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Background: Major depressive disorder (MDD) is characterized by hippocampal volume reduction, impacting cognitive function. Inflammation, particularly elevated tumor necrosis factor‐alpha (TNF‐α) levels, is consistently implicated in MDD pathophysiology. This study investigates the relationships between TNF‐α levels, hippocampal volume, beta‐amyloid (Aβ) burden, and cognitive abilities in MDD patients, aiming to illuminate the complex interplay among inflammatory markers, pathology indicators, structural brain alterations, and cognitive performance in non‐demented MDD individuals. Method: Fifty‐two non‐demented MDD patients, comprising 25 with mild cognitive impairment (MCI), were recruited along with 10 control subjects. Each participant underwent a thorough assessment encompassing TNF‐α blood testing, 18F‐florbetapir positron emission tomography, magnetic resonance imaging scans, and neuropsychological testing. Statistical analyses, adjusted for age and education, were performed to investigate the associations between TNF‐α levels, adjusted hippocampal volume (HVa), global Aβ burden, and cognitive performance. Results: MCI MDD patients displayed elevated TNF‐α levels and reduced HVa relative to controls. Correlation analyses demonstrated inverse relationships between TNF‐α level and HVa in MCI MDD, all MDD, and all subjects groups. Both TNF‐α level and HVa exhibited significant correlations with processing speed across all MDD and all subjects. Notably, global 18F‐florbetapir standardized uptake value ratio did not exhibit significant correlations with TNF‐α level, HVa, and cognitive measures. Conclusion: This study highlights elevated TNF‐α levels and reduced hippocampal volume in MCI MDD patients, indicating a potential association between peripheral inflammation and structural brain alterations in depression. Furthermore, our results suggest that certain cases of MDD may be affected by non‐amyloid‐mediated process, which impacts their TNF‐α and hippocampal volume. These findings emphasize the importance of further investigating the complex interplay among inflammation, neurodegeneration, and cognitive function in MDD. [ABSTRACT FROM AUTHOR]

Introduction: 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 noncognitively impaired brain and those with MCI or AD. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Genome-wide association studies identified variants around the BIN1 (bridging integrator 1) gene locus as prominent risk factors for late-onset Alzheimer disease. In the present study, we decreased the expression of BIN1 in mouse hippocampal neurons to investigate its neuronal function. Bin1 knockdown via RNAi reduced the dendritic arbor size in primary cultured hippocampal neurons as well as in mature Cornu Ammonis 1 excitatory neurons. The AAV-mediated Bin1 RNAi knockdown also generated a significant regional volume loss around the injection sites at the organ level, as revealed by 7-Tesla structural magnetic resonance imaging, and an impaired spatial reference memory performance in the Barnes maze test. Unexpectedly, Bin1 knockdown led to concurrent activation of both macroautophagy/autophagy and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Autophagy inhibition with the lysosome inhibitor chloroquine effectively mitigated the Bin1 knockdown-induced dendritic regression. The subsequent molecular studydemonstrated that increased expression of ULK3 (unc-51 like kinase 3), which is MTOR-insensitive, supported autophagosome formation in BIN1 deficiency. Reducing ULK3 activity with SU6668, a receptor tyrosine kinase inhibitor, or decreasing neuronal ULK3 expression through AAV-mediated RNAi, significantly attenuated Bin1 knockdown-induced hippocampal volume loss and spatial memory decline. In Alzheimer disease patients, the major neuronal isoform of BIN1 is specifically reduced. Our work suggests this reduction is probably an important molecular event that increases the autophagy level, which might subsequently promote brain atrophy and cognitive impairment through reducing dendritic structures, and ULK3 is a potential interventional target for relieving these detrimental effects.Abbreviations: AV: adeno-associated virus; Aβ: amyloid-β; ACTB: actin, beta; AD: Alzheimer disease; Aduk: Another Drosophila Unc-51-like kinase; AKT1: thymoma viral proto-oncogene 1; AMPK: AMP-activated protein kinase; AP: autophagosome; BafA1: bafilomycin A1; BDNF: brain derived neurotrophic factor; BIN1: bridging integrator 1; BIN1-iso1: BIN1, isoform 1; CA1: cornu Ammonis 1; CA3: cornu Ammonis 3; CLAP: clathrin and adapter binding; CQ: chloroquine; DMEM: Dulbecco’s modified Eagle medium; EGFP: enhanced green fluorescent protein; GWAS: genome-wide association study; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MRI: magnetic resonance imaging; MTOR; mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; PET: positron emission tomography; qRT-PCR: real-time quantitative reverse transcription PCR; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; TFEB: transcription factor EB; ULK1: unc-51 like kinase 1; ULK3: unc-51 like kinase 3. [ABSTRACT FROM AUTHOR]

Background: Research work has shown that hippocampal subfields are atrophic to varying extents in multiple sclerosis (MS) patients. However, studies examining the functional implications of subfield-specific hippocampal damage in early MS are limited. We aim to gain insights into the relationship between hippocampal atrophy and memory function by investigating the correlation between global and regional hippocampal atrophy and memory performance in early MS patients. Methods: From the Italian Neuroimaging Network Initiative (INNI) dataset, we selected 3D-T1-weighted brain MRIs of 219 early relapsing remitting (RR)MS and 246 healthy controls (HC) to identify hippocampal atrophic areas. At the time of MRI, patients underwent Selective-Reminding-Test (SRT) and Spatial-Recall-Test (SPART) and were classified as mildly (MMI-MS: n.110) or severely (SMI-MS: n:109) memory impaired, according to recently proposed cognitive phenotypes. Results: Early RRMS showed lower hippocampal volumes compared to HC (p < 0.001), while these did not differ between MMI-MS and SMI-MS. In MMI-MS, lower hippocampal volumes correlated with worse memory tests (r = 0.23–0.37, p ≤ 0.01). Atrophic voxels were diffuse in the hippocampus but more prevalent in cornu ammonis (CA, 79%) than in tail (21%). In MMI-MS, decreased subfield volumes correlated with decreases in memory, particularly in the right CA1 (SRT-recall: r = 0.38; SPART: r = 0.34, p < 0.01). No correlations were found in the SMI-MS group. Conclusion: Hippocampal atrophy spreads from CA to tail from early disease stages. Subfield hippocampal atrophy is associated with memory impairment in MMI-MS, while this correlation is lost in SMI-MS. This plays in favor of a limited capacity for an adaptive functional reorganization of the hippocampi in MS patients. [ABSTRACT FROM AUTHOR]

Background/Objectives: COPD patients who are frail have been reported to develop brain atrophy, but no non-invasive diagnostic tool has been developed to detect this condition. Our study aimed to explore the diagnostic utility of the Kihon Checklist (KCL), a frailty questionnaire, in assessing hippocampal volume loss in patients with COPD. Methods: We recruited 40 COPD patients and 20 healthy individuals using the KCL to assess frailty across seven structural domains. Hippocampal volumes were obtained from T1-weighted MRI images, and ROC analysis was performed to detect hippocampal atrophy. Results: Our results showed that patients with COPD had significantly greater atrophic left hippocampal volumes than healthy subjects (p < 0.05). The univariate correlation coefficient between the left hippocampal volume and KCL (1–20), which pertains to instrumental and social activities of daily living, was the largest (ρ = −0.54, p < 0.0005) among the KCL subdomains. Additionally, both KCL (1–25) and KCL (1–20) demonstrated useful diagnostic potential (93% specificity and 90% sensitivity, respectively) for identifying individuals in the lowest 25% of the left hippocampal volume (AUC = 0.82). Conclusions: Our study suggests that frailty questionnaires focusing on daily vulnerability, such as the KCL, can effectively detect hippocampal atrophy in COPD patients. [ABSTRACT FROM AUTHOR]

