Differences In Hippocampal Volume Research Articles

Hippocampal subfields in remitted schizophrenia.

Current evidence of volume changes in hippocampal subdivisions in schizophrenia remains inconsistent, and few studies have investigated the relationship between regional hippocampal volumes and symptom remission. In this cross-sectional study, we recruited 31 patients with schizophrenia and 31 healthy controls (HCs). Symptomatic remission in schizophrenia was determined according to Remission in Schizophrenia Working Group criteria. The volumes of hippocampal longitudinal subregions and transverse subfields were measured using manual and automatic techniques, respectively. Between-group regional hippocampal volume differences were analyzed using multivariate analysis of covariance followed by univariate analysis of covariance. Compared with the HCs, the patients with schizophrenia had smaller bilateral heads and tails along the longitudinal axis; they also had reduced volumes of the bilateral CA1, CA3, CA4, GC-ML-DG, molecular layer, tail, left subiculum, left HATA, and right parasubiculum along the transverse axis in the hippocampus (all corrected p < 0.05). Furthermore, compared with the HCs and patients with remitted schizophrenia, the patients with non-remitted schizophrenia had smaller bilateral hippocampal tail subfields (corrected p < 0.05). Our results indicated that the pathophysiology and symptomatic remission of schizophrenia are related to changes in the volumes of hippocampal subdivisions. These volume changes might be clinically relevant as biomarkers for schizophrenia identification and treatment.

Memory impairment in Amyloidβ-status Alzheimer's disease is associated with a reduction in CA1 and dentate gyrus volume: In vivo MRI at 7T

IntroductionIn Alzheimer's disease (AD), early diagnosis facilitates treatment options and leads to beneficial outcomes for patients, their carers and the healthcare system. The neuropsychological battery of the Uniform Data Set (UDSNB3.0) assesses cognition in ageing and dementia, by measuring scores across different cognitive domains such as attention, memory, processing speed, executive function and language. However, its neuroanatomical correlates have not been investigated using 7 Tesla MRI (7T MRI). MethodsWe used 7T MRI to investigate the correlations between hippocampal subfield volumes and the UDSNB3.0 in 24 individuals with Amyloidβ-status AD and 18 age-matched controls, with respective age ranges of 60 (42–76) and 62 (52–79) years. AD participants with a Medial Temporal Atrophy scale of higher than 2 on 3T MRI were excluded from the study. ResultsA significant difference in the entire hippocampal volume was observed in the AD group compared to healthy controls (HC), primarily influenced by CA1, the largest hippocampal subfield. Notably, no significant difference in whole brain volume between the groups implied that hippocampal volume loss was not merely reflective of overall brain atrophy. UDSNB3.0 cognitive scores showed significant differences between AD and HC, particularly in Memory, Language, and Visuospatial domains. The volume of the Dentate Gyrus (DG) showed a significant association with the Memory and Executive domain scores in AD patients as assessed by the UDSNB3.0.. The data also suggested a non-significant trend for CA1 volume associated with UDSNB3.0 Memory, Executive, and Language domain scores in AD. In a reassessment focusing on hippocampal subfields and MoCA memory subdomains in AD, associations were observed between the DG and Cued, Uncued, and Recognition Memory subscores, whereas CA1 and Tail showed associations only with Cued memory. DiscussionThis study reveals differences in the hippocampal volumes measured using 7T MRI, between individuals with early symptomatic AD compared with healthy controls. This highlights the potential of 7T MRI as a valuable tool for early AD diagnosis and the real-time monitoring of AD progression and treatment efficacy. ClinicalTrials.govID NCT04992975 (Clinicaltrial.gov 2023)

Parkinson's disease CA2-CA3 hippocampal atrophy is accompanied by increased cholinergic innervation in patients with normal cognition but not in patients with mild cognitive impairment.

