Hippocampal Volume Changes Research Articles

Impact of amyloid and cardiometabolic risk factors on prognostic capacity of plasma neurofilament light chain for neurodegeneration

BackgroundPlasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer’s disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid-β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer’s Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL.MethodsNon-demented participants (cognitively unimpaired or mild cognitive impairment) underwent repeated assessments including the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, hippocampal volumes, and white matter hyperintensity (WMH) volumes at 6- or 12-month intervals. Linear mixed-effect models were employed to examine the interaction between plasma NfL and various variables of interest, such as Aβ (evaluated using Florbetapir positron emission tomography), hypertension, DM, impaired kidney function, or obesity.ResultsOver a mean follow-up period of 62.5 months, participants with a mean age of 72.1 years (n = 720, 48.8% female) at baseline were observed. Higher plasma NfL levels at baseline were associated with steeper increases in ADAS-Cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p-values < 0.001). Notably, Aβ at baseline significantly enhanced the association between plasma NfL and longitudinal changes in ADAS-Cog scores (p-value 0.005) and hippocampal volumes (p-value 0.004). Regarding ADAS-Cog score and WMH volume, the impact of Aβ was more prominent in cognitively unimpaired than in mild cognitive impairment. Hypertension significantly heightened the association between plasma NfL and longitudinal changes in ADAS-Cog scores, hippocampal volumes, and WMH volumes (all p-values < 0.001). DM influenced the association between plasma NfL and changes in ADAS-Cog scores (p-value < 0.001) without affecting hippocampal and WMH volumes. Impaired kidney function did not significantly alter the association between plasma NfL and longitudinal changes in any outcome variables. Obesity heightened the association between plasma NfL and changes in hippocampal volumes only (p-value 0.026).ConclusionThis study suggests that the prognostic capacity of plasma NfL may be amplified in individuals with Aβ or hypertension. This finding emphasizes the importance of considering these factors in the NfL-based prognostic model for neurodegeneration in non-demented older adults.

Differential increase of hippocampal subfield volume after socio-affective mental training relates to reductions in diurnal cortisol

The hippocampus is a central modulator of the HPA-axis, impacting the regulation of stress on brain structure, function, and behavior. The current study assessed whether three different types of 3 months mental Training Modules geared towards nurturing (a) attention-based mindfulness, (b) socio-affective, or (c) socio-cognitive skills may impact hippocampal organization by reducing stress. We evaluated mental training-induced changes in hippocampal subfield volume and intrinsic functional connectivity, by combining longitudinal structural and resting-state fMRI connectivity analysis in 332 healthy adults. We related these changes to changes in diurnal and chronic cortisol levels. We observed increases in bilateral cornu ammonis volume (CA1-3) following the 3 months compassion-based module targeting socio-affective skills (Affect module), as compared to socio-cognitive skills (Perspective module) or a waitlist cohort with no training intervention. Structural changes were paralleled by relative increases in functional connectivity of CA1-3 when fostering socio-affective as compared to socio-cognitive skills. Furthermore, training-induced changes in CA1-3 structure and function consistently correlated with reductions in cortisol output. Notably, using a multivariate approach, we found that other subfields that did not show group-level changes also contributed to changes in cortisol levels. Overall, we provide a link between a socio-emotional behavioural intervention, changes in hippocampal subfield structure and function, and reductions in cortisol in healthy adults.

Differential increase of hippocampal subfield volume after socio-affective mental training relates to reductions in diurnal cortisol.

The hippocampus is a central modulator of the HPA-axis, impacting the regulation of stress on brain structure, function, and behavior. The current study assessed whether three different types of 3 months mental Training Modules geared towards nurturing (a) attention-based mindfulness, (b) socio-affective, or (c) socio-cognitive skills may impact hippocampal organization by reducing stress. We evaluated mental training-induced changes in hippocampal subfield volume and intrinsic functional connectivity, by combining longitudinal structural and resting-state fMRI connectivity analysis in 332 healthy adults. We related these changes to changes in diurnal and chronic cortisol levels. We observed increases in bilateral cornu ammonis volume (CA1-3) following the 3 months compassion-based module targeting socio-affective skills (Affect module), as compared to socio-cognitive skills (Perspective module) or a waitlist cohort with no training intervention. Structural changes were paralleled by relative increases in functional connectivity of CA1-3 when fostering socio-affective as compared to socio-cognitive skills. Furthermore, training-induced changes in CA1-3 structure and function consistently correlated with reductions in cortisol output. Notably, using a multivariate approach, we found that other subfields that did not show group-level changes also contributed to changes in cortisol levels. Overall, we provide a link between a socio-emotional behavioural intervention, changes in hippocampal subfield structure and function, and reductions in cortisol in healthy adults.

