Total Hippocampal Volume Research Articles

Brain Reward System And Its Volumetric Investigations In Alcohol Addiction

IntroductionAlcohol use disorder (AUD) is a diagnosis that includes both addiction and abuse concepts that entered our lives with the DSM-5. The prevalence of AUD is 8.1% in men and 1.7% in women in Türkiye, and it is getting more and more common. Biopsychosocial factors play a role in the etiology of AUD.ObjectivesThe brain reward system, which includes many cortical and subcortical structures, plays an active role in the initiation and maintenance of alcohol dependence. In this study, we aimed to reveal the structural changes in alcohol dependence.Methods15 cases with AUD and 17 healthy controls were compared in terms of total white matter, total gray matter, nucleus accumbens, amygdala and hippocampus volumes. AUDIT, MAST and alcohol addiction severity scale were administered to all participants. Magnetic resonance imaging of all participants was performed. Then, the relevant regions were painted cross-sectionally and volume measurements were made. The case group was evaluated for the diagnosis of AUD with SCID-V. Volume averages were evaluated with Student’s t test. ANCOVA was used to remove confounding factors and re-evaluate the difference between volumes.ResultsAlthough there were differences between volumes in the first analyzes with Student’s t test, they were not statistically significant.Age and gender variables, which were determined by the literature to have an effect on volume measurements, were re-evaluated with the ANCOVA test. When the effects of age and gender variables were removed in the evaluation, the right hippocampus volume was found to be significantly reduced in the AUD group compared to the control group (F=5.26, p=0.03). Again, no significant difference was observed in the two groups in terms of areas other than the volume of the right hippocampus. Pearson correlation analysis was used to evaluate the relationship between scale scores, duration of alcohol use and amount taken, and volumetric measurements, but no statistically significant relationship was found.ConclusionsDifferent findings have been reported in the literature regarding the examined region volumes. Our study found volumetric changes consistent with most previous studies. For more generalizable results, studies with a large number of participants are needed.Disclosure of InterestNone Declared

Neurovascular Development in Pten and Tsc2 Mouse Mutants.

Hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is linked to more than a dozen neurologic diseases, causing a range of pathologies, including excess neuronal growth, disrupted neuronal migration, cortical dysplasia, epilepsy and autism. The mTOR pathway also regulates angiogenesis. For the present study, therefore, we queried whether loss of Pten or Tsc2, both mTOR negative regulators, alters brain vasculature in three mouse models: one with Pten loss restricted to hippocampal dentate granule cells [DGC-Pten knock-outs (KOs)], a second with widespread Pten loss from excitatory forebrain neurons (FB-Pten KOs) and a third with focal loss of Tsc2 from cortical excitatory neurons (f-Tsc2 KOs). Total hippocampal vessel length and volume per dentate gyrus were dramatically increased in DGC-Pten knock-outs. DGC-Pten knock-outs had larger dentate gyri overall, however, and when normalized to these larger structures, vessel density was preserved. In addition, tests of blood-brain barrier integrity did not reveal increased permeability. FB-Pten KOs recapitulated the findings in the more restricted DGC-Pten KOs, with increased vessel area, but preserved vessel density. FB-Pten KOs did, however, exhibit elevated levels of the angiogenic factor VegfA. In contrast to findings with Pten, focal loss of Tsc2 from cortical excitatory neurons produced a localized increase in vessel density. Together, these studies demonstrate that hypervascularization is not a consistent feature of mTOR hyperactivation models and suggest that loss of different mTOR pathway regulatory genes exert distinct effects on angiogenesis.

Exploring the combined effects of sleep apnea and APOE-e4 on biomarkers of Alzheimer's disease.

