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Objective Methods Results Interpretation Despite treatments which reduce relapses in multiple sclerosis (MS), many patients continue to experience progressive disability accumulation. MS is associated with metabolic disruptions and cerebral metabolic stress predisposes to tissue injury and possibly impaired remyelination. Additionally, myelin homeostasis is metabolically expensive and reliant on glycolysis. We investigated cerebral metabolic changes in MS and when in the disease course they occurred, and assessed their relationship with microstructural changes.This study used combined fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) to measure cerebral metabolic rate of glucose and oxygen, thereby quantifying glycolysis. Twelve healthy controls, 20 patients with relapsing MS, and 13 patients with non‐relapsing MS were studied. Relapsing patients with MS were treatment naïve and scanned pre‐ and post‐initiation of high efficacy disease modifying therapy.In normal appearing white matter, we observed increased glucose utilization and reduced oxygen utilization in newly diagnosed MS, consistent with increased glycolysis. Increased glycolysis was greater in patients with a longer disease duration course and higher disability. Among newly diagnosed patients, different treatments had differential impacts on glucose utilization. Last, whereas hypermetabolism within lesions was clearly associated with inflammation, no such relationship was found within normal appearing white matter.Increased white matter glycolysis is a prominent feature of cerebral metabolism in MS. It begins early in the disease course, increases with disease duration and is independent of microstructural evidence of inflammation in normal appearing white matter. Optimization of the metabolic environment may be an important component of therapies designed to reduce progressive disability. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid‐β plasma biomarker positivity was approximately half the rate in 300 non‐MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid‐β pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024;96:453–459 [ABSTRACT FROM AUTHOR]

ImportanceAutosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile.ObjectiveTo assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD.Design, setting, and participantsWe analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites.Main outcomes and measuresFor both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs.ResultsA decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers.Conclusions and relevanceResting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivity magnetic resonance imaging may be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.

Objective: This study was undertaken to apply established and emerging cerebrospinal fluid (CSF) biomarkers to improve diagnostic accuracy in patients with rapidly progressive dementia (RPD). Overlap in clinical presentation and results of diagnostic tests confounds etiologic diagnosis in patients with RPD. Objective measures are needed to improve diagnostic accuracy and to recognize patients with potentially treatment‐responsive causes of RPD. Methods: Biomarkers of Alzheimer disease neuropathology (amyloid‐β 42/40 ratio, phosphorylated tau [p‐tau181, p‐tau231]), neuroaxonal/neuronal injury (neurofilament light chain [NfL], visinin‐like protein‐1 [VILIP‐1], total tau), neuroinflammation (chitinase‐3‐like protein [YKL‐40], soluble triggering receptor expressed on myeloid cells 2 [sTREM2], glial fibrillary acidic protein [GFAP], monocyte chemoattractant protein‐1 [MCP‐1]), and synaptic dysfunction (synaptosomal‐associated protein 25kDa, neurogranin) were measured in CSF obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative, vascular, and autoimmune/inflammatory diseases; 35 age‐ and sex‐matched patients with typically progressive neurodegenerative disease; and 72 cognitively normal controls. Biomarker levels were compared across etiologic diagnoses, by potential treatment responsiveness, and between patients with typical and rapidly progressive presentations of neurodegenerative disease. Results: Alzheimer disease biomarkers were associated with neurodegenerative causes of RPD. High NfL, sTREM2, and YKL‐40 and low VILIP‐1 identified patients with autoimmune/inflammatory diseases. MCP‐1 levels were highest in patients with vascular causes of RPD. A multivariate model including GFAP, MCP‐1, p‐tau181, and sTREM2 identified the 44 patients with treatment‐responsive causes of RPD with 89% accuracy. Minimal differences were observed between typical and rapidly progressive presentations of neurodegenerative disease. Interpretation: Selected CSF biomarkers at presentation were associated with etiologic diagnoses and treatment responsiveness in patients with heterogeneous causes of RPD. The ability of cross‐sectional biomarkers to inform upon mechanisms that drive rapidly progressive neurodegenerative disease is less clear. ANN NEUROL 2024;95:299–313 [ABSTRACT FROM AUTHOR]