Early Life Adversity Predicts Reduced Hippocampal Volume in the Adolescent Brain Cognitive Development Study

PurposeCross-sectional studies in adults have demonstrated associations between early life adversity (ELA) and reduced hippocampal volume, but the timing of these effects is not clear. The present study sought to examine whether ELA predicts changes in hippocampal volume over time in a large sample of early adolescents. MethodsThe Adolescent Brain Cognitive Development Study provides a large dataset of tabulated neuroimaging, youth-reported adverse experiences, and parent-reported financial adversity from a sample of children around the United States. Linear mixed effects modeling was used to determine the relationship between ELA and hippocampal volume change within youth (n = 7036) from ages 9–10 to 11–12 years. ResultsResults of the models indicated that the number of early adverse events predicted bilateral hippocampal volume change (β = −0.02, t = −2.02, p < .05). Higher adversity was associated with lower hippocampal volume at Baseline (t = 5.55, p < .01) and at Year 2 (t = 6.14, p < .001). DiscussionThese findings suggest that ELA may affect hippocampal development during early adolescence. Prevention and early intervention are needed to alter the course of this trajectory. Future work should examine associations between ELA, hippocampal development, and educational and socioemotional outcomes.

Effect of chemotherapy on hippocampal volume and shape in older long-term breast cancer survivors.

The objective of this study was to assess changes in hippocampal volume and shape in older long-term breast cancer survivors who were exposed to chemotherapy 5-15 years prior. This study recruited female long-term breast cancer survivors aged 65 years or older with a history of chemotherapy (C+), age-matched breast cancer survivors who did not receive chemotherapy (C-), and healthy controls (HC). The participants were recruited 5-15 years after chemotherapy at time point 1 (TP1) and were followed up for 2 years at time point 2 (TP2). Assessments included hippocampal volume and shape from brain MRI scans and neuropsychological (NP) tests. At TP1, each of the three groups was comprised of 20 participants. The C+ group exhibited a hippocampal volume loss estimated in proportion with total intracranial volume (ICV) in both the left and right hemispheres from TP1 to TP2. Regarding the hippocampal shape at TP1, the C+ group displayed inward changes compared to the control groups. Within the C+ group, changes in right hippocampal volume adjusted with ICV were positively correlated with crystalized composite scores (R = 0.450, p = 0.044). Additionally, in C+ groups, chronological age was negatively correlated with right hippocampal volume adjusted with ICV (R = -0.585, p = 0.007). The observed hippocampal volume reduction and inward shape deformation within the C+ group may serve as neural basis for cognitive changes in older long-term breast cancer survivors with history of chemotherapy treatment.

Hippocampal subfield plasticity is associated with improved spatial memory

Physical exercise studies are generally underrepresented in young adulthood. Seventeen subjects were randomized into an intervention group (24.2 ± 3.9 years; 3 trainings/week) and 10 subjects into a passive control group (23.7 ± 4.2 years), over a duration of 6 months. Every two months, performance diagnostics, computerized spatial memory tests, and 3 Tesla magnetic resonance imaging were conducted. Here we find that the intervention group, compared to controls, showed increased cardiorespiratory fitness, spatial memory performance and subregional hippocampal volumes over time. Time-by-condition interactions occurred in right cornu ammonis 4 body and (trend only) dentate gyrus, left hippocampal tail and left subiculum. Increases in spatial memory performance correlated with hippocampal body volume changes and, subregionally, with left subicular volume changes. In conclusion, findings support earlier reports of exercise-induced subregional hippocampal volume changes. Such exercise-related plasticity may not only be of interest for young adults with clinical disorders of hippocampal function, but also for sedentary normal cohorts.

