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To the Editor: The study by Dwivedi and colleagues (Oct. 26 issue) 1 on the efficacy of surgery in children with drug-resistant epilepsy includes more patients than either of the two previous randomized, controlled trials of epilepsy surgery. Also, it covers the whole pediatric age span and includes diverse surgical procedures. 2,3 However, we have a concern related to the report of serious adverse events in 33% of the patients in the surgery group. Usually, major unexpected complications are reported in less than 5% of the patients in studies of epilepsy surgery. 4,5 The explanation is probably that expected adverse events (e.g., the . . .

Background Traditional pen‐and‐paper neuropsychological assessments fail to capture subtle cognitive changes in the early stages of Alzheimer’s disease (AD). Remote and unsupervised digital assessments available on smartphones, tablets, and personal computers may offer a solution to this by increasing the amount and types of data available to researchers and clinicians, while simultaneously improving ecological validity and alleviating patient burden. As these remote and unsupervised digital cognitive assessment tools become more widely available, it is important that they are validated in a systematic way. In this review, we evaluate the validity of available remote tools, focusing on active assessment tools with which the patient interacts with (i.e., cognitive tests, active speech) that have been used to investigate subtle cognitive differences in preclinical AD, defined as clinically unimpaired individuals with biomarkers indicating increased risk of dementia due to AD. Methods We performed a systematic literature review on PubMed, Web of Science, and PsycInfo using terms such as “digital,” “remote,” “unsupervised,” “cognition,” “aging,” and “Alzheimer’s,” which resulted in a total of 1,453 unique peer‐reviewed articles and pre‐prints. After filtering for tools that were remotely self‐administered in humans, and excluding papers detailing findings in populations with other diseases than AD (e.g., multiple sclerosis, Parkinson’s disease) or papers reporting findings of intervention studies, 14 papers reporting the use or planned use of 14 tools to detect AD pathology in preclinical AD were selected (as of Jan. 2024). Results We evaluate each tool with regards to its use‐case and usability, as well as various types of validity, and suggest a framework with which future tools may also be evaluated. Additionally, we discuss current directions in the field of remote and unsupervised digital cognitive assessment in early AD. Conclusion With this review, we hope to show that the systematic and validated use of such tools will increase our understanding of subtle changes in cognition due to AD pathology, as well as make screening for clinical trials and treatment more accessible.

Background Objective Subtle Cognitive Decline (obj‐SCD) can be identified through standardized neuropsychological tests and may precede the development of Mild Cognitive Impairment (MCI). Nevertheless, current clinical and research criteria lack a standardized protocol for identifying obj‐SCD. This study introduces cutting‐edge sensitive methods to characterize obj‐SCD, defined through Alzheimer’s disease (AD) biomarker‐based longitudinal cognitive performance in episodic memory. Neurocognitive characterization of obj‐SCD is supported by Voxel‐Based Morphometry (VBM) analyses, examining longitudinal changes in Grey Matter volume (GMv) at the preclinical stage of the Alzheimer’s continuum. Method Three hundred cognitively unimpaired (CU) individuals (mean age: 60, SD: 4.76) from the ALFA+ cohort study (three‐year follow‐up) were included. AT(N) profiles were defined at baseline with Cerebrospinal Fluid (CSF) biomarkers. AD biomarker‐based reliable change indices adjusted for practice effect (A‐T‐[N]‐ longitudinal performance as reference) were computed for the assessment of episodic memory (Free‐Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale‐IV). Considering the relationship between the number of neuropsychological measures and the base rate of impaired scores, obj‐SCD was defined as longitudinal biomarker‐based performance below ‐1.645 SD (<5th percentile) in at least 3/11 variables. Magnetic Resonance Imaging scans were performed with 3T‐scanner and a high‐resolution 3D T1‐weighted sequence (voxel‐size: 0.75mm3). Intra‐individual changes in GMv were voxel‐wise computed using longitudinal scans, smoothed at 8mm3. The associations between obj‐SCD and GMv changes were analyzed with VBM linear regression models, selecting a voxel‐wise statistical threshold of p<0.005 with a cluster‐extent correction of 100 voxels. Result According to the above‐defined criteria 19 (6.33%) participants exhibited episodic memory obj‐SCD, with significant differences considering AT profiles (Table‐1). Episodic memory obj‐SCD was associated with longitudinal reductions of GMv bilaterally in the hippocampus and the left cerebellum, as well as widespread increments of GMv involving AD‐vulnerable cortical regions (Table‐2, Figure‐1). Conclusion Episodic memory obj‐SCD captured longitudinal changes in GMv indicative of AD‐progression (i.e., hippocampus). These results suggested that episodic memory obj‐SCD is a consistent marker of AD‐related impairment. Characterizing obj‐SCD enhances preclinical stage identification, with implications for advancing early detection and intervention strategies in Alzheimer’s disease, informing about an elevated risk of AD‐dementia in an otherwise CU population.

