[Features of the clinical and neuroimaging picture in patients with early-onset Alzheimer's disease]. / Osobennosti klinicheskoi i neirovizualizatsionnoi kartiny u patsientov s bolezn'yu Al'tsgeimera s rannim nachalom.

The most common cause of severe cognitive impairment in adults is Alzheimer's disease (AD). Depending on the age of onset, AD is divided into early (<65 years) and late (≥65 years) forms. Early-onset AD (EOAD) is significantly less common than later-onset AD (LOAD) and accounts for only about 5-10% of cases. However, its medical and social significance, as a disease leading to loss of ability to work and legal capacity, as well as premature death in patients aged 40-64 years, is extremely high. Patients with EOAD compared with LOAD have a greater number of atypical clinical variants - 25% and 6-12.5%, respectively, which complicates the differential diagnosis of EOAD with other neurodegenerative diseases. However, the typical classical amnestic variant predominates in both EOAD and LOAD. Also, patients with EOAD have peculiarities according to neuroimaging data: when performing MRI of the brain, patients with EOAD often have more pronounced parietal atrophy and less pronounced hippocampal atrophy compared to patients with LOAD. The article pays attention to the features of the clinical and neuroimaging data in patients with EOAD; a case of a patient with EOAD is presented.

Electroacupuncture modulates abnormal brain connectivity after ischemia reperfusion injury in rats: A graph theory-based approach.

BACKGROUND: Electroacupuncture (EA) has been shown to facilitate brain plasticity-related functional recovery following ischemic stroke. The functional magnetic resonance imaging technique can be used to determine the range and mode of brain activation. After stroke, EA has been shown to alter brain connectivity, whereas EA's effect on brain network topology properties remains unclear. An evaluation of EA's effects on global and nodal topological properties in rats with ischemia reperfusion was conducted in this study. METHODS AND RESULTS: There were three groups of adult male Sprague-Dawley rats: sham-operated group (sham group), middle cerebral artery occlusion/reperfusion (MCAO/R) group, and MCAO/R plus EA (MCAO/R + EA) group. The differences in global and nodal topological properties, including shortest path length, global efficiency, local efficiency, small-worldness index, betweenness centrality (BC), and degree centrality (DC) were estimated. Graphical network analyses revealed that, as compared with the sham group, the MCAO/R group demonstrated a decrease in BC value in the right ventral hippocampus and increased BC in the right substantia nigra, accompanied by increased DC in the left nucleus accumbens shell (AcbSh). The BC was increased in the right hippocampus ventral and decreased in the right substantia nigra after EA intervention, and MCAO/R + EA resulted in a decreased DC in left AcbSh compared to MCAO/R. CONCLUSION: The results of this study provide a potential basis for EA to promote cognitive and motor function recovery after ischemic stroke.

Effectiveness of Personalized Hippocampal Network-Targeted Stimulation in Alzheimer Disease: A Randomized Clinical Trial.

Importance: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a safe and promising intervention for Alzheimer disease (AD). Objective: To investigate the effect of a 4-week personalized hippocampal network-targeted rTMS on cognitive and functional performance, as well as functional connectivity in AD. Design, Setting, and Participants: This randomized clinical trial, which was sham-controlled and masked to participants and evaluators, was conducted between May 2020 and April 2022 at a single Korean memory clinic. Eligible participants were between ages 55 and 90 years and had confirmed early AD with evidence of an amyloid biomarker. Participants who met the inclusion criteria were randomly assigned to receive hippocampal network-targeted rTMS or sham stimulation. Participants received 4-week rTMS treatment, with assessment conducted at weeks 4 and 8. Data were analyzed between April 2022 and January 2024. Interventions: Each patient received 20 sessions of personalized rTMS targeting the left parietal area, functionally connected to the hippocampus, based on fMRI connectivity analysis over 4 weeks. The sham group underwent the same procedure, excluding actual magnetic stimulation. A personalized 3-dimensional printed frame to fix the TMS coil to the optimal target site was produced. Main Outcomes and Measures: The primary outcome was the change in the AD Assessment Scale-Cognitive Subscale test (ADAS-Cog) after 8 weeks from baseline. Secondary outcomes included changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SOB) and Seoul-Instrumental Activity Daily Living (S-IADL) scales, as well as resting-state fMRI connectivity between the hippocampus and cortical areas. Results: Among 30 participants (18 in the rTMS group; 12 in the sham group) who completed the 8-week trial, the mean (SD) age was 69.8 (9.1) years; 18 (60%) were female. As the primary outcome, the change in ADAS-Cog at the eighth week was significantly different between the rTMS and sham groups (coefficient [SE], -5.2 [1.6]; P = .002). The change in CDR-SOB (-4.5 [1.4]; P = .007) and S-IADL (1.7 [0.7]; P = .004) were significantly different between the groups favoring rTMS groups. The fMRI connectivity analysis revealed that rTMS increased the functional connectivity between the hippocampus and precuneus, with its changes associated with improvements in ADAS-Cog (r = -0.57; P = .005). Conclusions and Relevance: This randomized clinical trial demonstrated the positive effects of rTMS on cognitive and functional performance, and the plastic changes in the hippocampal-cortical network. Our results support the consideration of rTMS as a potential treatment for AD. Trial Registration: ClinicalTrials.gov Identifier: NCT04260724.