Hippocampal subfields volume changes and its correlation with memory functions in patients with mild cognitive impairment

BackgroundThis study examined hippocampal subfields volumes in patients with mild cognitive impairment (MCI) as potential non-invasive predictive neuroimaging markers of cognitive decline. MethodsT1-weighted images and Addenbrooke's cognitive examination III (ACE-III) data were obtained from 36 healthy controls and 27 MCI patients. The hippocampal subfields volumes were extracted using Freesurfer software, and group differences and correlation were assessed using general linear model (GLM) with age, sex, and total intracranial volume (TIV) as covariates. ResultsMCI participants exhibited significant decrease in memory scores and notable volumetric changes in hippocampal subfields, including the bilateral hippocampal tail, subiculum, CA1, CA3, molecular layer, as well as the left presubiculum, parasubiculum, CA4, GC-ML-DG, and HATA. Moreover, the left presubiculum, left parasubiculum, and left GC-ML-DG showed significant positive correlations with ACE memory scores in MCI patients. ConclusionsThe alterations in hippocampal subfields in MCI patients may indicate underlying neurodegenerative processes associated with Alzheimer's disease (AD) pathology.

Hippocampal volume changes after (R,S)-ketamine administration in patients with major depressive disorder and healthy volunteers

The hippocampus and amygdala have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Preclinical models suggest that stress-related changes in these regions can be reversed by antidepressants, including ketamine. Clinical studies have identified reduced volumes in MDD that are thought to be potentiated by early life stress and worsened by repeated depressive episodes. This study used 3T and 7T structural magnetic resonance imaging data to examine longitudinal changes in hippocampal and amygdalar subfield volumes associated with ketamine treatment. Data were drawn from a previous double-blind, placebo-controlled, crossover trial of healthy volunteers (HVs) unmedicated individuals with treatment-resistant depression (TRD) (3T: 18 HV, 26 TRD, 7T: 17 HV, 30 TRD) who were scanned at baseline and twice following either a 40 min IV ketamine (0.5 mg/kg) or saline infusion (acute: 1–2 days, interim: 9–10 days post infusion). No baseline differences were noted between the two groups. At 10 days post-infusion, a slight increase was observed between ketamine and placebo scans in whole left amygdalar volume in individuals with TRD. No other differences were found between individuals with TRD and HVs at either field strength. These findings shed light on the timing of ketamine’s effects on cortical structures.

Is vestibular function related to human hippocampal volume?

Recent studies implicate the effect of vestibular loss on cognitive decline, including hippocampal volume loss. As hippocampal atrophy is an important biomarker of Alzheimer's disease, exploring vestibular dysfunction as a risk factor for dementia and its role in hippocampal atrophy is of interest. To replicate previous literature on whole-brain and hippocampal volume in semicircular canal dysfunction (bilateral vestibulopathy; BV) and explore the association between otolith function and hippocampal volume. Hippocampal and whole-brain MRI volumes were compared in adults aged between 55 and 83 years. Participants with BV (n = 16) were compared to controls individually matched on age, sex, and hearing status (n = 16). Otolith influence on hippocampal volume in preserved semicircular canal function was evaluated (n = 34). Whole-brain and targeted hippocampal approaches using volumetric and surface-based measures yielded no significant differences when comparing BV to controls. Binary support vector machines were unable to classify inner ear health status above chance level. Otolith parameters were not associated with hippocampal volume in preserved semicircular canal function. No significant differences in whole-brain or hippocampal volume were found when comparing BV participants with healthy controls. Saccular parameters in subjects with preserved semicircular canal function were not associated with hippocampal volume changes.

Exploring the Value of MRI Measurement of Hippocampal Volume for Predicting the Occurrence and Progression of Alzheimer's Disease Based on Artificial Intelligence Deep Learning Technology and Evidence-Based Medicine Meta-Analysis.

Alzheimer's disease (AD), a major dementia cause, lacks effective treatment. MRI-based hippocampal volume measurement using artificial intelligence offers new insights into early diagnosis and intervention in AD progression. This study, involving 483 AD patients, 756 patients with mild cognitive impairment (MCI), and 968 normal controls (NC), investigated the predictive capability of MRI-based hippocampus volume measurements for AD risk using artificial intelligence and evidence-based medicine. Utilizing data from ADNI and OASIS-brains databases, three convolutional neural networks (InceptionResNetv2, Densenet169, and SEResNet50) were employed for automated AD classification based on structural MRI imaging. A multitask deep learning model and a densely connected 3D convolutional network were utilized. Additionally, a systematic meta-analysis explored the value of MRI-based hippocampal volume measurement in predicting AD occurrence and progression, drawing on 23 eligible articles from PubMed and Embase databases. InceptionResNetv2 outperformed other networks, achieving 99.75% accuracy and 100% AUC for AD-NC classification and 99.16% accuracy and 100% AUC for MCI-NC classification. Notably, at a 512×512 size, InceptionResNetv2 demonstrated a classification accuracy of 94.29% and an AUC of 98% for AD-NC and 97.31% accuracy and 98% AUC for MCI-NC. The study concludes that MRI-based hippocampal volume changes effectively predict AD onset and progression, facilitating early intervention and prevention.