We determined the interactive associations of apolipoprotein e4 (APOE-e4), and obstructive sleep apnea (OSA) on biomarkers of Alzheimer's disease and examined for racial/ethnic differences of this association. We used data from the National Alzheimer's Coordinating Center Uniform Dataset (NACC UDS). All participants undergo annual observations, including demographic survey, battery of neuropsychological tests, blood draw (with genotyping), and a clinical evaluation with medical and cognitive/dementia status assessment, while a subset of participants have cerebrospinal fluid (CSF) biomarkers and neuroimaging data. Biomarkers of AD were characterized as the presence of abnormally low amyloid in CSF, via validated Aβ42 cut off protocols, and total segmented hippocampal volume, and volume of white matter hyper intensities (WMH). While clinical markers (to preview cognitive relationships) were characterized via the Montreal Cognitive Assessment (MOCA). Biomarker and clinical marker data were derived from 1,387 participants at baseline (mean age = 69.73 ± 8.32; 58.6% female; 13.7% Black/African American), 18.4% of the sample had sleep apnea, and 37.9% were APOE-e4 carriers. Our results confirmed previous reports that OSA and APOE-e4 were independently associated with AD through abnormal levels of amyloid (F (1,306) = 4.27; p = 0.040; F (1,285) = 60.88; p < 0.000, respectively), WMH volume (F (1,306) = 4.27; p = 0.040; F (1,285) = 60.88; p < 0.000, respectively), and MOCA scores (F (1,306) = 4.27; p = 0.040; F (1,285) = 60.88; p < 0.000, respectively). No significant interaction between OSA and APOE-e4 relative to amyloid emerged, however, race stratified analyses indicated the interaction of OSA and APOE-e4 and was significantly associated with WMH and hippocampal volume in Black/African American, but not white participants. OSA and APOE-e4 are interactively associated with WHM in Black/African Americans. This interaction may partially explicate increased levels of risk in this population.

Changes in the hippocampal volume in chronic migraine, episodic migraine, and medication overuse headache patients.

<p>Hippocampi are the structures located in the medial depths of both temporal lobes, mainly responsible for memory, navigation and regulation of emotions, and activated during the processing of pain and the modification of nociceptive stimuli. Chronic pain is thought to have stress-like detrimental modulatory effects on the hippocampal neurogenesis, and adults with chronic pain have been showed to have lower hippocampal volumes. The present study aims to show the relationship between headaches and hippocampal volume by comparing the right, left and total hippocampal volumes of patients with Episodic Migraine (EM), Chronic Migraine (CM) and Medication Overuse Headache (MOH) to those of the healthy control group using the Magnetic Resonance Imaging (MRI) technique, also by looking into the correlation between the number of painful days and attacks and the current hippocampal volumes.</p>. <p>A total of 30 patients (10 EM, 10 CM, 10 MOH) from 18 to 45 years of age diagnosed with migraine and also followed up by the neurology outpatient clinic from February to May 2022 and 30 healthy volunteers of similar ages and sexes to the patient group were included in the study. In addition to the routine cranial MRI protocols of all the participants, further cranial images were taken with the addition of the T1W 3D FSPGR sequence adjusted to the hippocampal body in the coronal plane and covering the whole brain. Hippocampal volumes were measured manually.</p>. <p>There were 27 females and 3 males in the patient group versus 28 females and 2 males in the control group, and no statistically significant differences in age and sex were found between the groups. The control group had higher average right, left and total hippocampal volumes than the whole patient group, but only the total hippocampal volume was significantly different between the groups. There was a negative correlation between the number of painful days and the measured right hippocampal and total hippocampal volumes; however, the measured values were not statistically significant.&nbsp;</p>. <p>It was concluded that the changes in the hippocampal volume in migraine might be associated with the pain characteristics of the disorder.&nbsp;</p>.

Effect of physical exercise on the hippocampus and global grey matter volume in breast cancer patients: A randomized controlled trial (PAM study)

