Brain T2 Research Articles

Abstract WMP13: The Modifying Effects of Psychosocial Health on the Association Between Cerebrovascular Health and Dementia Risk: The Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study

Introduction: Associations between magnetic resonance imaging (MRI) markers of vascular pathology and dementia risk in older adults have been established, but it remains less clear how lifestyle factors may modify this association. We hypothesized that a weaker association between MRI markers of vascular pathology and incident dementia will be present among older adults with strong as compared to poor psychosocial health in mid-life. Methods: Social support and social isolation were assessed among ARIC participants, aged 46 - 68, via self-reported questionnaires (1990 - 1992). Following categorization of both factors, participants were classified as having strong or poor mid-life psychosocial health. From 2011 - 2013, 1977 participants, aged 67 - 90, underwent 3T brain MRI quantifying white matter hyperintensity (WMH) volume, subcortical cerebral microbleeds (sCMB), infarcts, and white matter integrity through diffusion tensor imaging. Incident dementia cases were identified from time of imaging through December 31, 2019 (median follow-up: 6.4 years) with ongoing surveillance. Relative contributions of psychosocial health and MRI markers to incident dementia were evaluated with demographic and vascular risk factor-adjusted Cox-proportional hazard regression models. Results: Among 1612 dementia-free participants with measures of psychosocial health, MRI markers were associated with dementia risk in the hypothesized direction. Mid-life psychosocial health significantly modified the associations between sCMB and WMH, each, with incident dementia risk (Table 1; greater risk of dementia shown in individuals with poor psychosocial health). Conclusions: The elevated risk of dementia associated with sCMB and WMH is reduced in participants with strong psychosocial health in mid-life. Future studies evaluating social factors through the life course and the mechanisms by which they modify the relationship between pathology and dementia are needed.

Serum Placental Growth Factor as a Marker of Cerebrovascular Disease Burden in Alzheimer's Disease.

Concomitant cerebrovascular diseases (CeVD) have been identified as an important determinant of Alzheimer's disease (AD) progression. Development of robust blood-based biomarkers will provide critical tools to evaluate prognosis and potential interventional strategies for AD with CeVD. This study investigated circulating placental growth factor (PlGF), a potent pro-angiogenic factor related to endothelial dysfunction and vascular inflammation, in an Asian memory clinic cohort of non-demented individuals as well as AD, including its associations with neuroimaging markers of CeVD. 109 patients with AD, 76 cognitively impaired with no dementia (CIND), and 56 non-cognitively impaired (NCI) were included in this cross-sectional study. All subjects underwent 3T brain magnetic resonance imaging to assess white matter hyperintensities (WMH), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays. Serum PlGF was elevated in AD, but not CIND, compared to the NCI controls. Adjusted concentrations of PlGF were associated with AD only in the presence of significant CeVD. Elevated PlGF was significantly associated with higher burden of WMH and with CMBs in AD patients. Serum PlGF has potential utility as a biomarker for the presence of CeVD, specifically WMH and CMBs, in AD. Further studies are needed to elucidate the underlying pathophysiological mechanisms linking PlGF to CeVD, as well as to further assess PlGF's clinical utility.

Perivascular space burden interacts with APOE-ε4 status on cognition in older adults

Enlarged perivascular spaces (ePVS) may adversely affect cognition. Little is known about how basal ganglia ePVS interact with apolipoprotein (APOE)-ε4 status. Vanderbilt Memory and Aging Project participants (n = 326, 73 ± 7, 59% male) underwent 3 T brain MRI at baseline to assess ePVS and longitudinal neuropsychological assessments. The interaction between ePVS volume and APOE-ε4 carrier status was related to baseline outcomes using ordinary least squares regressions and longitudinal cognition using linear mixed-effects regressions. ePVS volume interacted with APOE-ε4 status on cross-sectional naming performance (β = −0.002, p = 0.002), and executive function excluding outliers (β = 0.001, p = 0.009). There were no significant longitudinal interactions (p-values>0.10) except for Coding excluding outliers (β = 0.002, p = 0.05). While cross-sectional models stratified by APOE-ε4 status indicated greater ePVS related to worse cognition mostly in APOE-ε4 carriers, longitudinal models stratified by APOE-ε4 status showed greater ePVS volume related to worse cognition among APOE-ε4 non-carriers only. Results indicated that greater ePVS volume interacts with APOE-ε4 status on cognition cross-sectionally. Longitudinally, the association of greater ePVS volume and worse cognition appears stronger in APOE-ε4 non-carriers, possibly due to the deleterious effects of APOE-ε4 on cognition across the lifespan.