In Vivo Reactive Astrocyte Imaging in Patients With Schizophrenia Using Fluorine 18-Labeled THK5351.

Importance: In vivo imaging studies of reactive astrocytes are crucial for understanding the pathophysiology of schizophrenia because astrocytes play a critical role in glutamate imbalance and neuroinflammation. Objective: To investigate in vivo reactive astrocytes in patients with schizophrenia associated with positive symptoms using monoamine oxidase B (MAO-B)-binding fluorine 18 ([18F])-labeled THK5351 positron emission tomography (PET). Design, Setting, and Participants: In this case-control study, data were collected from October 1, 2021, to January 31, 2023, from the internet advertisement for the healthy control group and from the outpatient clinics of Seoul National University Hospital in Seoul, South Korea, for the schizophrenia group. Participants included patients with schizophrenia and age- and sex-matched healthy control individuals. Main Outcomes and Measures: Standardized uptake value ratios (SUVrs) of [18F]THK5351 in the anterior cingulate cortex (ACC) and hippocampus as primary regions of interest (ROIs), with other limbic regions as secondary ROIs, and the correlation between altered SUVrs and Positive and Negative Syndrome Scale (PANSS) positive symptom scores. Results: A total of 68 participants (mean [SD] age, 32.0 [7.0] years; 41 men [60.3%]) included 33 patients with schizophrenia (mean [SD] age, 32.3 [6.3] years; 22 men [66.7%]) and 35 healthy controls (mean [SD] age, 31.8 [7.6] years; 19 men [54.3%]) who underwent [18F]THK5351 PET scanning. Patients with schizophrenia showed significantly higher SUVrs in the bilateral ACC (left, F = 5.767 [false discovery rate (FDR)-corrected P = .04]; right, F = 5.977 [FDR-corrected P = .04]) and left hippocampus (F = 4.834 [FDR-corrected P = .04]) than healthy controls. Trend-level group differences between the groups in the SUVrs were found in the secondary ROIs (eg, right parahippocampal gyrus, F = 3.387 [P = .07]). There were positive correlations between the SUVrs in the bilateral ACC and the PANSS positive symptom scores (left, r = 0.423 [FDR-corrected P = .03]; right, r = 0.406 [FDR-corrected P = .03]) in patients with schizophrenia. Conclusions and Relevance: This case-control study provides novel in vivo imaging evidence of reactive astrocyte involvement in the pathophysiology of schizophrenia. Reactive astrocytes in the ACC may be a future target for the treatment of symptoms of schizophrenia, especially positive symptoms.

Carbon monoxide poisoning with hippocampi lesions on MRI: cases report and literature review.

BACKGROUND: Carbon monoxide (CO) poisoning is now one of the leading causes of poisoning-related mortality worldwide. The central nervous system is the most vulnerable structure in acute CO poisoning. MRI is of great significance in the diagnosis and prognosis of CO toxic encephalopathy. The imaging features of CO poisoning are diverse. We report atypical hippocampal lesions observed on MRI in four patients after acute CO exposure. CASE PRESENTATIONS: We report four patients who presented to the emergency department with loss of consciousness. The diagnosis of CO poisoning was confirmed on the basis of their detailed history, physical examination and laboratory tests. Brain MRI in all of these patients revealed abnormal signal intensity in hippocampi bilaterally. They all received hyperbaric oxygen therapy. The prognosis of all four patients was poor. CONCLUSION: Hippocampi, as a relatively rare lesion on MRI of CO poisoning, is of important significance both in the early and delayed stages of acute CO poisoning. In this article, we summarize the case reports of hippocampal lesions on MRI in patients with CO poisoning in recent years, in order to provide reference for the diagnosis and prognosis of CO poisoning.