Association of mild and complex multimorbidity with structural brain changes in older adults: A population-based study.

We quantified the association of mild (ie, involving one or two body systems) and complex (ie, involving ≥3 systems) multimorbidity with structural brain changes in older adults. We included 390 dementia-free participants aged 60+ from the Swedish National Study on Aging and Care in Kungsholmen who underwent brain magnetic resonance imaging at baseline and after 3 and/or 6 years. Using linear mixed models, we estimated the association between multimorbidity and changes in total brain tissue, ventricular, hippocampal, and white matter hyperintensities volumes. Compared to non-multimorbid participants, those with complex multimorbidity showed the steepest reduction in total brain (β*time -0.03, 95% CI -0.05, -0.01) and hippocampal (β*time -0.05, 95% CI -0.08, -0.03) volumes, the greatest ventricular enlargement (β*time 0.03, 95% CI 0.01, 0.05), and the fastest white matter hyperintensities accumulation (β*time 0.04, 95% CI 0.01, 0.07). Multimorbidity, particularly when involving multiple body systems, is associated with accelerated structural brain changes, involving both neurodegeneration and vascular pathology. Multimorbidity accelerates structural brain changes in cognitively intact older adults These brain changes encompass both neurodegeneration and cerebrovascular pathology The complexity of multimorbidity is associated with the rate of brain changes' progression.

Changes in hippocampal volume, synaptic plasticity and amylin sensitivity in an animal model of type 2 diabetes are associated with increased vulnerability to amyloid-beta in advancing age.

Type-2 diabetes (T2D) is a metabolic disorder that is considered a risk factor for Alzheimer's disease (AD). Cognitive impairment can arise due to hypoglycemia associated with T2D, and hyperamylinemia associated with insulin resistance can enhance AD pathology. We explored whether changes occur in the hippocampus in aging (6-12 months old) female V-Lep○b-/- transgenic (tg) mice, comprising an animal model of T2D. We also investigated whether an increase in vulnerability to Aβ (1-42), a known pathological hallmark of AD, is evident. Using magnetic resonance imaging we detected significant decreases in hippocampal brain volume in female tg-mice compared to wild-type (wt) littermates. Long-term potentiation (LTP) was impaired in tg compared to wt mice. Treatment of the hippocampus with Aβ (1-42) elicited a stronger debilitation of LTP in tg compared to wt mice. Treatment with an amylin antagonist (AC187) significantly enhanced LTP in wt and tg mice, and rescued LTP in Aβ (1-42)-treated tg mice. Taken together our data indicate that a T2D-like state results in an increased vulnerability of the hippocampus to the debilitating effects of Aβ (1-42) and that effects are mediated in part by changes in amylin receptor signaling.

Nicotine use during late adolescence and young adulthood is associated with changes in hippocampal volume and memory performance.

With the advent of electronic nicotine delivery systems, the use of nicotine and tobacco products (NTPs) among adolescents and young adults remains high in the US. Use of e-cigarettes additionally elevates the risk of problematic use of other substances like cannabis, which is often co-used with NTPs. However, their effects on brain health, particularly the hippocampus, and cognition during this neurodevelopmental period are poorly understood. Healthy late adolescents/young adults (N = 223) ages 16-22 completed a structural MRI to examine right and left hippocampal volumes. Memory was assessed with the NIH Toolbox Picture Sequence Memory Test (PSMT) and Rey Auditory Verbal Learning Test (RAVLT). Cumulative 6-month NTP and cannabis episodes were assessed and modeled continuously on hippocampal volumes. Participants were then grouped based on 6-month NTP use to examine relationships with the hippocampus and memory: current users (CU) endorsed weekly or greater use; light/abstinent users (LU) endorsed less than weekly; and never users (NU). NTP use predicted larger hippocampal volumes bilaterally while cannabis use had no impact nor interacted with NTP use. For memory, larger left hippocampal volumes were positively associated with PSMT performance, RAVLT total learning, short delay and long delay recall for the NU group. In contrast, there was a negative relationship between hippocampal volumes and performances for LU and CU groups. No differences were detected between NTP-using groups. These results suggest that the hippocampus is sensitive to NTP exposure during late adolescence/young adulthood and may alter typical hippocampal morphometry in addition to brain-behavior relationships underlying learning and memory processes.

