Gray Matter Loss Research Articles

Dementia Disorders: A Narrative Review

This narrative review of research includes summaries of 40 papers on dementia disorders that were published during 2023. The publications of this period are primarily randomized controlled trials and systematic reviews/ meta-analyses of randomized controlled trials. A few of these are focused on the prevalence of dementia which approximated one per cent of the world’s population. Only a few studies focused on effects of dementia disorders including memory loss, discrimination, pain, depression and suicidality. Most of the studies addressed predictors of dementia disorders including neurotic personality, frequent tv/computer use and excessive exposure to metals. Loss of short-term memory and other negative experiences including negative life events, loneliness, stress and depression were also significant predictor variables in this recent literature. Physical conditions that were predictive of dementia included pain, hypertension, atrial fibrillation, multi-morbidities, inflammation, encephalitis and neuropathology. Potential underlying mechanisms included dysfunctional neurotransmitter systems (serotonergic, noradrenergic and dopaminergic) and gray matter loss in prefrontal, temporal and other regions associated with memory. Several research groups reported on effective interventions including a Mediterranean diet, plant-based diets, medicinal plants, psychedelics, second generation antidepressants, blood pressure medication, music therapy, aromatherapy and other alternative therapies. Methodological problems relate to the variability in the assessments of dementia disorders, the self-report measures and the cross-sectional data that are not definitive about directionality of predictors and effects of dementia disorders.

Natalizumab reduces loss of gray matter and thalamic volume in patients with relapsing-remitting multiple sclerosis: A post hoc analysis from the randomized, placebo-controlled AFFIRM trial

Background: Loss of brain gray matter fractional volume predicts multiple sclerosis (MS) progression and is associated with worsening physical and cognitive symptoms. Within deep gray matter, thalamic damage is evident in early stages of MS and correlates with physical and cognitive impairment. Natalizumab is a highly effective treatment that reduces disease progression and the number of inflammatory lesions in patients with relapsing-remitting MS (RRMS). Objective: To evaluate the effect of natalizumab on gray matter and thalamic atrophy. Methods: A combination of deep learning–based image segmentation and data augmentation was applied to MRI data from the AFFIRM trial. Results: This post hoc analysis identified a reduction of 64.3% (p = 0.0044) and 64.3% (p = 0.0030) in mean percentage gray matter volume loss from baseline at treatment years 1 and 2, respectively, in patients treated with natalizumab versus placebo. The reduction in thalamic fraction volume loss from baseline with natalizumab versus placebo was 57.0% at year 2 (p < 0.0001) and 41.2% at year 1 (p = 0.0147). Similar findings resulted from analyses of absolute gray matter and thalamic fraction volume loss. Conclusion: These analyses represent the first placebo-controlled evidence supporting a role for natalizumab treatment in mitigating gray matter and thalamic fraction atrophy among patients with RRMS. ClinicalTrials.gov identifier: NCT00027300 URL: https://clinicaltrials.gov/ct2/show/NCT00027300

Role of the Cerebellum in Bipolar Disorder: A Systematic Literature Review.

The aim of this systematic literature review was to investigate the role of the cerebellum in the affective symptoms observed in patients with bipolar disorder. The present systematic literature review included clinical studies conducted from 2013-2023 among adult populations with bipolar I and II disorders, along with their specifiers. With regard to cerebellar pathology, it was found that those with bipolar disorder performed worse than their healthy counterparts in their ability to comprehend the mental states of others and in identifying negative mental states. Additionally, individuals with bipolar disorder had reduced gray matter loss in regions such as lobules I-IX, crus I, and crus II, different functional activation patterns of the thalamus, striatum, and hippocampus on functional magnetic resonance imaging (fMRI), and increased cortical thickness. Cerebro-cerebellar functional connectivities were altered in patients with bipolar disorder. The effects of lamotrigine and lithium on cerebellar volume and abnormalities are also discussed in this paper. The present systematic literature review illustrates the emerging involvement of the cerebellum in bipolar disorder and its affective symptoms and paves the way for future research and a better understanding of bipolar disorder.

Cerebellar Volumetry in Ataxias: Relation to Ataxia Severity and Duration.

Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebellar type (MSA-C). Our cross-sectional data set comprised mutation carriers of SCA1 (N=12), SCA3 (N=62), SCA6 (N=14), as well as MSA-C patients (N=16). Cerebellar volumes were obtained from T1-weighted magnetic resonance images. To compare the different atrophy patterns, we performed a z-transformation and plotted the intercept of each patient group's model at the mean of 7 years of ataxia duration as well as at the mean ataxia severity of 14 points in the SARA sum score. In addition, we plotted the extrapolation at ataxia duration of 0 years as well as 0 points in the SARA sum score. Patients with MSA-C demonstrated the most pronounced volume loss, particularly in the cerebellar white matter, at the late time intercept. Patients with SCA6 showed a pronounced volume loss in cerebellar grey matter with increasing ataxia severity compared to all other patient groups. MSA-C, SCA1 and SCA3 showed a prominent atrophy of the cerebellar white matter. Our results (i) confirmed SCA6 being considered as a pure cerebellar grey matter disease, (ii) emphasise the involvement of cerebellar white matter in the neuropathology of SCA1, SCA3 and MSA-C, and (iii) reflect the rapid clinical progression in MSA-C.

Opposing effects of thyroid hormones on hypothalamic subunits and limbic structures in hyperthyroidism patients: A comprehensive volumetric study.

Thyroid hormones play a critical role in brain development, but paradoxically, patients with hyperthyroidism often exhibit cognitive decline and irritability. This study aims to explore the pattern of atrophy in hyperthyroid patients, changes in specific areas of the brain, including hypothalamic subfields and limbic structures, and their relationships with hormonal levels and psychometric tests. This prospective cross-sectional study involves 19 newly diagnosed, untreated hyperthyroid patients, and 15 age and gender-matched control subjects. The participants underwent psychometric and cognitive tests and volumetric MRI. The hypothalamic subfield (anterior-inferior, anterior-superior, superior-tubular, inferior-tubular, and posterior hypothalamus) and limbic structures (fornix, basal forebrain, nucleus accumbens, and septal nucleus) were segmented using voxel-based morphometry, surface-based morphometry, and deep learning algorithms. The groups were compared using the t-test, and correlation analyses were performed between clinical parameters and volumetric measurements. The correlation between hormonal parameters and volumetric measurements in patient and control groups was assessed with the Meng test. Hyperthyroid patients displayed widespread grey matter loss and sulcal shallowing in the left hemisphere. However, no local gyrification index changes or cortical thickness variations were detected. The limbic structures and hypothalamic subunits did not show any volume discrepancies. Free thyroxine in the patient group negatively correlated with bilateral anterior-inferior and right septal nucleus, but positively correlated with left anterior-inferior in the control group. Thyroid stimulating hormone in the patient group showed a positive correlation with bilateral fornix volume, a correlation absent in the control group. Disease duration negatively correlated with right anterior-inferior, right tubular inferior, and right septal nucleus. Changes in cognitive and psychometric test scores in the patient group correlated with the bilateral septal nucleus volume. Hyperthyroidism primarily leads to a reduction in grey matter volume and sulcal shallowing. Thyroid hormones have differing volumetric effects in limbic structures and hypothalamic subunits under physiological and hyperthyroid conditions.

Ocrelizumab reduces cortical and deep grey matter loss compared to the S1P-receptor modulator in multiple sclerosis.

Ocrelizumab (OCR) and Fingolimod (FGL) are two high-efficacy treatments in multiple sclerosis which, besides their strong anti-inflammatory activity, may limit neurodegeneration. To compare the effect of OCR and FGL on clinical and MRI endpoints. 95 relapsing-remitting patients (57 OCR, 38 FGL) clinically followed for 36months underwent a 3-Tesla MRI at baseline and after 24months. The annualized relapse rate, EDSS, new cortical/white matter lesions and regional cortical and deep grey matter volume loss were evaluated. OCR reduced the relapse rate from 0.48 to 0.04, FGL from 0.32 to 0.05 (both p < 0.001). Compared to FGL, OCR-group experienced fewer new white matter lesions (12% vs 32%, p = 0.005), no differences in new cortical lesions, lower deep grey matter volume loss (- 0.12% vs - 0.66%; p = 0.002, Cohen's d = 0.54), lower global cortical thickness change (- 0.45% vs - 0.70%; p = 0.036; d = 0.42) and reduced cortical thinning/volume loss in several regions of interests, including those of parietal gyrus (d-range = 0.65-0.71), frontal gyrus (d-range = 0.47-0.60), cingulate (d-range = 0.41-0.72), insula (d = 0.36), cerebellum (cortex d = 0.72, white matter d = 0.44), putamen (d = 0.35) and thalamus (d = 0.31). The effect on some regional thickness changes was confirmed in patients without focal lesions. When compared with FGL, patients receiving OCR showed greater suppression of focal MRI lesions accumulation and lower cortical and deep grey matter volume loss.