BackgroundPhysical exercise in cancer patients is a promising intervention to improve cognition and increase brain volume, including hippocampal volume. We investigated whether a 6-month exercise intervention primarily impacts total hippocampal volume and additionally hippocampal subfield volumes, cortical thickness and grey matter volume in previously physically inactive breast cancer patients. Furthermore, we evaluated associations with verbal memory. MethodsChemotherapy-exposed breast cancer patients (stage I-III, 2–4 years post diagnosis) with cognitive problems were included and randomized in an exercise intervention (n = 70, age = 52.5 ± 9.0 years) or control group (n = 72, age = 53.2 ± 8.6 years). The intervention consisted of 2x1 hours/week of supervised aerobic and strength training and 2x1 hours/week Nordic or power walking. At baseline and at 6-month follow-up, volumetric brain measures were derived from 3D T1-weighted 3T magnetic resonance imaging scans, including hippocampal (subfield) volume (FreeSurfer), cortical thickness (CAT12), and grey matter volume (voxel-based morphometry CAT12). Physical fitness was measured with a cardiopulmonary exercise test. Memory functioning was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R total recall) and Wordlist Learning of an online cognitive test battery, the Amsterdam Cognition Scan (ACS Wordlist Learning). An explorative analysis was conducted in highly fatigued patients (score of ≥ 39 on the symptom scale ‘fatigue’ of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), as previous research in this dataset has shown that the intervention improved cognition only in these patients. ResultsMultiple regression analyses and voxel-based morphometry revealed no significant intervention effects on brain volume, although at baseline increased physical fitness was significantly related to larger brain volume (e.g., total hippocampal volume: R = 0.32, B = 21.7 mm3, 95 % CI = 3.0 – 40.4). Subgroup analyses showed an intervention effect in highly fatigued patients. Unexpectedly, these patients had significant reductions in hippocampal volume, compared to the control group (e.g., total hippocampal volume: B = −52.3 mm3, 95 % CI = −100.3 – −4.4)), which was related to improved memory functioning (HVLT-R total recall: B = −0.022, 95 % CI = −0.039 – −0.005; ACS Wordlist Learning: B = −0.039, 95 % CI = −0.062 – −0.015). ConclusionsNo exercise intervention effects were found on hippocampal volume, hippocampal subfield volumes, cortical thickness or grey matter volume for the entire intervention group. Contrary to what we expected, in highly fatigued patients a reduction in hippocampal volume was found after the intervention, which was related to improved memory functioning. These results suggest that physical fitness may benefit cognition in specific groups and stress the importance of further research into the biological basis of this finding.

Heart failure associations with cerebral structure: combined analysis from the Multi‐Ethnic Study of Atherosclerosis (MESA) and the SECRET‐II trial of heart failure with preserved ejection fraction

AbstractBackgroundHeart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF in adults 65 and older, but little is known about its relationship with neurocognitive outcomes. We compared brain magnetic resonance imaging (MRI) markers in older adults across stages of preclinical HF and clinical HFpEF.MethodAll participants completed baseline HF evaluation of risk factors, echocardiography, electrocardiography, and cardiopulmonary exercise by ACC/AHA stages; 3T brain MRI; and cognitive testing using harmonized protocols and teams at Wake Forest School of Medicine (2016‐2021). MESA participants without symptomatic HF were assigned to: Stage 0, no risk factors for HF (n = 30); Stage A, risk factors for HF without cardiac structural abnormalities (n = 111); or Stage B, abnormal cardiac structure or function without HF symptoms (n = 66). Participants with stable clinical HFpEF were recruited from the SECRET‐II trial and assigned to Stage C (n = 43). We compared intracranial volume‐adjusted total gray matter (GM), hippocampal, and white matter hyperintensity lesion (WMH) volumes across HF stages using multivariable linear regression adjusted for age, sex, and race, and report standardized least‐squares (LS) means estimates in SD units with 95% CI and Dunnett‐adjusted p‐values (referent = Stage 0).ResultThe combined sample (N = 250) was aged 72±7 years, 64% female, 47% white, and completed 15±3 years of education. Participants with Stage C HFpEF were younger (69±5 vs. 73±7 years, p&lt;0.001) and more likely to be female (85% vs. 59%, p&lt;0.001) than participants in lower stages. Stage B and Stage C participants had significantly lower GM volume than Stage 0 (0.38 [0.07, 0.69] vs. ‐0.12 [‐0.33, 0.09] in Stage B, p = 0.019; ‐0.36 [‐0.64, ‐0.09] in Stage C HFpEF, p = 0.001; Figure A), and Stages A‐C had non‐significant trends toward lower hippocampal volume (Stage 0 vs. Stage C p = 0.053; Figure B) and greater WMH volume (Stage 0 vs. Stages A‐C combined p = 0.073; Figure C). There were no interactions by sex or race.ConclusionIn this combined analysis from harmonized and diverse cohorts, higher HF stages and clinical HFpEF were associated with significantly lower gray matter volume. Observed trends toward lower hippocampal volume and higher WMH volume in HF Stages A‐C warrant further investigation.