The relationship between hippocampal changes in healthy aging and Alzheimer's disease: a systematic literature review.

Neurobiological changes in the hippocampus are a common consequence of aging. However, there are differences in the rate of decline and overall volume loss in people with no cognitive impairment compared to those with mild cognitive impairment (MCI) and Alzheimer's disease (AD). This systematic literature review was conducted to determine the relationship between hippocampal atrophy and changes in hippocampal volume in the non-cognitively impaired brain and those with MCI or AD. This systematic review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. The PubMed database was searched up to September 15, 2022, for longitudinal magnetic resonance imaging studies reporting hippocampal atrophy or volume change in cognitively normal aging individuals and patients with MCI and/or AD. Study selection was divided into two steps: (1) identification and retrieval of relevant studies; (2) screening the studies by (a) title/abstract and (b) full text. Two teams, each consisting of two independent reviewers, determined whether the publications met the inclusion criteria for the systematic review. An evidence table was populated with data extracted from eligible publications and inclusion in the final systematic review was confirmed. The systematic search identified 357 publications that were initially screened by title/abstract, of which, 115 publications were retrieved and reviewed by full text for eligibility. Seventeen publications met the eligibility criteria; however, during data extraction, two studies were determined to not meet the inclusion criteria and were excluded. The remaining 15 studies were included in the systematic review. Overall, the results of these studies demonstrated that the hippocampus and hippocampal subfields change over time, with both decreased hippocampal volume and increased rate of hippocampal atrophy observed. Hippocampal changes in AD were observed to be greater than hippocampal changes in MCI, and changes in MCI were observed to be greater than those in normal aging populations. Published literature suggests that the rate of hippocampal decline and extent of loss is on a continuum that begins in people without cognitive impairment and continues to MCI and AD, and that differences between no cognitive impairment, MCI, and AD are quantitative rather than qualitative.

Aerobic exercise and volumetric change in the human hippocampus: A meta‐analysis of randomized controlled trials in healthy older individuals

AbstractBackgroundThere is promising, albeit equivocal, evidence that aerobic exercise training (AET) increases human hippocampal volume. The evidence is unclear, as recent randomized controlled trials (RCTs) have failed to replicate AET’s previously reported favorable effects on hippocampal volume in cognitively unimpaired older individuals. We thus conducted a meta‐analysis of RCTs investigating the effects of AET on hippocampal volume and cardiorespiratory fitness (CRF) in cognitively unimpaired, healthy older individuals.MethodA meta‐analysis of RCTs that delivered AET interventions to older individuals. Inclusion criteria were: 1) cognitively unimpaired, healthy individuals aged ≥ 50; 2) AET intervention delivered for at least four weeks; 3) at least one intervention group and one control group; 4) reported data of the effects of AET on hippocampal volume. Two authors independently screened titles, abstracts, and full texts, performed data extraction and methodological quality assessment of included studies. We performed meta‐analyses with random‐effects robust variance estimation models and meta‐regression analyses to test associations between changes in CRF and hippocampal volume. The primary outcome was changes in hippocampal volume, and the secondary outcome was changes in CRF.ResultEight parent trials and one secondary outcome article were eligible. The meta‐analytic summary of 17 effect sizes indicated no significant effects of AET on hippocampal volume (SMD = 0.10, 95%CI ‐0.01 to 0.21, p = 0.073). Meta‐analysis of nine studies and effect sizes showed that AET moderately improved cardiorespiratory fitness (SMD = 0.30, 95%CI 0.12 to 0.48, p = 0.005). Improvement in CRF was not statistically associated with changes in hippocampal volume (bSE = 0.05, SE = 0.51, p = 0.923). Methodological quality was poor in one, fair in three, good in four, and excellent in one trial.ConclusionAET did not show robust effects on hippocampal volume in cognitively unimpaired, healthy older individuals. Since AET significantly improved CRF, a lack of training fidelity is unlikely to explain our findings. The biologically still plausible favorable effects of AET on hippocampal volume in cognitively unimpaired older individuals might be masked by methodological weaknesses and the inclusion of only nine studies. Future studies need to address: the lack of harmonization of hippocampus quantification methods and insufficient power to detect meaningful changes in hippocampal volume across studies.