Abstract Background Major depressive disorder (MDD) is characterized by hippocampal volume reduction, impacting cognitive function. Inflammation, particularly elevated tumor necrosis factor‐alpha (TNF‐α) levels, is consistently implicated in MDD pathophysiology. This study investigates the relationships between TNF‐α levels, hippocampal volume, beta‐amyloid (Aβ) burden, and cognitive abilities in MDD patients, aiming to illuminate the complex interplay among inflammatory markers, pathology indicators, structural brain alterations, and cognitive performance in non‐demented MDD individuals. Method Fifty‐two non‐demented MDD patients, comprising 25 with mild cognitive impairment (MCI), were recruited along with 10 control subjects. Each participant underwent a thorough assessment encompassing TNF‐α blood testing, 18F‐florbetapir positron emission tomography, magnetic resonance imaging scans, and neuropsychological testing. Statistical analyses, adjusted for age and education, were performed to investigate the associations between TNF‐α levels, adjusted hippocampal volume (HVa), global Aβ burden, and cognitive performance. Results MCI MDD patients displayed elevated TNF‐α levels and reduced HVa relative to controls. Correlation analyses demonstrated inverse relationships between TNF‐α level and HVa in MCI MDD, all MDD, and all subjects groups. Both TNF‐α level and HVa exhibited significant correlations with processing speed across all MDD and all subjects. Notably, global 18F‐florbetapir standardized uptake value ratio did not exhibit significant correlations with TNF‐α level, HVa, and cognitive measures. Conclusion This study highlights elevated TNF‐α levels and reduced hippocampal volume in MCI MDD patients, indicating a potential association between peripheral inflammation and structural brain alterations in depression. Furthermore, our results suggest that certain cases of MDD may be affected by non‐amyloid‐mediated process, which impacts their TNF‐α and hippocampal volume. These findings emphasize the importance of further investigating the complex interplay among inflammation, neurodegeneration, and cognitive function in MDD.

Background: Sphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults. Methods: Brain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP. Results: In the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction = <0.001), such that ceramide d18:1/20:0 associated with higher odds for infarcts in women [OR = 1.26 (95%CI: 1.07, 1.49), PFDR = 0.03]. We did not observe any associations with GFAP blood levels, white matter grade, ventricular grade, mean bilateral hippocampal volume, or total brain volume. Conclusion: Overall, our comprehensive investigation supports the evidence that ceramides and sphingomyelins are associated with increased aging brain pathology and that the direction of association depends on the fatty acid attached to the sphingosine backbone. [ABSTRACT FROM AUTHOR]

Depression is a prevalent occurrence among Alzheimer's disease (AD) patients, yet its underlying mechanism remains unclear. Recent investigations have revealed that several pathophysiological changes associated with Alzheimer's disease can lead to mood disorders. These alterations include irregularities in monoamine neurotransmitters, disruptions in glutamatergic synaptic transmission, neuro-inflammation, dysfunction within the hypothalamic-pituitary-adrenocortical (HPA) axis, diminished levels of brain-derived neurotrophic factor (BDNF), and hippocampal atrophy. This review consolidates research findings from pertinent fields to elucidate the mechanisms underlying depression in Alzheimer's disease, aiming to provide valuable insights for the study of its mechanisms and clinical treatment. [ABSTRACT FROM AUTHOR]

IntroductionNeurobiological 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.MethodsThis 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.ResultsThe 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.ConclusionPublished 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.

This study aimed to elucidate the long-term progression of mild cognitive impairment (MCI) within a comprehensive longitudinal dataset, distinguish it from healthy aging, explore the influence of a dementia subtype on this progression, and identify potential contributing factors. Patients with prodromal and preclinical cases underwent regular neuropsychological assessments utilizing various tools. The study included a total of 140 participants with MCI, categorized into Alzheimer's disease (AD) and non-AD subtypes. Our dataset revealed an overall progression rate of 92.8% from MCI to the clinical stage of dementia during the follow-up period, with an annual rate of 15.7%. Notably, all prodromal cases of Lewy body dementia/Parkinson's disease (LBD/PDD) and frontotemporal dementia (FTD) advanced to clinical stages, whereas 7% of vascular dementia (VaD) cases and 8.4% of AD cases remained in the prodromal stage throughout follow-up. Furthermore, we observed a faster progression rate in MCI-AD cases compared to non-AD sufferers (53.9% vs. 35.5%, Entropy: 0.850). This study revealed significant cognitive changes in individuals with MCI over time. The mini-mental state examination (MMSE), global deterioration scale (GDS), and calculation tests were the most effective tests for evaluation of MCI. These findings may offer valuable insights for the development of personalized interventions and management strategies for individuals with MCI. [ABSTRACT FROM AUTHOR]

Previous work has associated polymorphisms in the dopamine transporter gene (rs6347 in DAT1 / SLC6A3) and brain derived neurotrophic factor gene (Val66Met in BDNF) with atrophy and memory decline. However, it is unclear whether these polymorphisms relate to atrophy and cognition through associations with Alzheimer's disease pathology. We tested for effects of DAT1 and BDNF polymorphisms on cross-sectional and longitudinal β-amyloid (Aβ) and tau pathology (measured with positron emission tomography (PET)), hippocampal volume, and cognition. We analyzed a sample of cognitively normal older adults (cross-sectional n = 321) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). DAT1 and BDNF interacted to predict Aβ-PET, tau-PET, and hippocampal atrophy. Carriers of both "non-boptimal" DAT1 C and BDNF Met alleles demonstrated greater pathology and atrophy. Our findings provide novel links between dopamine and neurotrophic factor genes and AD pathology, consistent with previous research implicating these variants in greater risk for developing AD. • DAT1 and BDNF polymorphisms relate to Aβ and tau pathology in healthy older adults. • Carriers of both DAT1 CC and BDNF Met exhibit higher Aβ and tau. • DAT1 CC and BDNF Met are also linked with greater hippocampal atrophy. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a degenerative neuronal brain disorder resulting in memory loss, skills, and cognitive changes. The disorder’s primary diagnostic tests are defined as total brain atrophy and hippocampal atrophy. Early diagnosis is significant, and automatic systems design is necessary for this disorder. Potential biomarkers for AD are described using a hippocampal magnetic resonance imaging volumetry system with certain limitations. For the definite identification of the hippocampus region, pre-processing of the 3D MRI images of AD is necessary. The filtering and histogram-based pre-processing techniques enhance the region of interest, which helps in effectively segmenting the biomarker, the hippocampus. The median and eight histogram clippings are defined to be 98% efficient pre-processing techniques with the comparison of image quality parameters and statistical analysis. Thus an algorithm for pre-processing of the 3D MRI images of stages of AD is designed for the further process of identification. [ABSTRACT FROM AUTHOR]

Many wild otariids (sea lions and fur seals) strand along the California coast annually with seizures following presumed exposure to harmful algal blooms (HABs). This is a long-term case study of a stranded subadult male Guadalupe fur seal (Arctocephalus townsendi) that stranded in 2001 and within days after admission began demonstrating seizure activity. The epilepsy was stabilized with antiepileptic drug (AED) therapy and advanced imaging was performed. Magnetic resonance (MR) scans showed signs of encephalopathy consistent with domoic acid (DA) toxicosis. This fur seal was deemed "non-releasable" and over the following 19 years, he received supportive veterinary care and AED treatment at a permitted facility. In the summer of 2020, the fur seal showed progressive behavioral and functional deterioration whereupon humane euthanasia was performed. Post-mortem MR and diffusion tensor images (DTI) were acquired. A volumetric comparison with historic scans showed evidence of severe progressive unilateral right hippocampal atrophy. Histopathology confirmed severe chronic right and mild left hippocampal atrophy. The progressive degenerative brain changes demonstrate how adaptive brain function can be with neuronal atrophy secondary to DA exposure. This case highlights some considerations and decision-making processes needed for the rehabilitation and placement of wild stranded otariids with acquired epilepsy secondary to DA toxicity. [ABSTRACT FROM AUTHOR]