Comparison of plasma and neuroimaging biomarkers to predict cognitive decline in non-demented memory clinic patients.

BACKGROUND: Plasma biomarkers of Alzheimer's disease (AD) pathology, neurodegeneration, and neuroinflammation are ideally suited for secondary prevention programs in self-sufficient persons at-risk of dementia. Plasma biomarkers have been shown to be highly correlated with traditional imaging biomarkers. However, their comparative predictive value versus traditional AD biomarkers is still unclear in cognitively unimpaired (CU) subjects and with mild cognitive impairment (MCI). METHODS: Plasma (Aß42/40, p-tau181, p-tau231, NfL, and GFAP) and neuroimaging (hippocampal volume, centiloid of amyloid-PET, and tau-SUVR of tau-PET) biomarkers were assessed at baseline in 218 non-demented subjects (CU = 140; MCI = 78) from the Geneva Memory Center. Global cognition (MMSE) was evaluated at baseline and at follow-ups up to 5.7 years. We used linear mixed-effects models and Cox proportional-hazards regression to assess the association between biomarkers and cognitive decline. Lastly, sample size calculations using the linear mixed-effects models were performed on subjects positive for amyloid-PET combined with tau-PET and plasma biomarker positivity. RESULTS: Cognitive decline was significantly predicted in MCI by baseline plasma NfL (ß=-0.55), GFAP (ß=-0.36), hippocampal volume (ß = 0.44), centiloid (ß=-0.38), and tau-SUVR (ß=-0.66) (all p < 0.05). Subgroup analysis with amyloid-positive MCI participants also showed that only NfL and GFAP were the only significant predictors of cognitive decline among plasma biomarkers. Overall, NfL and tau-SUVR showed the highest prognostic values (hazard ratios of 7.3 and 5.9). Lastly, we demonstrated that adding NfL to the inclusion criteria could reduce the sample sizes of future AD clinical trials by up to one-fourth in subjects with amyloid-PET positivity or by half in subjects with amyloid-PET and tau-PET positivity. CONCLUSIONS: Plasma NfL and GFAP predict cognitive decline in a similar manner to traditional imaging techniques in amyloid-positive MCI patients. Hence, even though they are non-specific biomarkers of AD, both can be implemented in memory clinic workups as important prognostic biomarkers. Likewise, future clinical trials might employ plasma biomarkers as additional inclusion criteria to stratify patients at higher risk of cognitive decline to reduce sample sizes and enhance effectiveness.

New insights into the effects of type and timing of childhood maltreatment on brain morphometry.

Childhood maltreatment (CM) is known to influence brain development. To obtain a better understanding of related brain alterations, recent research has focused on the influence of the type and timing of CM. We aimed to investigate the association between type and timing of CM and local brain volume. Anatomical magnetic resonance images were collected from 93 participants (79 female/14 male) with a history of CM. CM history was assessed with the German Interview Version of the "Maltreatment and Abuse Chronology of Exposure" scale, "KERF-40 + ". Random forest regressions were performed to assess the impact of CM characteristics on the volume of amygdala, hippocampus and anterior cingulate cortex (ACC). The volume of the left ACC was predicted by neglect at age 3 and 4 and abuse at age 16 in a model including both type and timing of CM. For the right ACC, overall CM severity and duration had the greatest impact on volumetric alterations. Our data point to an influence of CM timing on left ACC volume, which was most pronounced in early childhood and in adolescence. We were not able to replicate previously reported effects of maltreatment type and timing on amygdala and hippocampal volume.

Longitudinal alcohol-related brain changes in older adults: The Sydney Memory and Ageing Study.