Computerized Games versus Crosswords Training in Mild Cognitive Impairment: The COG‐IT trial

AbstractBackgroundMild cognitive impairment (MCI) increases the risk of dementia. The efficacy of cognitive training in MCI is unclear.MethodIn a two‐site, single‐blinded, 78‐week trial, participants with MCI — stratified by age, severity (early/late MCI), and site — were randomly assigned to 12 weeks of intensive, home‐based, computerized training with Web‐based cognitive games or Web‐based crossword puzzles, followed by six booster sessions. In mixed‐model analyses, the primary outcome was change from baseline in the 11‐item Alzheimer’s Disease Assessment Scale‐Cognitive (ADAS‐Cog) score, adjusted for baseline. Secondary outcomes included change from baseline in neuropsychological composite score and Functional Activities Questionnaire score at 78 weeks, adjusted for baseline. Changes in hippocampal volume and cortical thickness on magnetic resonance imaging were assessed.ResultAmong 107 participants (n = 51 [games]; n = 56 [crosswords]), ADAS‐Cog11 score worsened slightly for games and improved for crosswords at week 78 (least squares [LS] means difference, 21.44; 95% CI 22.83 to 20.06; P = 0.04). From baseline to week 78, mean ADAS‐Cog score worsened for games (9.53 to 9.93) and improved for crosswords (9.59 to 8.61). The late MCI subgroup showed similar results (LS means difference, 22.45; SE, 0.89; 95% CI 24.21 to 20.70). Among secondary outcomes, the Functional Activities Questionnaire score worsened more with games than with crosswords at week 78 (LS means difference, 21.08; 95% CI 21.97 to 20.18, p = 0.02). Other secondary outcomes showed no differences. Decreases in hippocampal volume and cortical thickness were greater for games than for crosswords (LS means difference, 34.07; SE, 17.12; 95% CI 0.51 to 67.63, p &lt; .05 [hippocampal volume]; LS means difference, 0.02; SE, 0.01; 95% CI, 0.00 to 0.04, p = .02 [cortical thickness]).ConclusionHome‐based computerized training with crosswords demonstrated superior efficacy to games at 78 weeks. Common directionality was observed in the primary outcome of ADAS‐Cog (cognition) and the secondary outcomes of FAQ (function) score and changes in MRI hippocampal volume and cortical thickness (neurodegeneration). If these effects are replicated and expanded in future trials with the inclusion of a control group that does not receive cognitive training, crossword puzzles training could become a home‐based, scalable, cognitive enhancement tool for individuals with MCI.

Higher glucose parameters at baseline are related to hippocampal volume decline after a 2‐year multidomain lifestyle intervention to prevent cognitive decline in people at risk of developing Alzheimer’s disease: Exploratory results from the FINGER study

