Ciaran Michael Considine

The parasagittal dural (PSD) space has been shown to harbor meningeal lymphatic vessels and may play a fundamental role in neurofluid egress and neuroimmune surveillance. Recent work has reported PSD hyperplasia associated with disease severity in Huntington disease (HD); however, beyond volumetric measures, imaging tools for probing PSD space composition non-invasively in vivo are still lacking. Here, we develop and apply a quantitative MRI relaxometry method to test the hypothesis that PSD T2 is lengthened in HD, consistent with neurofluid retention.A 1-mm isotropic, multi-echo turbo-spin-echo MRI sequence was implemented at 3-Tesla. The T2 relaxation time was fit voxel-wise, and a variational Bayesian-Gaussian-mixture clustering model was applied to assess relaxation-defined PSD compartments. In healthy adults, we assessed measurement reproducibility, the relationship between PSD T2 and venous oxygenation, and circadian variation. Additionally, participants were enrolled to evaluate the dependence of each compartment on group, age, and sex, using linear regression.Reproducibility assessments yielded excellent agreement (ICC=0.91; median PSD T2=131.2±27.9 ms). Unconclusive association with venous oxygenation or diurnal circadian oscillations were observed. Analysis indicated elevated relaxation time in both pre-manifest HD (+21.2 ms, p=0.01) and motor-manifest HD (+24.4 ms, p<0.01) compared to adult healthy controls. Compartment-level analyses localized this effect primarily to the higher-fluid PSD stromal compartment, where the largest effect size was noted (f²=0.24).Findings extend earlier volumetric work to provide evidence that PSD space T2 can be assessed reproducibly, and furthermore, that hyperplasia with neurofluid retention is present in the setting of HD.

Background and ObjectivesPlasma growth differentiation factor 15 (GDF15), a TGFbeta family cytokine, has been robustly identified from proteomics discovery work as linked to adverse brain aging; im...

Background and Objectives: Converging evidence hints at neurodevelopmental effects in genetic frontotemporal degeneration (FTD). In cross-sectional studies, for some genes, young adult FTD variant carriers show differences in brain volumes and cognition compared to familial non-carriers. However, longitudinal trajectories may more sensitively capture FTD-related neurodevelopmental vs. neurodegenerative changes than cross-sectional approaches. This study examined longitudinal trajectories of brain volumes, executive function, and plasma biomarkers in young adult carriers compared to familial non-carriers, as measures of neurodevelopmental and neurodegenerative outcomes of FTD-causing variants. Methods: This longitudinal cohort study comprised participants, aged 18-30 years, from the FTD Prevention Initiative across Europe, Canada, and the USA. Genetic groups included C9orf72 (47%), MAPT (30%), and GRN (23%). Linear mixed-effects models were computed to assess longitudinal outcomes across age between groups, controlling for sex, scanner (for brain volumes), and education (for executive function); random effects accounted for between-subject variability nested within family membership. Results: Variant carriers ( n =147) and familial non-carriers ( n =113) did not differ in age (mean±SD, 25.9±3.2 years), sex (53% female), or number of visits (2.1±1.7). Young adult C9orf72 repeat expansion carriers exhibited smaller thalamic volumes than non-carriers at the reference age of 26 years ( b =-982.8mm ³ , SE=317.0, p= 0.0046, f ² =0.32), with relatively stable trajectories across ages 18-30 (i.e., no change over time). Trajectories of rostral anterior cingulate volumes differed in C9orf72 carriers and non-carriers across age, where carriers showed relatively stable trajectories and non-carriers showed age-appropriate declines ( b =64.4mm ³ , SE=29.9, p= 0.035, f ² =0.07). For MAPT and GRN , there were little to no differences in total brain, cortical, or subcortical volumes between groups and over time. No longitudinal differences were observed between carriers and non-carriers in executive function, or plasma NfL or GFAP for any genetic group. Discussion: C9orf72 repeat expansions were linked to smaller average thalamic volumes and stable trajectories between ages 18 to 30, supporting potential neurodevelopmental origins. The modest evidence supporting an absence of difference in neurodegenerative biomarkers and executive function suggests minimal early neurodegeneration and functional preservation in young adulthood.