BackgroundSphingolipids are implicated in neurodegeneration and neuroinflammation. We assessed the potential role of circulating ceramides and sphingomyelins in subclinical brain pathology by investigating their association with brain magnetic resonance imaging (MRI) measures and circulating biomarkers of brain injury, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in the Cardiovascular Health Study (CHS), a large and intensively phenotyped cohort of older adults.MethodsBrain MRI was offered twice to CHS participants with a mean of 5 years between scans, and results were available from both time points in 2,116 participants (mean age 76 years; 40% male; and 25% APOE ε4 allele carriers). We measured 8 ceramide and sphingomyelin species in plasma samples and examined the associations with several MRI, including worsening grades of white matter hyperintensities and ventricular size, number of brain infarcts, and measures of brain atrophy in a subset with quantitative measures. We also investigated the sphingolipid associations with serum NfL and GFAP.ResultsIn the fully adjusted model, higher plasma levels of ceramides and sphingomyelins with a long (16-carbon) saturated fatty acid were associated with higher blood levels of NfL [β = 0.05, false-discovery rate corrected P (PFDR) = 0.004 and β = 0.06, PFDR = < 0.001, respectively]. In contrast, sphingomyelins with very long (20- and 22-carbon) saturated fatty acids tended to have an inverse association with levels of circulating NfL. In secondary analyses, we found an interaction between ceramide d18:1/20:0 and sex (P for interaction =

Many wild otariids (sea lions and fur seals) strand along the California coast annually with seizures following presumed exposure to harmful algal blooms (HABs). This is a long-term case study of a stranded subadult male Guadalupe fur seal (Arctocephalus townsendi) that stranded in 2001 and within days after admission began demonstrating seizure activity. The epilepsy was stabilized with antiepileptic drug (AED) therapy and advanced imaging was performed. Magnetic resonance (MR) scans showed signs of encephalopathy consistent with domoic acid (DA) toxicosis. This fur seal was deemed “non-releasable” and over the following 19 years, he received supportive veterinary care and AED treatment at a permitted facility. In the summer of 2020, the fur seal showed progressive behavioral and functional deterioration whereupon humane euthanasia was performed. Post-mortem MR and diffusion tensor images (DTI) were acquired. A volumetric comparison with historic scans showed evidence of severe progressive unilateral right hippocampal atrophy. Histopathology confirmed severe chronic right and mild left hippocampal atrophy. The progressive degenerative brain changes demonstrate how adaptive brain function can be with neuronal atrophy secondary to DA exposure. This case highlights some considerations and decision-making processes needed for the rehabilitation and placement of wild stranded otariids with acquired epilepsy secondary to DA toxicity.

Background: Non-Alzheimer's dementias, including vascular dementia (VaD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and Parkinson's disease dementia (PDD), possess unique characteristics and prognostic factors that remain poorly understood. This study aims to investigate the temporal course of these subtypes and identify the impact of functional, neuropsychiatric, and comorbid medical conditions on prognosis. Additionally, the relationship between hippocampal atrophy, white matter intensities, and disease progression will be examined, along with the identification of key covariates influencing slow or fast progression in non-Alzheimer's dementias. Methods: A total of 196 patients with non-Alzheimer's dementias who underwent at least three comprehensive evaluations were included, with proportions of VaD, FTD, LBD, and PDD being 50, 19.39, 19.90, and 10.71%, respectively. Patient demographics, comorbidities, neuropsychiatric and neuroimaging parameters, and global evaluation were analyzed using appropriate statistical methods. The study followed patients for a mean duration of 62.57+33.45 months (ranging from 11 to 198 months). Results: The results from three different visits for each non-AD dementia case demonstrated significant differences in various measures across visits, including functional capacity (BDLAS), cognition (MMSE), and other neuropsychological tests. Notably, certain genotypes and hippocampal atrophy grades were more prevalent in specific subtypes. The results indicate that Fazekas grading and hippocampal atrophy were significant predictors of disease progression, while epilepsy, extrapyramidal symptoms, thyroid dysfunction, coronary artery disease, diabetes mellitus, hypertension, stroke, hyperlipidemia, sleep disorders, smoking, and family history of dementia were not significant predictors. BDLAS and EDLAS scores at the first and second visits showed significant associations with disease progression, while scores at the third visit did not. Group-based trajectory analysis revealed that non-AD cases separated into two reliable subgroups with slow/fast prognosis, showing high reliability (Entropy = 0.790, 51.8 vs. 48.2%). Conclusion: This study provides valuable insights into the temporal course and prognostic factors of non-Alzheimer's dementias. The findings underscore the importance of considering functional, neuropsychological, and comorbid medical conditions in understanding disease progression. The significant associations between hippocampal atrophy, white matter intensities, and prognosis highlight potential avenues for further research and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: There is conflicting data regarding the predictors of Alzheimer's Disease (AD), the most common form of dementia. The main objective of the study is to evaluate potential predictors of AD progression using a comprehensive follow-up dataset that includes functional/cognitive assessments, clinical and neuropsychiatric evaluations, and neuroimaging biomarkers such as hippocampal atrophy or white matter intensities (WMIs). Method: A total of 161 AD cases were recruited from a dementia database consisting of individuals who consulted the Dementia Outpatient Clinic of the Neurology Department at Mersin University Medical Faculty between 2000 and 2022, under the supervision of the same senior author have at least 3 full evaluation follow-up visit including functional, clinical, biochemical, neuropsychological, and radiological screening. Data were exported and analyzed by experts accordingly. Results: Mean follow-up duration of study sample was 71.66 ± 41.98, min 15 to max 211 months. The results showed a fast and slow progressive subgroup of our AD cases with a high sensitivity (Entropy = 0.836), with a close relationship with several cofactors and the level of disability upon admittance. Hippocampal atrophy and WMIs grading via Fazekas were found to be underestimated predictors of AD progression, and functional capacity upon admittance was also among the main stakeholders. Conclusion: The study highlights the importance of evaluating multiple potential predictors for AD progression, including functional capacity upon admittance, hippocampal atrophy, and WMIs grading via Fazekas. Our findings provide insight into the complexity of AD progression and may contribute to the development of effective strategies for managing and treating AD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is one of the most common neurodegenerative conditions in the world and, when combined with dementia, can lead to immense cerebral volume loss. Of significant importance among all cerebral regions, is the hippocampus. This region plays a pivotal role in memory, and understanding its pathological alterations can answer vital questions regarding dementia. As such, we designed this study to compare the hippocampal volumes of PD patients with dementia (PDD) versus PD without dementia. Methods: PubMed, Web of Science, Scopus, and Embase were searched for relevant studies. We also searched the references sections of all included studies. The original search began in March 2022 and was extended to the end of July 2022. All related data were extracted from the studies. If the studies were conducted on patients from comparable patient groups, the most recent study with the most extensive data set would be included. Results: A statistically significant difference was observed comparing the raw hippocampal volumes in participants with PDD and PD (p value = 0.01). In a comparison of normalized hippocampal volume between PDD and PD, there was a statistically significant difference (p value < 0.01), as well. Conclusion: Although further research is required to illuminate the temporal relation between the onset of dementia and hippocampal atrophy in demented PD individuals, the present study highlights the importance of utilizing volumetric studies on memory‐related cerebral regions to diagnose the initiation of dementia in the early stages. Key points: The present study highlights the importance of utilizing volumetric studies on memory‐related cerebral regions to diagnose the initiation of dementia in the early stages. Compare the hippocampal volumes between Parkinson's disease patients with and without dementia. [ABSTRACT FROM AUTHOR]

Abstract Background Parkinson's disease (PD) is one of the most common neurodegenerative conditions in the world and, when combined with dementia, can lead to immense cerebral volume loss. Of significant importance among all cerebral regions, is the hippocampus. This region plays a pivotal role in memory, and understanding its pathological alterations can answer vital questions regarding dementia. As such, we designed this study to compare the hippocampal volumes of PD patients with dementia (PDD) versus PD without dementia. Methods PubMed, Web of Science, Scopus, and Embase were searched for relevant studies. We also searched the references sections of all included studies. The original search began in March 2022 and was extended to the end of July 2022. All related data were extracted from the studies. If the studies were conducted on patients from comparable patient groups, the most recent study with the most extensive data set would be included. Results A statistically significant difference was observed comparing the raw hippocampal volumes in participants with PDD and PD (p value = 0.01). In a comparison of normalized hippocampal volume between PDD and PD, there was a statistically significant difference (p value

BackgroundThere is conflicting data regarding the predictors of Alzheimer’s Disease (AD), the most common form of dementia. The main objective of the study is to evaluate potential predictors of AD progression using a comprehensive follow-up dataset that includes functional/cognitive assessments, clinical and neuropsychiatric evaluations, and neuroimaging biomarkers such as hippocampal atrophy or white matter intensities (WMIs).MethodA total of 161 AD cases were recruited from a dementia database consisting of individuals who consulted the Dementia Outpatient Clinic of the Neurology Department at Mersin University Medical Faculty between 2000 and 2022, under the supervision of the same senior author have at least 3 full evaluation follow-up visit including functional, clinical, biochemical, neuropsychological, and radiological screening. Data were exported and analyzed by experts accordingly.ResultsMean follow-up duration of study sample was 71.66 ± 41.98, min 15 to max 211 months. The results showed a fast and slow progressive subgroup of our AD cases with a high sensitivity (Entropy = 0.836), with a close relationship with several cofactors and the level of disability upon admittance. Hippocampal atrophy and WMIs grading via Fazekas were found to be underestimated predictors of AD progression, and functional capacity upon admittance was also among the main stakeholders.ConclusionThe study highlights the importance of evaluating multiple potential predictors for AD progression, including functional capacity upon admittance, hippocampal atrophy, and WMIs grading via Fazekas. Our findings provide insight into the complexity of AD progression and may contribute to the development of effective strategies for managing and treating AD.

