Evaluating the Effect of Alzheimer's Disease-Related Biomarker Change in Corticobasal Syndrome and Progressive Supranuclear Palsy.

OBJECTIVES: To evaluate the effect of Alzheimer's disease (AD) -related biomarker change on clinical features, brain atrophy and functional connectivity of patients with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). METHODS: Data from patients with a clinical diagnosis of CBS, PSP, and AD and healthy controls were obtained from the 4-R-Tauopathy Neuroimaging Initiative 1 and 2, the Alzheimer's Disease Neuroimaging Initiative, and a local cohort from the Toronto Western Hospital. Patients with CBS and PSP were divided into AD-positive (CBS/PSP-AD) and AD-negative (CBS/PSP-noAD) groups based on fluid biomarkers and amyloid PET scans. Cognitive, motor, and depression scores; AD fluid biomarkers (cerebrospinal p-tau, t-tau, and amyloid-beta, and plasma ptau-217); and neuroimaging data (amyloid PET, MRI and fMRI) were collected. Clinical features, whole-brain gray matter volume and functional networks connectivity were compared across groups. RESULTS: Data were analyzed from 87 CBS/PSP-noAD and 23 CBS/PSP-AD, 18 AD, and 30 healthy controls. CBS/PSP-noAD showed worse performance in comparison to CBS/PSP-AD in the PSPRS [mean(SD): 34.8(15.8) vs 23.3(11.6)] and the UPDRS scores [mean(SD): 34.2(17.0) vs 21.8(13.3)]. CBS/PSP-AD demonstrated atrophy in AD signature areas and brainstem, while CBS/PSP-noAD patients displayed atrophy in frontal and temporal areas, globus pallidus, and brainstem compared to healthy controls. The default mode network showed greatest disconnection in CBS/PSP-AD compared with CBS/PSP-no AD and controls. The thalamic network connectivity was most affected in CBS/PSP-noAD. INTERPRETATION: AD biomarker positivity may modulate the clinical presentation of CBS/PSP, with evidence of distinctive structural and functional brain changes associated with the AD pathology/co-pathology. ANN NEUROL 2024;96:99-109.

Examining litter specific variability in mice and its impact on neurodevelopmental studies.

Our current understanding of litter variability in neurodevelopmental studies using mice may limit translation of neuroscientific findings. Higher variance of measures across litters than within, often termed intra-litter likeness, may be attributable to both pre- and postnatal environment. This study aimed to assess the litter-effect within behavioral assessments (2 timepoints) and anatomy using T1-weighted magnetic resonance images across 72 brain region volumes (4 timepoints) (36 C57bl/6J inbred mice; 7 litters: 19F/17M). Between-litter comparisons of brain and behavioral measures and their associations were evaluated using univariate and multivariate techniques. A power analysis using simulation methods was then performed on modeled neurodevelopment and to evaluate trade-offs between number-of-litters, number-of-mice-per-litter, and sample size. Our results show litter-specific developmental effects, from the adolescent period to adulthood for brain structure volumes and behaviors, and for their associations in adulthood. Our power simulation analysis suggests increasing the number-of-litters in experimental designs to achieve the smallest total sample size necessary for detecting different rates of change in specific brain regions. Our results demonstrate how litter-specific effects may influence development and that increasing the litters to the total sample size ratio should be strongly considered when designing neurodevelopmental studies.

Alpha-Synuclein RT-QuIC in Idiopathic Normal Pressure Hydrocephalus.

This study quantified the occurrence of an underlying synucleinopathy in 50 patients with idiopathic normal pressure hydrocephalus by means of real-time quaking-induced conversion, a highly sensitive and specific technique capable of detecting and amplifying misfolded aggregated forms of α-synuclein in the cerebrospinal fluid. Seven patients were positive and they did not differ from negative cases, except for a more frequent L-dopa responsiveness and gait characterized by a wider base. The two groups did not differ in terms of response rate to tap test or shunt surgery, although step length and gait velocity improved by a lesser extent in positive cases. ANN NEUROL 2022;92:985-991.

