Global Atrophy Research Articles

White and Gray Matter Changes are Associated With Neurocognitive Decline in HIV Infection.

To investigate the relationship between neurocognitive deficits and structural changes on brain magnetic resonance imaging in people living with HIV (PLWH) with good virological control on combination antiretroviral therapy, compared with socioeconomically matched control participants recruited from the same communities. Brain magnetic resonance imaging scans, and clinical and neuropsychological data were obtained from virologically controlled PLWH (viral load of <50 c/mL and at least 1 year of combination antiretroviral therapy) and socioeconomically matched control participants. Magnetic resonance imaging was carried out on 3 T scanner with 8-channel head coils and segmented using Classification using Derivative-based Features. Multiple regression analysis was performed to examine the association between brain volume and various clinical and neuropsychiatric parameters adjusting for age, race, and sex. To evaluate longitudinal changes in brain volumes, a random coefficient model was used to evaluate the changes over time (age) adjusting for sex and race. The cross-sectional study included 164 PLWH and 51 controls, and the longitudinal study included 68 PLWH and 20 controls with 2 or more visits (mean 2.2 years, range 0.8-5.1 years). Gray matter (GM) atrophy rate was significantly higher in PLWH compared with control participants, and importantly, the GM and global atrophy was associated with the various neuropsychological domain scores. Higher volume of white matter hyperintensities were associated with increased atherosclerotic cardiovascular disease risk score, and decreased executive functioning and memory domain scores in PLWH. These findings suggest ongoing neurological damage even in virologically controlled participants, with significant implications for clinical management of PLWH. ANN NEUROL 2024;95:941-950.

Abstract WP135: Coexistence of Enlarged Perivascular Spaces and Other MRI Markers of Cerebral Small Vessel Diseases

Objective: Enlarged Perivascular Spaces (EPVS) have gained recognition as potential indicators of cerebrovascular pathologies. In this study, we investigated the association between the presence and severity of EPVS and other MRI Markers of cerebral small vessel diseases. Method: Our study was conducted on a subset of the Geisinger DiscovEHR Initiative Cohort. A predefined protocol was employed to evaluate each brain magnetic resonance imaging (MRI) data by two trained reviewers. The total numbers of EPVS were categorized into five grades (0-4) in centrum semiovale and basal ganglia regions. We compared patients with EPVS and an age-, gender-, body mass index-, and hypertension-propensity-score-matched cohort lacking EPVS. Results: Out of 3054 (mean age of 67.5 years, 97% white of Caucasian descent) randomly selected participants, 1465 (47.9%, mean age 69.9 years) showed evidence of EPVS in their imaging. Propensity score matching resulted in 1310 participants in each group. The presence of EPVS in basal ganglia was linked to higher white matter hyperintensity according to the Fazekas scale in deep white matter (OR, 1.4; 95% CI, 1.2-1.6), as well as global cortical atrophy (OR, 1.22; 95% CI, 1.1-1.4) on MRI scans. Other factors, such as cerebral aneurysm (OR, 2.3; 95% CI, 1.4-3.8), heart failure (OR, 1.85; 95% CI, 1.3-2.6), smoking (OR, 1.43; 95% CI, 1.1-1.8) exhibited associations. Moreover, an increased burden of EPVS correlated with higher Fazekas scales in periventricular and deep white matter. Conclusion: The presence and severity of EPVS exhibited are associated with MRI markers of white matter hyperintensity and global cortical atrophy. EPVS may be a marker of an aging brain and cerebral small vessel diseases. It might be associated with cerebrovascular risk factors.

Abstract WMP69: Brain Atrophy and White Matter Disease Agreement on NCCT and MRI in Ischemic Stroke

Background: NCCT is the most widely used parenchymal imaging for acute stroke. Evaluations of brain frailty measures like atrophy and white matter disease (WMD) are becoming increasingly relevant in stroke outcome prediction but are conventionally thought to be best seen on MRI. We assessed the agreement between baseline NCCT and follow-up MRI ratings of brain atrophy and WMD and compared their predictive validity in relation to 90-day functional outcomes in acute ischemic stroke. Methods: In this post-hoc analysis of baseline NCCT and follow-up MRI data from the Alteplase compared to Tenecteplase (AcT) randomised-controlled trial, expert readers (stroke neurologists and radiologists) assessed atrophy using the global cortical atrophy (GCA), Koedam, and medial temporal lobe atrophy scales. WMD was measured using the Fazekas scale. Binary agreement (none-mild vs. moderate-severe) and agreement across the full range of scores between atrophy and WMD measures on NCCT and MRI were calculated using Gwet’s agreement coefficient (AC1). Logistic regressions and Delong’s test were used to compare the area under the curve (AUC) for the prediction of 90-day modified Rankin score (mRS) 0-1 when using NCCT vs MRI-based ratings for each atrophy and WMD variable. Results: Of 1577 patients included in the AcT trial, 491 had interpretable NCCT+MRI. Binary agreement was substantial (AC1:0.68-0.80) for deep and total WMD scores, Koedam scale and frontal GCA. Almost perfect binary agreement (AC1:0.81-0.97) was found for all other measures. Deep white matter showed a significant difference between NCCT and MRI ratings for predicting 90-day mRS 0-1 (MRI AUC = 0.61 [0.56-0.66], CT AUC = 0.56 [0.50-0.60], p = 0.01, Delong p = 0.02) There was no significant difference in predicting 90-day mRS for the other variables (all p &gt; 0.12, GCA: MRI AUC = 0.54 [0.49-0.60] CT AUC = 0.53 [0.47-0.58], p = 0.58, Delong p = 0.86). Conclusion: NCCT ratings of brain atrophy and WMD by experts have substantial to almost-perfect agreement with MRI atrophy and WMD ratings and achieve similar prediction of 90-day mRS 0-1 functional outcomes in acute stroke patients. This implies that it is reasonable to use NCCT scans to evaluate these brain frailty measures in clinical practice and in stroke trials.