ObjectivesTo study the interactive effect of white matter hyperintensities (WMH) and hippocampal atrophy on cognition in the oldest old.DesignOngoing longitudinal study.SettingIn Southern California, brain magnetic resonance imaging (MRI) scans were conducted between May 2014 and December 2017.ParticipantsIndividuals from The 90+ Study with a valid brain MRI scan (N = 141; 94 cognitively normal and 47 with cognitive impairment).MeasurementsCognitive testing was performed every 6 months with a mean follow-up of 2 years and included these tests: Mini-Mental State Examination (MMSE), modified MMSE (3MS), California Verbal Learning Test (CVLT) immediate recall over four trials and delayed recall, Digit Span Backward, Animal Fluency, and Trail Making Test (TMT) A, B, and C. We used one linear mixed model for each cognitive test to study the baseline and longitudinal association of WMH and hippocampal volume (HV) with cognition. Models were adjusted for age, sex, and education.ResultsMean age was 94.3 years (standard deviation [SD] = 3.2 y). At baseline, higher WMH volumes were associated with worse scores on the 3MS, CVLT immediate and delayed recall, and TMT B. Lower HVs were associated with worse baseline scores on all cognitive tests, except for the Digit Span Backward. Longitudinally, higher WMH and lower HVs were associated with faster decline in the 3MS and MMSE, and lower HV was also associated with faster decline in the CVLT immediate recall. No association was observed between WMH and HV and no interaction between WMH and HV in their association with baseline cognition or cognitive decline.ConclusionWe show that WMH and hippocampal atrophy have an independent, negative effect on cognition that make these biomarkers relevant to evaluate in the diagnostic work-up of the oldest-old individuals with cognitive complaints. However, the predictive value of WMH for cognitive decline seems to be less evident in the oldest-old compared with a younger group of older adults. J Am Geriatr Soc 67:1827-1834, 2019.

Abstract Background Sirtuin 1 (Sirt1) is a recognized longevity gene and has been shown to be associated with aging and its related diseases. Hippocampal volume is considered to be the most sensitive brain imaging phenotype for cognition, but the effect of Sirt1 on hippocampal morphology during aging has not been reported. Results Herein, we investigated the effect of conditional Sirt1 knockdown on hippocampal volume in middle-aged mice, as well as its cognitive function and the underlying molecular mechanisms. Brain structural magnetic resonance imaging (MRI) showed that adeno-associated virus (AAV) mediated hippocampal Sirt1 knockdown caused hippocampal atrophy in 8-month-old mice. Open field test (OFT) and Morris Water Maze (MWM) test revealed that hippocampal Sirt1 knockdown significantly weakened spatial learning and memory of mice without effect on anxiety and exploratory behavior. Western blotting analysis showed that P-tau levels at serine 396 epitope were significantly increased with slightly decreased T-tau levels, while PSD95 and NMDAR2B levels were obviously reduced, indicating that hippocampal Sirt1 knockdown could activate tau hyperphosphorylation and synaptic damage. Conclusions This work revealed that Sirt1 is an important protective gene against hippocampal atrophy and its induced cognitive impairment during aging, providing potential therapeutic targets for the prevention and intervention of aging-related neuropsychic diseases.

Alzheimer's disease (AD) primarily affects older adults. In this report, we present the case of a 19-year-old male with gradual memory decline for 2 years and World Health Organization-University of California Los Angeles Auditory Verbal Learning Test (WHO-UCLA AVLT) results also showing memory impairment. Positron emission tomography-magnetic resonance imaging with 18F fluorodeoxyglucose revealed atrophy of the bilateral hippocampus and hypometabolism in the bilateral temporal lobe. Examination of the patient's cerebrospinal fluid showed an increased concentration of p-tau181 and a decreased amyloid-β 42/40 ratio. However, through whole-genome sequencing, no known gene mutations were identified. Considering the above, the patient was diagnosed with probable AD. [ABSTRACT FROM AUTHOR]

It has rarely been documented that permanent alteration of cerebral structures occurs by focal status epilepticus (FSE). We report the case of a 16-year-old boy with FSE in whom serial T1-weighted magnetic resonance volumetry and conventional magnetic resonance imaging were useful for investigating an evolving pattern of morphological changes during and after the FSE, including cortical laminar necrosis (CLN), increased T2 signal intensities, and marked regional atrophy on the corresponding areas. Despite cessation of FSE after adequate medication (combination therapy including clobazam of 1 mg/kg/day), further significant cerebral atrophy was detected at the limited regions where discrete CLN had occurred during the FSE.

Background: It is essential to detect morphological changes in the brain prior to the onset of cognitive decline. Although hippocampal volumes have been reported to be correlated with scores on neuropsychological tests, this relationship is still unclear among Japanese non-demented older adults. Thus, this exploratory retrospective study aimed to identify neuropsychological tests that correlate with the degree of hippocampal atrophy in Japanese non-demented older adults. Methods: Thirteen non-demented Japanese older adults aged 71.2 ± 5.2 years were included. Hippocampal atrophy was evaluated by assessing the participants’ MRI scans using the voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) software. Spearman’s partial correlation analyses were conducted to reveal relationships between VSRAD scores and neuropsychological test scores, including Raven’s Colored Progressive Matrices test (RCPM), the Standard Verbal Paired Associate Learning test (SP-A), and the Trail Making Test (TMT) scores by controlling for age, sex, and years of education. Results: The Spearman’s partial correlation analysis results revealed that there were significant correlations between the degree of hippocampal atrophy and RCPM (rho = -0.691, p = 0.027), TMT part B (rho = 0.823, p = 0.003), and the related SP-A test scores (rho = -0.663, p = 0.027). Conclusions: Our results indicate that neuropsychological tests, particularly the TMT part B, might be used in assessing the degree of hippocampal atrophy in non-demented Japanese elderly individuals and should be studied further in the future to develop screening methods to detect brain atrophy.