Gray matter biomarkers for major depressive disorder and manic disorder using logistic regression

The study investigates morphometric changes using surface-based measures and logistic regression in Major depressive-disorder (MDD) and Manic-disorder patients as compared to controls.MDD (n = 21) and manic (n = 20) subjects were recruited from psychiatric clinics, along with 19 healthy-controls from local population, after structured and semi-structured clinical interview (DSM-IV, brief Psychotic-Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Hamilton depression rating scale (HDRS), cognitive function by postgraduate Institute Battery of Brain Dysfunction (PGIBBD)).Using 3D T1-weighted images, gray matter (GM) cortical thickness and GM-based morphometric signatures (using logistic regression) were compared among MDD, manic disorder and controls using analysis of covariance (ANCOVA). No significant difference was found between the MDD and manic disorder patients. When compared to controls, cortical thinning was observed in bilateral rostral middle frontal gyrus and parsopercularis, right lateral occipital cortex, right lingual gyrus in MDD; and bilateral rostral middle frontal and superior frontal gyrus, right middle temporal gyrus, left supramarginal and left precentral gyrus in Manic disorders.Logistic regression analysis exhibited GM cortical thinning in the bilateral parsopercularis, right lateral occipital cortex and lingual gyrus in MDD; and bilateral rostral middle, superior frontal gyri, right middle temporal gyrus in Manic with a sensitivity and specificity of 85.7 % and 94.7 % and 90.0 % and 94.7 %, respectively in comparison with controls. Both groups exhibited GM loss in bilateral rostral middle frontal gyrus brain regions compared to controls. Multivariate analysis revealed common changes in GM in MDD and manic disorders associated with mood temperament, but differences when compared to controls.

Neurofilament light chain concentration mediates the association between regional medial temporal lobe structure and memory in adults with Down syndrome.

Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS. T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory. Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory. The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

Interaction of Alzheimer Disease and Traumatic Brain Injury on Cortical Thickness.

Traumatic brain injury (TBI) is associated with an accelerated course of dementia, although biological relationships are incompletely understood. The study examined 1124 participants, including 343 with Alzheimer disease (AD), 127 with AD with TBI, 266 cognitively normal adults with TBI, and 388 cognitively normal adults without TBI. Cortical thickness was quantified from T1-weighted magnetic resonance imaging data. Multiple linear regression was used to determine the interaction between AD and TBI on cortical thickness. Among those with AD, TBI was associated with an earlier age of AD onset but, counterintuitively, less cortical thinning in frontotemporal regions relative to non-AD controls. AD with TBI represents a distinct group from AD, likely with distinct pathologic contributions beyond gray matter loss. This finding has important implications for the diagnosis and treatment of AD in the presence of TBI and indicates that models of AD, aging, and neural loss should account for TBI history.

Brain growth until adolescence after a neonatal focal injury: sex related differences beyond lesion effect.