Exploring graded profiles of hippocampal atrophy along the anterior-posterior axis in semantic dementia and Alzheimer’s disease

Mounting evidence indicates marked hippocampal degeneration in semantic dementia (SD) however, the spatial distribution of hippocampal atrophy profiles in this syndrome remains unclear. Using a recently developed parcellation approach, we extracted hippocampal volumes from four distinct subregions running from anterior to posterior along the longitudinal axis (anterior, intermediate rostral, intermediate caudal, and posterior). Volumetric differences in hippocampal subregions were compared between 21 SD, 24 matched Alzheimer’s disease (AD), and 27 healthy older Control participants. Despite comparable overall hippocampal volume loss, SD and AD groups diverged in terms of the magnitude of atrophy along the anterior-posterior axis of the hippocampus. Global hippocampal atrophy was observed in AD, with no discernible gradation or lateralisation. In contrast, SD patients displayed graded bilateral hippocampal atrophy, most pronounced on the left-hand side, and concentrated in anterior relative to posterior subregions. Finally, we found preliminary evidence that disease-specific vulnerability along the anterior-posterior axis of the hippocampus was associated with canonical clinical features of these syndromes.

Arterial Hypertension, Structural Damage of the Brain and Cognitive Test

The arterial hypertension cause brain vascular damage (white matter lesion) and the burden and progression determine their cognitive consequences. Therefore, arterial hypertension is considered the main modifiable vascular risk factor for cognitive impairment and dementia. Therefore, the aim of the current study was to evaluate the results of cognitive tests in a sample of hypertensive patients and to establish possible associations with structural brain lesions (atrophy, white matter lesions) identified by magnetic resonance imaging Were included 70 hypertensive patients from Heart-Brain study in Argentina with magnetic resonance imaging and cognitive test. Fazekas scale and the Global Cortical Atrophy were used to quantify the white matter lesions and the brain atrophy, respectively. The Mini-Mental Status Examination, Clock Drawing test and Mini-Boston Naming test were used to evaluate the cognitive status. average age 69.7 ± 10.6 years, 55.7% female). Based on the linear regression analysis, Fazekas scale and cognitive tests were inversely associated. For each grade of increase in Fazekas scale, the clock drawing test (Coef -0.56, CI 95% -1.01 -0.10, p=0.01) and the Mini-mental Status Examination (Coef -0.7, CI 95% -1.27 -0.13, p=0.01) scores decreased. The subcortical atrophy was significantly associated with the clock drawing test (OR 3.29, CI 95% 1.25-8.63; p=0.016). Conclusion: The cognitive tests, particularly the clock drawing test could be used (in the clinical routine practice) as “subrrogate” of the brain structural hypertension-mediated damage.

The Association of Retinal Microvasculature With Gray Matter Changes and Structural Covariance Network: A Voxel-Based Morphometry Study.

Increasing evidence suggests that retinal microvasculature may reflect global cerebral atrophy. However, little is known about the relation of retinal microvasculature with specific brain regions and brain networks. Therefore, we aimed to unravel the association of retinal microvasculature with gray matter changes and structural covariance network using a voxel-based morphometry (VBM) analysis. One hundred and forty-four volunteers without previously known neurological diseases were recruited from West China Hospital, Sichuan University between April 1, 2021, and December 31, 2021. Retinal microvasculature of superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP) were measured by optical coherence tomography angiography using an automatic segmentation. The VBM and structural covariance network analyses were applied to process brain magnetic resonance imaging (MRI) images. The associations of retinal microvasculature with voxel-wise gray matter volumes and structural covariance network were assessed by linear regression models. In the study, 137 participants (mean age = 59.72 years, 37.2% men) were included for the final analysis. Reduced perfusion in SVP was significantly associated with reduced voxel-wise gray matter volumes of the brain regions including the insula, putamen, occipital, frontal, and temporal lobes, all of which were located in the anterior part of the brain supplied by internal carotid artery, except the occipital lobe. In addition, these regions were also involved in visual processing and cognitive impairment (such as left inferior occipital gyrus, left lingual gyrus, and right parahippocampal gyrus). In regard to the structural covariance, the perfusions in SVP were positively related to the structural covariance of the left lingual gyrus seed with the left middle occipital gyrus, the right middle occipital gyrus, and the left middle frontal gyrus. Poor perfusion in SVP was correlated with reduced voxel-wise gray matter volumes and structural covariance networks in regions related to visual processing and cognitive impairment. It suggests that retinal microvasculature may offer a window to identify aging related cerebral alterations.