Highlights on the link between vitamin D and lipid panel in Egyptian multiple sclerosis patients

Abstract Background Diversity of risk factors, namely, vitamin D and lipid panel abnormalities, are connected to multiple sclerosis (MS) etiology and may possess an influential role on disease course. In a cross-sectional study, we correlated the demographic, clinical and radiological characteristics of 111 relapsing–remitting MS (RRMS) patients with their serum levels of vitamin D and lipid profile to evaluate the consequences of their abnormalities on disease activity and/or its progression. Results In the study group, the mean serum level of vitamin D was 18.93 ± 9.85 ng/mL, over 80% had insufficient level ( < 30 ng/mL) and significantly lower in females (P = 0.011). Insufficient vitamin D significantly associated with high relapse frequency (P = 0.005). Measurement the direction of this association showed that each 1 ng/mL increase in vitamin D was correlated with both decrease in annualized relapse rate (ARR) of 0.02 relapse/year (P = 0.017) and with decrease in number of relapses during last 2 years of 0.02 relapse (P = 0.045). Analysis of serum lipid panel showed a direct link between higher levels of TC and LDL to increased total number of relapses (P < 0.001 and 0.003, respectively) and EDSS (P = 0.001 and 0.022), also between higher TG and EDSS (P = 0.001). This link became indirect between HDL and both total number of relapse and EDSS (P = 0.001 and 0.001). Radiologically, positively linked confluent brain lesion to elevated TC and TG levels (P = 0.001 and 0.002, respectively) and cord lesions to elevated TC (P = 0.007). Longer disease duration positively associated with all lipids-related variables. As a direct effect on lipid metabolism, each 1 ng/mL increase in vitamin D was associated with reduction in serum TC of 1.48 mg/dL (P = 0.002) and rise in HDL of 0.35 mg/dL (P = 0.028). Conclusions Management of vitamin D insufficiency may decrease risk of higher ARR and the same for dyslipidemia in reduction of disability and confluent brain T2 lesion. Increasing vitamin D was positively correlated with HDL but negatively with TC.

Brain MRI Findings in CKD Patients with and without Parkinsonism, A Case-Control Study

Background: Chronic kidney disease (CKD) poses a major public health concern on a global scale. Patients with CKD have a heightened risk of developing multiple movement disorders like parkinsonism. Timely diagnosis through imaging and effective management may hold the key to mitigating disease symptoms. Methods: 28 individuals with CKD were categorized into two groups, nine patients showing signs of parkinsonism and a control group of nineteen patients without. All participants underwent non-contrast brain MRI scans, including T1, T2, DWI, and FLAIR sequences. We examined the presence or absence of brain MRI findings. The data obtained were analyzed using SPSS-24 and STATA for statistical analysis. Results: Nine patients exhibited parkinsonism symptoms, while nineteen did not. Brain MRI revealed hypointensities in structures like the putamen, globus pallidus, and cerebellar dentate nucleus in both groups. Comparative analysis showed no statistically significant differences in the percentages of these findings (p > 0.05). Similarly, the presence of cerebral atrophy and cerebrovascular disease did not significantly differ between the groups. Factors such as diabetes, hypertension, and history of dialysis also failed to show significant distinctions (p less than 0.05 for all). Conclusion: The correlation between brain MRI alterations in CKD patients with parkinsonism symptoms and those without was not significant. Nevertheless, there was a strong association between the duration of CKD in patients and the presence of parkinsonism-related signs.

Multimodal neuroimaging in Long-COVID and its correlates with cognition 1.8 years after SARS-CoV-2 infection: a cross-sectional study of the Aliança ProHEpiC-19 Cognitiu.