Increases in harmful drinking among older adults indicate the need for a more thorough understanding of the relationship between later-life alcohol use and brain health. The current study investigated the relationships between alcohol use and progressive grey and white matter changes in older adults using longitudinal data. A total of 530 participants (aged 70 to 90 years; 46.0% male) were included. Brain outcomes assessed over 6 years included total grey and white matter volume, as well as volume of the hippocampus, thalamus, amygdala, corpus callosum, orbitofrontal cortex and insula. White matter integrity was also investigated. Average alcohol use across the study period was the main exposure of interest. Past-year binge drinking and reduction in drinking from pre-baseline were additional exposures of interest. Within the context of low-level average drinking (averaging 11.7 g per day), higher average amount of alcohol consumed was associated with less atrophy in the left (B = 7.50, pFDR = 0.010) and right (B = 5.98, pFDR = 0.004) thalamus. Past-year binge-drinking was associated with poorer white matter integrity (B = -0.013, pFDR = 0.024). Consuming alcohol more heavily in the past was associated with greater atrophy in anterior (B = -12.73, pFDR = 0.048) and posterior (B = -17.88, pFDR = 0.004) callosal volumes over time. Across alcohol exposures and neuroimaging markers, no other relationships were statistically significant. Within the context of low-level drinking, very few relationships between alcohol use and brain macrostructure were identified. Meanwhile, heavier drinking was negatively associated with white matter integrity.

TDP-43 Is Associated with Subiculum and Cornu Ammonis 1 Hippocampal Subfield Atrophy in Primary Age-Related Tauopathy.

Background: TAR DNA binding protein 43 (TDP-43) has been shown to be associated with whole hippocampal atrophy in primary age-related tauopathy (PART). It is currently unknown which subregions of the hippocampus are contributing to TDP-43 associated whole hippocampal atrophy in PART. Objective: To identify which specific hippocampal subfield regions are contributing to TDP-43-associated whole hippocampal atrophy in PART. Methods: A total of 115 autopsied cases from the Mayo Clinic Alzheimer Disease Research Center, Neurodegenerative Research Group, and the Mayo Clinic Study of Aging were analyzed. All cases underwent antemortem brain volumetric MRI, neuropathological assessment of the distribution of Aß (Thal phase), and neurofibrillary tangle (Braak stage) to diagnose PART, as well as assessment of TDP-43 presence/absence in the amygdala, hippocampus and beyond. Hippocampal subfield segmentation was performed using FreeSurfer version 7.4.1. Statistical analyses using logistic regression were performed to assess for associations between TDP-43 and hippocampal subfield volumes, accounting for potential confounders. Results: TDP-43 positive patients (n = 37, 32%), of which 15/15 were type-α, had significantly smaller whole hippocampal volumes, and smaller volumes of the body and tail of the hippocampus compared to TDP-43 negative patients. Subfield analyses revealed an association between TDP-43 and the molecular layer of hippocampal body and the body of cornu ammonis 1 (CA1), subiculum, and presubiculum regions. There was no association between TDP-43 stage and subfield volumes. Conclusions: Whole hippocampal volume loss linked to TDP-43 in PART is mainly due to volume loss occurring in the molecular layer, CA1, subiculum and presubiculum of the hippocampal body.

Investigating the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism in participants with major depressive disorder.

Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal (HPA) axis. To examine this in humans, hippocampal volume and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and hypothalamus metabolism changes in response to treatment.

Differential Vulnerability of Hippocampal Subfields to Amyloid and Tau Deposition in the Lewy Body Diseases.

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) copathologies of ß-amyloid and tau are common in the Lewy body diseases (LBD), dementia with Lewy bodies (DLB) and Parkinson disease (PD), and target distinct hippocampal subfields compared with Lewy pathology, including subiculum and CA1. We investigated the hypothesis that AD copathologies impact the pattern of hippocampal subregion volume loss and cognitive function in LBD. METHODS: This was a cross-sectional and longitudinal, single-center, observational cohort study. Participants underwent neuropsychological testing and 3T-MRI with hippocampal segmentation using FreeSurferV7. PiB-PET and flortaucipir-PET imaging of comorbid ß-amyloid (A) and tau (T) were acquired. The association of functional cognition, ß-amyloid, and tau loads with hippocampal subregion volume was assessed. The contribution of subregion volumes to the relationship of AD-related deposits on functional cognition was examined with mediation analysis. The effects of AD-related deposits on the rate of subregion atrophy were evaluated with mixed-effects models. RESULTS: Of 103 participants (mean age: 70.3 years; 37.3% female), 52 had LBD with impaired cognition (LBD-I), 26 had normal cognition (LBD-N), and 25 were A- healthy controls (HCs). Volumes of hippocampal subregions prone to AD copathologies, including subiculum (F = 6.9, p = 0.002), presubiculum (F = 7.3, p = 0.001), and parasubiculum (F = 5.9, p = 0.004), were reduced in LBD-I compared with LBD-N and HC. Volume was preserved in CA2/3, Lewy pathology susceptible subregions. In LBD-I, reduced CA1, subiculum, and presubiculum volumes were associated with greater functional cognitive impairment (all p < 0.05). Compared with HC, subiculum volume was reduced in A+T+ but not A-T- participants (F = 2.62, p = 0.043). Reduced subiculum volume mediated the effect of amyloid on functional cognition (0.12, 95% CI: 0.005 to 0.26, p = 0.040). In 26 longitudinally-evaluated participants, baseline tau deposition was associated with faster CA1 (p = 0.021) and subiculum (p = 0.002) atrophy. DISCUSSION: In LBD, volume loss in hippocampal output subregions-particularly the subiculum-is associated with functional cognition and AD-related deposits. Tau deposition appears to accelerate subiculum and CA1 atrophy, whereas Aß does not. Subiculum volume may have value as a biomarker of AD copathology-mediated neurodegeneration and disease progression.