Role of Neuroimaging in Suspected Dementia Patients: Utilization of Structural Imaging Algorithmic‐Based Diagnosis in Resource Limited Settings

AbstractBackgroundIn 2050, it is estimated that the number of dementia patients in the sub Saharan Africa is expected to reach 5.05 million, an increase of 136% from the previous estimate of 2.14 million. The objectives of the present study were to assess the neuroimaging findings and associated factors in dementia suspected patients.MethodA retrospective survey of the medical records of 121 suspected dementia patients whom presented to the Yehuleshet Specialty Clinic with subjective forgetfulness were reviewed. The study duration was between January 1, 2020 and December 31, 2021. Both descriptive and analytical statistics were used to analyze the data.ResultThe mean age was 70.4 (1SD = 10.3) years. Sixty four (52.9%) participants were age below 70. Male accounted for 57.9%. Hyperlipidemia was the commonest (38%) identified vascular risk factor followed by prevalence of hypertension (32.2%) and diabetes mellitus (22.3%). HIV infection was observed in 3.3%. Low mean serum vitamin D level (below 20ng/mL) was observed in individuals with focal &amp; global cortical atrophy and those with white matter hyperintensity. Fifty two (43%) participants fulfilled the clinical and imaging criteria of vascular cognitive impairment (VCI). Nearly quarter of the patients had imaging evidences of focal or global cortical atrophy. Eleven (9.1%) had imaging evidences of surgical causes of dementia. the presences of comorbid hypertension, previous stroke, and Parkinsonism were independent predictors of vascular dementia.ConclusionThe present study shows high burden of vascular cognitive impairment among individuals suspected of dementia.Furthermore, the presences of comorbid hypertension, previous stroke, and Parkinsonism were independent predictors of vascular dementia.

Longitudinal biomarkers in Dementia with Lewy bodies: A systematic review and meta‐analysis

AbstractBackgroundDementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease (AD). DLB is a clinically and biologically heterogeneous disease, and little is known about longitudinal trajectories of patients with DLB. Disease progression can be measured with biomarkers capturing structural, functional, and pathological processes, aiding in understanding disease mechanism and discovering potential drug targets. We aimed to perform a systematic review to explore longitudinal patterns of biomarkers in DLB.MethodsSearches were conducted within five different databases, including cohort studies and case series on DLB patients with repeated measures of fluid or imaging biomarkers, and at least six months follow‐up. Fourteen studies were included (Figure 1), reporting data on longitudinal MRI, DaT‐Scan, PiB and flortaucipir‐PET, plasma p‐tau, and HMPAO SPECT, with up to 2,5 years of follow‐up (Table 1). No data on cerebrospinal fluid biomarkers were available. We could only perform a meta‐analysis on annualized brain atrophy rates, with a random effect model and standardized mean differences (SMD).ResultsProgressive putaminal atrophy is seen in DLB patients, even when DaT‐scans are initially normal. In the meta‐analysis, brain atrophy rates were not significantly higher in pure DLB compared to cognitively unimpaired controls, with the exception of accelerated ventricular expansion rates (SMD 0.57 [0.03‐1.10], p = 0.04, 2 studies, 58 patients). Autopsy‐confirmed AD copathology resulted in greater global atrophy rates compared to pure DLB (SMD 0.72 [0.21‐1.31], p = 0.006, Figure 2), similar to AD. AD copathology accelerates temporal lobe and striatal atrophy rates. In one study, brain amyloid accumulation in DLB initially accelerated and then decelerated, similar to AD and cognitively unimpaired subjects, with absolute SUVr lower than AD. In another study, brain tau accumulation rate correlated with brain atrophy rates in the middle temporal pole in DLB patients.ConclusionsOnly a few studies reported longitudinal data on biomarkers in DLB. DLB patients do not have significantly higher brain atrophy rates compared to controls, while the presence of AD copathology accelerates global and regional atrophy. Future studies with longer follow‐ups and multimodal biomarkers are needed to further characterize disease progression and elucidate clinical and biological heterogeneity.

Predicting cognitive decline in amyloid‐positive patients with mild cognitive impairment or mild dementia