There is a growing interest in the effect of Long-COVID (LC) on cognition, and neuroimaging allows us to gain insight into the structural and functional changes underlying cognitive impairment in LC. We used multimodal neuroimaging data in combination with neuropsychological evaluations to study cognitive complaints in a cohort of LC patients with mild to moderate severity symptoms. We conducted a 3T brain magnetic resonance imaging (MRI) study with diffusion tensor imaging (DTI) and functional MRI (fMRI) sequences on 53 LC patients 1.8 years after acute COVID-19 onset. We administered neuropsychological tests to evaluate cognitive domains and examined correlations with Tract-Based Spatial Statistics (TBSS) and resting state. We included 53 participants with LC (mean age, 48.23 years; 88.7% females). According to the Frascati criteria, more than half of the participants had deficits in the executive (59%) and attentional (55%) domains, while 40% had impairments in the memory domain. Only one participant (1.89%) showed problems in the visuospatial and visuoconstructive domain. We observed that increased radial diffusivity in different white matter tracts was negatively correlated with the memory domain. Our results showed that higher resting state activity in the fronto-parietal network was associated with lower memory performance. Moreover, we detected increased functional connectivity among the bilateral hippocampus, the right hippocampus and the left amygdala, and the right hippocampus and the left middle temporal gyrus. These connectivity patterns were inversely related to memory and did not survive false discovery rate (FDR) correction. People with LC exhibit cognitive impairments linked to long-lasting changes in brain structure and function, which justify the cognitive alterations detected.

Sulcal pits of the superior temporal sulcus in schizophrenia patients with auditory verbal hallucinations.

Auditory verbal hallucinations (AVHs) are among the most common and disabling symptoms of schizophrenia. They involve the superior temporal sulcus (STS), which is associated with language processing; specific STS patterns may reflect vulnerability to auditory hallucinations in schizophrenia. STS sulcal pits are the deepest points of the folds in this region and were investigated here as an anatomical landmark of AVHs. This study included 53 patients diagnosed with schizophrenia and past or present AVHs, as well as 100 healthy control volunteers. All participants underwent a 3-T magnetic resonance imaging T1 brain scan, and sulcal pit differences were compared between the two groups. Compared with controls, patients with AVHs had a significantly different distributions for the number of sulcal pits in the left STS, indicating a less complex morphological pattern. The association of STS sulcal morphology with AVH suggests an early neurodevelopmental process in the pathophysiology of schizophrenia with AVHs.

Neural basis of writing in prodromal to mild dementia with lewy bodies.

We have previously demonstrated difficulties in written production in dementia with Lewy bodies (DLB) patients. We now aim to determine the neural correlates of writing production in DLB, combining clinical data and structural MRI measures. Sixteen prodromal to mild DLB patients were selected to participate in the study. The GREMOTS test was used to assess writing production. Using three-dimensional T1 brain MRI images, correlations between the GREMOTS test and grey matter (GM) volume were performed using voxel-based morphometry (VBM; SPM12, XjView and Matlab R2021b softwares). VBM analysis (p<0.001, uncorrected) revealed a positive and significant correlation between both left anterior insula and left supramarginal gyrus GM volumes and DLB patients' ability to write logatoms using the phonological route. The handwriting deficit was negatively and significantly correlated to the supplementary motor area. The parkinsonism-like characteristics of agraphia were negatively and significantly correlated with both right anterior and right posterior cerebellum GM volumes. Our study also revealed a negative and significant correlation between grammatical spelling impairments and an area of the orbitofrontal gyrus, and a negative and significant correlation between supramarginal gyrus and general slowness in dictation tasks. Writing disorders in early DLB patients appears to be GM decreases in several brain regions, such as the left anterior insula, the left supramaginal gyrus, as well as two areas of the right cerebellum.

Anxiety and Perception of Disease Control in Multiple Sclerosis Subjects Treated with Natalizumab.