Early focal brain injuries lead to long-term disabilities with frequent cognitive impairments, suggesting global dysfunction beyond the lesion. While plasticity of the immature brain promotes better learning, outcome variability across individuals is multifactorial. Males are more vulnerable to early injuries and neurodevelopmental disorders than females, but long-term sex differences in brain growth after an early focal lesion have not been described yet. With this MRI longitudinal morphometry study of brain development after a Neonatal Arterial Ischemic Stroke (NAIS), we searched for differences between males and females in the trajectories of ipsi- and contralesional gray matter growth in childhood and adolescence, while accounting for lesion characteristics. We relied on a longitudinal cohort (AVCnn) of patients with unilateral NAIS who underwent clinical and MRI assessments at ages 7 and 16 were compared to age-matched controls. Non-lesioned volumes of gray matter (hemispheres, lobes, regions, deep structures, cerebellum) were extracted from segmented T1 MRI images at 7 (Patients: 23 M, 16 F; Controls: 17 M, 18 F) and 16 (Patients: 18 M, 11 F; Controls: 16 M, 15 F). These volumes were analyzed using a Linear Mixed Model accounting for age, sex, and lesion characteristics. Whole hemisphere volumes were reduced at both ages in patients compared to controls (gray matter volume: -16% in males, -10% in females). In ipsilesional hemisphere, cortical gray matter and thalamic volume losses (average -13%) mostly depended on lesion severity, suggesting diaschisis, with minimal effect of patient sex. In the contralesional hemisphere however, we consistently found sex differences in gray matter volumes, as only male volumes were smaller than in male controls (average -7.5%), mostly in territories mirroring the contralateral lesion. Females did not significantly deviate from the typical trajectories of female controls. Similar sex differences were found in both cerebellar hemispheres. These results suggest sex-dependent growth trajectories after an early brain lesion with a contralesional growth deficit in males only. The similarity of patterns at ages 7 and 16 suggests that puberty has little effect on these trajectories, and that most of the deviation in males occurs in early childhood, in line with the well-described perinatal vulnerability of the male brain, and with no compensation thereafter.

Brain Volumetric changes in patients with Spinocerebellar Ataxia Type 2

Aim: Spinocerebellar ataxia type 2 (SCA2) is a trinucleotide repeat disorder characterized by mutations in the ataxin-2 gene. Although the primary symptoms of this disease are related to cerebellar involvement, such as ataxia and dysarthria, cognitive disorders associated with supratentorial involvement, depression, and extrapyramidal symptoms are also common. The aim of this study was to investigate volumetric changes in patients with SCA2. Materials and Methods: Nine SCA2 patients and sixteen age and gender-matched healthy controls were included in the study. Voxel-based morphometry (VBM) was used to explore changes in whole brain gray and white matter, while surface-based morphometry (SBM) was employed to investigate changes in cortical thickness (CT), local gyrification index (LGI), sulcal depth (SD), and fractal dimension (FD). Deep learning methods were utilized for the automatic segmentation of subcortical gray matter structures and extrapyramidal system structures. Comparisons between groups were made using GLM, T-Test, and Mann-Whitney U test. Results: VBM results showed widespread gray matter loss in the cerebellum and widespread white matter loss in the brain stem (Cluster size: 25918 voxels for gray matter, 24557 voxels for white matter). SBM findings indicated a decrease in cortical thickness (Cluster size:19276 vertices for left hemisphere; 17276 vertices for right hemisphere), more pronounced in the supratentorial frontoparietal region, while FD, LGI, and SD did not differ between groups. Volume loss was observed in the subthalamic nucleus, globus pallidus internus and externus, and red nucleus in SCA2 patients. Conclusion: SCA2 patients exhibit white and gray matter volume loss in the infratentorial region. Additionally, they show a decrease in frontoparietal cortical thickness, while FD, LGI, and SD do not show any changes. Moreover, atrophy is also observed in the extrapyramidal system structures.

Reduced Age-Related Gray Matter Loss in the Orbitofrontal Cortex in Long-Term Meditators.

The orbitofrontal cortex (OFC) is a functionally heterogeneous brain region contributing to mental processes relating to meditation practices. The OFC has been reported to decline in volume with increasing age and differs in volume between meditation practitioners and non-practitioners. We hypothesized that the age-related decline of the OFC is diminished in meditation practitioners. We tested this hypothesis in a sample of 50 long-term meditators and 50 matched controls by correlating chronological age with regional gray matter volumes of the left and right OFC, as well as in seven left and right cytoarchitectonically defined subregions of the OFC (Fo1-Fo7). In both meditators and controls, we observed a negative relationship between age and OFC (sub)volumes, indicating that older participants have smaller OFC volumes. However, in meditators, the age-related decline was less steep compared to controls. These age-related differences reached significance for left and right Fo2, Fo3, Fo4, and Fo7, as well as left Fo5 and right Fo6. Since different subregions of the OFC are associated with distinct brain functions, further investigations are required to explore the functional implications of these findings in the context of meditation and the aging brain.