AbstractBackgroundCognitive decline rates in Alzheimer’s disease (AD) vary greatly. Disease‐modifying treatments (DMT) may alter cognitive decline trajectories, rendering their prediction increasingly relevant. We aimed to construct clinically applicable prediction models of cognitive decline in amyloid‐positive patients with mild cognitive impairment (MCI) or mild dementia.MethodsFrom the Amsterdam Dementia Cohort, we selected amyloid‐positive participants with MCI (n = 317, 66±7yrs, 45%Female, baseline MMSE 26±2) or mild dementia (n = 666, 65±7yrs, 49%Female, MMSE 22±4) and ≥2 annual MMSEs. Follow‐up was 3±2yrs with 4±2 MMSEs. Amyloid positivity was based on cerebrospinal fluid (CSF) AD biomarker concentrations or amyloid PET. We used linear mixed modelling to predict MMSE over time. First, decline trajectories were described with cubic time curves (S‐shaped). Then, we backwards selected predictors from baseline MMSE, age, sex, APOE ε4 dose, magnetic resonance imaging (MRI; visual scores: medial temporal lobe [MTA], global atrophy), CSF concentrations (phosphorylated tau [pTau], Aβ1‐42), and their interactions with linear time. MCI and mild dementia were modelled separately as stratification increased log‐likelihood.ResultsFor MCI and mild dementia, rates of cognitive decline increased over time. In MCI, average MMSE declined from 26.4(95%CI:26.2‐26.7) to 25.8(25.5‐26.1) after 18 months, to 24.2(23.7‐24.6) after three years, and to 21.0(20.1‐21.7) after five years. In mild dementia, MMSE declined from 22.4(95%CI:22.0‐22.6) to 19.8(19.4‐20.2), 15.3(14.6‐15.9), and 7.8(6.7‐8.9). For MCI, selected predictors of future MMSE were baseline MMSE, and interactions of time with age, MTA and pTau (table 1). For mild dementia, additional selected interactions with time were baseline MMSE, Aβ1‐42, and APOE ε4. Figure 1 shows the predicted decline distribution. As an example; predicted MMSE after three years for a 65yrs female MCI patient with baseline MMSE 27, would be 26.3 with MTA 0 and pTau 20pg/ml, compared to 23.8 with MTA 1 and pTau 40pg/ml (figure 2a;2b). In the latter case, 27% slower decline would lengthen follow‐up to a predicted MMSE of twenty by fourteen months.ConclusionWe constructed models for MCI and mild dementia that predict MMSE over time. These models could inform patients about their potential cognitive trajectory and aid in conversations about DMT initiation and the evaluation of their potential effect.

Diurnal cortisol, neuroinflammation, and neuroimaging visual rating scales in memory clinic patients

AbstractBackgroundNeuroinflammation is considered a hallmark of the Alzheimer’s disease (AD) pathogenic process. Dysregulations in stress hormones (cortisol) may increase AD risk and are related to brain atrophy. This cross‐sectional study aims to examine interactions of cortisol patterns and neuroinflammation markers in their association with neuroimaging correlates.Method188 participants were recruited from the Karolinska University Hospital memory clinic (Stockholm, Sweden), and underwent magnetic resonance imaging or computed tomography. Four visual rating scales were applied to the scans: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (Fazekas), and posterior atrophy (Koedam). Additionally, participants provided saliva to assess diurnal cortisol patterns, and underwent lumbar punctures for cerebrospinal fluid (CSF) sampling. Five cortisol measures were used: awakening levels, bedtime levels, cortisol awakening response (CAR), total daily output, and the ratio of awakening to bedtime levels (AM/PM ratio). Nineteen CSF neuroinflammation markers were categorized into five composite scores (mean z‐scores): proinflammatory cytokines (Interleukin (IL‐)6, IL‐8, IL‐15, IL‐12/IL‐23 p40, CC chemokine ligand (CCL)4, CXC chemokine ligand 10), other cytokines (IL‐5, IL‐16, CCL17), angiogenesis markers (Vascular endothelial growth factor (VEGF), VEGF‐D, VEGF‐receptor 1, Placental growth factor), vascular injury markers (Serum amyloid A, C‐reactive protein, Vascular cell adhesion molecule‐1, Intercellular adhesion molecule‐1), and glial activation markers (YKL‐40, CCL2). Ordinal logistic regressions were conducted to assess associations between cortisol patterns, neuroinflammation scores, and visual rating scales, and interactions between cortisol patterns and neuroinflammation composite scores in predicting visual rating scales.ResultHigher levels of angiogenesis markers were associated with greater odds of more severe white matter lesions. Furthermore, awakening cortisol levels, bedtime levels, CAR, and total daily output independently interacted with ‘other cytokines’ scores to predict MTA, CAR and total daily output independently interacted with ‘proinflammatory cytokines’ scores to predict white matter lesions, and the AM/PM ratio interacted with angiogenesis markers to predict GCA. No associations were found between cortisol patterns and visual rating scales.ConclusionThis study provides evidence for potential interplay between diurnal cortisol patterns and neuroinflammation. While this study does not provide information on causality, these findings suggest that neuroinflammation is involved in the pathway between chronic stress and AD.

Brain Reserve Score on Acute Trauma Head CT is Correlated with Pre‐TBI MCI/Dementia and is an Independent Predictor of Post‐TBI Cognitive Outcome