Although brain cholinergic denervation has been largely associated with cognitive decline in patients with Parkinson's disease (PD), new evidence suggests that cholinergic upregulation occurs in the hippocampus of PD patients without cognitive deficits. The specific hippocampal sectors and potential mechanisms of this cholinergic compensatory process have been further studied here, using MRI volumetry and morphometry coupled with molecular imaging using the PET radiotracer [18F]-Fluoroethoxybenzovesamicol ([18F]-FEOBV). Following a thorough screening procedure, 18 participants were selected and evenly distributed in three groups, including cognitively normal PD patients (PD-CN), PD patients with mild cognitive impairment (PD-MCI), and healthy volunteers (HV). Participants underwent a detailed neuropsychological assessment, structural MRI, and PET imaging with [18F]-FEOBV. Basal forebrain Ch1-Ch2 volumes were measured using stereotaxic mapping. Hippocampal subfields were automatically defined using the MAGeT-Brain segmentation algorithm. Cholinergic innervation density was quantified using [18F]-FEOBV uptake. Compared with HV, both PD-CN and PD-MCI displayed significantly reduced volumes in CA2-CA3 bilaterally. We found no other hippocampal subfield nor Ch1-Ch2 volume differences between the three groups. PET imaging revealed higher [18F]-FEOBV uptake in CA2-CA3 of the PD-CN compared with HV or PD-MCI. A positive correlation was observed between cognitive performances and [18F]-FEOBV uptake in the right CA2-CA3 subfield. Reduced volume, together with increased [18F]-FEOBV uptake, were observed specifically in the CA2-CA3 hippocampal subfields. However, while the volume change was observed in both PD-CN and PD-MCI, increased [18F]-FEOBV uptake was present only in the PD-CN group. This suggests that a cholinergic compensatory process takes place in the atrophied CA2-CA3 hippocampal subfields and might underlie normal cognition in PD.

Longitudinal changes in brain-derived neurotrophic factor (BDNF) but not cytokines contribute to hippocampal recovery in anorexia nervosa above increases in body mass index.

Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity. Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable. Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI). These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.

Is vestibular function related to human hippocampal volume?

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

Investigating the synergistic effects of hormone replacement therapy, apolipoprotein E and age on brain health in the UK Biobank.

Global prevalence of Alzheimer's Disease has a strong sex bias, with women representing approximately two-thirds of the patients. Yet, the role of sex-specific risk factors during midlife, including hormone replacement therapy (HRT) and their interaction with other major risk factors for Alzheimer's Disease, such as apolipoprotein E (APOE)-e4 genotype and age, on brain health remains unclear. We investigated the relationship between HRT (i.e., use, age of initiation and duration of use) and brain health (i.e., cognition and regional brain volumes). We then consider the multiplicative effects of HRT and APOE status (i.e., e2/e2, e2/e3, e3/e3, e3/e4 and e4/e4) via a two-way interaction and subsequently age of participants via a three-way interaction. Women from the UK Biobank with no self-reported neurological conditions were included (N = 207,595 women, mean age = 56.25 years, standard deviation = 8.01 years). Generalised linear regression models were computed to quantify the cross-sectional association between HRT and brain health, while controlling for APOE status, age, time since attending centre for completing brain health measure, surgical menopause status, smoking history, body mass index, education, physical activity, alcohol use, ethnicity, socioeconomic status, vascular/heart problems and diabetes diagnosed by doctor. Analyses of structural brain regions further controlled for scanner site. All brain volumes were normalised for head size. Two-way interactions between HRT and APOE status were modelled, in addition to three-way interactions including age. Results showed that women with the e4/e4 genotype who have used HRT had 1.82% lower hippocampal, 2.4% lower parahippocampal and 1.24% lower thalamus volumes than those with the e3/e3 genotype who had never used HRT. However, this interaction was not detected for measures of cognition.No clinically meaningful three-way interaction between APOE, HRT and age was detected when interpreted relative to the scales of the cognitive measures used and normative models of ageing for brain volumes in this sample. Differences in hippocampal volume between women with the e4/e4 genotype who have used HRT and those with the e3/e3 genotype who had never used HRT are equivalent to approximately 1-2 years of hippocampal atrophy observed in typical health ageing trajectories in midlife (i.e., 0.98%-1.41% per year). Effect sizes were consistent within APOE e4/e4 group post hoc sensitivity analyses, suggesting observed effects were not solely driven by APOE status and may, in part, be attributed to HRT use. Although, the design of this study means we cannot exclude the possibility that women who have used HRT may have a predisposition for poorer brain health.

Neurite density of the hippocampus is associated with trace eyeblink conditioning latency in 4- to 6-year-olds.