A Population‐Based Meta‐Analysis of Plasma Glial Fibrillary Acidic Protein for Cognitive Decline and Incident Dementia

AbstractBackgroundExpression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, co‐localizes with neuropathology in the brain. Blood‐derived levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population‐based level are necessary to broaden generalizability and assess the biomarker’s potential efficacy in community settings.MethodPlasma GFAP levels were assayed using a Simoa HD‐1 analyzer in 4,338 adults without prevalent dementia from four longitudinal cohort studies, the Framingham Heart Study (FHS), the Cardiovascular Health Study (CHS), the Age, Gene/Environment Susceptibility – Reykjavik Study (AGES), and the Coronary Artery Risk Development in Young Adults Study (CARDIA). The associations between plasma GFAP levels with a general cognition score derived from multiple cognitive tests, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all‐cause and Alzheimer’s disease dementia were evaluated with adjusted Cox proportional hazard models. Meta‐analysis was performed on the estimates derived from each cohort using random effects models with inverse variance weighting. The Sidik‐Jonkman estimator was used to report overall associations across studies.ResultMeta‐analysis indicated that higher plasma GFAP associated with lower general cognition (ß=‐0.09, [95% confidence interval [CI]: ‐0.15 to ‐0.03], p=0.005), but not with total brain or hippocampal volume (p&gt;0.05 for all). However, higher GFAP was significantly associated with a 2.5‐fold higher risk of incident all‐cause (Hazard Ratio [HR]: 2.47 (95% CI: 1.52‐4.01)) and Alzheimer’s disease dementia (HR: 2.54 (95% CI: 1.42‐4.53) per standard deviation increase over up to 15‐years of follow‐up.ConclusionThe findings suggest that elevations in plasma GFAP may be detectable several years prior to a clinical diagnosis, highlighting the potential value of the biomarker for aiding dementia risk prediction at a population‐based level

Psychosocial risk factors on hippocampal subfield volumes: the Medea‐7T study

AbstractBackgroundSpecific subfields within the hippocampus have shown vulnerability to chronic stress, highlighting the importance of looking regionally within the hippocampus to understand the role of psychosocial risk factors in the development of neurodegenerative diseases. The current study had two aims: to perform a systematic review on psychosocial factors and hippocampal subfield volume and to explore the association of psychosocial factors with hippocampal volume, both total volume and among subfields, using high‐field 7T MRI.MethodWithin the Memory Depression and Aging (Medea)‐7T study, 333 participants without dementia underwent 7T MRI and answered psychosocial questionnaires. Hippocampal subfields were automatically segmented from T2‐weighted images using ASHS software. Generalized linear models accounting for correlated outcomes were used to assess the association between subfields (i.e., entorhinal cortex, subiculum, Cornu Ammonis (CA)1, CA2, CA3, dentate gyrus, and tail) and each psychosocial factor (i.e., depressive symptoms, anxiety symptoms, childhood maltreatment, recent life events, and social support), adjusting for age, sex, and intracranial volume.ResultNeither depression nor anxiety was associated with specific hippocampal (sub)volumes. Recent life events were associated with greater total volume (B = 0.17, 95% CI: 0.07; 0.27). However, reporting childhood maltreatment was associated with smaller total hippocampal volume (B per standard deviation = ‐0.20, 95% CI: ‐0.31; ‐0.10). Among subfields, high social support was associated with greater volume in the CA3 (B = 0.47, 95% CI: 0.21; 0.73).ConclusionThis study suggests possible differential effects among hippocampal (sub)volumes and psychosocial factors, specifically reporting childhood maltreatment and social support. The systematic review highlighted inconsistencies in results, highlighting the need for future studies validating these results.

Aerobic exercise training reduces central arterial stiffness and improves cerebral blood flow in older adults

Background: Evidence of the benefits of aerobic exercise training (AET) on brain structure, function, and perfusion in older adults is inconclusive.&#x0D; Methods: We conducted two randomized controlled trials (RCT) in sedentary older adults with or without mild cognitive impairment (MCI) to address this question.1-3 The trial’s intervention arm was a progressive moderate-to-vigorous intensity AET, and the active control arm was stretching-and-toning (SAT). Outcome measures included neurocognitive function focused on memory and executive function, global and regional brain volume and cortical thickness measured with structural magnetic resonance imaging (MRI), cerebral blood flow (CBF) and CBF pulsatility measured in the large cerebral arteries (the internal carotid artery, the vertebral artery, and the middle cerebral artery) with 2D duplex ultrasonography and transcranial Doppler, central arterial stiffness measured with arterial applanation tonometry, and cardiorespiratory fitness measured with treadmill peak oxygen consumption (V̇O2peak). The duration of both trials was one year.&#x0D; Results: In both studies, we observed that AET increased V̇O2peak significantly by ∼10% while it did not change with SAT. Cognitive composite scores and domain-specific scores improved in both the AET and SAT groups, although no group differences were observed (likely reflected by cognitive test practice effects). Total brain and hippocampal volume and mean cortical thickness decreased in both groups over one year. Conversely, AET increased CBF, and decreased central arterial stiffness and CBF pulsatility. Increases in V̇O2peak with AET were correlated with increases in CBF and decreases in cerebrovascular resistance (CVR). Further, the improved memory score in the AET group was associated with decreased CVR and central arterial stiffness measured with carotid β-stiffness index.&#x0D; Conclusions: Taken together, these findings demonstrated that one-year moderate-to-vigorous intensity AET increased CBF and decreased central arterial stiffness in older adults with or without MCI. We speculate that improvement in cerebrovascular function with AET may precede its potential effects on brain structure and neurocognitive function in older adults. (The research findings presented herein were supported by the National Institutes of Health R01AG033106 and R01HL102457)