Neurofluids, including cerebrospinal fluid (CSF) and interstitial fluid, circulate through regulated central nervous system pathways to clear cerebral waste and support brain health, with elevated CSF flow hyperdynamicity and regurgitation through the cerebral aqueduct associating with aging and neurodegeneration. Sleep exerts state-dependent effects on neurofluid circulation, yet similar modulation during unique waking states, such as meditation, remains underexplored. Notably, mindfulness meditation shares several regulatory features with sleep, with core meditation practices representing distinct arousal states. We investigated whether the focused attention (FA) style of mindfulness meditation modulates neurofluid dynamics directionally opposite to aging and consistent with sleep. Using phase-contrast MRI, we assessed absolute CSF flow and velocity through the aqueduct, and using blood oxygenation level–dependent (BOLD) MRI, we assessed CSF fluctuations near the cervicomedullary junction together with total supratentorial gray matter fluctuations. Assessments were repeated in meditation-naïve adults during mind wandering (MW) without (n = 13; repeatability controls) and with (n = 14; breath controls) respiration rate modulation and in adept meditators (n = 23) during MW and FA meditation. No aqueduct CSF flow changes were observed in control groups. In meditators, aqueduct absolute CSF flow motion decreased from MW to FA meditation (4.60 ± 2.27 mL/min to 4.17 ± 2.10 mL/min, P = 0.005) owing to reduced regurgitant cranially directed CSF flow velocity. On BOLD, this paralleled increased low-frequency (0.0614 to 0.0887 Hz) CSF fluctuations ( P = 0.0138), which were inversely correlated with gray matter fluctuations during FA meditation. Findings suggest that mindfulness meditation may represent a nonpharmacological, waking state capable of modulating neurofluid dynamics in a directionally similar manner to sleep and opposite to aging and neurodegeneration.

Objective: To evaluate the feasibility of a 12-week community-based, non-contact rock-steady-boxing (RSB) program in individuals with Parkinson disease (PD) and to assess potential improvements in motor and cognitive functioning after intervention. Method: Over 12 weeks, 26 PD participants completed 24 RSB classes. Motor and cognitive assessments were conducted at baseline and follow-up, with a sub-group (n = 14) wearing clinical actigraphy. Linear mixed-effects models investigated compliance and changes in motor and cognitive functions. Multiple linear regression assessed correlations of clinical changes with clinicodemographic factors and actigraphy variables (two-sided p < .05). Results: PD participants showed significantly improved motor performance on the Mini Balance Evaluation Systems Test following RSB (p < .01, β = 0.69, 95% C.I. [0.40, 0.99]). No significant cognitive improvements were observed after false discovery correction, though higher scores with moderate effect sizes were suggested on HVLT-Total Recall (p = .23, β = 0.30, 95% C.I. [0.033, 0.58]), HVLT-Delayed Recall (p = .23, β = 0.25, 95% C.I. [0.03,0.46]), Stroop-Color (p = .23, β = 0.26, 95% C.I. [0.04, 0.48]), and Stroop-Interference tests (p = .15, β = 0.39, 95% C.I. [0.13, 0.64]). No significant changes were observed for actigraphy-based activity and sleep metrics. Exploratory analysis provided effect sizes and confidence intervals of associations between actigraphy variables and clinical assessments. Conclusions: RSB intervention led to better motor functioning and potential, though uncertain, cognitive benefits independent of age, sex, or disease severity. Cautious interpretation of exploratory analyses suggests changes in activity and sleep may relate to motor and cognitive changes following RSB. Findings support compliance with RSB in PD and motivate larger, randomized trials investigating the role of exercise in facilitating PD symptom improvement.

Huntington disease (HD) is a genetic neurodegenerative disorder. Given the focus on motor manifestations, nonmotor symptoms are frequently underappreciated in clinical evaluations, despite frequently contributing to primary functional impairment. A diagnosis of motor-onset as the definition of manifest symptoms misrepresents the complex nature of HD presentation. Despite recent attempt to integrate nonmotor diagnostic criteria, practical guidelines are necessary to inform clinical diagnosis. We propose an HD diagnostic framework and staging system that prioritizes genetic testing, integrates motor and nonmotor symptom considerations in the determination of clinical disease onset and severity, and acknowledges the secondary role of clinically indicated diagnostic assessments, incorporating the broad symptom profiles observed in clinical practice. The proposed diagnostic criteria more accurately reflect the presentation of HD and provide greater opportunities for health care professionals to provide appropriate clinical care guidelines for adults with gene-expanded HD.