Limited options exist to evaluate the development of hippocampal function in young children. Research has established that trace eyeblink conditioning (EBC) relies on a functional hippocampus. Hence, we set out to investigate whether trace EBC is linked to hippocampal structure, potentially serving as a valuable indicator of hippocampal development. Our study explored potential associations between individual differences in hippocampal volume and neurite density with trace EBC performance in young children. We used onset latency of conditioned responses (CR) and percentage of conditioned responses (% CR) as measures of hippocampal-dependent associative learning. Using a sample of typically developing children aged 4 to 6years (N = 30; 14 girls; M = 5.70years), participants underwent T1- and diffusion-weighted MRI scans and completed a 15-min trace eyeblink conditioning task conducted outside the MRI. % CR and CR onset latency were calculated based on all trials involving tone-puff presentations and tone-alone trials. Findings revealed a connection between greater left hippocampal neurite density and delayed CR onset latency. Children with higher neurite density in the left hippocampus tended to blink closer to the onset of the unconditioned stimulus, indicating that structural variations in the hippocampus were associated with more precise timing of conditioned responses. No other relationships were observed between hippocampal volume, cerebellum volume or neurite density, hippocampal white matter connectivity and any EBC measures. Preliminary results suggest that trace EBC may serve as a straightforward yet innovative approach for studying hippocampal development in young children and populations with atypical development.

Proof-of-concept recall-by-genotype study of extremely low and high Alzheimer’s polygenic risk reveals autobiographical deficits and cingulate cortex correlates

BackgroundGenome-wide association studies demonstrate that Alzheimer’s disease (AD) has a highly polygenic architecture, where thousands of independent genetic variants explain risk with high classification accuracy. This AD polygenic risk score (AD-PRS) has been previously linked to preclinical cognitive and neuroimaging features observed in asymptomatic individuals. However, shared variance between AD-PRS and neurocognitive features are small, suggesting limited preclinical utility.MethodsHere, we recruited sixteen clinically asymptomatic individuals (mean age 67; range 58–76) with either extremely low / high AD-PRS (defined as at least 2 standard deviations from the wider sample mean (N = 4504; NEFFECTIVE = 90)) with comparable age sex and education level. We assessed group differences in autobiographical memory and T1-weighted structural neuroimaging features.ResultsWe observed marked reductions in autobiographical recollection (Cohen’s d = − 1.66; PFDR = 0.014) and midline structure (cingulate) thickness (Cohen’s d = − 1.55, PFDR = 0.05), with no difference in hippocampal volume (P > 0.3). We further confirm the negative association between AD-PRS and cingulate thickness in a larger study with a comparable age (N = 31,966, β = − 0.002, P = 0.011), supporting the validity of our approach.ConclusionsThese observations conform with multiple streams of prior evidence suggesting alterations in cingulate structures may occur in individuals with higher AD genetic risk. We were able to use a genetically informed research design strategy that significantly improved the efficiency and power of the study. Thus, we further demonstrate that the recall-by-genotype of AD-PRS from wider samples is a promising approach for the detection, assessment, and intervention in specific individuals with increased AD genetic risk.

Hippocampal Enlargement and White Matter Hyperintensities in Obstructive Sleep Apnea Patients

AbstractBackgroundObstructive sleep apnea (OSA), which results from recurrent collapses of the upper airway system, affects around 27% of the geriatric population with mild cognitive impairment (MCI) and causes intermittent hypoxia and sleep fragmentation (Mubashir et al., 2019). Prior research suggests that OSA results in brain ischemic preconditioning, causing hippocampal enlargement due to adaptive hippocampal neurogenesis (Rosenzweig et al., 2013). OSA has also been linked to increased white matter hyperintensities (WMHs) through hypoxic‐ ischemic injury, which contribute to cognitive decline in dementias such as Alzheimer’s disease (Zacharias et al., 2021). Previous research necessitates studying the effects of apnea in an elderly population with MCI.MethodIn the Memories2 study, subjects aged 55‐85 underwent a polysomnography and were assigned to the no OSA (OSA‐) group if their apnea‐hypopnea index (AHI) was &lt;5 events/hour or to the OSA (OSA+) group if their AHI was ≥15. Amnestic MCI status was determined with a neuropsychological battery using standard criteria. The subjects received an optional MRI, in which hippocampal and WMH volumetry were derived from a T1‐weighted structural scan and a whole‐brain fluid‐attenuated inversion recovery (FLAIR) scan, respectively. Statistical analyses (two‐sample t‐tests and Wilcoxon‐Mann‐Whitney test) were performed to understand group differences in hippocampal volume and WMH at baseline. Hippocampal volume data (N = 131) was obtained for 67 OSA+ and 64 OSA‐ subjects. WMH data (N = 129) was obtained for 66 OSA+ and 63 OSA‐ subjects.ResultOSA+ subjects had significantly greater right hippocampal volume (p = 0.0374) and left hippocampal volume (0.0336) than the OSA‐ subjects. OSA+ subjects also had higher levels of white matter hyperintensities as compared to the OSA‐ subjects (p = 0.0340) (Table 1).ConclusionIncreased WMH burden is suggestive of hypoxic‐ischemic injury and supports the hypothesis that hippocampal enlargement may be a response to intermittent hypoxia in OSA. These findings reveal the need for early evaluation for sleep apnea. The future direction of this work includes analyzing the group differences adjusting for covariates, detecting and verifying outliers, and rerunning analyses with the complete baseline data. Future data from the Memories2 study will examine the effects of OSA treatment in MCI patients using continuous positive airway pressure (CPAP).