Hippocampal adaptation to high altitude: a neuroanatomic profile of hippocampal subfields in Tibetans and acclimatized Han Chinese residents.

The hippocampus is highly plastic and vulnerable to hypoxia. However, it is unknown whether and how it adapts to chronic hypobaric hypoxia in humans. With a unique sample of Tibetans and acclimatized Han Chinese individuals residing on the Tibetan plateau, we aimed to build a neuroanatomic profile of the altitude-adapted hippocampus by measuring the volumetric differences in the whole hippocampus and its subfields. High-resolution T1-weighted magnetic resonance imaging was performed in healthy Tibetans (TH, n = 72) and healthy Han Chinese individuals living at an altitude of more than 3,500 m (HH, n = 27). In addition, healthy Han Chinese individuals living on a plain (HP, n = 72) were recruited as a sea-level reference group. Whereas the total hippocampal volume did not show a significant difference across groups when corrected for age, sex, and total intracranial volume, subfield-level differences within the hippocampus were found. Post hoc analyses revealed that Tibetans had larger core hippocampal subfields (bilateral CA3, right CA4, right dentate gyrus); a larger right hippocampus-amygdala transition area; and smaller bilateral presubiculum, right subiculum, and bilateral fimbria, than Han Chinese subjects (HH and/or HP). The hippocampus and all its subfields were found to be slightly and non-significantly smaller in HH subjects than in HP subjects. As a primary explorational study, our data suggested that while the overall hippocampal volume did not change, the core hippocampus of Tibetans may have an effect of adaptation to chronic hypobaric hypoxia. However, this adaptation may have required generations rather than mere decades to accumulate in the population.

Association of Red Blood Cell Omega-3 Fatty Acids With MRI Markers and Cognitive Function in Midlife: The Framingham Heart Study.

Diet may be a key contributor to brain health in midlife. In particular, omega-3 fatty acids have been related to better neurologic outcomes in older adults. However, studies focusing on midlife are lacking. We investigated the cross-sectional association of red blood cell (RBC) omega-3 fatty acid concentrations with MRI and cognitive markers of brain aging in a community-based sample of predominantly middle-aged adults and further explore effect modification by APOE genotype. We included participants from the Third-Generation and Omni 2 cohorts of the Framingham Heart Study attending their second examination. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentrations were measured from RBC using gas chromatography, and the Omega-3 index was calculated as EPA + DHA. We used linear regression models to relate omega-3 fatty acid concentrations to brain MRI measures (i.e., total brain, total gray matter, hippocampal, and white matter hyperintensity volumes) and cognitive function (i.e., episodic memory, processing speed, executive function, and abstract reasoning) adjusting for potential confounders. We further tested for interactions between omega-3 fatty acid levels and APOE genotype (e4 carrier vs noncarrier) on MRI and cognitive outcomes. We included 2,183 dementia-free and stroke-free participants (mean age of 46 years, 53% women, 22% APOE-e4 carriers). In multivariable models, higher Omega-3 index was associated with larger hippocampal volumes (standard deviation unit beta ±standard error; 0.003 ± 0.001, p = 0.013) and better abstract reasoning (0.17 ± 0.07, p = 0.013). Similar results were obtained for DHA or EPA concentrations individually. Stratification by APOE-e4 status showed associations between higher DHA concentrations or Omega-3 index and larger hippocampal volumes in APOE-e4 noncarriers, whereas higher EPA concentrations were related to better abstract reasoning in APOE-e4 carriers. Finally, higher levels of all omega-3 predictors were related to lower white matter hyperintensity burden but only in APOE-e4 carriers. Our results, albeit exploratory, suggest that higher omega-3 fatty acid concentrations are related to better brain structure and cognitive function in a predominantly middle-aged cohort free of clinical dementia. These associations differed by APOE genotype, suggesting potentially different metabolic patterns by APOE status. Additional studies in middle-aged populations are warranted to confirm these findings.