Objective: To improve the timely recognition of patients with treatment‐responsive causes of rapidly progressive dementia (RPD). Methods: A total of 226 adult patients with suspected RPD were enrolled in a prospective observational study and followed for up to 2 years. Diseases associated with RPD were characterized as potentially treatment‐responsive or non‐responsive, referencing clinical literature. Disease progression was measured using Clinical Dementia Rating® Sum‐of‐Box scores. Clinical and paraclinical features associated with treatment responsiveness were assessed using multivariable logistic regression. Findings informed the development of a clinical criterion optimized to recognize patients with potentially treatment‐responsive causes of RPD early in the diagnostic evaluation. Results: A total of 155 patients met defined RPD criteria, of whom 86 patients (55.5%) had potentially treatment‐responsive causes. The median (range) age‐at‐symptom onset in patients with RPD was 68.9 years (range 22.0–90.7 years), with a similar number of men and women. Seizures, tumor (disease‐associated), magnetic resonance imaging suggestive of autoimmune encephalitis, mania, movement abnormalities, and pleocytosis (≥10 cells/mm3) in cerebrospinal fluid at presentation were independently associated with treatment‐responsive causes of RPD after controlling for age and sex. Those features at presentation, as well as age‐at‐symptom onset <50 years (ie, STAM3P), captured 82 of 86 (95.3%) cases of treatment‐responsive RPD. The presence of ≥3 STAM3P features had a positive predictive value of 100%. Interpretation: Selected features at presentation reliably identified patients with potentially treatment‐responsive causes of RPD. Adaptation of the STAM3P screening score in clinical practice may minimize diagnostic delays and missed opportunities for treatment in patients with suspected RPD. ANN NEUROL 2024;95:237–248 [ABSTRACT FROM AUTHOR]

Carriers of mutations responsible for dominantly inherited Alzheimer disease provide a unique opportunity to study potential imaging biomarkers. Biomarkers based on routinely acquired clinical MR images, could supplement the extant invasive or logistically challenging) biomarker studies. We used 1104 longitudinal MR, 324 amyloid beta, and 87 tau positron emission tomography imaging sessions from 525 participants enrolled in the Dominantly Inherited Alzheimer Network Observational Study to extract novel imaging metrics representing the mean (μ) and standard deviation (σ) of standardized image intensities of T1‐weighted and Fluid attenuated inversion recovery (FLAIR) MR scans. There was an exponential decrease in FLAIR‐μ in mutation carriers and an increase in FLAIR and T1 signal heterogeneity (T1‐σ and FLAIR‐σ) as participants approached the symptom onset in both supramarginal, the right postcentral and right superior temporal gyri as well as both caudate nuclei, putamina, thalami, and amygdalae. After controlling for the effect of regional atrophy, FLAIR‐μ decreased and T1‐σ and FLAIR‐σ increased with increasing amyloid beta and tau deposition in numerous cortical regions. In symptomatic mutation carriers and independent of the effect of regional atrophy, tau pathology demonstrated a stronger relationship with image intensity metrics, compared with amyloid pathology. We propose novel MR imaging intensity‐based metrics using standard clinical T1 and FLAIR images which strongly associates with the progression of pathology in dominantly inherited Alzheimer disease. We suggest that tau pathology may be a key driver of the observed changes in this cohort of patients. [ABSTRACT FROM AUTHOR]

Throughout middle-childhood, inhibitory processes, which underlie many higher order cognitive tasks, are developing. Little is known about how inhibitory processes change as a task becomes conceptually more difficult during these important years. In adults, as Go/NoGo tasks become more difficult there is a systematic decrease in the P3 NoGo response, indicating the use of effective inhibitory strategies (Maguire et al., 2009). This paper investigates the age at which children employ similar inhibitory strategies by studying behavioral and Event Related Potential (ERP) measures of response inhibition for three Go/NoGo tasks. Seventeen 7-8 year-olds and twenty 10-11-year-olds completed three Go/NoGo tasks that differed in the level of categorization necessary to respond. Both age groups displayed slower reaction times as the tasks became more difficult. Further, both groups displayed the predicted Go vs. NoGo P3 amplitude differences in the two simplest tasks, but no significant P3 differences for the most complex task. The reason for this pattern of responses was different in the different age groups. Similar to adults in previous work, the oldest children showed an attenuation of the P3 NoGo response with task difficulty, and no corresponding changes in the Go amplitude. The younger children displayed the opposite pattern, a significant increase in the Go amplitude with task difficulty, and no changes in the NoGo response. These response patterns indicate that efficient inhibitory strategies are developing throughout middle-childhood.