Progressive loss of cortical gray matter in first episode psychosis patients with auditory hallucinations

BackgroundPrevious longitudinal magnetic resonance imaging studies have shown progressive gray matter (GM) reduction during the earliest phases of schizophrenia. It is unknown whether these progressive processes are homogeneous in all groups of patients. One way to obtain more valid findings is to focus on the symptoms. Auditory hallucinations (AHs) are frequent and reliable symptoms of psychosis. The present study aims to analyze whether longitudinal changes in structural abnormalities in cortical regions are related to the presence of AHs and the intensity of psychotic symptoms in a large sample. MethodsA Magnetic Resonance (MR) voxel-based morphometry analysis was applied to a group of 128 first episodes psychosis (FEP) patients (63 patients with AHs and 65 patients without AHs) and 78 matched healthy controls at baseline and at a 2-year follow-up. ResultsAt baseline, FEP patients exhibited significant GM volume reductions in the temporal, frontal and precentral regions. At follow-up, FEP patients exhibited GM volume changes in the temporal, Rolandic, frontal, precentral and insula regions. At baseline, no significant differences were found between FEP patients with and without AHs. At follow-up, while FEP patients with AHs showed less GM volume in temporal and frontal lobes, non-AH FEP patients showed reductions in the frontal, precentral and fusiform areas. PANSS scores showed statistically significant correlations with GM volume reductions at baseline and follow-up. ConclusionsBrain cortical loss in the early phases of psychosis is not associated with potentially transitory AHs; however, brain structural changes may emerge as AHs appear in chronic patients.

Serum biomarkers for prognosis and monitoring in asymptomatic Alzheimer’s Disease

AbstractBackgroundPrognostic and monitoring capabilities of blood‐based biomarkers for early cognitive decline, amyloid‐β (Aβ) accumulation and grey matter (GM) loss in the asymptomatic phase of Alzheimer disease require further investigation over extended time periods. This longitudinal study investigated serum glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and Aβ1‐42/Aβ1‐40 as potential prognostic and monitoring biomarkers in cognitively unimpaired (CU) elderly.MethodWe included 184 CU older adults (Table 1) who underwent baseline serum sampling and 2‐yearly neuropsychological assessment for up to 10 years (median: 6 years, Figure 1). A subset (N = 109) underwent serial blood sampling, Aβ‐PET and structural MRI at 2 (N = 73), 3 (N = 34), or 4 (N = 2) time points (time interval: 2‐10 years, median: 6 years). Cognition was evaluated in memory, language and executive functioning domains through conversion of neuropsychological tests scores to standardised z‐scores and subsequent averaging per domain. Aβ‐accumulation and GM loss were analysed in a voxelwise manner using Voxelstats with cluster‐level p RFT&lt;.05 and voxel‐level puncorrected&lt;.001 significance thresholds.[1] Aβ1‐42/Aβ1‐40 was inverted to facilitate biomarker comparison. Linear‐mixed effects models were used to (i) identify the predictive value of serum biomarkers for longitudinal cognitive decline, Aβ‐accumulation and GM loss, (ii) calculate annual serum biomarker rates of change and (iii) investigate associations between longitudinal biomarker changes and longitudinal changes in cognition, Aβ‐PET and GM volume.ResultHigh baseline GFAP and NfL predicted a longitudinal decline in memory (βGFAP*time = ‐0.020, pFDR = 0.03; βNfL*time = ‐0.031, pFDR = 0.002) and language (βGFAP*time = ‐0.025, pFDR&lt;0.001, βNfL*time = ‐0.017, pFDR = 0.04), and longitudinal GM loss within the hippocampus. Low Aβ1‐42/Aβ1‐40 predicted memory decline (βAβ1‐42/Aβ1‐40*time = ‐0.022, pFDR = 0.03) as well as Aβ accumulation within Aβ‐vulnerable regions (Figure 1). Serum GFAP (βtime = 0.022, pFDR&lt;.001) and NfL (βtime = 0.040, pFDR&lt;.001) increased over time. Longitudinal serum NfL increases were associated with a concomitant decline in memory (β∆NfL*time = ‐0.031, pFDR= .004), language (β∆NfL*time = ‐0.022, pFDR= .01) and GM volume (Figure 2). Serum GFAP increases were associated with precuneal Aβ accumulation. Aβ1‐42/Aβ1‐40 decreases were stronger in Aβ‐ subjects (pFDR&lt;.001) and did not associate with Aβ accumulation, nor any other longitudinal marker.ConclusionSerum GFAP, NfL and Aβ1‐42/Aβ1‐40 are prognostic and/or monitoring biomarkers providing complementary information by reflecting different Aβ‐dependent or ‐independent pathophysiological processes.REFERENCE[1] Mathotaarachchi et al. Front Neuroinform 2016.