Frontotemporal lobar degeneration (FTLD) includes different clinical syndromes with distinct patterns of symptoms and neuroanatomical locations of neurodegeneration. However, FTLD is clinically heterogeneous (with overlapping symptoms across several domains) and neuroanatomically heterogeneous (with brain atrophy in different locations in different patients). Traditional methods struggle to fully account for this heterogeneity. In this study, we use a relatively new neuroimaging approach, atrophy network mapping, to localize clinical symptoms in patients with FTLD to specific brain networks transdiagnostically. Data were obtained from the Frontotemporal Lobar Degeneration Neuroimaging Initiative and 4-Repeat Tauopathy Neuroimaging Initiative. Inclusion required T1-weighted MRI and a diagnosis of behavioral-variant frontotemporal dementia (bvFTD), semantic-variant primary progressive aphasia (svPPA), nonfluent primary progressive aphasia (nfvPPA), progressive supranuclear palsy Richardson syndrome (PSP-rs), corticobasal syndrome (CBS), or normal cognition. Measures of social cognition (Interpersonal Reactivity Index, Revised Self-Monitoring Scale), language (Boston Naming Test, Animal Fluency), and motor function (Unified Parkinson Disease Rating Scale Part III, PSP Rating Scale) were correlated with neuroimaging measures, including cortical thickness, volume, and atrophy network mapping, a newer method that localizes regions connected to brain atrophy using a functional connectome from cognitively normal persons (n = 1,000). Fifty-seven patients with bvFTD (age 61.2 ± 6.8 years, 35% female), 41 PSP-rs (age 69.7 ± 7.4 years, 54% female), 39 CBS (age 66.2 ± 6.2 years, 51% female), 37 svPPA (age 63.0 ± 6.0 years, 46% female), and 36 nfvPPA (age 68.3 ± 7.3 years, 53% female) and 135 healthy age-matched controls (age 63.3 ± 7.4 years, 58% female) were included. Compared with atrophy alone, atrophy network mapping showed more consistent neuroimaging results across patients with the same clinical syndrome (Dice index mean 0.68 vs 0.11, paired t = 263.1, df = 4,452, p < 0.001), more strongly explained social cognition (F(1, 84) = 10.2, p = 0.002) and motor symptoms (F(1, 185) = 91.3, p < 0.001) across different syndromes, and showed novel neuroanatomical associations, with the temporal parietal junction relating to social cognition; Wernicke area relating to language symptoms; and association sensorimotor cortex, thalamus, and cerebellum relating to motor symptoms. Atrophy network mapping can improve understanding of brain-behavior relationships in clinically and neuroanatomically heterogeneous disorders such as FTLD.

Neurologic evidence, including MRI, PET, and EEG, has been introduced in more than 2,800 criminal cases in the past decade, including 12% of all murder trials and 25% of death penalty trials, to argue whether neurologic diseases are present, contribute to ...

Objective: The evaluation of self-reported symptoms is a standard component of concussion assessment and management. Clinicians typically evaluate a total symptom severity score rather than scores corresponding to specific symptom domains (i.e., cognitive, sleep-arousal, physical, and affective symptoms). This study examined (i) whether elevations in specific symptom domains would be missed when interpreting only the total symptom severity score and (ii) if a single symptom domain elevation was more common than having elevated symptoms across multiple domains. Method: Adolescent student-athletes (N = 1,008) with concussion history (i.e., ≥6 months since last concussion) completed the Post-Concussion Symptom Scale (PCSS). The PCSS total score and cognitive, sleep-arousal, physical, and affective domain scores were calculated. To determine if symptoms were elevated, scores were compared to normative data matched on gender and pre-existing conditions, with scores considered elevated if they were ≥84th percentile. The frequency of total and domain score elevations were calculated and stratified by gender and number of prior concussions (i.e., 1 or ≥2 prior concussions). Results: Overall, 26% of student-athletes had an elevated symptom domain score without being elevated on the total score. The most common symptom presentation was to have a single elevated symptom domain (21%), followed by two (11%), three (8%), or four elevated domains (6%). Conclusions: Interpreting PCSS symptom domains may be beneficial in detecting student-athletes with elevated symptoms following a remote concussion. Roughly a quarter of student-athletes have domain-specific symptom elevations that would be missed by interpreting the total score alone.

Background: The clinical diagnosis of manifest Huntington's disease (HD) relies on a high level of clinical confidence (99% confidence) of HD‐consistent motor signs. Longitudinal data have reliably identified cognitive and behavioral dysfunction predating clinical motor diagnosis by up to 15 years. Reliance on motor signs to establish a diagnosis of HD increases risk of early misdiagnosis or delayed diagnosis. Clinical neuropsychologists are uniquely positioned to advise on the clinical application of the Movement Disorder Society Task Force's recently proposed non‐motor diagnostic criteria for HD.Objectives: To provide (1) a recommended clinical approach toward non‐motor diagnostic criteria in persons with HD and facilitation of accurate diagnosis; (2) recommended practices for medical treatment providers to screen and longitudinally monitor non‐motor signs of HD.Methods: The Huntington Study Group re‐established the Neuropsychology Working Group, then recruited a multi‐disciplinary group of neuropsychologists, neurologists, and psychiatrists to conduct an unstructured literature review and discuss expert opinions on practice, to facilitate an informal consensus opinion to accomplish the objectives.Results: The opinion and an example protocol for medical treatment providers to screen, monitor, and triage non‐motor signs and symptoms of Huntington's disease is provided.Conclusions: Clinical diagnosis of non‐motor HD is empirically justified and clinically important. Screening and triage by non‐neuropsychologist clinicians can aid in detecting and monitoring non‐motor Huntington's disease manifestation. The Neuropsychology Working Group consensus advances good clinical practice, clinical research, and quality of life. A companion position paper presenting the details of our consensus opinion regarding evidence‐based guidelines for neuropsychological practice is forthcoming.