AbstractBackgroundPre‐injury brain reserve may contribute to the substantial heterogeneity observed in cognitive outcome after mild traumatic brain injury (mTBI), including risk for cognitive decline and dementia. However, no tools exist to quantify pre‐injury brain reserve in an acute trauma setting, thereby limiting research. We aimed to develop and validate a visually‐rated Brain Reserve Score (BRS) to quantify baseline brain reserve on head CTs obtained to rule out intracranial trauma in adults presenting acutely with mTBI.MethodsData are from the Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK‐TBI) and TRACK‐Geriatric TBI (TRACK‐GERI) studies, multi‐center prospective cohort studies of adults age 18+ presenting within 24 hours (TRACK‐TBI) or adults age 65y+ presenting within 72 hours (TRACK‐GERI) of TBI who received head CT and multi‐domain clinical follow‐up for one year. BRS was developed by adapting existing MRI visual rating scales of global cortical atrophy, hippocampal atrophy, and white matter change for use in trauma head CTs and then by refining the scoring guide to optimize rater reliability. To establish concurrent validity, we assessed correlation of BRS with pre‐injury cognitive status (measured in TRACK‐GERI using informant‐reported Clinical Dementia Rating interviews). To establish predictive validity, we assessed association of BRS with good versus poor 12‐month cognitive outcome in TRACK‐TBI using logistic regression adjusted for baseline demographics, medical/psychiatric comorbidities, injury characteristics, and trauma severity on CT.ResultsFinal BRS score ranged from 0‐10 (10 is highest burden of neuropathology); inter‐ and intra‐rater reliability were moderate‐substantial (weighted kappa 0.54‐0.80). Among N = 100 TRACK‐GERI participants BRS was significantly correlated with pre‐injury CDR (r = 0.37, p&lt;0.01). Among N = 656 TRACK‐TBI participants, BRS of 6+ was independently associated with poor 12‐month cognitive outcome (fully adjusted odds ratio 4.35, 95% confidence interval 1.35‐13.99, p = 0.01).ConclusionBRS is a reliable visually rated score of brain reserve on acute trauma head CT that correlates with pre‐injury cognitive status and independently predicts poor cognitive outcome one year post‐mTBI. BRS may be a useful tool to facilitate inclusion of older adults in acute TBI research thereby advancing clinical care and research on mechanisms of accelerated post‐TBI cognitive decline and dementia.

Sleep disturbances, cortisol, and neuroimaging correlates among memory clinic patients

AbstractBackgroundSleep disturbances are increasingly acknowledged as a preclinical marker for Alzheimer’s disease (AD), however, the mechanisms underlying the association between sleep disturbances and dementia remain unclear. Sleep disturbances may affect AD through brain morphology changes and vascular damage, as sleep disturbances are known to be linked with altered grey‐ and white‐matter integrity. Moreover, sleep and brain changes may be linked with cortisol levels. Sleep disturbances have been proposed to parallel cortisol dysregulation, and older individuals with preclinical AD have altered awakening cortisol, a feature that is intensified among people also suffering from sleep disturbances.MethodThe study is based on 146 memory clinic patients from the Karolinska University Hospital memory clinic (Sweden). Participants are in the age range 47‐86 years and diagnosed with either subjective cognitive impairment or mild cognitive impairment. Self‐reported sleep disturbances are measured by the Karolinska Sleep Questionnaire. Brain imaging (MRI or CT) was used to semi‐quantify brain atrophy using four visual rating scales: Medial Temporal Atrophy, Global Cortical Atrophy, Koedam (posterior brain atrophy) and Fazekas (white‐matter lesions) scales. Lastly, saliva cortisol has been sampled 6 times daily to measure diurnal cortisol patterns.ResultOrdinal logistic regressions show significant associations between sleep disturbances and brain parameters. Insufficient sleep (OR = 1.30, p = 0.048) is associated with greater odds of white‐matter lesions, and apnea (OR = 1.26, p = 0.036) and snoring (OR = 1.38, p = 0.045) are associated with greater odds of posterior brain atrophy. Increased daytime sleepiness is associated with both reduced awakening cortisol (β = ‐0.03, p = 0.025) and a flattened cortisol curve (β = ‐0.04, p = 0.019). Apnea is associated with reduced awakening cortisol (β = ‐0.06, p = 0.013). However, cortisol was not found to significantly interact with sleep in predicting brain outcomes.ConclusionThese results show that various sleep disturbance parameters (short sleep duration, apnea, and snoring) are associated with neuroimaging correlates, while daytime sleepiness and apnea are associated with markers of dysregulated cortisol patterns. The results suggest that neuroimaging correlates and cortisol measures may clarify the mechanisms underlying the associations between sleep disturbance and cognitive impairment, and the combination of objective sleep measures and neuroimaging markers in future studies may further reveal the mechanisms.

Will Changes in the COVID‐19 Brain MRI Signature Region Affect Subsequent Dementia Outcomes? Linking Pre‐Pandemic Brain MRIs to Long‐Term Dementia Incidence in UK Biobank Participants

AbstractBackgroundNeurocognitive sequelae of SARS‐CoV‐2 infection have been suggested as potentially leading to a higher incidence of dementia, but the underlying mechanisms remain unclear. By comparing brain magnetic resonance imaging (MRI) between participants with and without a history of SARS‐CoV‐2 infection, prior work identified infection‐related structural changes, including reduced cortical thickness and gray‐white matter contrast. We characterized the COVID‐19 signature region (COVIDsig) in MRIs taken prior to the pandemic and evaluated whether changes in this region predicted incident dementia.MethodUsing pre‐pandemic data on UK Biobank participants aged 55+, we examined the association between the COVID‐19 brain MRI signature region and dementia incidence up to March 2020 (N = 39,119 dementia‐free participants with a median of 1.8 years of follow‐up). The COVIDsig comprised the lateral orbitofrontal cortex and parahippocampal gyrus and the exposures included COVIDsig cortical thickness and COVIDsig gray‐white matter contrast. Dementia diagnoses were obtained from linked hospital, primary care, and death registry data. We used Cox proportional‐hazards models and adjusted for sex, APOE‐ε4, education, material deprivation, body mass index, and assessment center. To test if COVIDsig predicts dementia risk independently of global cerebral atrophy, we further adjusted for an Alzheimer’s disease signature region (ADsig) or a non‐COVID‐19 signature region (cerebral cortex except COVIDsig). In sensitivity analysis, we repeated the primary analysis on each component of COVIDsig (lateral orbitofrontal cortex and parahippocampal gyrus) separately.ResultThe mean age of the participants was 64.7 years (SD = 7.4; Table 1) and 65 dementia cases were identified during follow‐up. The age‐adjusted dementia incidence rate was 2.5 per 1,000 person‐years. One standard deviation decrease in COVIDsig cortical thickness and gray‐white matter contrast was associated with a 49% and a 52% increase in the hazard of dementia diagnosis (HR for cortical thickness = 1.49, 95% CI = 1.19‐1.88; HR for gray‐white matter contrast = 1.52, 95% CI = 1.20‐1.94; Table 2), respectively. After adjusting for ADsig or non‐COVID‐19 signature region, associations were attenuated (Figure 1).ConclusionThese results should be evaluated in independent samples and the persistence of post‐COVID‐19 structural brain changes assessed. If confirmed, findings suggest SARS‐CoV‐2 infection may increase dementia incidence via structural brain changes.