Functional and structural changes of cholinergic basal forebrain in asymptomatic PSEN1 E280A mutation carriers compared with non‐mutation carriers from the API ADAD Colombia cohort

AbstractBackgroundImaging studies showed early atrophy of the cholinergic basal forebrain in prodromal sporadic Alzheimer’s disease (AD) and alterations of the posterior basal forebrain functional connectivity in amyloid positive, but cognitively normal people. Similar investigations in familial cases of AD are still lacking. Here we investigated whether basal forebrain volume, metabolism, and posterior connectivity were already reduced in preclinical stages of autosomal dominant AD.MethodWe analyzed baseline data from 242 cognitively unimpaired subjects (69% PSEN1 E280A mutation carriers; mean age = 38 years; 62% female; mean education = 9 years) enrolled in the API ADAD Colombia Trial including available MRI, FDG‐PET and cognitive measures. We determined volume and metabolism of the basal forebrain, and of the hippocampus as a comparison region. In addition, we created connectivity maps from resting state fMRI data using anterior and posterior BF seed regions. We carried out Bayesian ANCOVA to determine evidence in favor or against an effect of carriers’ status on volumes, metabolism, functional connectivity and cognitive scores.ResultWe found inconclusive to moderate evidence in favor of no effect of carrier status on basal forebrain (BF10 = 0.884) and hippocampal volumes (BF10 = 0.964) or metabolism (BF10 = 0.187) (see Figure) in preclinical (CDR = 0) and prodromal (CDR = 0.5) subjects. However, we found extreme evidence that delayed memory was decreased already in preclinical mutation carriers (BF10 = 4066.73). Yet, we found no conclusive evidence that this subtle memory impairment was associated with basal forebrain (BF10 = 0.582) or hippocampal (BF10 = 0.906) atrophy.ConclusionOur findings indicate absence of basal forebrain and hippocampus atrophy or metabolic impairment in preclinical mutation carriers. Interestingly, memory impairment was already present in preclinical mutation carriers. This is consistent with results of the Dominantly Inherited Alzheimer Network (DIAN) cohort showing early cognitive impairment in mutation carriers, but no significant group differences in hippocampal volume until later stages of the disease. These previous and our findings may suggest that different brain regions and networks are affected in preclinical stages of familial AD than in preclinical sporadic AD, which should be investigated in future studies.

Age-related differences in hippocampal subfield volumes across the human lifespan: A meta-analysis.