Multiple sclerosis subjects treated with natalizumab face anxiety about developing progressive multifocal leukoencephalopathy (PML), besides the psychological distress caused by the disease. The aim of this study is to investigate whether increasing the frequency of neurological and nuclear magnetic resonance screening may affect anxiety and the perception of disease control in patients treated with natalizumab. A total of 62 relapsing-remitting multiple sclerosis patients were recruited from 2019 to 2020. All patients received conventional infusion treatments with natalizumab, along with a screening protocol for PML. Three clinical assessments were considered: at the beginning of the study (T0), after 3 months (T1) and after 6 months (T2). Patients were classified into three levels of risk, where level 1 represented a low risk of PML and level 3 a high risk. This classification determined treatment and screening protocol, i.e., the frequency of performing the Stratify test and the brain 3T NMR exam, as well as the frequency of infusion treatments. Anxiety and perception of disease control were assessed at T0, T1, and T2 by a skilled psychologist. The Friedman test and the Wilcoxon signed-rank test were used to compare outcomes at baseline with the two follow-ups. Statistical test results showed that the risk of PML (per 1000 patients) was significantly lower in women than in men (W = 198.5; p = 0.01). Moreover, significant differences between baseline and the two follow-ups were found, both for anxiety (F(2) = 122.6, p < 0.001) and for perception of disease control (F(2) = 123.5, p < 0.001). In both cases, there was significant improvement between baseline (T0) and the end of the study (T2) in any risk level (p < 0.001). An increase in the number of follow-ups, as well as an increase in instrumental investigations, might have a positive effect on both anxiety and the perception of disease control. However, there are many variables involved in the disease process that have an impact on patients' psychological well-being. Therefore, further and more extensive studies are necessary to evaluate how, and how much, each variable impacts the disease course.

Brain Magnetic Resonance Imaging Findings in Chronic Kidney Disease Patients with and without Parkinsonism: A Case-Control Study

Introduction: Chronic kidney disease (CKD) poses a major public health concern on a global scale. Patients with CKD have a heightened risk of developing multiple movement disorders like parkinsonism. Timely diagnosis through imaging and effective management may hold the key to mitigating disease symptoms. Material and Methods: Twenty-eight individuals with CKD were categorized into two groups, nine patients showing signs of parkinsonism and a control group of nineteen patients without parkinsonism. All participants underwent non-contrast brain magnetic resonance imaging (MRI) scans, including T1, T2, DWI, and FLAIR sequences. The data were statistically analyzed using SPSS-24 and STATA software. Results: Nine patients exhibited parkinsonism symptoms, while nineteen did not. Brain MRI revealed hypointensities in structures like the putamen, globus pallidus, and cerebellar dentate nucleus in both groups. Comparative analysis showed no statistically significant differences in the percentages of these findings (P&gt;0.05). Similarly, the presence of cerebral atrophy and cerebrovascular disease did not significantly differ between the groups. Factors such as diabetes, hypertension, and history of dialysis also failed to show significant distinctions (P&gt;0.05 for all). Conclusion: The correlation between brain MRI alterations in CKD patients with parkinsonism symptoms and those without was not significant. Nevertheless, there was a strong association between the duration of CKD in patients and the presence of parkinsonism-related signs.

Association of urine dicarboxylic acid levels with intracranial volume–normalized brain regions and with white matter hypo‐intensities

AbstractBackgroundNon‐invasive molecules related to AD imaging biomarkers can reveal disease mechanisms and may help in the mass screening of an aging population. Our study aims to determine if urine dicarboxylic acids (DCA) that changed in AD are coupled with brain volume changes.MethodStudy participants (&gt; 65 years) were recruited in an ongoing HMRI Brain aging study, and MRI data were acquired and analyzed using NeuroQuant. The data were normalized to the intracranial volume (icv). DCAs were quantified using gas chromatography/mass spectrometry. We compared DCA and icv‐normalized brain region volumes in two ways: first, we used descriptive statistics to obtain the median (Q2) for short‐chain DCAs (C4+C5), medium‐chain DCAs (C7+C8+C9) and the ratio of short to medium chain DCAs ((C4+C5)/(C7+C8+C9)). Brain regions were then sorted to correspond to less than (&lt;Q2) or greater than the DCA medians (&gt;Q2). Differences were determined using two‐sample t‐tests and Wilcoxon rank‐sum tests with adjustment for multiple comparisons using FDR. Secondly, icv‐normalized brain regions and T1 hypo‐intensity were compared with DCA levels using a two‐tailed student’s t‐test.ResultThere was no significant difference in the DCA levels of participants with low (icv&lt;Q2) or high icv (icv&gt;Q2) (Fig.1A). In contrast, C4+C5 levels were higher, while C7+C8+C9 were lower in participants with higher whole brain volumes (WBV) (Fig. 1B). In addition, hippocampal volumes were greater when participants had a higher urine C4+C5 and lower C7+C8+C9. We identified 19 other icv‐normalized brain regions that were bigger when urine C4+C5 levels were high. In addition, participants with higher white matter hypo‐intensities had lower urine C4+C5 and a higher C7+C8+C9 DCA levels (Table 1).ConclusionThese data suggest that urine lipid composition is linked to icv‐normalized brain volumes. Higher mitochondrial‐associated lipids reflected larger brain volumes, while oxidized lipids indicated lower brain volumes. Thus, urine lipid levels can be used as surrogate biomarkers in clinical trials targeting brain volume changes. We will use a bigger sample size normalized for ApoE genotype, age, and sex to further examine lipids and brain volumes in participants with different cognitive states.

In vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in frontotemporal degeneration and corticobasal syndrome.

AbstractBackgroundNeuropathological studies have shown alterations in both locus coeruleus (LC) and basal forebrain in frontotemporal degeneration (FTD) and corticobasal syndrome (CBS) particularly in progressive supranuclear palsy (PSP). We aimed to investigate in vivo the LC and nucleus basalis of Meynert (NBM) integrity in patients with FTD and CBS.MethodWe compared the LC signal intensity (LC‐I), which reflects the LC integrity, and the NBM volume on 3T MRI in i) FTD patients (n = 17) ii) CBS patients (n = 8;) iii) prodromal/mild AD (n = 34) and iv) amyloid‐negative controls (n = 15). PiB‐PET and/or AD CSF biomarkers were negative in all FTD and CBS patients, and positive in all AD patients. All subjects underwent a complete neuropsychological assessment and 3T brain MRI performed on the same scan. The four groups were age‐matched. The MMSE score did not differ significantly between the 3 groups of patients.ResultCompared to controls, LC‐I and NBM volume were significantly decreased in FTD (p = 0.05 and 0.00015, respectively) and AD patients (p = 0.0005 and 0.002, respectively). LC‐I and NBM volume were also decreased in CBS in comparison with controls but the difference was not statistically significant. In addition, we found no statistically significant difference in LC‐I and NBM volume between the three groups of patients. We observed no correlation between LC‐I or NBM volume and amyloid load, either when considering the whole group of patients or AD and FTD/CBS patients separately.ConclusionOur results are in line with neuropathological data and suggest that both cholinergic and noradrenergic systems are altered in AD and FTD. Post mortem data have suggested that, in FTD, both structures were more impaired in tau than in TDP‐43 proteinopathy, which cannot be explored in our study. In CBS, our results are less clear‐cut, probably due to the small sample size. Taken together, our data support the pathophysiological model in which both LC and NBM play a critical role not only in AD but also in other diseases and proteinopathies like FTD.

Diverse patterns of Tau radiotracer binding progression in Alzheimer’s disease: A two‐year tau PET imaging study

AbstractBackgroundPositron emission tomography (PET) imaging enables the in vivo detection of amyloid and tau pathologies. The longitudinal progression of [18F]‐flortaucipir PET imaging could be of interest to better understand the spatial and temporal relationships between tauopathy, cortical atrophy, and the cognitive decline.MethodWe explored the longitudinal progression of the tau radiotracer binding and of cortical atrophy over 2 years in a cohort of 27 prodromal/mild AD patients (positive CSF biomarkers and amyloid‐PET) compared with twelve amyloid‐negative controls. All subjects underwent a complete neuropsychological assessment, 3T brain MRI, [11C]‐PiB and [18F]‐flortaucipir PET imaging (Tau1), and were monitored annually over 2 years, with a second brain MRI and tau PET imaging (Tau2) after 2 years. We studied the longitudinal progression of tau radiotracer binding (Tau2‐Tau1) in AD patients and used mixed effects models to explore the relations between the progression of tau binding or cortical atrophy and cognitive decline.ResultWe found an average longitudinal increase in tau radiotracer binding in most cortical regions, especially in the frontal cortex, but an average decrease in the lateral temporoparietal cortex. In this region, individual analyses revealed two distinct evolutions of tau radiotracer binding according to Tau1 uptake: low‐Tau1 AD patients (SUVr&lt;1.6) demonstrated an increase in tau radiotracer uptake in all cortical regions and a slow clinical progression, whereas high‐Tau1 patients demonstrated a paradoxical plateauing or decrease of tau tracer uptake in the temporoparietal cortex and a faster clinical progression. Cognitive decline was weakly associated with Tau2‐Tau1, but strongly associated with the regional cortical atrophy progression.ConclusionOur results suggest that tau PET imaging could detect patients with a “more aggressive” biological form of AD characterized by high temporo‐parietal Tau1 binding. In these patients, the decrease of temporo‐parietal tau tracer binding over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. This information may be considered to improve the design of clinical trials and the definition of the neuroimaging outcomes (choice of the tau‐PET regions of interest, consideration of the evolution of cortical atrophy as a reliable reflection of the clinical progression).