Genotype Phenotype characterisation, Imaging profile and novel genetic mutations from a large cohort of Frontotemporal Dementia from India

AbstractBackgroundDegenerative dementia like Frontotemporal dementia (FTD) are complex heterogeneous disorders with variable phenotypes, patterns of atrophy and pathogenicity. Advanced genetic studies from India are sparse and earlier techniques mostly reported negative results. Current study aims to evaluate the clinical, radiological and genetic profile of FTD/FTD overlap syndromes, to perform whole exome sequencing and to explore genotype phenotype correlations.MethodSubjects with dementia fulfilling standard criteria’s for FTD/FTD Overlap and AD were recruited from Dept. of Neurology, NIMHANS, India Demography, pedigree analysis, clinical, cognitive and neuropsychological evaluation and blood sampling for genetic analysis by next generation sequencing and MRI as per ADNI protocol were performed. RT‐PCR was done for analysing c9orf.Results133 FTD/FTD overlap were recruited. Mean age at onset was 56 ± 9.8 years in FTD There were 87 men and 75 women. Family history was documented in 43%. 42% had family history in first degree relatives, 11% had history in second degree and 4% in third degree relatives. Mean ACE scores were 43.8± 24.7. Frontotemporal atrophy was noted in 90% in MRI (n = 115). 41% had Grade 1 (mild) global cortical atrophy score .MRI also revealed characteristic features like diffusion restriction, white matter lesions (CSF1R) basal ganglia calcification with bone cysts(TYROBP) and Corpus callosal atrophy(TREM2)11 novel gene mutations including one each of CSF1R, TREM2, TYROBP, SQSTM1, GRN, MAPT, PSEN2 and four cases of C9orf were detected (Pathogenic in 11 and Variant of unknown significance in 26), out of the 100 samples sequenced and analysed (ACMG guidelines). VUS like GBA, PANK2, PLAG26, PRNP, LRRK2, DCNT etc. were also identified. Sanger validation confirmed the pathogenic mutations. Novel variants of CSF1R, TREM2 and TYROBP, primary microgliopathy as causative genes are being first time described from India. SQSTM1 presented as bvFTD without ALS overlap, GRN as non‐fluent aphasia, MAPT as bvFTD and PSEN2 as non‐fluent PPA and two patients with C9orf presented as bvFTD and two others as FTD‐ALS.ConclusionGenotype‐phenotype correlations along with neuroimaging and pedigree analysis has aided in early diagnosis, prognostication and novel and unique genetics causes shedding light on underlying FTD mechanism from our cohort.

Disease progression in the first 5 years of treatment in multiple sclerosis: Predictive value of early brain and lesion volume changes

Background: Whether the degree of inflammation (and its resolution) and neurodegeneration after treatment initiation predicts disease progression in multiple sclerosis (MS) remains unclear. Objectives: To assess the predictive value of magnetic resonance imaging (MRI)-derived brain and lesion volume (LV) changes in years 1 and 2 of treatment for disease progression. Methods: Patients receiving early interferon beta-1a treatment in REFLEX/REFLEXION (N = 262) were included. Predictive regression models included new/enlarging LV (positive activity), disappearing/shrinking LV (negative activity), and global/central atrophy during years 1 and 2. Results: Faster global atrophy and/or pseudo-atrophy and positive lesion activity in years 1 and 2 related to an increased probability and faster conversion to clinically definite multiple sclerosis (CDMS). Negative lesion activity in year 1 and slower central atrophy in year 2 were predictive of confirmed disability progression (9-Hole Peg Test). Positive lesion activity in year 2 was predictive of faster global atrophy, while positive lesion activity in years 1 and 2 was predictive of faster central atrophy. Conclusions: A higher degree of global atrophy and/or pseudo-atrophy in year 1 was predictive of CDMS. Positive lesion activity in any year was related to CDMS and neurodegeneration. Disability was related to negative lesion activity in year 1 and slower central atrophy in year 2.