The human hippocampus (Hc) is critical for memory function across the lifespan. It is comprised of cytoarchitectonically distinct subfields: dentate gyrus (DG), cornu ammonis sectors (CA) 1-4, and subiculum, each of which may be differentially susceptible to neurodevelopmental and neurodegenerative mechanisms. Identifying age-related differences in Hc subfield volumes can provide insights into neural mechanisms of memory function across the lifespan. Limited evidence suggests that DG and CA3 volumes differ across development while other regions remain relatively stable, and studies of adulthood implicate a downward trend in all subfield volumes with prominent age effects on CA1. Due to differences in methods and limited sampling for any single study, the magnitude of age effects on Hc subfield volumes and their probable lifespan trajectories remain unclear. Here, we conducted a meta-analysis on cross-sectional studies (n = 48,278 participants, ages = 4-94 years) to examine the association between age and Hc subfield volumes in development (n = 11 studies), adulthood (n = 30 studies), and a combined lifespan sample (n = 41 studies) while adjusting estimates for sample sizes. In development, age was positively associated with DG and CA3-4 volumes, whereas in adulthood a negative association was observed with all subfield volumes. Notably, the observed age effects were not different across subfield volumes within each age group. All subfield volumes showed a nonlinear age pattern across the lifespan with DG and CA3-4 volumes showing a more distinct age trajectory as compared to the other subfields. Lastly, among all the study-level variables, only female percentage of the study sample moderated the age effect on CA1 volume: a higher female-to-male ratio in the study sample was linked to thegreater negative association between age and CA1 volume. These results document that Hc subfield volumes differ as a function of age offering broader implications for constructing theoretical models of lifespan memory development.

Trait anxiety mediates the association between hippocampal–insula functional connectivity and anxiety symptom severity in adults with and without generalized anxiety disorder

BackgroundTrait anxiety is a vulnerability factor for the development of generalized anxiety disorder (GAD). The hippocampus has been implicated in trait anxiety in normal and GAD populations. However, the exact neural mechanism of hippocampal functional connectivity (FC) and its association with clinical symptoms and trait anxiety in GAD patients remains unknown. MethodsWe recruited 68 participants (37 drug-naïve non-comorbidity GAD patients and 31 matched healthy controls (HC)), assessed their trait and state anxiety, scanned them with structural and resting-state functional magnetic resonance imaging (fMRI), and compared their hippocampal FC and volumes. We explored the relationships between hippocampal FC, clinical symptoms, and trait anxiety using partial correlation analyses; we also investigated the mediating effects of trait anxiety on the association between hippocampal FC and GAD symptom severity. ResultsThe GAD group showed increased right hippocampal FC with left insula, which was positively correlated with the Self-Rating Anxiety Scale (SAS), State Anxiety Inventory (SAI), and Trait Anxiety Inventory (TAI). Trait anxiety mediated the relationship between hippocampal FC and anxiety levels. We found no significant difference in hippocampal volumes between GAD and HC. LimitationsThe sample size was moderate. The exclusion of comorbidity may reduce the generalizability of our results in normal clinical settings. ConclusionsThe GAD patients showed no structural change but had functional alterations in the hippocampus. More importantly, future psychotherapy for this disorder should consider that trait anxiety might play a crucial role in the altered hippocampal FC in GAD.

Hippocampal and amygdala volumes vary with residential proximity to toxicants at Birmingham, Alabama's 35th Avenue Superfund site.

Exposure to environmental toxicants have serious implications for the general health and well-being of children, particularly during pivotal neurodevelopmental stages. The Environmental Protection Agency's (EPA) Superfund program has identified several areas (Superfund sites) across the United States with high levels of environmental toxicants, which affect the health of many residents in nearby communities. Exposure to these environmental toxicants has been linked to changes in the structure and function of the brain. However, limited research has investigated the relationship between the proximity of childhood homes to a Superfund site and the development of subcortical structures like the hippocampus and amygdala. The present study investigated the hippocampal and amygdala volumes of young adults in relation to the proximity of their childhood homes to Birmingham, Alabama's 35th Avenue Superfund site. Forty participants who either lived within or adjacent to the Superfund site (Proximal group; n = 20) or who lived elsewhere in the greater Birmingham metropolitan area (Distal group; n = 20) were included in this study. Both groups were matched on age, sex, race, and years of education. Magnetic resonance imaging (MRI) was used to compare the gray matter volume of the hippocampus and amygdala between groups. Differences in bilateral hippocampal and left amygdala volumes were observed. Specifically, hippocampal and amygdala volumes were greater in the Proximal than Distal group. These findings suggest that the proximity of children's homes to environmental toxicants may impact the development of the hippocampus and amygdala. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Age-related differences in associative memory recognition of Chinese characters and hippocampal subfield volumes