The hippocampus and implicit memory.

The traditional memory-systems view is that explicit (conscious) long-term memory is associated with the hippocampus and implicit (nonconscious) memory is associated with non-hippocampal brain regions. This special issue of Cognitive Neuroscience focuses on whether the hippocampus is associated with implicit memory. An empirical fMRI paper by Miller, Kennard, Gowland, Antoniades, and Rosenthal (this issue) evaluated recognition memory performance of autobiographical amnesia patients with bilateral damage to hippocampal sub-region CA3 and found they had greater than chance recognition memory performance for spatial sequence learning, spatial item learning-same location, and non-spatial item learning, but chance performance for non-spatial sequence learning and spatial item learning-different location. These results are at odds with the view that the hippocampus is generally involved in sequence learning and complex event recognition. A discussion paper by Steinkrauss and Slotnick (this issue) considered whether fMRI studies have provided evidence that the hippocampus is associated with implicit memory. It was argued that all previous studies have been confounded by explicit memory, attentional states, stimuli, or novelty. This discussion paper is followed by commentaries from Hannula (this issue), Henke and Ruch (this issue), Rosenthal (this issue), Spaak (this issue), Thakral et al. (this issue), and Züst (this issue). The articles in this special issue illustrate that the association between the hippocampus and implicit memory is under active investigation and debate. It is hoped that the evidence and discourse in this issue will provide directions for future research.

Interactions between physical exercise, associative memory, and genetic risk for Alzheimer's disease.

The ε4 allele of the APOE gene heightens the risk of late onset Alzheimer's disease. ε4 carriers, may exhibit cognitive and neural changes early on. Given the known memory-enhancing effects of physical exercise, particularly through hippocampal plasticity via endocannabinoid signaling, here we aimed to test whether a single session of physical exercise may benefit memory and underlying neurophysiological processes in young ε3 carriers (ε3/ε4 heterozygotes, risk group) compared with a matched control group (homozygotes for ε3). Participants underwent fMRI while learning picture sequences, followed by cycling or rest before a memory test. Blood samples measured endocannabinoid levels. At the behavioral level, the risk group exhibited poorer associative memory performance, regardless of the exercising condition. At the brain level, the risk group showed increased medial temporal lobe activity during memory retrieval irrespective of exercise (suggesting neural compensatory effects even at baseline), whereas, in the control group, such increase was only detectable after physical exercise. Critically, an exercise-related endocannabinoid increase correlated with task-related hippocampal activation in the control group only. In conclusion, healthy young individuals carrying the ε4 allele may present suboptimal associative memory performance (when compared with homozygote ε3 carriers), together with reduced plasticity (and functional over-compensation) within medial temporal structures.

The hippocampus supports the representation of abstract concepts: Implications for the study of recognition memory.

Words, unlike images, are symbolic representations. The associative details inherent within a word's meaning and the visual imagery it generates, are inextricably connected to the way words are processed and represented. It is well recognised that the hippocampus associatively binds components of a memory to form a lasting representation, and here we show that the hippocampus is especially sensitive to abstract word processing. Using fMRI during recognition, we found that the increased abstractness of words produced increased hippocampal activation regardless of memory outcome. Interestingly, word recollection produced hippocampal activation regardless of word content, while the parahippocampal cortex was sensitive to concreteness of word representations, regardless of memory outcome. We reason that the hippocampus has assumed a critical role in the representation of uncontextualized abstract word meaning, as its information-binding ability allows the retrieval of the semantic and visual associates that, when bound together, generate the abstract concept represented by word symbols. These insights have implications for research on word representation, memory, and hippocampal function, perhaps shedding light on how the human brain has adapted to encode and represent abstract concepts.