Misfolded α-Synuclein in Cerebrospinal Fluid of Contact Sport Athletes.

BACKGROUND: Misfolded α-synuclein in Parkinson's disease (PD) and dementia with Lewy bodies (DLB) can be detected using the real-time quaking-induced conversion (RT-QuIC) technique in cerebrospinal fluid (CSF). OBJECTIVES: The objectives are (1) to examine misfolded CSF α-synuclein incidence, and (2) to compare clinical presentation, sports history, brain volumes, and RT-QuIC α-synuclein positivity in former athletes. METHODS: Thirty former athletes with magnetic resonance imaging, neuropsychological testing, and CSF analyzed for phosphorylated tau 181 (p-tau), total tau (t-tau), amyloid-ß 42 (Aß42), and neurofilament light chain (NfL). CSF α-synuclein was detected using RT-QuIC. RESULTS: Six (20%) former athletes were α-synuclein positive. α-Synuclein positive athletes were similar to α-synuclein negative athletes on demographics, sports history, clinical features, CSF p-tau, t-tau, Aß42, and NfL; however, had lower grey matter volumes in the right inferior orbitofrontal, right anterior insula and right olfactory cortices. CONCLUSIONS: α-Synuclein RT-QuIC analysis of CSF may be useful as a prodromal biofluid marker of PD and DLB. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Investigating the association between a history of depression and biomarkers of Alzheimer's disease, cerebrovascular disease, and neurodegeneration in patients with dementia.

The association between depression and dementia, particularly Alzheimer's disease (AD) and cerebrovascular disease (CVD), remains an active area of research. This study aimed to investigate the relationship between a history of depression and biomarkers of AD and CVD in patients with dementia in a clinical setting. A total of 126 patients from the University Health Network (UHN) Memory Clinic with comprehensive clinical evaluations, including neuropsychological testing and medical examinations, were included. Lumbar puncture was performed to collect cerebrospinal fluid (CSF) for biomarker analysis, and brain magnetic resonance imaging (MRI) scans were obtained to assess white matter hyperintensity (WMH) burden. The presence of depression was determined through medical records. The study findings did not reveal significant differences between participants with and without a history of depression in terms of AD biomarkers, WMH burden, neurofilament light chain levels, cognitive scores, age of symptom onset, disease duration, or vascular risk scores. Logistic regression analysis did not indicate a meaningful predictive value of these variables for depression status. This clinical study contributes to our understanding regarding the association between depression and AD/CVD biomarkers in patients with cognitive impairment. Further research is needed to elucidate the complex relationship between depression and dementia and to explore the potential mechanisms linking depression, AD, and CVD.

Fluid biomarkers of white matter hyperintensities in cerebrovascular disease and neurodegeneration: a systematic review protocol.

OBJECTIVE: The goal of this systematic review is to evaluate the association between fluid biomarkers and white matter hyperintensities (WMH) in cerebrovascular disease and neurodegenerative disorders. While previous research has examined the etiology of WMH in specific diseases, we propose a comprehensive framework encompassing WMH of both vascular and non-vascular origin. INTRODUCTION: Although WMH have been mostly described in aging populations with cerebrovascular disease, extensive lesions also occur in non-vascular diseases. Such lesions are traditionally treated as a separate pathological entity from vascular ones, but recent work has challenged the appropriateness of that framework when probing WMH etiology. Comparing biomarkers associated with WMH across various pathologies may improve our understanding of their etiology. INCLUSION CRITERIA: The review will focus on cerebrovascular disease and neurodegenerative disorders and exclude infectious, metabolic, drug-induced, or radiation-induced white matter diseases. Original, peer-reviewed research on the relationship of WMH on magnetic resonance imaging with blood/cerebrospinal fluid biomarkers will be considered for inclusion. Postmortem studies will guide the selection of biomarkers of interest and the interpretation of our findings. Genomic markers will be excluded. METHODS: The review will be conducted in accordance with PRISMA and JBI guidelines. English articles of interest published between 2000 and 2020 will be identified in MEDLINE and Embase. Two reviewers will perform abstract and full-text screening, standardized data extraction, and quality assessments of the selected studies. The relationship between each biomarker and WMH burden will be meta-analyzed, if possible, with subgroup or meta-regression analyses to assess differences between diseases. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42020218298.