Associative memory is a type of hippocampal-dependent episodic memory that declines with age. Studies have examined the neural substrates underlying associative memory and considered the hippocampus holistically; however, the association between associative memory decline and volumetric change in hippocampal subfields in the context of normal aging remains uncharacterized. Leveraging the distinct linguistic features of Chinese characters to evaluate distinct types of false recognition, we investigated age-related differences in associative recognition and hippocampal subfield volumes, as well as the relationship between behavioral performance and hippocampal morphometry in 25 younger adults and 32 older adults. The results showed an age-related associative memory deficit, which was exacerbated after a 30-min delay. Older adults showed higher susceptibility to false alarm errors with recombined and orthographically related foils compared to phonologically or semantically related ones. Moreover, we detected a disproportionately age-related, time-dependent increase in orthographic errors. Older adults exhibited smaller volumes in all hippocampal subfields when compared to younger adults, with a less pronounced effect observed in the CA2/3 subfield. Group-collapsed correlational analyses revealed associations between specific hippocampal subfields and associative memory but not item memory. Additionally, multi-subfield regions had prominent associations with delayed recognition. These findings underscore the significance of multiple hippocampal subfields in various hippocampal-dependent processes including associative memory, recollection-based retrieval, and pattern separation ability. Moreover, our observations of age-related difficulty in differentiating perceptually similar foils from targets provide a unique opportunity for examining the essential contribution of individual hippocampal subfields to the pattern separation process in mnemonic recognition.

Hippocampal morphology in Huntington's disease, implications for plasticity and pathogenesis: The IMAGE-HD study

While striatal changes in Huntington's Disease (HD) are well established, few studies have investigated changes in the hippocampus, a key neuronal hub. Using MRI scans obtained from the IMAGE-HD study, hippocampi were manually traced and then analysed with the Spherical Harmonic Point Distribution Method (SPHARM-PDM) in 36 individuals with presymptomatic-HD, 37 with early symptomatic-HD, and 36 healthy matched controls. There were no significant differences in overall hippocampal volume between groups. Interestingly we found decreased bilateral hippocampal volume in people with symptomatic-HD who took selective serotonin reuptake inhibitors compared to those who did not, despite no significant differences in anxiety, depressive symptoms, or motor incapacity between the two groups. In symptomatic-HD, there was also significant shape deflation in the right hippocampal head, showing the utility of using manual tracing and SPHARM-PDM to characterise subtle shape changes which may be missed by other methods. This study confirms previous findings of the lack of hippocampal volumetric differentiation in presymptomatic-HD and symptomatic-HD compared to controls. We also find novel shape and volume findings in those with symptomatic-HD, especially in relation to decreased hippocampal volume in those treated with SSRIs.

Longitudinal changes in hippocampal texture from healthy aging to Alzheimer's disease.

Early detection of Alzheimer's disease is essential to develop preventive treatment strategies. Detectible change in brain volume emerges relatively late in the pathogenic progression of disease, but microstructural changes caused by early neuropathology may cause subtle changes in the MR signal, quantifiable using texture analysis. Texture analysis quantifies spatial patterns in an image, such as smoothness, randomness and heterogeneity. We investigated whether the MRI texture of the hippocampus, an early site of Alzheimer's disease pathology, is sensitive to changes in brain microstructure before the onset of cognitive impairment. We also explored the longitudinal trajectories of hippocampal texture across the Alzheimer's continuum in relation to hippocampal volume and other biomarkers. Finally, we assessed the ability of texture to predict future cognitive decline, over and above hippocampal volume. Data were acquired from the Alzheimer's Disease Neuroimaging Initiative. Texture was calculated for bilateral hippocampi on 3T T1-weighted MRI scans. Two hundred and ninety-three texture features were reduced to five principal components that described 88% of total variance within cognitively unimpaired participants. We assessed cross-sectional differences in these texture components and hippocampal volume between four diagnostic groups: cognitively unimpaired amyloid-β- (n = 406); cognitively unimpaired amyloid-β+ (n = 213); mild cognitive impairment amyloid-β+ (n = 347); and Alzheimer's disease dementia amyloid-β+ (n = 202). To assess longitudinal texture change across the Alzheimer's continuum, we used a multivariate mixed-effects spline model to calculate a 'disease time' for all timepoints based on amyloid PET and cognitive scores. This was used as a scale on which to compare the trajectories of biomarkers, including volume and texture of the hippocampus. The trajectories were modelled in a subset of the data: cognitively unimpaired amyloid-β- (n = 345); cognitively unimpaired amyloid-β+ (n = 173); mild cognitive impairment amyloid-β+ (n = 301); and Alzheimer's disease dementia amyloid-β+ (n = 161). We identified a difference in texture component 4 at the earliest stage of Alzheimer's disease, between cognitively unimpaired amyloid-β- and cognitively unimpaired amyloid-β+ older adults (Cohen's d = 0.23, Padj = 0.014). Differences in additional texture components and hippocampal volume emerged later in the disease continuum alongside the onset of cognitive impairment (d = 0.30-1.22, Padj < 0.002). Longitudinal modelling of the texture trajectories revealed that, while most elements of texture developed over the course of the disease, noise reduced sensitivity for tracking individual textural change over time. Critically, however, texture provided additional information than was provided by volume alone to more accurately predict future cognitive change (d = 0.32-0.63, Padj < 0.0001). Our results support the use of texture as a measure of brain health, sensitive to Alzheimer's disease pathology, at a time when therapeutic intervention may be most effective.