Early cortical atrophy is related to depression in patients with neuropathologically confirmed Parkinson's disease

ObjectiveDepression is a common comorbidity in Parkinson's disease (PD) and other synucleinopathies. In non-PD geriatric patients, cortical atrophy has previously been connected to depression. Here, we investigated cortical atrophy and vascular white matter hyperintensities (WMHs) in autopsy-confirmed parkinsonism patients with the focus on clinical depression. MethodsThe sample consisted of 50 patients with a postmortem confirmed neuropathological diagnosis (30 Parkinson's disease [PD], 10 progressive supranuclear palsy [PSP] and 10 multiple system atrophy [MSA]). Each patient had been scanned with brain computerized tomography (CT) antemortem (median motor symptom duration at scanning = 3.0 years), and 19 patients were scanned again after a mean interval of 2.7 years. Medial temporal atrophy (MTA), global cortical atrophy (GCA) and WMHs were evaluated computationally from CT scans using an image quantification tool based on convolutional neural networks. Depression and other clinical parameters were recorded from patient files. ResultsDepression was associated with increased MTA after controlling for diagnosis, age, symptom duration, and cognition (p = 0.006). A similar finding was observed with GCA (p = 0.017) but not with WMH (p = 0.47). In PD patients alone, the result was confirmed for MTA (p = 0.021) with the same covariates. In the longitudinal analysis, GCA change per year was more severe in depressed patients than in nondepressed patients (p = 0.029). ConclusionsEarly medial temporal and global cortical atrophy, as detected with automated analysis of CT-images using convolutional neural networks, is associated with clinical depression in parkinsonism patients. Global cortical atrophy seems to progress faster in depressed patients.

Reliability of the global cortical atrophy visual rating scale applied to computed tomography versus magnetic resonance imaging scans in acute stroke

IntroductionResearch using magnetic resonance imaging (MRI) suggests regional cerebral atrophy measures (e.g., frontal lobe, temporal lobe) may predict post-stroke outcomes. Clinical CT scans have excellent potential for use in research but it is unclear whether regional atrophy measures from CT are reliable compared to MRI reference standards.MethodsWe used the Global Cortical Atrophy (GCA) scale to investigate reliability of atrophy measures on CT versus MRI scans from stroke patients originally recruited to the Oxford Cognitive Screening programme. Two raters provided standardised visual ratings at two timepoints. Weighted Kappa statistics assessed the reliability of regional atrophy scores. Spearman’s correlation and a two-way repeated measures ANOVA assessed the reliability of the total score.ResultsOn clinically acquired neuroimaging from 98 stroke patients (mean/SD age = 70.97/11.99, 42 female, 84 ischaemic stroke), regional GCA scores on CT versus MRI showed fair to almost perfect intra-rater agreement (κ = .50–.87), substantial to almost perfect intra-rater agreement on CT (κ = .67–.88), and moderate to almost perfect intra-rater reliability on MRI (κ = .50–.89). Regional GCA scores showed mostly moderate to substantial inter-rater reliability on both CT and MRI (κ = .43–.69), except the temporal horns and parieto-occipital region. There was a strong correlation between total GCA scores on CT and MRI (r (96) = .87–.88, p < .001).ConclusionsThese results support the use of cerebral atrophy measures from CT in clinical research, as visual ratings showed generally good agreement between CT and MRI, between raters, and between timepoints.

Role of Magnetic Resonance Imaging in Dementia

Background: Dementia is a condition of elderly individuals, marked with emotional and cognitive disabilities which are severe enough to impair their routine daily life and its quality. It is mainly a disease affecting elderly population with an approximate prevalence rate of 1% at the age of 60 years and quadruples every 10 years, up to 30%–50% by the age of 85 years. There are about 5.5 crore people suffering with dementia with more than 60% in developing countries.To overcome this, a multipronged strategy with timely diagnosis is the need of the hour. Materials and Methods: The present study was conducted at the Department of Radiodiagnosis and Department of Psychiatry of J. N. Medical College and Hospital, Aligarh, over a period of 2 years. Forty-five patients in the age group of more than 55 years who presented with the complaints of cognitive impairment and were referred for magnetic resonance imaging (MRI) head after clinical examination and Mini–Mental State Examination (MMSE) score assessment were included in the study. On MRI images are assessed using the Global Cortical Atrophy (GCA) scale, medial temporal lobe (MTL) atrophy scale, and Fazekas Scale, then findings are correlated with clinical MMSE scores. Results: There were 45 patients with the age group of more than 50 years, among 66.67% of patients were males and 33.33% of patients were females. In 60.00% of patients, socioeconomic status was lower middle class, 46.67% of patients were illiterate followed by studied till primary school (22.22%). In 66.67% of patients, mini–mental score examination score was mild. Among the imaging scales, 82.22% of patients showed moderate GCA scale; in 55.56% of patients, interpretation of MTL atrophy scale was widening of choroid fissure and temporal horn of lateral ventricle. 33.33% of patients showed Fazekas 3 Scale with large confluent lesions. All these imaging scales showed a significant negative correlation with MMSE scores. Conclusion: MRI plays an important role in the assessment of structural changes in patients presenting with cognitive impairment as well as it points toward the diagnosis of certain type of dementia depending on the involvement of specific areas or lesions and their distribution in the cerebral hemispheres. Visual assessment using various scales has helped in assessing the severity as well as possible type. There has been establishment of significant correlation between the MRI scales of atrophy and clinical MMSE scoring system.