Inter‐ and intra‐individual variation in brain structural‐cognition relationships in aging

AbstractBackgroundThe sources of inter‐ and intra‐individual variability in age‐related cognitive decline remain poorly understood. We examined the association between 20‐year trajectories of cognitive decline and multimodal brain structure and morphology in older age.MethodWe used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age = 69.52 ± 4.9) and 5 repeated cognitive performance assessments between mid‐life (mean age = 53.2 ±4.9 years) and late‐life (mean age = 67.7 ± 4.9). Using non‐negative matrix factorisation, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities (Figure 1).ResultWe observed two latent variables describing distinct brain‐cognition associations. The first describes variations in 5 structural components associated with low mid‐life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid‐life performance in fluency and memory, but retention of multiple abilities (Figure 2). Expression of latent variables predicts future cognition 3.2 years later (mean age = 70.87 ± 4.9) (Figure 3).ConclusionLongitudinal cognitive decline and maintenance across diverse cognitive functions are both positively and negatively associated with distinct markers of cortical structure. Latent brain‐behaviour relationships predict future cognitive performance.

Cognitive status modifies the association between elevated cerebrospinal fluid phosphorylated tau and longitudinal cerebral blood flow changes over a 7‐year follow‐up period

AbstractBackgroundAlzheimer’s disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.ResultsIn main effect models, neither CSF Aβ42 (p‐values&gt;0.31) nor p‐tau (p‐values&gt;0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values&gt;0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values&lt;0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005).ConclusionsResults linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082

Proteomic‐based Biological Aging Clock and MRI Markers of Cerebrovascular Disease: Atherosclerosis Risk in Community Study

AbstractBackgroundBiological aging state can be quantified by composite metrics called aging clocks using proteomics. Proteomic aging clocks (PACs) are accurate, easily measured, and are associated with age‐related diseases including Alzheimer’s Disease and Related Dementias. We aim to investigate whether an accelerated biological aging (a discrepancy between chronological age and PAC) is associated with subclinical cerebrovascular structural changes.Method1494 participants from the Atherosclerosis Risk in Communities (ARIC) Study with proteomics and 3T brain MRI data at ARIC visit 5 in 2011‐13 (mean age 76, 59% female, 25% Black) were included. Nearly 5000 plasma proteins were measured using the SomaScan assay. PAC was developed using elastic net regression model and was internally validated. Age acceleration was calculated as residuals after regressing PAC on chronological age (positive value indicates biological age is higher than the person’s chronological age). Linear and logistic regression models were used to assess the associations of age acceleration with white matter hyperintensity volume (in cm3, log2 transformed, median [IQR]: 11[6‐20]) and the presence of: subcortical (n = 281), lacunar (n = 263), and cortical infarcts (n = 150), and microbleeds (n = 355).ResultAccelerated age (median [IQR]:‐0.04[‐1.4,1.3]; correlation with chronological age = 0) was associated with MRI markers of cerebrovascular disease after adjusting for demographic, cardiovascular risk factors, education, and kidney function. Every five years higher age acceleration was associated with larger white matter hyperintensity volume (Difference:0.34[95%CI 0.19,0.49]), higher odds of lacunar (OR:1.61[1.13,2.30]), subcortical (OR:1.63[1.15, 2.32]), and cortical infarcts (OR:1.72[1.11,2.67]). There was no association with presence of microbleeds (OR:1.25[0.91,1.73]) (Figure). Findings were consistent after excluding participants with clinical stroke and there was no difference between APOEe4+ and APOEe4‐ participants.ConclusionHigher accelerated age is cross‐sectionally associated with a greater prevalence of MRI markers of cerebrovascular disease. Understanding this relation has potential to help with risk stratification and personalized prevention and treatment strategies to promote brain health.