BrightFocus Foundation sponsored the third iteration of the "Common Features of Neurodegenerative Disease: Exploring the Brain-Eye Connection and Beyond" pre-conference symposium that preceded the 15th International Conference on Alzheimer's and Parkinson's Diseases (AD/PD 2021). Keywords: Alzheimer's disease (AD) and related dementias; Glaucoma; Age-related macular degeneration (AMD); Vascular cognitive impairment and dementia (VCID); Cerebral amyloid angiopathy (CAA); Neurodegeneration; Cellular senescence; Aging; Maintenance; Vascular contributions; Neurovascular unit; Blood brain barrier (BBB); Blood retina barrier (BRB); Thrombosis; Ischemic; Stroke; Vasodilation; Vasoconstriction; Retinal ganglion cells (RGC); Endothelial cells; Skeletal cells; Axon; Pericytes; Inter-pericyte tunneling nanotubes (IP-TNT); Astrocytes; Microglia; Hippocampal atrophy; Inflammation; Genetic; Intraocular pressure; Biomarker; Electrophysiology; Imaging EN Alzheimer's disease (AD) and related dementias Glaucoma Age-related macular degeneration (AMD) Vascular cognitive impairment and dementia (VCID) Cerebral amyloid angiopathy (CAA) Neurodegeneration Cellular senescence Aging Maintenance Vascular contributions Neurovascular unit Blood brain barrier (BBB) Blood retina barrier (BRB) Thrombosis Ischemic Stroke Vasodilation Vasoconstriction Retinal ganglion cells (RGC) Endothelial cells Skeletal cells Axon Pericytes Inter-pericyte tunneling nanotubes (IP-TNT) Astrocytes Microglia Hippocampal atrophy Inflammation Genetic Intraocular pressure Biomarker Electrophysiology Imaging 1 5 5 11/03/22 20221101 NES 221101 Sharyn L. Rossi and Preeti Subramanian both contributed equally. B Session III, "Why are the vascular components and blood-brain/blood-retina barriers of the brain and eye important contributors to the tipping point between health and disease?". [Extracted from the article]

Aim: The aim of this article is to describe the hippocampal characteristics among children with calcified neurocysticercosis (cNCC). Materials and Methods: This cross-sectional study was conducted among children with epilepsy aged 3-14 years diagnosed with cNCC. Patients showing evidence of cNCC, with prior serial imaging evidence of active NCC, were enrolled. Eligible participants were subjected to magnetic resonance imaging (MRI)-based protocol and sleep-deprived electroencephalography. Hippocampal characteristics on the MRI were described. Results: A total of 31 children with mean (SD) age of 10.3 (3.2) years with cNCC were enrolled in the study. We observed that 42% (13/31) of children with cNCC had borderline (10-20% difference in the volumes of right and left hippocampi) (n = 8) or clear (>20% difference) (n = 5) hippocampal atrophy. Among 31 children with cNCC, 27 (87.1%) had nidus within the lesion and 21 (67.7%) had perilesional gliosis. Conclusion: Children with cNCC are at risk of seizure recurrence on tapering anti-seizure medications. Our study with limited sample size revealed that hippocampal atrophy and perilesional gliosis are prevalent among children with cNCC, predisposing them to the risk of epilepsy. [ABSTRACT FROM AUTHOR]

Brain atrophy induced by traumatic brain injury (TBI) progresses in parallel with epileptogenesis over time, and thus accurate placement of intracerebral electrodes to monitor seizure initiation and spread at the chronic postinjury phase is challenging. We evaluated in adult male Sprague Dawley rats whether adjusting atlas-based electrode coordinates on the basis of magnetic resonance imaging (MRI) increases electrode placement accuracy and the effect of chronic electrode implantations on TBI-induced brain atrophy. One group of rats (EEG cohort) was implanted with two intracortical (anterior and posterior) and a hippocampal electrode right after TBI to target coordinates calculated using a rat brain atlas. Another group (MRI cohort) was implanted with the same electrodes, but using T2-weighted MRI to adjust the planned atlas-based 3D coordinates of each electrode. Histological analysis revealed that the anterior cortical electrode was in the cortex in 83% (25% in targeted layer V) of the EEG cohort and 76% (31%) of the MRI cohort. The posterior cortical electrode was in the cortex in 40% of the EEG cohort and 60% of the MRI cohort. Without MRI-guided adjustment of electrode tip coordinates, 58% of the posterior cortical electrodes in the MRI cohort will be in the lesion cavity, as revealed by simulated electrode placement on histological images. The hippocampal electrode was accurately placed in 82% of the EEG cohort and 86% of the MRI cohort. Misplacement of intracortical electrodes related to their rostral shift due to TBI-induced cortical and hippocampal atrophy and caudal retraction of the brain, and was more severe ipsilaterally than contralaterally (p < 0.001). Total lesion area in cortical subfields targeted by the electrodes (primary somatosensory cortex, visual cortex) was similar between cohorts (p > 0.05). MRI-guided adjustment of coordinates for electrodes improved the success rate of intracortical electrode tip placement nearly to that at the acute postinjury phase (68% vs. 62%), particularly in the posterior brain, which exhibited the most severe postinjury atrophy. Overall, MRI-guided electrode implantation improved the quality and interpretation of the origin of EEG-recorded signals. [ABSTRACT FROM AUTHOR]

Introduction: Calcifications are the end stage of many parenchymal brain cysticerci and may occur either spontaneously or as the result of treatment with cysticidal drugs. These lesions, traditionally considered inert and asymptomatic, have been associated with several complications that seem to be mostly related to brain damage and inflammation ensuing as the result of the exposure of the host's immune system to parasitic antigens trapped within calcifications., Areas Covered: This review, based on the search of different electronic databases up to May 2024, focuses on the reported correlates and complications of calcified cysticerci (chronic headaches, seizures/epilepsy, hippocampal atrophy/sclerosis, gliomas), and the different interventions developed for their prevention and treatment. Common analgesics, non-steroidal anti-inflammatory drugs, corticosteroids, and antiseizure medications have been used with success but, with the exception of the latter, these drugs offer temporary relief of symptoms and support for their use is based on level 3 evidence., Expert Opinion: Several strategies may reduce the severity of clinical consequences of calcified cysticerci. Probably, the most relevant intervention would be the prevention of their occurrence or reduction in their size. In this view, the use of bisphosphonates appears as a potential option that needs to be tested in humans.

Introduction: The apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive., Methods: The present study enrolled 54 patients diagnosed with late-onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non-carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) analysis of peripheral blood mononuclear cells (PBMCs)., Results: Plasma tumor necrosis factor α, interferon γ, and interleukin (IL)-33 levels increased in the APOE ε4 carriers but IL-7 expression notably decreased. A negative correlation was observed between plasma IL-7 level and the hippocampal atrophy degree. Additionally, the expression of IL-7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA-seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells., Discussion: These findings shed light on the role of the downregulated IL-7/IL-7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy., Highlights: The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)-7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL-7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL-7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL-7/IL-7R signal pathways enriches T cells., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Abstract Background We recently reported that CSF phosphorylated tau (p-Tau181) relative to Aβ40 (CSF p-Tau/Aβ40 ratio) was less noisy and increased associations with Alzheimer’s disease (AD) biomarkers compared to CSF p-Tau181 alone. While elevations of CSF p-Tau/Aβ40 can occur in amyloid-β (Aβ) negative (Aβ-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aβ positivity. Methods We examined relationships between CSF p-Tau/Aβ40, and CSF Aβ42/Aβ40, Aβ PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer’s disease (AD) pathway due to negative Aβ status on both CSF and PET. Subgroups had 18F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aβ40 associations with these measures as well. Results Elevated CSF p-Tau/Aβ40 was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aβ42/Aβ40, higher WMH, and hypertension but not age, sex, Aβ PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aβ40 increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ40 and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements. Conclusions These data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aβ. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aβ are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy.

Background: Hippocampal atrophy is a well-known biomarker of neurodegeneration, such as that observed in Alzheimer's disease (AD). Although distributions of hippocampal volume trajectories for asymptomatic individuals often reveal substantial heterogeneity, it is unclear whether interpretable trajectory classes can be objectively detected and used for prediction analyses.Objective: To detect and predict hippocampal trajectory classes in a computationally competitive context using established AD-related risk factors/biomarkers.Methods: We used biomarker/risk factor and longitudinal MRI data in asymptomatic adults from the AD Neuroimaging Initiative (n = 351; Mean = 75 years; 48.7% female). First, we applied latent class growth analyses to left (LHC) and right (RHC) hippocampal trajectory distributions to identify distinct classes. Second, using random forest analyses, we tested 38 multi-modal biomarkers/risk factors for their relative importance in discriminating the lower (potentially elevated atrophy risk) from the higher (potentially reduced risk) class.Results: For both LHC and RHC trajectory distribution analyses, we observed three distinct trajectory classes. Three biomarkers/risk factors predicted membership in LHC and RHC lower classes: male sex, higher education, and lower plasma Aβ1-42. Four additional factors selectively predicted membership in the lower LHC class: lower plasma tau and Aβ1-40, higher depressive symptomology, and lower body mass index.Conclusion: Data-driven analyses of LHC and RHC trajectories detected three classes underlying the heterogeneous distributions. Machine learning analyses determined three common and four unique biomarkers/risk factors discriminating the higher and lower LHC/RHC classes. Our sequential analytic approach produced evidence that the dynamics of preclinical hippocampal trajectories can be predicted by AD-related biomarkers/risk factors from multiple modalities. [ABSTRACT FROM AUTHOR]