Involvement of a BH3-only apoptosis sensitizer gene Blm-s in hippocampus-mediated mood control.

Mood disorders are an important public health issue and recent advances in genomic studies have indicated that molecules involved in neurodevelopment are causally related to mood disorders. BLM-s (BCL-2-like molecule, small transcript isoform), a BH3-only proapoptotic BCL-2 family member, mediates apoptosis of postmitotic immature neurons during embryonic cortical development, but its role in the adult brain is unknown. To better understand the physiological role of Blm-s gene in vivo, we generated a Blm-s-knockout (Blm-s−/−) mouse. The Blm-s−/− mice breed normally and exhibit grossly normal development. However, global depletion of Blm-s is highly associated with depression- and anxiety-related behaviors in adult mutant mice with intact learning and memory capacity. Functional magnetic resonance imaging of adult Blm-s−/− mice reveals reduced connectivity mainly in the ventral dentate gyrus (vDG) of the hippocampus with no alteration in the dorsal DG connectivity and in total hippocampal volume. At the cellular level, BLM-s is expressed in DG granule cells (GCs), and Blm-s−/− mice show reduced dendritic complexity and decreased spine density in mature GCs. Electrophysiology study uncovers that mature vGCs in adult Blm-s−/− DG are intrinsically more excitable. Interestingly, certain genetic variants of the human Blm homologue gene (VPS50) are significantly associated with depression traits from publicly resourced UK Biobank data. Taken together, BLM-s is required for the hippocampal mood control function. Loss of BLM-s causes abnormality in the electrophysiology and morphology of GCs and a disrupted vDG neural network, which could underlie Blm-s-null-associated anxiety and depression.

Healthy Lifestyle, Genetic Risk and Brain Health: A Gene-Environment Interaction Study in the UK Biobank.

Genetic susceptibility and lifestyle affect the risk of dementia but there is little direct evidence for their associations with preclinical changes in brain structure. We investigated the association of genetic dementia risk and healthy lifestyle with brain morphometry, and whether effects from elevated genetic risk are modified by lifestyle changes. We used prospective data from up to 25,894 UK Biobank participants (median follow-up of 8.8 years), and defined healthy lifestyle according to American Heart Association criteria as BMI < 30, no smoking, healthy diet and regular physical activity). Higher genetic risk was associated with lower hippocampal volume (beta −0.16 cm3, 95% CI −0.22, −0.11) and total brain volume (−4.34 cm3, 95% CI −7.68, −1.01) in participants aged ≥60 years but not <60 years. Healthy lifestyle was associated with higher total brain, grey matter and hippocampal volumes, and lower volume of white matter hyperintensities, with no effect modification by age or genetic risk. In conclusion, adverse effects of high genetic risk on brain health were only found in older participants, while adhering to healthy lifestyle recommendations is beneficial regardless of age or genetic risk.

A population-based meta-analysis of circulating GFAP for cognition and dementia risk.

ObjectiveExpression of glial fibrillary acidic protein (GFAP), a marker of reactive astrocytosis, colocalizes with neuropathology in the brain. Blood levels of GFAP have been associated with cognitive decline and dementia status. However, further examinations at a population‐based level are necessary to broaden generalizability to community settings.MethodsCirculating GFAP levels were assayed using a Simoa HD‐1 analyzer in 4338 adults without prevalent dementia from four longitudinal community‐based cohort studies. The associations between GFAP levels with general cognition, total brain volume, and hippocampal volume were evaluated with separate linear regression models in each cohort with adjustment for age, sex, education, race, diabetes, systolic blood pressure, antihypertensive medication, body mass index, apolipoprotein E ε4 status, site, and time between GFAP blood draw and the outcome. Associations with incident all‐cause and Alzheimer's disease dementia were evaluated with adjusted Cox proportional hazard models. Meta‐analysis was performed on the estimates derived from each cohort using random‐effects models.ResultsMeta‐analyses indicated that higher circulating GFAP associated with lower general cognition (ß = −0.09, [95% confidence interval [CI]: −0.15 to −0.03], p = 0.005), but not with total brain or hippocampal volume (p > 0.05). However, each standard deviation unit increase in log‐transformed GFAP levels was significantly associated with a 2.5‐fold higher risk of incident all‐cause dementia (Hazard Ratio [HR]: 2.47 (95% CI: 1.52–4.01)) and Alzheimer's disease dementia (HR: 2.54 [95% CI: 1.42–4.53]) over up to 15‐years of follow‐up.InterpretationResults support the potential role of circulating GFAP levels for aiding dementia risk prediction and improving clinical trial stratification in community settings.