AbstractBackgroundLifestyle interventions for preventing cognitive decline have provided promising results in older at‐risk individuals. Two modifiable risk factors are insulin resistance and diabetes mellitus, since they’ve been associated with higher risk of cognitive decline. However, it remains unclear if healthy individuals with higher normal glucose levels are free from suffering the negative effect of pathological glucose values on brain and cognition. The Oral Glucose Tolerance Test (OGTT) is a sensitive measurement for non‐detected glucose metabolism disorders and might be related with changes in brain structure and cognition. In this study we hypothesised that changes in glucose parameters will be associated with brain structural changes.Method1.259 participants of the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) were included [Table 1]. A sample of 132 participants had brain MRI scans, and 47 also underwent PiB‐PET and FDG‐PET scans. Global GMv, hippocampal volumes, WMHv and cortical thickness measurements were analysed to assess the association between brain structural changes and glucose homeostasis. AD‐signature composites were also calculated from FDG‐PET and PiB‐PET scans data for the analysis. SPSS was used for linear regression models.ResultsBaseline AUC‐OGTT, 120min‐OGTT and fasting glucose were negatively associated (p&lt;0.05) with 2‐year change in hippocampal volume [Table 2]. A negative association was also found between baseline AUC and change in FDG‐PET‐AD‐composite (p = 0.028). Three negative associations were additionally found at baseline between AUC‐OGTT and cortical thickness (p = 0.015), fasting glucose and total GMv (p = 0.015), and HbA1c and FDG‐PET‐AD‐composite (p = 0.033) [Table 3]. Interestingly, a positive association was found in a smaller sample (n = 38) between the TyG index and change in PiB‐PET‐AD‐composite (0.014). No associations were found between glucose parameters and the remaining imaging data.ConclusionIn a sample of participants at risk for dementia, baseline higher measures of peripheral glucose metabolism such as AUC‐OGTT and 120min‐OGTT glucose were related to greater decline in hippocampal volume, irrespective of the randomisation group and after considering abnormal glucose metabolism. These results suggest that glucose homeostasis might have an impact on brain structure in participants with higher normal glucose parameters measurements.

Reduction of Hippocampal Atrophy and Lateral Ventricle Enlargement Correlates with Clinical Benefit in APOE4 Carriers with Early AD: 1‐Year Results from a Phase 2 Biomarker Study with Oral Anti‐Amyloid Oligomer Inhibitor ALZ‐801

AbstractBackgroundALZ‐801 is an oral inhibitor of amyloid oligomer formation in development as a disease‐modifying Alzheimer’s treatment, including a Phase 3 trial in APOE4/4 homozygotes and a Phase 2 biomarker study in APOE4 carriers. We analyzed correlations between brain volume and cognitive effects of ALZ‐801 after 1 year in the Phase 2 study. We previously reported that at 1‐year timepoint, plasma p‐tau181 (primary outcome) was significantly reduced by 41% from baseline, and hippocampal volume (HV) showed ∼20% less atrophy compared to external matched controls.MethodThe study is conducted at 7 European sites and enrolled 84 APOE4 carriers (MMSE 22‐30) with positive amyloid/tau biomarkers who receive ALZ‐801 265 mg BID for 104 weeks. Primary outcome is plasma p‐tau181 at 104 weeks, and primary imaging outcome is hippocampal volume (HV) atrophy. Volumetric vMRI measures (baseline, 52 and 104 weeks) are performed by Clario, and MMSE conducted. A PK sub‐study was conducted at 65 weeks (n = 23) with bioanalysis at DDS (UK) and non‐compartmental PK analyzed by WinNonlin. Pearson correlations of MMSE changes to BSI changes of HV and lateral ventricle volume (LVV) were conducted, with two‐sided p‐values reported.ResultAt 52 and 65 weeks, changes of MMSE from baseline showed significant correlations to HV (r = 0.32 and 0.34; p&lt;0.01, n = 66) and LVV changes (r = ‐0.42 and ‐0.44; p&lt;0.001, n = 65). Correlations between DMMSE and DLVV were significant for both genders (range r = ‐0.54 to ‐0.42, p&lt;0.02); correlations were observed for DHV in females (range r = 0.39‐0.47; p&lt;0.05) and males (range r = 0.26‐0.23; p&lt;0.18, ns). PK/PD analysis in 23 subjects showed trends (r = 0.21‐0.16, ns) between decreased HV atrophy/LVV expansion and plasma AUC24h of tramiprosate+3‐SPA (active and primary metabolite). ALZ‐801 exhibited favorable safety; main treatment‐related adverse event was mild nausea. No ARIA‐E was observed.ConclusionEarly AD subjects treated with ALZ‐801 for 65 weeks in the Phase 2 biomarker study showed strong correlations between MMSE stability, HV reduction, and decreased ventricular enlargement in overall group, and by genders. The significant correlations between cognitive and brain volume effects support the clinical benefits of ALZ‐801 in APOE4 carriers with early AD. Oral ALZ‐801 showed favorable safety and no brain edema/ARIA‐E.