Arterial spin‐labeling spatial coefficient of variation is associated with cerebral small vessel disease

AbstractBackgroundCerebral small vessel disease (SVD) is the most common pathology to co‐occur with Alzheimer’s disease but pathophysiologic mechanisms leading to SVD are poorly understood. The arterial spin‐labeling (ASL) spatial coefficient of variation (sCoV), a proxy marker of arterial transit time (ATT), may better reflect SVD‐related hemodynamic disturbances than ASL‐derived cerebral blood flow (CBF). We investigated whether grey matter CBF and grey matter sCoV each related to neuroimaging markers of SVD, including white matter hyperintensities (WMHs), basal ganglia enlarged perivascular spaces (ePVS), cerebral microbleeds (CMBs), and lacunes.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia and stroke at study entry (n = 312, 73±7 years, 39% mild cognitive impairment, 41% female) underwent multimodal 3T brain magnetic resonance imaging to quantify ASL parameters and SVD burden. Pseudo‐continuous ASL assessed CBF in total grey matter. Grey matter sCoV was calculated as σ(CBFGrey Matter)/μ(CBFGrey Matter). WMHs and ePVS volumes were quantified using automated methods and ePVS volumes were standardized to basal ganglia volume. CMBs and lacune counts were quantified by an expert rater. Ordinary least squares regression models cross‐sectionally related grey matter CBF and sCoV individually to log‐transformed burden of each SVD marker. Models were adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile (minus age), intracranial volume, grey matter volume, and apolipoprotein E‐ε4 status.ResultsGrey matter CBF was unrelated to all SVD outcomes (p‐values&gt;0.25). Higher grey matter sCoV was associated with greater WMHs (β = 2.1, p = 0.001), ePVS (β = 0.004, p = 0.0003), and lacunar infarcts (β = 1.4, p = 0.0006) but not CMBs (β = 1.0, p = 0.06).ConclusionsOur findings align with previous results showing that grey matter sCoV is a valuable marker of SVD. In contrast to previous work, we found an association between higher grey matter sCoV and higher basal ganglia ePVS burden. Potentially, our use of volumetric ePVS quantification rather than qualitative ePVS burden increased our ability to detect this association. As sCoV is a proxy marker of ATT, future work should consider quantifying sCoV or ATT in addition to CBF to better characterize SVD‐related hemodynamic disturbances. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, P20‐AG068082

The Influence of White Matter Lesion Volume on Hippocampal Shape in Patients Along the Alzheimer’s Disease Continuum

AbstractBackgroundAlzheimer’s Disease (AD) is a progressive neurocognitive disorder with irreversible hippocampal atrophy and degradation of cognitive function. Hippocampal atrophy can be assessed by volume and shape changes on MRI, and hippocampal volume is a sensitive marker for AD diagnosis and progression; however, it does not reflect regional changes within the hippocampus. Interest in shape analysis of the hippocampus is growing, as it provides more detailed assessment of morphological changes that highlight regional atrophic differences. Cerebral small vessel disease (CSVD) burden quantified as white matter lesion volume from MRI is strongly associated with hippocampal volume loss in AD and mild cognitive impairment (MCI). Our goal was to examine relationships between hippocampal morphometric features and white matter hyperintensity (WMH) volume, a measure of CSVD burden, across the AD continuum.MethodWe analyzed baseline data from 186 participants from the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort whose cognitive diagnosis was adjudicated by an expert panel in accordance with NIA‐AA guidelines (without reference to AD biomarkers). Participants ranged from cognitively normal (CN) (n = 62, 72±8y), to MCI (n = 62, 73±7y), and dementia (n = 62, 73±9y). We focused on the left hippocampus and used T1‐weighted images from 3T brain MRI to generate left hippocampal segmentations and total intracranial volume estimates. Total WMH volume was estimated from FLAIR images using the lesion segmentation toolbox for SPM, it was then normalized to intracranial volume and log transformed to address skewness. Hippocampal shape analysis was performed using SlicerSALT, and a multivariate linear model was implemented to relate WMH volume to hippocampal shape features while adjusting for diagnosis, age, sex, and years of education.ResultOn the superior aspect of the hippocampus, greater WMH volume was associated with more surface contraction of the anterior portions of the CA1, CA2, CA3 and subiculum as shown in Figure 1A. Similar effects were seen on the inferior aspect as shown in Figure 1B.ConclusionThese finding suggest that higher WMH volume is associated with selective hippocampal subfield degeneration in the anterior portions of the hippocampus which may be more vulnerable to CSVD buildup.