Predictors of seizure outcomes of autoimmune encephalitis: A clinical and morphometric quantitative analysis study

ObjectiveAutoimmune encephalitis can be followed by treatment-resistant epilepsy. Understanding its predictors and mechanisms are crucial to future studies to improve autoimmune encephalitis outcomes. Our objective was to determine the clinical and imaging predictors of postencephalitic treatment-resistant epilepsy. MethodsWe performed a retrospective cohort study (2012–2017) of adults with autoimmune encephalitis, both antibody positive and seronegative but clinically definite or probable. We examined clinical and imaging (as defined by morphometric analysis) predictors of seizure freedom at long term follow-up. ResultsOf 37 subjects with adequate follow-up data (mean 4.3 yrs, SD 2.5), 21 (57 %) achieved seizure freedom after a mean time of 1 year (SD 2.3), and one third (13/37, 35 %) discontinued ASMs. Presence of mesial temporal hyperintensities on the initial MRI was the only independent predictor of ongoing seizures at last follow-up (OR 27.3, 95 %CI 2.48–299.5). Morphometric analysis of follow-up MRI scans (n = 20) did not reveal any statistically significant differences in hippocampal, opercular, and total brain volumes between patients with postencephalitic treatment-resistant epilepsy and those without. SignificancePostencephalitic treatment-resistant epilepsy is a common complication of autoimmune encephalitis and is more likely to occur in those with mesial temporal hyperintensities on acute MRI. Volume loss in the hippocampal, opercular, and overall brain on follow-up MRI does not predict postencephalitic treatment-resistant epilepsy, so additional factors beyond structural changes may account for its development.

Altered Sex Differences in Hippocampal Subfield Volumes in Schizophrenia.

The hippocampus is a heterogenous brain structure that differs between the sexes and has been implicated in the pathophysiology of psychiatric illnesses. Here, we explored sex and diagnostic group differences in hippocampal subfield volumes, in individuals with schizophrenia spectrum disorder (SZ), bipolar disorders (BD), and healthy controls (CTL). One thousand and five hundred and twenty-one participants underwent T1-weighted magnetic resonance imaging (SZ, n = 452, mean age 30.7 ± 9.2 [SD] years, males 59.1%; BD, n = 316, 33.7 ± 11.4, 41.5%; CTL, n = 753, 34.1 ± 9.1, 55.6%). Total hippocampal, subfield, and intracranial volumes were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple regression models were fitted to examine sex-by-diagnostic (sub)group interactions in volume. In SZ and BD, separately, associations between volumes and clinical as well as cognitive measures were examined between the sexes using regression models. Significant sex-by-group interactions were found for the total hippocampus, dentate gyrus, molecular layer, presubiculum, fimbria, hippocampal-amygdaloid transition area, and CA4, indicating a larger volumetric deficit in male patients relative to female patients when compared with same-sex CTL. Subgroup analyses revealed that this interaction was driven by males with schizophrenia. Effect sizes were overall small (partial η < 0.02). We found no significant sex differences in the associations between hippocampal volumes and clinical or cognitive measures in SZ and BD. Using a well-powered sample, our findings indicate that the pattern of morphological sex differences in hippocampal subfields is altered in individuals with schizophrenia relative to CTL, due to higher volumetric deficits in males.

Cross-sectional field study comparing hippocampal subfields in patients with post-traumatic stress disorder, major depressive disorder, post-traumatic stress disorder with comorbid major depressive disorder, and adjustment disorder using routine clinical data.