Forming cognitive maps for abstract spaces: the roles of the human hippocampus and orbitofrontal cortex.

How does the human brain construct cognitive maps for decision-making and inference? Here, we conduct an fMRI study on a navigation task in multidimensional abstract spaces. Using a deep neural network model, we assess learning levels and categorized paths into exploration and exploitation stages. Univariate analyses show higher activation in the bilateral hippocampus and lateral prefrontal cortex during exploration, positively associated with learning level and response accuracy. Conversely, the bilateral orbitofrontal cortex (OFC) and retrosplenial cortex show higher activation during exploitation, negatively associated with learning level and response accuracy. Representational similarity analysis show that the hippocampus, entorhinal cortex, and OFC more accurately represent destinations in exploitation than exploration stages. These findings highlight the collaboration between the medial temporal lobe and prefrontal cortex in learning abstract space structures. The hippocampus may be involved in spatial memory formation and representation, while the OFC integrates sensory information for decision-making in multidimensional abstract spaces.

Subclinical epileptiform discharges in Alzheimer's disease are associated with increased hippocampal blood flow.

BACKGROUND: In epilepsy, the ictal phase leads to cerebral hyperperfusion while hypoperfusion is present in the interictal phases. Patients with Alzheimer's disease (AD) have an increased prevalence of epileptiform discharges and a study using intracranial electrodes have shown that these are very frequent in the hippocampus. However, it is not known whether there is an association between hippocampal hyperexcitability and regional cerebral blood flow (rCBF). The objective of the study was to investigate the association between rCBF in hippocampus and epileptiform discharges as measured with ear-EEG in patients with Alzheimer's disease. Our hypothesis was that increased spike frequency may be associated with increased rCBF in hippocampus. METHODS: A total of 24 patients with AD, and 15 HC were included in the analysis. Using linear regression, we investigated the association between rCBF as measured with arterial spin-labelling MRI (ASL-MRI) in the hippocampus and the number of spikes/sharp waves per 24 h as assessed by ear-EEG. RESULTS: No significant difference in hippocampal rCBF was found between AD and HC (p-value = 0.367). A significant linear association between spike frequency and normalized rCBF in the hippocampus was found for patients with AD (estimate: 0.109, t-value = 4.03, p-value < 0.001). Changes in areas that typically show group differences (temporal-parietal cortex) were found in patients with AD, compared to HC. CONCLUSIONS: Increased spike frequency was accompanied by a hemodynamic response of increased blood flow in the hippocampus in patients with AD. This phenomenon has also been shown in patients with epilepsy and supports the hypothesis of hyperexcitability in patients with AD. The lack of a significant difference in hippocampal rCBF may be due to an increased frequency of epileptiform discharges in patients with AD. TRIAL REGISTRATION: The study is registered at clinicaltrials.gov (NCT04436341).

Less is more: Smaller hippocampal subfield volumes predict greater improvements in posttraumatic stress disorder symptoms over 2 years.

Posttraumatic stress disorder (PTSD) is a heterogeneous disorder, and symptom severity varies over time. Neurobiological factors that predict PTSD symptoms and their chronicity remain unclear. This study investigated whether the volume of the hippocampus and its subfields, particularly cornu ammonis (CA) 1, CA3, and dentate gyrus, are associated with current PTSD symptoms and whether they predict PTSD symptom changes over 2 years. We examined clinical and structural magnetic resonance imaging measures from 252 trauma-exposed post-9/11 veterans (159 with Time 1 PTSD diagnosis) during assessments approximately 2 years apart. Automated hippocampal subfield segmentation was performed with FreeSurfer Version 7.1, producing 19 bilateral subfields. PTSD symptoms were measured at each assessment using the Clinician-Administered PTSD Scale-IV (CAPS). All models included total intracranial volume as a covariate. First, similar to previous reports, we showed that smaller overall hippocampal volume was associated with greater PTSD symptom severity at Time 1. Notably, when examining regions of interest (CA1, CA3, dentate gyrus), we found that smaller Time 1 hippocampal volumes in the bilateral CA1-body and CA2/3-body predicted decreased PTSD symptom severity at Time 2. These findings were not accounted for by combat exposure or treatment history. Additionally, both Time 1 CA1-body and CA2/3-body volume showed unique associations with changes in avoidance/numbing, but not with changes in reexperiencing or hyperarousal symptoms. This supports a more complex and nuanced relationship between hippocampal structure and PTSD symptoms, where during the posttrauma years bigger may not always mean better, and suggests that the CA1-body and CA2/3-body are important factors in the maintenance of PTSD symptoms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Changes in responses of the amygdala and hippocampus during fear conditioning are associated with persecutory beliefs.