Despite the importance of semantic relationships to our understanding of semantic knowledge, the nature of the neural processes underlying these abilities are not well understood. In order to investigate these processes, 20 healthy adults listened to thematically related (e.g., leash-dog), taxonomically related (e.g., horse-dog), or unrelated (e.g., desk-dog) noun pairs as their EEG was recorded. The data were analyzed using both event-related potentials (ERP) and event-related spectral perturbation (ERSP) analyses. The spatiotemporal ERP and ERSP results were analyzed further with principal component analysis (PCA). When comparing unrelated to related word pairs, the expected N400 effect was confirmed, as well as differences in theta and alpha oscillations. When comparing thematically and taxonomically related word pairs, the ERP revealed no significant differences, but the ERSP did. Specifically, theta power increased over right frontal areas for thematic versus taxonomic relationships and alpha power increased over parietal areas for taxonomic versus thematic relationships. The different oscillatory patterns over different brain regions suggest that thematic and taxonomic relationships engage distinct neural processes. Specifically, thematic relationships engage memory processes, while taxonomic relationships may require additional inhibitory or attention processes. (Contains 6 figures.)

In daily activities, humans must attend and respond to a range of important items and inhibit and not respond to unimportant distractions. Our current understanding of these processes is largely based on perceptually simple stimuli. This study investigates the interaction of conceptual-semantic categorization and inhibitory processing using Event Related Potentials (ERPs). Participants completed three Go-NoGo tasks that increased systematically in the degree of conceptual-semantic information necessary to respond correctly (from single items to categories of objects and animals). Findings indicate that the N2 response reflects inhibitory processing but does not change significantly with task difficulty. The P3 NoGo amplitude, on the other hand, is attenuated by task difficulty. Further, the latency of the peak of the P3 NoGo response elicited by the most difficult task is significantly later than are the peaks detected during performance of the other two tasks. Thus, the level of complexity of conceptual-semantic representations influences inhibitory processing in a systematic way. This inhibition paradigm may be a key for investigating inhibitory dysfunction in patient populations. (Contains 5 tables and 4 figures.)

• Thalamic tissue damage in multiple sclerosis (MS) exhibits a distinct gradient from the ventricular surface. • Quantitative gradient-recalled echo (qGRE) MRI analysis reveals a steeper periventricular thalamic gradient of tissue integrity in MS patients compared to healthy controls. • Increased thalamic gradient correlates with longer disease duration and higher expanded disability status scale (EDSS) scores, suggesting a link between periventricular thalamic gradient and clinical disability in MS. Thalamic tissue damage in multiple sclerosis (MS) follows a 'surface-in' gradient from the ventricular surface. The clinical consequences of this gradient are not completely understood. Using quantitative gradient-recalled echo (qGRE) MRI, we evaluated a periventricular thalamic gradient of tissue integrity in MS and its relationship with clinical variables. Structural and qGRE MRI scans were acquired for a cohort of MS patients and healthy controls (HC). qGRE-derived R2t* values were used as a measure of tissue integrity. Thalamic segmentations were divided into 1-mm concentric bands radiating from the ventricular surface, excluding the CSF-adjacent band. Median R2t* values within these bands were used to calculate the periventricular thalamic gradient. We included 44 MS patients and 17 HC. R2t* increased slightly with distance from the ventricular surface in HC. MS patients had a steeper periventricular thalamic gradient compared to HC (mean slope 0.55 vs. 0.36; p < 0.001), which correlated with longer disease duration (β = 0.001 /year; p = 0.027) and higher Expanded Disability Status Scale (EDSS) score (β = 0.07 /EDSS point; p = 0.019). Left and right thalamus were symmetrically affected. We detected an increased thalamic gradient in MS in vivo using qGRE MRI, which correlated with disease duration and greater clinical disability. These findings further support the 'surface-in' pathology hypothesis in MS and suggest a CSF-mediated process given symmetric bi-thalamic involvement. [ABSTRACT FROM AUTHOR]