Brain Changes and Fast Cognitive and Motor Decline in Older Adults.

To identify brain magnetic resonance imaging (MRI) signatures characterizing people with different patterns of decline in cognition and motor function. In the Swedish National Study on Aging and Care in Kungsholmen, Stockholm, 385 participants had available repeated brain MRI examinations, where markers of brain volumes and white matter integrity were assessed. The speed of cognitive and motor decline was estimated as the rate of a Mini-Mental State Examination and gait speed decline over 12 years (linear mixed models), and further dichotomized into the upper (25% fastest rate of decline) versus the lower quartiles. Participants were grouped in slow/no decliners (reference), isolated motor decliners, isolated cognitive decliners, and cognitive and motor decliners. We estimated the associations between changes in brain markers (linear mixed models) and baseline diffusion tensor imaging measures (linear regression model) and the 4 decline patterns. Individuals with concurrent cognitive and motor decline (n = 51) experienced the greatest loss in the total brain (β: -12.3; 95% confidence interval [CI]: -18.2; -6.38) and hippocampal (β: -0.25; 95% CI: -0.34; -0.16) volumes, the steepest accumulation of white matter hyperintensities (β: 1.61; 95% CI: 0.54; 2.68), and the greatest ventricular enlargement (β: 2.07; 95% CI: 0.67; 3.47). Compared to the reference, those only experiencing cognitive decline presented with steeper hippocampal volume loss, whereas those exhibiting only motor decline displayed a greater white matter hyperintensities burden. Lower microstructural white matter integrity was associated with concurrent cognitive and motor decline. Concurrent cognitive and motor decline is accompanied by rapidly evolving and complex brain pathology involving both gray and white matter. Isolated cognitive and motor declines seem to exhibit brain damage with different qualitative features.

A-117 Posterior Cortical Atrophy Case Study: Neuropsychological Assessment Remains Gold Standard Diagnostic Tool of Choice

Abstract Objective: Posterior cortical atrophy (PCA) is a rare, early onset, neurodegenerative syndrome that is characterized by impaired visuospatial/visual-constructional skills. Patients describe vague visual symptoms; however, ocular assessments are usually normal. Alzheimer's disease is the most common underlying cause of PCA; however, brain MRI is often unrevealing early in the disease. As a result, accurate diagnosis is often delayed. Method: The patient was initially referred in 2016 for a concussion evaluation following a work-related head injury when she was 54. Initial MRI of the brain was unremarkable. Neuropsychological testing was repeated in 2019, which was the first diagnostic test to establish a diagnosis of PCA. Subsequently, MRI of the brain with volumetric analysis showed total hippocampal volume to be at the 99th percentile and no pattern of cerebral volume loss to suggest a specific diagnosis. However, CSF biomarker assays were consistent with a diagnosis of Alzheimer’s disease. Results: The patient’s initial cognitive profile in 2016 reflected mild cognitive impairment, multidomain type with severely impaired visual-constructional skills, which were unrelated to her concussion. Neuropsychological testing was repeated in 2019, which showed interval progressive cognitive and functional decline. Profound visual-constructional impairments were again noted (see image), and she met criteria for PCA. Neuropsychological testing was repeated in 2021 and showed progression to moderate dementia with features of Gerstmann's syndrome. Conclusions: In spite of sophisticated neuroimaging techniques and increasing access to CSF biomarker analysis, neuropsychological assessment remains the gold standard diagnostic tool of choice for neurologists faced with rare dementia syndromes, such as PCA. See patient video at: https://youtu.be/9HdAKSL5alg

Correlations between sleep disturbance and brain structures associated with neurodegeneration in the National Alzheimer's Coordinating Center Uniform Data Set