Identification of Attention-Deficit-Hyperactivity Disorder Subtypes Based on Structural MRI Grey Matter Volume and Phenotypic Information.

One of the neurodevelopmental disorders widely affecting school-aged children in recent years is attention deficit hyperactivity disorder (ADHD). In many neurodevelopmental disorders, grey matter may be used as a clinical indicator by looking at MRIs. The study aimed to segment grey matter from brain MRI using a proposed fuzzy c-means clustering-based technique for the detection of ADHD and its subtypes (ADHD-Inattentive, ADHDHyperactive, and ADHD-Combined). The grey matter volume, age, gender, and medication status of the subjects were investigated to identify ADHD subtypes. A modified fuzzy c-means with an elbow approach has been proposed to overcome the drawbacks of previous fuzzy c-means methods and improve segmentation performance. The volume of segmented grey matter was included with the phenotypic information of the ADHD-200 dataset for data analysis of typically developing (TD) and ADHD subtypes. The proposed segmentation exhibited a dice similarity index of 95%. ADHD-Inattentive exhibited a loss of grey matter in the prefrontal cortex, while ADHD-hyperactive exhibited a loss of grey matter in the cerebellum when compared to TD. The analysis of ADHD subtypes based on age and gender showed that children transitioning to adolescence are mostly affected by ADHD-inattentive and female kids are less prone to ADHD-hyperactive. The whole grey matter volume of ADHD-inattentive children, on average, was found to be approximately 4% less than ADHD-combined. Furthermore, the whole grey matter volume was less in non-medication naive children. This study may support healthcare providers in giving appropriate occupational therapy based on the identification of different ADHD subtypes.

Plasma biomarkers across the spectrum of Alzheimer’s and Parkinson’s disease: Association with cortical thickness and cognitive dysfunction

AbstractBackgroundPlasma biomarkers of phosphorylated‐tau(p‐tau), astrocytosis and axonal damage offer a reliable means of identifying and measuring multiple pathological processes in‐vivo. How these biomarkers are associated with cortical brain structure and cognition within, and across, disorders is unclear. Leveraging the Ontario Neurodegenerative Disease Research Initiative, we examined the cross‐sectional association between plasma biomarkers, cortical thickness, and multi‐domain cognition.Method290 participants diagnosed with AD or PD (in accordance with clinical guidelines) and healthy controls (HC) were included (MeanAge = 68.96;[41% women; 35% APOE4carriers]). Four groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 121), ii)PD with MCI or dementia(PDMCI/PDD;N = 78), iii)PD with normal cognition(PD‐NC;N = 43) and HC(N = 44; Table1). Plasma measures of p‐tau181‐UGOT, Neurofilament light chain (NfL) and GFAP, alongside FreeSurfer‐derived cortical thickness were included. A neuropsychological battery was administered. All models were adjusted for age, sex, and education.ResultThere was an effect of diagnostic group on global cortical thickness, with PD‐NC, ADMCI/ADD and PDMCI/ADD exhibiting a significant reduction relative to HC(Fig1A). Regional patterns of brain atrophy were significantly associated in ADMCI/ADD and PDMCI/ADD(Fig1B). Across groups, p‐tau181, GFAP and to a lesser extent NfL, were associated with cortical thinning, particularly in lateral temporal and medial parietal regions (Fig2A). Unlike global thickness, ADMCI/ADD and PDMCI/PDD, but not PD‐NC, showed reduced thickness in the regions associated with p‐tau181, GFAP and NfL (Fig2B). Diagnostic group*GFAP/NfL/ptau181 interactions were not significant. Mediation analysis showed the cortical thinning in lateral temporal and medial parietal regions mediated between 33% to 40% of association between p‐tau181 and delayed memory. Similarly, thinning in these areas mediated 22% to 33% of the relationship between GFAP and executive function(Fig2C).ConclusionWe conclude that there is a similar pattern of gray matter loss in MCI/Dementia due to AD and PD. Higher concentrations of plasma p‐tau181 and GFAP are associated with poorer memory and executive function, in part through cortical thinning in lateral temporal and medial parietal regions. In conclusion, pathological processes related to the deposition of amyloid and tau, as well as astrogliosis, may co‐exist across cognitively impaired individuals with AD and PD. This is consistent with autopsy findings showing that AD pathology is present in 33‐60% of PD patients.