P01.09.A THE NEUROCOGNITIVE FUNCTIONING OF LOWER GRADE GLIOMA PATIENTS BEFORE START OF RADIOTHERAPY IS ASSOCIATED WITH THE RADIOLOGICAL APPEARANCE OF THE BRAIN

Abstract BACKGROUND The cause for neurocognitive function (NCF) impairments in patients with lower grade glioma (LGG) is typically multifactorial. The aim of this study was to explore the relationship between NCF and the radiological appearance of the brain before start of radiotherapy (RT) in LGG patients. MATERIAL AND METHODS Around start of RT we evaluated NCF of LGG patients treated with proton therapy. The assessment included 10 neuropsychological tests with 20 measures that could be categorized over 6 cognitive domains. Raw test scores were converted to Z scores based on normative data. Mild cognitive impairment (MCI) was defined as a Z score of less than -2 on a single measure, or Z score of less than -1.5 on multiple measures. An impaired cognitive domain was defined as a mean composite Z score of less than -1.5. The radiological appearance of the brain outside the tumor region was assessed on a pre-RT planning MRI using the Fazekas score and Global Cortical Atrophy (GCA) score. For statistical analysis we used Chi Square tests and Mann-Whitney U tests. RESULTS Between 2018 and March 2022, 126 LGG patients started RT treatment, 119 patients (94%) had NCF assessment pre-RT and were available for analysis. Median age was 41 years, 51% of patients was male, reported comorbidities included hypertension in 7%, diabetes mellitus in 3% and cardiovascular 13% of patients. The World Health Organization (WHO) performance scores and the Neurologic Assessment in Neuro-Oncology (NANO) scores were 0 - 1, in 98%, and 92% of patients. The Fazekas score was 0 in 75%, 1 in 18% and 2 in 6% and 3 in 2% of patients. The GCA score was 0 in 59%, 1 in 38%, 2 in 3% of patients. In 77 (65%) patients the performance on the NCF assessment indicated the presence of MCI. Patients with MCI had a significant radiologically worse appearance of the brain (Fazekas score 1 or higher 31.2% versus 14.3%, p = 0.043; and GCA score 1 or higher 49.4% versus 26.2%, p = 0.014). Domain impairments were present in executive functions and attention (26%); verbal memory (23%); verbal functions (20%); non-verbal memory (20%); processing speed (18%); and working memory (14%). Fazekas score 1 or higher was significantly associated with lower composite Z scores of verbal functions (median (IQR) -0.84 (1.12) versus -0.40 (0.94), p=0.014); verbal memory (median (IQR) -0.66 (1.26) versus -0.20 (1.35), p=0.045) and non-verbal memory (median (IQR) -0.45 (2.10) versus -0.20 (1.36), p=0.037). There were no significant associations found between the GCA score and domain composite scores. CONCLUSION This cohort of LGG patients had a good clinical and neurological baseline function pre-RT. We found significant relationships between NCF and both white matter damage and atrophy of the brain. The Fazekas and GCA score are objective and easily obtained radiological measures, that could be a relevant parameter to record in LGG patients.

Neurodegeneration or dysfunction in Phelan-McDermid syndrome? A multimodal approach with CSF and computational MRI

BackgroundPhelan-McDermid syndrome (PMS) is a rare multisystem disease with global developmental delay and autistic features. Genetically, the disease is based on a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of the SHANK3 gene or heterozygous pathogenic variants in SHANK3. Pathophysiologically, this syndrome has been regarded as a synaptopathy, but current data suggest an additional concept, since axonal functions of neurons are also impaired, thus, the specific pathophysiological processes in this disease are not yet fully understood. Since symptoms of the autism spectrum, regression, and stagnation in development occur, we investigated whether neuroinflammatory and neurodegenerative processes may also play a role. To this end, we analysed biomarkers in cerebrospinal fluid (CSF) and parameters from magnetic resonance imaging with high-resolution structural T1w volumetry and diffusion tensor imaging analysis in 19 Phelan-McDermid syndrome patients.ResultsCSF showed no inflammation but abnormalities in tau protein and amyloid-ß concentrations, however, with no typical biomarker pattern as in Alzheimer’s disease. It could be demonstrated that these CSF changes were correlated with integrity losses of the fibres in the corticospinal tract as well as in the splenium and dorsal part of the cingulum. High CSF levels of tau protein were associated with loss of integrity of fibres in the corticospinal tract; lower levels of amyloid-ß were associated with decreasing integrity of fibre tracts of the splenium and posterior cingulate gyrus. Volumetric investigations showed global atrophy of the white matter, but not the grey matter, and particularly not in temporal or mesiotemporal regions, as is typical in later stages of Alzheimer’s disease.ConclusionsIn summary, alterations of neurodegenerative CSF markers in PMS individuals could be demonstrated which were correlated with structural connectivity losses of the corticospinal tract, the splenium, and the dorsal part of the cingulum, which can also be associated with typical clinical symptoms in these patients. These findings might represent a state of dysfunctional processes with ongoing degenerative and regenerative processes or a kind of accelerated aging. This study should foster further clinical diagnostics like tau- and amyloid-PET imaging as well as novel scientific approaches especially in basic research for further mechanistic proof.