This study aimed to 1) determine the association between sleep disturbance and brain structure volumes, 2) the moderation effect of apolipoprotein ε4 genotype on sleep disturbance and brain structures, and 3) the moderation effect of sleep disturbance on cognitive status and regional brain volumes.Using the National Alzheimer’s Coordinating Center Uniform Data Set (n = 1,533), multiple linear regressions were used to evaluate the association between sleep disturbance and brain volumes. Sleep disturbance was measured using one question from the NPI-Q.After controlling for intracranial volume, age, sex, years of education, race, ethnicity, and applying the FDR correction, total cerebrospinal fluid volume, left lateral ventricle volume, total lateral ventricle volume, and total third ventricle volume demonstrated significantly higher means for those with sleep disturbance. Total brain volume, total white and gray matter volume, total cerebrum brain volume (including gray but not white matter), left hippocampus volume, total hippocampal volume, the left, right, and total frontal lobe cortical gray matter volume, and the left, right, and total temporal lobe cortical gray matter volume demonstrated significantly lower mean volumes for those with sleep disturbance. Sleep disturbance moderated the association between cognitive status and lateral ventricular volumes. These findings suggest that disrupted sleep is associated with atrophy across multiple brain regions and ventricular hydrocephalus ex vacuo.

CYP2C19 expression modulates affective functioning and hippocampal subiculum volume—a large single-center community-dwelling cohort study

Given controversial findings of reduced depressive symptom severity and increased hippocampus volume in CYP2C19 poor metabolizers, we sought to provide empirical evidence from a large-scale single-center longitudinal cohort in the community-dwelling adult population—Colaus|PsyCoLaus in Lausanne, Switzerland (n = 4152). We looked for CYP2C19 genotype-related behavioral and brain anatomy patterns using a comprehensive set of psychometry, water diffusion- and relaxometry-based magnetic resonance imaging (MRI) data (BrainLaus, n = 1187). Our statistical models tested for differential associations between poor metabolizer and other metabolizer status with imaging-derived indices of brain volume and tissue properties that explain individuals’ current and lifetime mood characteristics. The observed association between CYP2C19 genotype and lifetime affective status showing higher functioning scores in poor metabolizers, was mainly driven by female participants (ß = 3.9, p = 0.010). There was no difference in total hippocampus volume between poor metabolizer and other metabolizer, though there was higher subiculum volume in the right hippocampus of poor metabolizers (ß = 0.03, pFDRcorrected = 0.036). Our study supports the notion of association between mood phenotype and CYP2C19 genotype, however, finds no evidence for concomitant hippocampus volume differences, with the exception of the right subiculum.

Global and local shape features of the hippocampus based on Laplace-Beltrami eigenvalues and eigenfunctions: a potential application in the lateralization of temporal lobe epilepsy.

Using magnetic resonance (MR) images to evaluate changes in the shape of the hippocampus has been an active research topic. This paper presents a new shape analysis approach to quantify and visualize deformations of the hippocampus in epilepsy. The proposed method is based on Laplace-Beltrami (LB) eigenvalues and eigenfunctions as isometric invariant shape features, and thus, the procedure does not require any image registration. In addition to the LB-based shape features, total hippocampal volume and surface area are calculated using manually segmented images. Theses shape and volumetric descriptors are used to distinguish the patients with temporal lobe epilepsy (TLE) (N = 55) from healthy control subjects (N = 12, age = 32.2 ± 9.1, sex (M/F) = 6/6) and patients with right TLE (N = 26, age = 45.1 ± 11.0, sex (M/F) = 9/17) from left TLE (N = 29, age = 45.4 ± 11.9, sex (M/F) = 10/19). Experimental results illustrate the usefulness of the proposed approach for the diagnosis and lateralization of TLE with 93.0% and 86.4% of the cases, respectively. Moreover, the proposed method outperforms the volumetric analysis in terms of both sensitivity (94.9% vs. 88.1%) and specificity (83.3% vs. 50.0%) of the lateralization. The analysis of local hippocampal thickness variations suggests significant deformation in both ipsilateral and contralateral hippocampi of epileptic patients, while there were no differences between right and left hippocampi in controls. It is anticipated that the proposed method could be advantageous in the presurgical evaluation of patients with drug-resistant epilepsy; however, further validation of the method using a larger dataset is required.

Elucidating the relationship between migraine risk and brain structure using genetic data.

Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = -0.11, P = 1 × 10-3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.