The persecutory delusion is the most common symptom of psychosis, yet its underlying neurobiological mechanisms are poorly understood. Prior studies have suggested that abnormalities in medial temporal lobe-dependent associative learning may contribute to this symptom. In the current study, this hypothesis was tested in a non-clinical sample of young adults without histories of psychiatric treatment (n = 64), who underwent classical Pavlovian fear conditioning while fMRI data were collected. During the fear conditioning procedure, participants viewed images of faces which were paired (the CS+) or not paired (the CS-) with an aversive stimulus (a mild electrical shock). Fear conditioning-related neural responses were measured in two medial temporal lobe regions, the amygdala and hippocampus, and in other closely connected brain regions of the salience and default networks. The participants without persecutory beliefs (n = 43) showed greater responses to the CS- compared to the CS+ in the right amygdala and hippocampus, while the participants with persecutory beliefs (n = 21) failed to exhibit this response. These between-group differences were not accounted for by symptoms of depression, anxiety or a psychosis risk syndrome. However, the severity of subclinical psychotic symptoms overall was correlated with the level of this aberrant response in the amygdala (p = .013) and hippocampus (p = .033). Thus, these findings provide evidence for a disruption of medial temporal lobe-dependent associative learning in young people with subclinical psychotic symptoms, specifically persecutory thinking.

The association between gray matter volume in the hippocampal subfield and antidepressant efficacy mediated by abnormal dynamic functional connectivity.

An abnormality of structures and functions in the hippocampus may have a key role in the pathophysiology of major depressive disorder (MDD). However, it is unclear whether structure factors of the hippocampus effectively impact antidepressant responses by hippocampal functional activity in MDD patients. We collected longitudinal data from 36 MDD patients before and after a 3-month course of antidepressant pharmacotherapy. Additionally, we obtained baseline data from 43 healthy controls matched for sex and age. Using resting-state functional magnetic resonance imaging (rs-fMRI), we estimated the dynamic functional connectivity (dFC) of the hippocampal subregions using a sliding-window method. The gray matter volume was calculated using voxel-based morphometry (VBM). The results indicated that patients with MDD exhibited significantly lower dFC of the left rostral hippocampus (rHipp.L) with the right precentral gyrus, left superior temporal gyrus and left postcentral gyrus compared to healthy controls at baseline. In MDD patients, the dFC of the rHipp.L with right precentral gyrus at baseline was correlated with both the rHipp.L volume and HAMD remission rate, and also mediated the effects of the rHipp.L volume on antidepressant performance. Our findings suggested that the interaction between hippocampal structure and functional activity might affect antidepressant performance, which provided a novel insight into the hippocampus-related neurobiological mechanism of MDD.

Combining neuropsychological assessment and structural neuroimaging to identify early Alzheimer's disease in a memory clinic cohort.

INTRODUCTION: The current study examined the contributions of comprehensive neuropsychological assessment and volumetric assessment of selected mesial temporal subregions on structural magnetic resonance imaging (MRI) to identify patients with amnestic mild cognitive impairment (aMCI) and mild probable Alzheimer's disease (AD) dementia in a memory clinic cohort. METHODS: Comprehensive neuropsychological assessment and automated entorhinal, transentorhinal, and hippocampal volume measurements were conducted in 40 healthy controls, 38 patients with subjective memory symptoms, 16 patients with aMCI, 16 patients with mild probable AD dementia. Multinomial logistic regression was used to compare the neuropsychological and MRI measures. RESULTS: Combining the neuropsychological and MRI measures improved group membership prediction over the MRI measures alone but did not improve group membership prediction over the neuropsychological measures alone. CONCLUSION: Comprehensive neuropsychological assessment was an important tool to evaluate cognitive impairment. The mesial temporal volumetric MRI measures contributed no diagnostic value over and above the determinations made through neuropsychological assessment.