Background: Sirtuin 1 (Sirt1) is a recognized longevity gene and has been shown to be associated with aging and its related diseases. Hippocampal volume is considered to be the most sensitive brain imaging phenotype for cognition, but the effect of Sirt1 on hippocampal morphology during aging has not been reported.Results: Herein, we investigated the effect of conditional Sirt1 knockdown on hippocampal volume in middle-aged mice, as well as its cognitive function and the underlying molecular mechanisms. Brain structural magnetic resonance imaging (MRI) showed that adeno-associated virus (AAV) mediated hippocampal Sirt1 knockdown caused hippocampal atrophy in 8-month-old mice. Open field test (OFT) and Morris Water Maze (MWM) test revealed that hippocampal Sirt1 knockdown significantly weakened spatial learning and memory of mice without effect on anxiety and exploratory behavior. Western blotting analysis showed that P-tau levels at serine 396 epitope were significantly increased with slightly decreased T-tau levels, while PSD95 and NMDAR2B levels were obviously reduced, indicating that hippocampal Sirt1 knockdown could activate tau hyperphosphorylation and synaptic damage.Conclusions: This work revealed that Sirt1 is an important protective gene against hippocampal atrophy and its induced cognitive impairment during aging, providing potential therapeutic targets for the prevention and intervention of aging-related neuropsychic diseases. [ABSTRACT FROM AUTHOR]

Brain disorders, including stroke, Alzheimer's disease, depression, and chronic pain, are difficult to effectively treat. These major brain disorders have high incidence and mortality rates in the general population, and seriously affect not only the patient's quality of life, but also increases the burden of social medical care. Aerobic physical exercise is considered an effective adjuvant therapy for preventing and treating major brain disorders. Although the underlying regulatory mechanisms are still unknown, systemic processes may be involved. Here, this review aimed to reveal that aerobic physical exercise improved depression and several brain functions, including cognitive functions, and provided chronic pain relief. We concluded that aerobic physical exercise helps to maintain the regulatory mechanisms of brain homeostasis through anti-inflammatory mechanisms and enhanced synaptic plasticity and inhibition of hippocampal atrophy and neuronal apoptosis. In addition, we also discussed the cross-system mechanisms of aerobic exercise in regulating imbalances in brain function, such as the "bone-brain axis." Furthermore, our findings provide a scientific basis for the clinical application of aerobic physical exercise in the fight against brain disorders. [ABSTRACT FROM AUTHOR]

Vitamin B12 deficiency is associated with cognitive impairment, hyperhomocysteinemia, and hippocampal atrophy. However, the recovery of cognition with vitamin B12 supplementation remains controversial. Of the 1716 patients who visited our outpatient clinic for dementia, 83 had vitamin B12 deficiency. Among these, 39 patients (mean age, 80.1 ± 8.2 years) had undergone Mini-Mental State Examination (MMSE) and laboratory tests for vitamin B12, homocysteine (Hcy), and folic acid levels. The hippocampal volume was estimated using the z-score of the MRI-voxel-based specific regional analysis system for Alzheimer's disease. This is multi-center, open-label, single-arm study. All the 39 patients were administered vitamin B12 and underwent reassessment to measure the retested for MMSE and Hcy after 21−133 days (median = 56 days, interquartile range (IQR) = 43–79 days). After vitamin B12 supplementation, the mean MMSE score improved significantly from 20.5 ± 6.4 to 22.9 ± 5.5 (p < 0.001). Hcy level decreased significantly from 22.9 ± 16.9 nmol/mL to 11.5 ± 3.9 nmol/mL (p < 0.001). Significant correlation was detected between the extent of change in MMSE scores and baseline Hcy values. The degree of MMSE score was not correlated with hippocampal atrophy assessed by the z-score. While several other factors should be considered, vitamin B12 supplementation resulted in improved cognitive function, at least in the short term, in patients with vitamin B12 deficiency. [ABSTRACT FROM AUTHOR]

The disruption of bidirectional communication between neuroendocrine and immune components by stressors leads to mental problems. The immunomodulation therapy of neuroinflammation-led psychiatric illness is an emerging area of research. Therefore, the present study aimed to evaluate immune modulation efficacy of PD 149163 (PD) against the lipopolysaccharide (LPS)-induced neuroinflammation. The Swiss albino mice (female/12 weeks) were divided into six groups (6 mice/group): (I) Control: 0.9% NaCl; (II) LPS: 1 mg/kg BW, for 5 days; (III) LPS + PD Low: LPS 1 mg/kg BW (for 5 days) after that PD 100 µg/kg BW (for 21 days); (IV) LPS + PD High: LPS 1 mg/kg BW (for 5 days) after that PD 300 µg/kg BW (for 21 days); (V) PD Low: PD 100 µg/kg BW (for 21 days); (VI) PD High: PD 300 µg/kg BW (for 21 days). All treatments were given intraperitoneal. The LPS-induced weight loss (body and brain) was normalized to control after PD treatment. The PD enhanced superoxide dismutase (SOD) activity while decreased lipid hydroperoxide (LOOH) level altered in LPS-exposed mice. The significantly increased pro-inflammatory cytokines (IL-6 and TNF-α) in LPS exposure were also decreased by PD. Likewise, the LPS-induced HPA axis activation was stabilized by PD. In the hippocampus, the pyramidal cell layer thickness, pyramidal neurons number and size of CA1 and CA3 regions were reduced along with misalignment, shrinkage, and impairment of cytoarchitecture. In the co-treated group, the LPS-induced hippocampus disruption was reversed after PD exposure. We suggested that the PD modulates the LPS-induced neuroinflammation and psychiatric illness in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is a neurodegenerative disease of unknown etiology that progresses progressively and is currently incurable. It is more common in the elderly that seriously affects the physical and mental health of patients, thus early detection is very important for the prevention of AD progression. By using PCANet and Broad Learning System (BLS), we propose a novel method to identify Alzheimer's patients according to the clinical symptom of hippocampal atrophy, which is the most important indicator of AD. T1-weighted magnetic resonance images (MRIs) are used in this study, containing 207 patients with AD, 209 patients with mild cognitive impairment (MCI) and 109 cognitively normal (CN) cohorts from ADNI dataset. The left and right hippocampus are segmented from MRI at the first step, then the PACNet is applied to extract features from these images, finally the BLS is used to distinguish the different types of patients. Compared with the traditional machine learning methods, PCANet is able to extract the most informative features inside pictures effectively, while BLS can reach over 95% accuracy rate with lower time consuming. Experimental results have revealed that our method improves the performance of computer-aided diagnosis of Alzheimer's disease in both accuracy and speed of classification task. [ABSTRACT FROM AUTHOR]

Early-onset Alzheimer's disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer's disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future. [ABSTRACT FROM AUTHOR]

Objective: Cognitive impairment in temporal lobe epilepsy is widely acknowledged as one of the most well-known comorbidities. This study aimed to explore cognitive impairment and to determine the potential clinical, radiological, and quantitative electroencephalography markers for cognitive impairment in temporal lobe epilepsy patients versus extra-temporal lobe epilepsy. Methods: Forty-five patients with temporal lobe epilepsy and forty-five patients with extra-temporal lobe epilepsy were recruited for an administered digit span test, verbal fluency test, mini-mental state examination, digital symbol test, and Montreal cognitive assessment. Also, they were subjected to magnetic resonance imaging assessment for hippocampal atrophy and a quantitative electroencephalography assessment for electroencephalography markers (median frequency, peak frequency, and the alpha-to-theta ratio). Results: Patients with extra-temporal lobe epilepsy showed non-significant higher epilepsy durations and a higher frequency of seizures. Temporal lobe epilepsy patients showed a more statistically significant family history of epilepsy (37.7%), more history of febrile convulsions (13.3%), higher hippocampal atrophy (17.8%), and lower cognitive scales, especially mini-mental state examination and Montreal cognitive assessment; lower digital symbol test, verbal fluency test, and backward memory of digit span test. Also, temporal lobe epilepsy patients had a strong negative correlation with electroencephalography markers: median frequency, peak frequency, and the alpha-to-theta ratio (r = − 0.68, P < 0.005 and r = − 0.64, P < 0.005 and r = − 0.66, P < 0.005 respectively). Conclusion: Cognitive impairment in patients with temporal lobe epilepsy was correlated with hippocampal atrophy and quantitative electroencephalography abnormalities, especially peak frequency, median frequency, and alpha-to-theta ratio that could be used alone for the identification of early cognitive impairment. Trial registration : Clinicaltrials.gov: NCT04376671. [ABSTRACT FROM AUTHOR]