CSF‐plasma albumin ratio differs by sex in community dwelling older adults

AbstractBackgroundBlood‐brain barrier (BBB) permeability is associated with Alzheimer’s disease (AD) and neurodegeneration. Cerebrospinal fluid (CSF)/plasma albumin ratio (QAlb) is a biomarker commonly used to approximate BBB and blood‐CSF barrier (BCSFB) integrity. While sex‐based differences in AD risk are well‐established, limited work has evaluated these differences with QAlb and neurodegeneration and neuropsychological outcomes. Here, we examine if sex modifies the association of QAlb with neuropsychological and structural neuroimaging markers of neurodegeneration in community‐dwelling older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, 72±7 years, 33% female) completed a fasting blood draw, lumbar puncture, neuropsychological assessment, and multimodal 3T brain magnetic resonance imaging (MRI) to capture grey matter volumes and white matter hyperintensities (WMHs). Ordinary least squares regressions cross‐sectionally related sex to QAlb. Follow‐up models tested a sex x QAlb interaction with neuropsychological and MRI outcomes. Models adjusted for age, sex, race/ethnicity, education, cognitive status, Framingham Stroke Risk Profile score (minus age), apolipoprotein (APOE)‐e4 status, and (for MRI outcomes) intracranial volume.ResultFemale sex was associated with lower QAlb (p&lt;0.001). However, sex did not interact with QAlb on any neuropsychological (p‐values&gt;0.7) or neuroimaging outcomes (p‐values&gt;0.2). Models stratified by sex were also null for neuropsychological (p‐values&gt;0.93) and neuroimaging outcomes (p‐values&gt;0.11).ConclusionElevated QAlb is believed to reflect disrupted brain‐barrier integrity such that blood‐based albumin (which lacks an active transport mechanism across the BBB) can enter the brain parenchyma and travel to the CSF. We found that female sex is associated with lower QAlb levels but does not interact with early cognitive or neuroimaging markers of AD‐associated neurodegeneration. The strong association between female sex and higher brain‐barrier integrity highlights the importance of considering sex differences when applying QAlb in clinical and research settings. Funding: R01‐AG034962, K24‐AG046373, T32‐AG058524, P20‐AG068082

Dynamic change of hierarchical core voxels of functional brain network in aging

AbstractBackgroundMany methods were developed to assess the functional intervoxel connectivity to better understand the brain function in individuals. In this study, k‐core percolation method was assessed to reveal the dynamic hierarchical structure on resting‐state fMRI (rsfMRI) on voxel‐level and the feasibility of the method was evaluated by applying it in the aging process.MethodTotal 150 individuals were included in this study; 38 young healthy individuals from Seoul National University (SNU), and 32 aged healthy, 22 mild cognitive impairment‐converter (MCI‐C), 26 mild cognitive impairment non‐converter (MCI‐NC), and 32 Alzheimer’s disease (AD) subjects from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. K‐core percolation method, a voxel‐based approach was applied to reveal the hierarchical structure of voxels in the brain. k max‐core and coreness k values derived from k‐core percolation characterizing the time‐varying core voxels were visualized on various plots to display the dynamic hierarchical structure more intuitively. Analysis was done in both static, dynamic studies, and in positive, negative correlations. Coreness k value map on brain T1 MRI was generated for further evaluation of the distribution of coreness k values.ResultDynamic hierarchical structure of voxels on various plots revealed time‐varying change of k max‐core voxels and coreness k values, reflecting the dynamic change of brain function in an individual, which was not fully reflected on static study. Dynamic flow pattern was different in positive and negative correlations, portraying the dynamic brain function in different neuronal networks. Asymmetric, unsynchronized distribution was deteriorated in the aging process on corneas k map and the asymmetry indexes of coreness k values revealed distinctive difference between young and aged healthy groups. The difference was more evident on dynamic study than static study. Also, as the age increased, coreness k values decreased, representing decreased connectivity in aging. However, asymmetry and decrease of coreness k values were not deteriorated by the severity of cognitive impairment.ConclusionInvestigation of dynamic functional connectivity with k‐core percolation on voxel‐level revealed time‐varying change of hierarchical structure of voxels in the aging process. With this method, characteristics of dynamic hierarchical structure of an individual can be discovered and have shown possibility of further clinical application.