Early or Late Gestational Exposure to Maternal Immune Activation Alters Neurodevelopmental Trajectories in Mice: An Integrated Neuroimaging, Behavioral, and Transcriptional Study.

BACKGROUND: Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental disorders later in life. The impact of the gestational timing of MIA exposure on downstream development remains unclear. METHODS: We characterized neurodevelopmental trajectories of mice exposed to the viral mimetic poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables for the time of greatest alteration (adolescence/early adulthood) and identified regions for further investigation using RNA sequencing. RESULTS: Early MIA exposure was associated with accelerated brain volume increases in adolescence/early adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation had less impact on anatomical and behavioral profiles. Multivariate maps associated anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional changes were observed in the dorsal hippocampus, with genes enriched for fibroblast growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA regulation. CONCLUSIONS: Leveraging an integrated hypothesis- and data-driven approach linking brain-behavior alterations to the transcriptome, we found that MIA timing differentially affects offspring development. Exposure in late gestation leads to subthreshold deficits, whereas exposure in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders.

Imaging the pituitary in psychopathologies: a review of in vivo magnetic resonance imaging studies.

The pituitary gland (PG) is a key component of the essential endocrine systems in humans and animals, including the hypothalamic-pituitary-adrenal, hypothalamic-pituitary-gonadal, and hypothalamic-pituitary-thyroid axes. Structural changes in the PG are observed in a number of psychiatric disorders. Psychiatric disorders are typically characterized by subtle, time-dependent anatomical changes in the brain, and their study necessitates highly powered, longitudinal investigations. Structural magnetic resonance imaging (MRI) is a non-invasive technology that is ideally suited to detect changes in anatomical structures over time. In this paper, we will review the main findings on pituitary function and structure in the context of healthy development and of psychiatric disorders, with particular emphasis on MRI studies. The latter have not always succeeded in providing a clear theoretical framework of mental disorders, which may be explained by low resolution and differences in preprocessing methods, imprecise segmentation rules that do not account for the anatomical and functional specificity of the anterior and posterior lobes of the PG, and inadequate categorization of clinical subjects. We review those limitations and propose solutions for future research.

Longitudinal assessment of the neuroanatomical consequences of deep brain stimulation: Application of fornical DBS in an Alzheimer's mouse model.

Following its success in the treatment of refractory movement disorders, deep brain stimulation (DBS) is currently under clinical investigation as a possible treatment for several neuropsychiatric disorders, including Alzheimer's disease (AD). DBS's mechanism of action, delivery regimen, optimal brain target, and timeline of behavioural and neuroanatomical outcomes are all open fields of investigation. There is a critical need to develop methodologies that allow us to examine the time course of both behavioural changes and neuroanatomical remodelling in response to DBS. Here we present a proof-of-concept methodology for DBS experiments which incorporates both brain imaging and behaviour in a longitudinal fashion. We implanted triple transgenic AD mouse models (expressing mutations for both amyloid and tau) with custom magnetic resonance imaging (MRI)-compatible, carbon based electrodes. Mice received DBS or sham stimulation to the fornix (a critical white matter node in the brain's memory circuit) for 1 h (100 Hz, 100 µs pulses, 100 µA). Treatment was followed with an adapted Morris water maze (to test learning and memory; performed weekly) and structural MRI (to assess neuroanatomy; 3 days before and 3 days after DBS with a 6 week follow-up). The acute DBS treatment improved learning and long term memory in a delayed, sex specific, and transient manner relative to sham-stimulated controls. Significant, persistent, volumetric changes were seen in diverse brains structures, also heavily mediated by sex. We believe this methodology may be used as a template for DBS-related experimentation and will encourage preclinical studies to use longitudinal designs.