Plasma biomarkers across the spectrum of Alzheimer’s and Parkinson’s disease: Association with cortical thickness and cognitive dysfunction

AbstractBackgroundPlasma biomarkers of phosphorylated‐tau(p‐tau), astrocytosis and axonal damage offer a reliable means of identifying and measuring multiple pathological processes in‐vivo. How these biomarkers are associated with cortical brain structure and cognition within, and across, disorders is unclear. Leveraging the Ontario Neurodegenerative Disease Research Initiative, we examined the cross‐sectional association between plasma biomarkers, cortical thickness, and multi‐domain cognition.Method290 participants diagnosed with AD or PD (in accordance with clinical guidelines) and healthy controls (HC) were included (MeanAge = 68.96;[41% women; 35% APOE4carriers]). Four groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 121), ii)PD with MCI or dementia(PDMCI/PDD;N = 78), iii)PD with normal cognition(PD‐NC;N = 43) and HC(N = 44; Table1). Plasma measures of p‐tau181‐UGOT, Neurofilament light chain (NfL) and GFAP, alongside FreeSurfer‐derived cortical thickness were included. A neuropsychological battery was administered. All models were adjusted for age, sex, and education.ResultThere was an effect of diagnostic group on global cortical thickness, with PD‐NC, ADMCI/ADD and PDMCI/ADD exhibiting a significant reduction relative to HC(Fig1A). Regional patterns of brain atrophy were significantly associated in ADMCI/ADD and PDMCI/ADD(Fig1B). Across groups, p‐tau181, GFAP and to a lesser extent NfL, were associated with cortical thinning, particularly in lateral temporal and medial parietal regions (Fig2A). Unlike global thickness, ADMCI/ADD and PDMCI/PDD, but not PD‐NC, showed reduced thickness in the regions associated with p‐tau181, GFAP and NfL (Fig2B). Diagnostic group*GFAP/NfL/ptau181 interactions were not significant. Mediation analysis showed the cortical thinning in lateral temporal and medial parietal regions mediated between 33% to 40% of association between p‐tau181 and delayed memory. Similarly, thinning in these areas mediated 22% to 33% of the relationship between GFAP and executive function(Fig2C).ConclusionWe conclude that there is a similar pattern of gray matter loss in MCI/Dementia due to AD and PD. Higher concentrations of plasma p‐tau181 and GFAP are associated with poorer memory and executive function, in part through cortical thinning in lateral temporal and medial parietal regions. In conclusion, pathological processes related to the deposition of amyloid and tau, as well as astrogliosis, may co‐exist across cognitively impaired individuals with AD and PD. This is consistent with autopsy findings showing that AD pathology is present in 33‐60% of PD patients.

Sequential grey matter atrophy related to Alzheimer’s disease in adults with Down’s syndrome

AbstractBackgroundDue to the triplication of the APP gene on chromosome 21, virtually all individuals with Down’s syndrome (DS) present AD neuropathological hallmarks by the age of 40, and have a lifetime risk of developing dementia &gt;90%. However, whether DS follows a stereotypical pattern of AD atrophy has not been investigated. Here, we aimed at defining the sequential grey matter (GM) volume loss across the whole AD continuum in adults with DS.MethodCross‐sectional design. 248 adults with DS (n = 145 asymptomatic [preclinical], n = 93 prodromal/demented AD) and 181 euploid cognitively unimpaired (CU) individuals from the Down Alzheimer Barcelona Neuroimaging Initiative underwent a 3T‐MRI protocol (Table.1). T1‐weighted images were preprocessed using CAT12. GM volumes adjusted for demographics (age, sex) and nuisance variables (TIV, MRI scanner) were computed for each cortical region of the Hammer Atlas and for each DS participant, using the CU group as a reference. Adjusted volumes (W‐scores) were binarized using a threshold of ‐2.33 (corresponding to a regional volume &lt;99th percentiles of the CU group) to examine the brain regions most frequently atrophied in DS compared to CU. Conditional probability analyses were additionally performed in DS to assess if a brain region was more likely to present with atrophy than another.ResultAdults with DS most frequently showed atrophy in the medial temporal lobe, anterior cingulate, and temporo‐parietal regions. This pattern remains essentially similar when using a dynamic range of thresholds (Fig1.A) and across clinical AD stages (Fig1.B), even though the proportion of individuals showing atrophy increased with disease progression (Fig1.C). Interestingly, the anterior cingulate was the most frequently atrophied region in asymptomatic but not prodromal/demented DS. Conditional probability analyses revealed that the hippocampus, amygdala, and anterior cingulate have a significantly higher probability of showing GM loss before any other regions. A second cluster of tempo‐parietal regions appears more likely to show atrophy than most other regions.ConclusionIn DS, GM atrophy appears to follow a stereotypical pattern that strongly resembles the one of sporadic AD. Brain developmental specificities (e.g., anterior cingulate) are coupled with AD‐like atrophy early in the disease and become less predominant with AD progression.