Background: Early-onset Alzheimer's disease is a rare condition that differs from the usual memory-disordered presentation of typical Alzheimer's disease. Early-onset Alzheimer's disease is believed to have a genetic basis, and sporadic Alzheimer's disease has been associated with sortilin-related receptor 1 polymorphism.Case presentation: This report describes and discusses the family report of a 59-year-old patient with early-onset Alzheimer's disease that may have been associated with a sortilin-related receptor 1 gene mutation. The patient was hospitalized in August 2008 for gradually progressive amnesia. Brain magnetic resonance imaging showed that the patient presented with whole-brain atrophy (especially in the bilateral medial temporal lobe and hippocampus). He had an initial Mini-Mental State Examination score of 15 (time orientation: 4/5; place orientation: 4/5; language immediate memory: 2/3; attention and calculation: 1/5; delayed memory: 0/3; naming: 1/2; language retelling, understanding, and expression: 3/6; visuospatial ability: 0/1). Whole-exome sequencing showed a sortilin-related receptor 1 gene mutation, c.3575G>A (chr11:121448104), which was detected in the patient and his children.Discussion: Patients with early-onset Alzheimer's disease present with obvious deficits in language, visuospatial abilities, praxis, or other nonmemory cognitive functions. In this case, the speech, memory, and visuospatial impairment of the patient may be associated with the sortilin-related receptor 1 gene mutation. Atrophy of the bilateral medial temporal lobe/hippocampus on magnetic resonance imaging may be an important marker of early-onset Alzheimer's disease. A sortilin-related receptor 1 gene mutation, c.3575G>A (chr11:121448104), may increase the risk of Alzheimer's disease.

Background and Purpose It is estimated that hippocampal damage is seen in 50 to 70% of patients with temporal lobe epilepsy (TLE). Although most magnetic resonance imaging (MRI) studies are adequate to detect gross hippocampal atrophy, subtle changes that may characterize early disease in TLE, such as visually nonappreciable volume loss, may often be missed if objective volumetric analysis is not undertaken. Materials and Methods We conducted a hospital-based prospective analytical study in which 40 patients with partial seizures of temporal lobe origin were included and their hippocampal volumes (HVs) were determined by manual volumetric analysis. The findings were recorded and correlated with the side of seizure and its duration. The quantitative assessment was allotted different grades accordingly. Also, the apparent diffusion coefficient (ADC) values of bilateral hippocampi were estimated and their correlation with the side of seizure was determined. Results Most patients in the study were in the age group of 11 to 20 years (37.5%). In total, 57.5% had seizures for a period of 1 to 5 years. While 67.5% (n = 27) had seizure on the right, 32.5% (n = 13) had on the left. The mean HV estimated on the right and left were correlated with the side of seizure and found to be statistically significant (p < 0.001 in those with right-sided seizures and p = 0.02 in those with left-sided seizures). Simultaneously the ADC values estimated were found to correlate with the laterality of seizures with a statistical difference (p < 0.01). Duration of seizures however did not show a positive correlation with the HV. Conclusion MRI with quantitative estimation of HV and ADC values can depict the presence and laterality in TLE with accuracy rates that exceed those achieved by visual inspection alone. Thus, quantitative MRI provides a useful means for translating volumetric analysis into clinical practice.

Background: Evaluating the risk of Alzheimer's disease (AD) in cognitively normal (CN) and patients with mild cognitive impairment (MCI) is extremely important. While MCI-to-AD progression risk has been studied extensively, few studies estimate CN-to-MCI conversion risk. The Cox proportional hazards (PH), a widely used survival analysis model, assumes a linear predictor-risk relationship. Generalizing the PH model to more complex predictor-risk relationships may increase risk estimation accuracy.Objective: The aim of this study was to develop a PH model using an Xgboost regressor, based on demographic, genetic, neuropsychiatric, and neuroimaging predictors to estimate risk of AD in patients with MCI, and the risk of MCI in CN subjects.Methods: We replaced the Cox PH linear model with an Xgboost regressor to capture complex interactions between predictors, and non-linear predictor-risk associations. We endeavored to limit model inputs to noninvasive and more widely available predictors in order to facilitate future applicability in a wider setting.Results: In MCI-to-AD (n = 882), the Xgboost model achieved a concordance index (C-index) of 84.5%. When the model was used for MCI risk prediction in CN (n = 100) individuals, the C-index was 73.3%. In both applications, the C-index was statistically significantly higher in the Xgboost in comparison to the Cox PH model.Conclusion: Using non-linear regressors such as Xgboost improves AD dementia risk assessment in CN and MCI. It is possible to achieve reasonable risk stratification using predictors that are relatively low-cost in terms of time, invasiveness, and availability. Future strategies for improving AD dementia risk estimation are discussed. [ABSTRACT FROM AUTHOR]

Background: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer's disease (AD), DMF is a potential therapeutic option for AD.Objective: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms.Methods: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways.Results: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition.Conclusion: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway. [ABSTRACT FROM AUTHOR]

Background: Hippocampal atrophy has been consistently reported in major depressive disorder with more recent focus on subfields. However, literature on hippocampal volume changes after antidepressant treatment has been limited. The first-line treatments for depression include antidepressant medication (ADM) or cognitive-behavior therapy (CBT). To understand the differential effects of CBT and ADM on the hippocampus, we investigated the volume alterations of hippocampal subfields with treatment, outcome, and chronicity in treatment-naïve depression patients. Methods: Treatment-naïve depressed patients from the PReDICT study were included in this analysis. A total of 172 patients who completed 12 weeks of randomized treatment with CBT (n = 45) or ADM (n = 127) were included for hippocampal subfield volume analysis. Forty healthy controls were also included for the baseline comparison. Freesurfer 6.0 was used to segment 26 hippocampal substructures and bilateral whole hippocampus from baseline and week 12 structural MRI scans. A generalized linear model with covariates of age and gender was used for group statistical tests. A linear mixed model for the repeated measures with covariates of age and gender was used to examine volumetric changes over time and the contributing effects of treatment type, outcome, and illness chronicity. Results: Of the 172 patients, 85 achieved remission (63/127 ADM, 22/45 CBT). MDD patients showed smaller baseline volumes than healthy controls in CA1, CA3, CA4, parasubiculum, GC-ML-DG, Hippocampal Amygdala Transition Area (HATA), and fimbria. Over 12 weeks of treatment, further declines in the volumes of CA1, fimbria, subiculum, and HATA were observed regardless of treatment type or outcome. CBT remitters, but not ADM remitters, showed volume reduction in the right hippocampal tail. Unlike ADM remitters, ADM non-responders had a decline in volume in the bilateral hippocampal tails. Baseline volume of left presubiculum (regardless of treatment type) and right fimbria and HATA in CBT patients were correlated with a continuous measure of clinical improvement. Chronicity of depression had no effect on any measures of hippocampal subfield volumes. Conclusion: Two first-line antidepressant treatments, CBT and ADM, have different effects on hippocampal tail after 12 weeks. This finding suggests that remission achieved via ADM may protect against progressive hippocampal atrophy by altering neuronal plasticity or supporting neurogenesis. Studies with multimodal neuroimaging, including functional and structural analysis, are needed to assess further the impact of two different antidepressant treatments on hippocampal subfields. [ABSTRACT FROM AUTHOR]

