use, number of relapses prior to study enrolment, MRI activity, relapse severity and affected functional system (FS).

Results: We included 430 first relapses, of which 405 (94.2%) recovered during follow-up, 400 (93%) by 1 year (median time to recovery of 71 days, 95% CI 66 to 75 days). More severe relapses and relapses involving the bowel and bladder FS took a longer time to recover. Corticosteroids hastened the recovery of relapses but did not influence eventual relapse recovery. ACES occurred in 38% of relapses and was more frequent in older people and participants treated with daclizumab.

Conclusions: Most relapses (94.2%) recover, but the process of recovery can take up to 1 year and depends mostly on relapse severity. Our findings challenge the concept of 3-month and 6-month confirmed disability progression as reliable markers of permanent disability in RRMS trials. ACES occurs frequently and is associated with age.

Background: Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening disease with frequent autonomic manifestations. Autonomic testing is not widely accessible, which might cause underdiagnosis of autonomic dysfunction and delay in treatment. This retrospective study evaluates ambulatory 24-hour blood pressure measurement (ABPM) as a screening tool for neurogenic orthostatic hypotension (nOH), postprandial hypotension and worsening of orthostatic tolerance postexercise by comparison with gold standard testing. Furthermore, it investigates circadian BP rhythm in ATTRv over time.

Methods: 93 patients and 12 asymptomatic TTR variant carriers had ABPM including autonomic diary and quantitative autonomic function testing (AFT; 30% females, mean age 57.6 years). A subset of individuals underwent a modified exercise and liquid meal test. 47 individuals had follow-up ABPM.

Results: Sensitivity/specificity of ABPM in detecting nOH and postprandial hypotension were 73%/98% and 86%/81%, respectively. ABPM captured worsening of orthostatic tolerance postexercise (p=0.007). 71/105 (68%) individuals showed an abnormal dipping profile (51 reduced dippers, 20 non- or reverse dippers), and 4/71 were carriers (all reduced dippers). All non- or reverse dippers presented with pathologic AFT. 7/8 (88%) carriers and 20/26 (77%) patients with normal ABPM had abnormal AFT. At follow-up, 21% showed progressive circadian rhythm abnormalities.

Conclusions: ABPM with an autonomic diary is a widely accessible screening tool to detect nOH, postprandial hypotension, and impaired circadian rhythm. However, it does not allow for a quantitative parasympathetic/sympathetic assessment confirming subtle autonomic dysfunction, which is why a formal AFT is still required. Pathologic BP profiles are common in ATTRv, including in certain carriers, and can show progression over time.

Background: Late-onset Pompe disease has a characteristic pattern of fat replacement and wasting of especially axial and hamstring muscles. This characteristic pattern of muscle degeneration is still to be explained but could relate to differences in how glycogen is deposited in the different muscles. This cross-sectional observational study investigates the glycogen levels of different muscle groups in young late-onset Pompe subjects and matched controls.

Methods: ¹³C-MR Spectroscopy at 7 Tesla field strength was used to quantify glycogen concentration in four muscle groups: the calf, hamstring, anterior thigh and lumbar muscles of patients with late-onset Pompe disease and healthy controls. An unpaired t-test with correction for multiple comparisons was used to test the difference between Pompe subjects and healthy controls for each muscle area.

Results: 11 late-onset Pompe patients (6 female, mean age 31, range 20-44) and 16 healthy volunteers (10 female, mean age 27, range 19-35) were included. We found that Pompe subjects had 1.8 (95% CI 1.56 to 2.16) times more glycogen in hamstring muscles (p≤0.001) and 2.2 (95% CI 1.24 to 2.48) times more in lumbar muscles (p≤0.004), 1.4 (95% CI 1.07 to 1.73) times more in the anterior thigh muscles (p=0.045) while levels were similar to healthy persons in the calf (95% CI 0.83 to 1.12, p=0.7).

Conclusions: The first muscles to degenerate in Pompe disease are hamstring and paraspinals. Our findings, therefore, suggest that high glycogen levels precede fatty degeneration of muscles, and that monitoring glycogen levels could be an important biomarker to assess treatment effect in Pompe disease.