The hippocampus is a central brain structure involved in stress processing. Previous studies have linked stress-related mental disorders, such as post-traumatic stress disorder (PTSD) and major depressive disorder (MDD), with changes in hippocampus volume. As PTSD and MDD have similar symptoms, clinical diagnosis relies solely on patients reporting their cognitive and emotional experiences, leading to an interest in utilizing imaging-based data to improve accuracy. Our field study aimed to determine whether there are hippocampal subfield volume differences between stress-related mental disorders (PTSD, MDD, adjustment disorders, and AdjD) using routine clinical data from a military hospital. Participants comprised soldiers (N = 185) with PTSD (n = 50), MDD (n = 70), PTSD with comorbid MDD (n = 38), and AdjD (n = 27). The hippocampus was segmented and volumetrized into subfields automatically using FreeSurfer. We used ANCOVA models with estimated total intracranial volume as a covariate to determine whether there were volume differences in the hippocampal subfields cornu ammonis 1 (CA1), cornu ammonis 2/3 (CA2/3), and dentate gyrus (DG) among patients with PTSD, MDD, PTSD with comorbid MDD, and AdjD. Furthermore, we added self-reported symptom duration and previous psychopharmacological and psychotherapy treatment as further covariates to examine whether there were associations with CA1, CA2/3, and DG. No significant volume differences in hippocampal subfields between stress-related mental disorders were found. No significant associations were detected between symptom duration, psychopharmacological treatment, psychotherapy, and the hippocampal subfields. Hippocampal subfields may distinguish stress-related mental disorders; however, we did not observe any subfield differences. We provide several explanations for the non-results and thereby inform future field studies.

Genetically identical twin-pair difference models support the amyloid cascade hypothesis.

The amyloid cascade hypothesis has strongly impacted the Alzheimer's disease research agenda and clinical trial designs over the past decades, but precisely how amyloid-β pathology initiates the aggregation of neocortical tau remains unclear. We cannot exclude the possibility of a shared upstream process driving both amyloid-β and tau in an independent manner instead of there being a causal relationship between amyloid-β and tau. Here, we tested the premise that if a causal relationship exists, then exposure should be associated with outcome both at the individual level as well as within identical twin-pairs, who are strongly matched on genetic, demographic and shared environmental background. Specifically, we tested associations between longitudinal amyloid-β PET and cross-sectional tau PET, neurodegeneration and cognitive decline using genetically identical twin-pair difference models, which provide the unique opportunity of ruling out genetic and shared environmental effects as potential confounders in an association. We included 78 cognitively unimpaired identical twins with [18F]flutemetamol (amyloid-β)-PET, [18F]flortaucipir (tau)-PET, MRI (hippocampal volume) and cognitive data (composite memory). Associations between each modality were tested at the individual level using generalized estimating equation models, and within identical twin-pairs using within-pair difference models. Mediation analyses were performed to test for directionality in the associations as suggested by the amyloid cascade hypothesis. At the individual level, we observed moderate-to-strong associations between amyloid-β, tau, neurodegeneration and cognition. The within-pair difference models replicated results observed at the individual level with comparably strong effect sizes. Within-pair differences in amyloid-β were strongly associated with within-pair differences in tau (β = 0.68, P < 0.001), and moderately associated with within-pair differences in hippocampal volume (β = -0.37, P = 0.03) and memory functioning (β = -0.57, P < 0.001). Within-pair differences in tau were moderately associated with within-pair differences in hippocampal volume (β = -0.53, P < 0.001) and strongly associated with within-pair differences in memory functioning (β = -0.68, P < 0.001). Mediation analyses showed that of the total twin-difference effect of amyloid-β on memory functioning, the proportion mediated through pathways including tau and hippocampal volume was 69.9%, which was largely attributable to the pathway leading from amyloid-β to tau to memory functioning (proportion mediated, 51.6%). Our results indicate that associations between amyloid-β, tau, neurodegeneration and cognition are unbiased by (genetic) confounding. Furthermore, effects of amyloid-β on neurodegeneration and cognitive decline were fully mediated by tau. These novel findings in this unique sample of identical twins are compatible with the amyloid cascade hypothesis and thereby provide important new knowledge for clinical trial designs.