Background Neuroimaging studies have revealed age and sex‐specific differences in Alzheimer’s disease (AD) trajectories. However, how age and sex modulate tau spreading remains unclear. Thus, we investigated how age and sex modulate the amyloid‐beta (Aβ)‐induced accumulation and spreading of tau pathology from local epicenters across connected brain regions. Method We included 313 ADNI participants (female/male, n = 167/146), i.e. 110 cognitively normal (CN) Aβ‐negative, and 203 Aβ‐positive subjects across the AD spectrum (i.e. CN/MCI/Dementia, n = 98/70/35) with baseline amyloid‐PET and longitudinal Flortaucipir tau‐PET. Annual tau‐PET change rates for 200 cortical regions of the Schaefer atlas were calculated. Sex‐specific resting‐state fMRI‐connectivity templates across the 200 Schaefer regions were determined in independent Aβ‐negative controls (female/male, n = 118/82) to determine the connectivity of tau epicenters to the rest of the brain. Using linear regression, we investigated interactions between age, sex and Aβ on tau accumulation and spread, controlling for APOE4‐status and diagnosis. Result Higher Aβ (i.e. centiloid) predicted faster tau accumulation, where this association was pronounced in younger individuals (i.e. age x centiloid interaction, b = ‐3.64, p<0.001, Fig. 1A). This age x centiloid interaction was stronger in men (b = ‐4.82, p<0.001, Fig. 1B) vs. women (b = ‐1.67, p = 0.029, Fig. 1C), suggesting that younger age promotes Aβ‐related tau accumulation predominantly in men. Bootstrapping analysis further confirmed this effect (Fig. 1D). In Aβ+, epicenters with highest baseline tau‐PET showed a similar temporal‐lobe distribution in men and women (Fig. 2A&B), yet epicenter connectivity to the rest of the brain was stronger in men vs. women (Fig. 2C). Stronger connectivity of tau epicenters to the rest of the brain was linked to faster tau accumulation especially in younger Aβ+ subjects (i.e. interaction age x epicenter connectivity, b = 4.41, p<0.001, Fig. 3A). However, this effect was clearly driven by men (b = 6.13, p<0.001, Fig. 3B) and not observed when tested in women only (b = 1.55, p = 0.252, Fig. 3C). Conclusion Aβ drives faster tau accumulation and this effect is particularly strong at younger age and even further pronounced in men, whose tau epicenters are more densely interconnected with the rest of the brain. Together, age and sex have clear modulating effects on tau spreading, and heterogeneous AD trajectories may be partly arisen due to sex‐specific differences in brain network architecture.

Background We recently developed a novel tau‐PET summary measure THETA, capturing regional heterogeneity and identifying tau status, using ground truth visual assessments from a large single‐center cross‐sectional dataset and validated on independent cohorts [1, 2]. In this study, we aimed to evaluate the performance of THETA on longitudinal and histopathology data. Method We included longitudinal tau‐PET ([18F]flortaucipir) data from 696 Mayo Clinic Study of Aging (MCSA) and ADRC participants, with histopathology in n = 90. Fig. 1 shows the model that uses regional standard uptake value ratios (SUVR) and a target of binary class of tau positivity for prediction of THETA. This model was applied to predict tau status on each followup scan. Slopes of the meta‐ROIs’ tau SUVRs and THETA were evaluated by diagnostic group and as a function of baseline amyloid SUVR in discordant CU participants (where meta‐ROI and visual assessments did not match at baseline) and in incident‐THETA+ CU participants (whose THETA moved from below to above 1 over serial tau‐PET scans). We evaluated tau measurements as a function of Braak stages for neurofibrillary tangles. Result Longitudinal plots of meta‐ROIs for diagnostic groups were very similar, but the expanded range of THETA based on visual positivity prediction clearly identified tau positive or tau‐negative scans. In discordant‐CU (n = 97) and incident‐THETA+ CU participants (n = 14 all amyloid positive at follow‐up but only 65% at baseline), the relationship between baseline amyloid and rate of tau increase was stronger for THETA than temporal meta‐ROI (Fig. 2). Separation between baseline and follow‐up was greater for THETA (t‐statistics = 90) compared to temporal meta‐ROI (t‐statistics = 20) (p<0.01) in the incident‐THETA+ CU participants. THETA showed a slightly stronger association with Braak stage than meta‐ROIs (rho = 0.87 vs. ≤0.83, p<0.05), with better separation of clinical diagnoses (Fig. 3). Conclusion THETA remained clearly negative or positive in MCI and AD, providing consistent information on underlying etiology of impairment at both baseline and follow‐up. Although binary in its construction, THETA both provided separation of values based on tau status and its change correlated with baseline amyloid burden especially in discordant‐CU where tau deposition is not in typical meta‐ROIs. Further work is needed to confirm if THETA captures early tau changes.

Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and 18F-fluorodeoxyglucose (18F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and 18F-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.