Artificial Intelligence and Machine Learning (AIML) approaches to empower genomics, drug, and biomarker discovery in ADRD

AbstractBackgroundIn 2021, the NIA launched the Artificial Intelligence and Machine Learning (AIML) Consortium, to develop novel AI and machine learning techniques to tackle pressing questions in Alzheimer’s disease research.MethodDrawing on vast repositories of data from the Alzheimer’s Disease Sequencing Project (ADSP) and other large public biobanks, the 8 awardees funded under this program meet monthly to present their innovations in data analytics in 4 main areas: (1) genome‐guided drug discovery and drug repositioning for AD; (2) discovery of novel genetic and molecular targets for AD therapeutics using whole genome and omics data; and (3) understanding the regulatory code of the genome using deep learning and bioinformatics, and (4) use of electronic health records (EHR) to study treatment outcomes in ADRD. A second branch of AIML activity draws on repositories of neuroimaging data (MRI/FLAIR, DTI, and amyloid‐ and tau‐sensitive PET) to (1) identify ADRD subtypes based on neuroimaging, clinical and neuropsychological data, that differ in terms of their genomic drivers and expected treatment response (for precision medicine and drug trial stratification), (2) perform genetic analysis of endophenotypes derived from brain images (such as longitudinal hippocampal volume changes, atrophy subtype scores, and PET or WMH signatures) for biomarker‐guided gene discovery, and (3) predict neuropathology (TDP‐43, CAA, LBD) from multimodal imaging using AI. The AIML initiative benefits from and helps the ADSP’s Phenotype Harmonization Consortium, as AI methods can also be used to adjust neuroimaging data for site and protocol effects (harmonization).ResultIn this overview of the AIML Consortium, we highlight some recent successes using (1) convolutional neural networks (CNNs), GANs and deep learning for ADRD subtyping and staging; (2) discovery of AD‐relevant motifs and networks in whole genome sequences and functional genomics data; (3) prognostic models of clinical outcomes based on WGS and biomarkers; and (4) novel methods from statistical physics, based on evolutionary action, which model the fitness effect of coding mutations analytically.ConclusionAIML investigators are hosting regular workshops at AAIC and upcoming genomics and clinical neurology conferences to disseminate and teach these approaches to the AD and broader scientific community.

Metformin and dietary restriction pathway are associated with neuroprotection in Alzheimer’s disease context. A key role for glial autophagy

AbstractBackgroundThe global rise of type 2 diabetes and obesity prevalence has elicited a great interest in understanding how changes in metabolic function lead to premature brain aging. The inflammation and insulin resistance interplay represent a potential target to prevent neurodegeneration.MethodWe evaluated the effect of the antidiabetic drug metformin‐considered a dietary restriction (DR) mimetic‐ on patients enrolled in ADNI, an observational and longitudinal study including patients from all around the world. We employed data from patients diagnosed with mild cognitive impairment (MCI) due to AD and we performed a principal component analysis focusing on biomarkers associated to AD measured in cerebrospinal fluid.We analyzed memory performance and hippocampal alterations in a model of AD, the PDAPP‐J20 transgenic mouse (Tg) and evaluated the effects of a periodic DR protocol (3 cycles of 40% DR for 5 days and ad libitum diet for 9 days).ResultMCI metformin‐treated patients were characterized as subjects with a better CSF biomarkers profile than the mean population of MCI patients (p&lt;0.05). Control subjects and T2D patients were paired by age, gender, ApoE allele and education, defining three groups: MCI, MCI+T2D and MCI+T2D+metformin. We evaluated the effect of T2D and metformin treatment employing the PACC score and composites defined from standardized ADNI variables to evaluate the memory/learning function. We found that MCI+T2D patients have a worse cognitive performance than MCI patients (p&lt;0.01), but this effect was absent in MCI+T2D+metformin patients. These cognitive variations were associated with changes in cortical thickness and hippocampal volume (p&lt;0.001). Our study shows a beneficial effect of metformin treatment on cognitive performance, CSF biomarkers profile and neuroanatomical measures in MCI due to AD patients.We observed cognitive impairment, low adult neurogenesis and progressive Aβ deposition in the hippocampus of Tg mice. Periodic DR was associated to cognitive improvement, increased hippocampal neurogenesis, and reduced hippocampal amyloid load; we found that autophagy is modulated in Tg mice with a high proportion of LC3/Aβ colocalizing in astrocytes, probably contributing to the reduction in amyloid plaques associated to DR.ConclusionOur data suggest that metformin and DR may be potential interventions to promote healthy aging and prevent dementia.