A longitudinal analysis of brain volume changes in myelin oligodendrocyte glycoprotein antibody-associated disease.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a relapsing demyelinating condition. There are several cross-sectional studies showing evidence of brain atrophy in people with MOGAD (pwMOGAD), but longitudinal brain volumetric assessment is still an unmet need. Current recommendations do not include monitoring with MRI and assume distinct attacks. Evidence of ongoing axon loss will have diagnostic and therapeutic implications. In this study, we assessed brain volume changes in pwMOGAD over a mean follow-up period of 2years and compared this to changes in people with multiple sclerosis (pwMS). This is a retrospective single-center study over a 7-year period from 2014 to 2021. MRI brain scans at the time of diagnosis and follow-up in remission were collected from 14 Caucasian pwMOGAD, confirmed by serum myelin oligodendrocyte glycoprotein immunoglobulin G antibody presence, detected by live cell-based assays. Total brain volume (TBV), white matter (WM), gray matter (GM), and demyelinating lesion volumes were assessed automatically using the Statistical Parametric Mapping and FMRIB automated segmentation tools. MRI brain scans at diagnosis and follow-up on remission were collected from 32-matched pwMS for comparison. Statistical analysis was done using analysis of variance. There is evidence of TBV loss, affecting particularly GM, over an approximately 2-year follow-up period in pwMOGAD (p<.05), comparable to pwMS. WM and lesion volume change over the same period were not statistically significant (p>.1). We found evidence of loss of GM and TBV over time in pwMOGAD, similar to pwMS, although the WM and lesion volumes were unchanged.

Prospective MRI and Neurocognitive Assessment of “Chemobrain” in Acute Myeloid Leukaemia: The Mineral Study

CONCLUSIONS “Chemobrain” is commonly reported by patients treated for Acute Myeloid Leukaemia (AML), potentially attributable to chemotherapy or iron overload. We aimed to determine whether “chemobrain” could be objectively detected in AML patients. We performed a prospective, observational, longitudinal cohort study in adults commencing chemotherapy for AML, powered to capture a potential 25% incidence of “chemobrain.” Participants underwent neurocognitive assessment (NCA) and brain magnetic resonance imaging (MRI), including iron quantitative susceptibility mapping (QSM), as a biomarker of neuro-inflammation, at three timepoints: pre-treatment (T1), end of treatment (T2), and 6 months later (T3). Longitudinal changes of minimum 1.64 SD were considered significant. The primary outcome was change in NCA score between T1-T2, with secondary correlation analyses between NCA, MRI, QSM and clinical data. This study was funded by a RBWH Foundation 2018 Diamond Care Grant. Between January 2019 and June 2021, 20 patients were enrolled; of these, 15 and 10 remained alive/enrolled for evaluation at T2 and T3 respectively. Overall NCA scores for the cohort between T1-T2 were similar; however, four (27%) participants performed significantly worse (-1.64SD) in Language or Verbal Memory, with three returning to baseline at T3. Objective NCA score did not correlate with subjective symptoms, and quality of life and physical fatigue improved T1-T2. Cohort brain volumes were similar T1-T2; however, correlation analysis identified interesting potential associations between worse Language performance and volume loss in grey matter (GM; p=0.021) and Wernicke's area (p=0.02), and suggested increased iron susceptibility in frontal lobe (p=0.041) and possibly cortical GM (p=0.055). Despite patient-reported symptoms, objective neurological toxicity appears uncommon in AML patients, and those with measurable impairment appear to subsequently return to baseline.