To investigate the incidence and number of occupational gaps 5years after stroke and find possible predictors and explanatory factors for increased number of experienced gaps.The participants were diagnosed with first-time stroke in Gothenburg during 2009-2010. Medical records from their hospital stay were used to obtain baseline data. The Occupational Gaps Questionnaire and the Swedish stroke registers follow-up questionnaire were sent out. Data from the Occupational Gaps Questionnaire were used as a dependent variable and baseline data and questions from the stroke registry were used as independent variables in logistic regression.Five years poststroke, 49.5% experienced a higher number of occupational gaps compared to a healthy reference population. Predictors for an increased number of gaps were higher age at stroke onset and a higher degree of functional dependency. Explanatory factors for an increased number of gaps in the study population were higher age at follow-up and feelings of depression.Older age at the time of stroke and functional dependency can predict an increased number of occupational gaps. Older age and feelings of depression are connected to an increased number of occupational gaps. Individuals at risk should be provided with additional interventions to reduce participation restrictions.

High-efficacy therapies in multiple sclerosis are traditionally used after unsuccessful treatment with first-line disease modifying therapies. We hypothesised that early commencement of high-efficacy therapy would be associated with reduced long-term disability. We therefore aimed to compare long-term disability outcomes between patients who started high-efficacy therapies within 2 years of disease onset with those who started 4–6 years after disease onset. In this retrospective international observational study, we obtained data from the MSBase registry and the Swedish MS registry, which prospectively collect patient data that are specific to multiple sclerosis as part of routine clinical care. We identified adult patients (aged ≥18 years) with relapsing-remitting multiple sclerosis, with at least 6 years of follow-up since disease onset, and who started the high-efficacy therapy (rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab) either 0–2 years (early) or 4–6 years (late) after clinical disease onset. We matched patients in the early and late groups using propensity scores calculated on the basis of their baseline clinical and demographic data. The primary outcome was disability, measured with the Expanded Disability Status Score (EDSS; an ordinal scale of 0–10, with higher scores indicating increased disability), at 6–10 years after disease onset, assessed with a linear mixed-effects model. We identified 6149 patients in the MSBase registry who had been given high-efficacy therapy, with data collected between Jan 1, 1975, and April 13, 2017, and 2626 patients in the Swedish MS Registry, with data collected between Dec 10, 1997, and Sept 16, 2019. Of whom, 308 in the MSBase registry and 236 in the Swedish MS registry were eligible for inclusion. 277 (51%) of 544 patients commenced therapy early and 267 (49%) commenced therapy late. For the primary analysis, we matched 213 patients in the early treatment group with 253 in the late treatment group. At baseline, the mean EDSS score was 2·2 (SD 1·2) in the early group and 2·1 (SD 1·2) in the late group. Median follow-up time for matched patients was 7·8 years (IQR 6·7–8·9). In the sixth year after disease onset, the mean EDSS score was 2·2 (SD 1·6) in the early group compared with 2·9 (SD 1·8) in the late group (p<0·0001). This difference persisted throughout each year of follow-up until the tenth year after disease onset (mean EDSS score 2·3 [SD 1·8] vs 3·5 [SD 2·1]; p<0·0001), with a difference between groups of −0·98 (95% CI −1·51 to −0·45; p<0·0001, adjusted for proportion of time on any disease-modifying therapy) across the 6–10 year follow-up period. High-efficacy therapy commenced within 2 years of disease onset is associated with less disability after 6–10 years than when commenced later in the disease course. This finding can inform decisions regarding optimal sequence and timing of multiple sclerosis therapy. National Health and Medical Research Council Australia and MS Society UK.

Introduction : Patients with multiple sclerosis (MS) are known to have an elevated suicide risk, but attempted suicide is incompletely investigated. Objectives : To estimate attempted suicide and completed suicide risks among MS patients using national registers and to assess if the inverse association of higher-level education with completed suicide is affected by MS. Methods : A total of 29,617 Swedish MS patients were identified through the Swedish Patient Register and matched (by birth year, sex, vital status at diagnosis and region) with 296,164 people without MS from the general population. Cox regression estimated hazard ratios (HR) (with 95% confidence intervals) for the association of MS with attempted and completed suicide, with adjustment for age, sex, education level, decade of study entry, and previous suicide attempts. Results : The adjusted HR for attempted suicide among MS patients is 2.18 (1.97-2.43) compared with the general population cohort. For completed suicide the HR is 1.87 (1.53-2.30). Overall, men were at higher risk of completing suicide, while women were at higher risk of attempting suicide. Higher education is inversely associated with completed suicide among the non-MS cohort with an HR of 0.68, (0.51-0.91), but not among MS patients, where the HR is 1.10, (0.60-2.04). MS patients were less likely to use a violent method than the non-MS cohort. Conclusion : MS patients are at higher risk of both attempted and completed suicide, and the risk increase is present in both men and women. Possibly the stress and perceived prognosis associated with an MS diagnosis increases the risk of suicide. MS appears to eliminate the protective association of higher education with completed suicide.