Background: Hippocampal atrophy has been consistently reported in major depressive disorder with more recent focus on subfields. However, literature on hippocampal volume changes after antidepressant treatment has been limited. The first-line treatments for depression include antidepressant medication (ADM) or cognitive-behavior therapy (CBT). To understand the differential effects of CBT and ADM on the hippocampus, we investigated the volume alterations of hippocampal subfields with treatment, outcome, and chronicity in treatment-naïve depression patients.Methods: Treatment-naïve depressed patients from the PReDICT study were included in this analysis. A total of 172 patients who completed 12 weeks of randomized treatment with CBT (n = 45) or ADM (n = 127) were included for hippocampal subfield volume analysis. Forty healthy controls were also included for the baseline comparison. Freesurfer 6.0 was used to segment 26 hippocampal substructures and bilateral whole hippocampus from baseline and week 12 structural MRI scans. A generalized linear model with covariates of age and gender was used for group statistical tests. A linear mixed model for the repeated measures with covariates of age and gender was used to examine volumetric changes over time and the contributing effects of treatment type, outcome, and illness chronicity.Results: Of the 172 patients, 85 achieved remission (63/127 ADM, 22/45 CBT). MDD patients showed smaller baseline volumes than healthy controls in CA1, CA3, CA4, parasubiculum, GC-ML-DG, Hippocampal Amygdala Transition Area (HATA), and fimbria. Over 12 weeks of treatment, further declines in the volumes of CA1, fimbria, subiculum, and HATA were observed regardless of treatment type or outcome. CBT remitters, but not ADM remitters, showed volume reduction in the right hippocampal tail. Unlike ADM remitters, ADM non-responders had a decline in volume in the bilateral hippocampal tails. Baseline volume of left presubiculum (regardless of treatment type) and right fimbria and HATA in CBT patients were correlated with a continuous measure of clinical improvement. Chronicity of depression had no effect on any measures of hippocampal subfield volumes.Conclusion: Two first-line antidepressant treatments, CBT and ADM, have different effects on hippocampal tail after 12 weeks. This finding suggests that remission achieved via ADM may protect against progressive hippocampal atrophy by altering neuronal plasticity or supporting neurogenesis. Studies with multimodal neuroimaging, including functional and structural analysis, are needed to assess further the impact of two different antidepressant treatments on hippocampal subfields.

Background: We recently reported that CSF phosphorylated tau (p-Tau181) relative to Aβ40 (CSF p-Tau/Aβ40 ratio) was less noisy and increased associations with Alzheimer's disease (AD) biomarkers compared to CSF p-Tau181 alone. While elevations of CSF p-Tau/Aβ40 can occur in amyloid-β (Aβ) negative (Aβ-) individuals, the factors associated with these elevations and their role in neurodegeneration and cognitive decline are unknown. We aim to explore factors associated with elevated tau in CSF, and how these elevated tau are related to neurodegeneration and cognitive decline in the absence of Aβ positivity. Methods: We examined relationships between CSF p-Tau/Aβ40, and CSF Aβ42/Aβ40, Aβ PET, and white matter hyperintensities (WMH) as well as vascular risk factors in 149 cognitively unimpaired and 52 impaired individuals who were presumably not on the Alzheimer's disease (AD) pathway due to negative Aβ status on both CSF and PET. Subgroups had 18F-fluorodeoxyglucose (FDG) PET and adjusted hippocampal volume (aHCV), and longitudinal measures of CSF, aHCV, FDG PET, and cognition data, so we examined CSF p-Tau/Aβ40 associations with these measures as well. Results: Elevated CSF p-Tau/Aβ40 was associated with older age, male sex, greater WMH, and hypertension as well as a pattern of hippocampal atrophy and temporoparietal hypometabolism characteristic of AD. Lower CSF Aβ42/Aβ40, higher WMH, and hypertension but not age, sex, Aβ PET, APOE-ε4 status, body mass index, smoking, and hyperlipidemia at baseline predicted CSF p-Tau/Aβ40 increases over approximately 5 years of follow-up. The relationship between CSF p-Tau/Aβ40 and subsequent cognitive decline was partially or fully explained by neurodegenerative measurements. Conclusions: These data provide surprising clues as to the etiology and significance of tau pathology in the absence of Aβ. It seems likely that, in addition to age, both cerebrovascular disease and subthreshold levels of Aβ are related to this tau accumulation. Crucially, this phenotype of CSF tau elevation in amyloid-negative individuals share features with AD such as a pattern of metabolic decline and regional brain atrophy. [ABSTRACT FROM AUTHOR]

Background: The differentiation of idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative diseases such as Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) is often challenging because of their non-specific symptoms. Therefore, various neuroradiological markers other than ventriculomegaly have been proposed. Despite the utility of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) for the appropriate selection of shunt surgery candidates, the specificity and neuropathology of this finding have not been sufficiently evaluated.Objective: Investigation of the clinicopathological features and comparison of the neuroradiological findings between DESH with postmortem neuropathological diagnoses (pDESH) and clinically-diagnosed iNPH (ciNPH) patients are the main purposes of this study.Method: In addition to the retrospective evaluation of clinicopathological information, quantitative, semiquantitative, and qualitative magnetic resonance imaging (MRI) indices were compared between pathologically-investigated 10 patients with pDESH and 10 patients with ciNPHResults:Excluding one patient with multiple cerebral infarctions, the postmortem neuropathological diagnoses of the pathologically-investigated patients were mainly neurodegenerative diseases (five AD, one DLB with AD pathologies, one DLB, one argyrophilic grain disease, and one Huntington's disease). In addition to the common neuroradiological featuresConclusion:Hippocampal atrophy and deformation with temporal horn enlargement seem to be characteristic neuroradiological findings of long-standing severely demented patients with DESH and neurodegenerative diseases, mainly advanced-stage AD. [ABSTRACT FROM AUTHOR]

Background: Differences exist regarding post-stroke cognitive outcomes.Objective: The aim of this study investigates the potential factors associated with post-stroke cognitive performance and trajectories.Methods: We performed a prospective cohort study using serial monitoring of cognitive function over a 1-year period after a first-ever ischemic stroke. Small vessel disease (SVD) burden and hippocampal atrophy (HA) were evaluated using the modified cerebral small vessel disease scores (mCSVD) and medial temporal atrophy score (MTA) scores. A generalized estimating equation (GEE) model and a group-based trajectory model (GBTM) was used to analyze the potential factors associated with post-stroke cognitive outcomes.Results: A total of 112 patients were enrolled. The GEE model showed that all patients, regardless of initial cognitive performance, had a tendency to show an increase in the Montreal Cognitive Assessment over time. The cognitive performance was better in male patients with higher education levels (p = 0.046 and p < 0.001, respectively), but tended to be worse in patients with higher SVD burden and HA. The GBTM model grouped patients into low, intermediate, and high performance (LP, IP, and HP) after stroke. A higher SVD burden, rather than HA and initial stroke severity and location, independently predicted a higher odds of poor post-stroke cognitive trajectory (being in the LP group) after stroke (adjusted odds ratio 2.74, 95%CI 1.09-6.86).Conclusion: In patients with first-ever mild stroke, cognitive improvement over time was evident. The detrimental impact of the SVD burden may outweigh the effect of HA or acute stroke insult on the post-stroke cognitive trajectory during the 1-year follow-up. [ABSTRACT FROM AUTHOR]

ObjectiveThe pathologic validation of European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP).MethodsTemporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post-mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six-micrometer-thick hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aβ, and tau burden for each hippocampal subfield were obtained.ResultsWe found significant correlations between hippocampal volume and Braak and Braak staging (ρ = -0.75, P = .001), tau (ρ = -0.53, P = .034), Aβ burden (ρ = -0.61, P = .012), and neuronal count (ρ = 0.77, P < .001). Exploratory subfield-wise significant associations were found for Aβ in Cornu Ammonis (CA)1 (ρ = -0.58, P = .019) and subiculum (ρ = -0.75, P = .001), tau in CA2 (ρ = -0.59, P = .016), and CA3 (ρ = -0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001).ConclusionsThe observed associations provide pathological confirmation of hippocampal morphometry as a valid biomarker for AD and pathologic validation of HarP.