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.

Shorter self-reported sleep duration is associated with worse virtual spatial navigation performance in men.

Sleep has been shown to impact navigation ability. However, it remains unclear how different sleep-related variables may be independently associated with spatial navigation performance, and as to whether gender may play a role in these associations. We used a mobile video game app, Sea Hero Quest (SHQ), to measure wayfinding ability in US-based participants. Wayfinding performance on SHQ has been shown to correlate with real-world wayfinding. Participants were asked to report their sleep duration, quality, daytime sleepiness and nap frequency and duration on a typical night (n = 766, 335 men, 431 women, mean age = 26.5 years, range = 18-59 years). A multiple linear regression was used to identify which self-reported sleep variables were independently associated with wayfinding performance. Shorter self-reported sleep durations were significantly associated with worse wayfinding performance in men only. Other self-reported sleep variables showed non-significant trends of association with wayfinding performance. When removing non-typical sleepers (< 6 or > 9 h of sleep on a typical night), the significant association between sleep duration and spatial navigation performance in men was no longer present. These findings from U.S.-based participants suggest that a longer self-reported sleep duration may be an important contributor to successful navigation ability in men.

Cut-off scores for mild and moderate dementia on the Addenbrooke's Cognitive Examination-III and the Mini-Addenbrooke's Cognitive Examination compared with the Mini-Mental State Examination.

AIMS AND METHOD: We aimed to establish cut-off scores to stage dementia on the Addenbrooke's Cognitive Examination-III (ACE-III) and the Mini-Addenbrooke's Cognitive Examination (M-ACE) compared with scores traditionally used with the Mini-Mental State Examination (MMSE). Our cross-sectional study recruited 80 patients and carers from secondary care services in the UK. RESULTS: A score ≤76 on the ACE-III and ≤19 on the M-ACE correlated well with MMSE cut-offs for mild dementia, with a good fit on the receiver operating characteristic analysis for both the ACE-III and M-ACE. The cut-off for moderate dementia had lower sensitivity and specificity. There were low to moderate correlations between the cognitive scales and scales for everyday functioning and behaviour. CLINICAL IMPLICATIONS: Our findings allow an objective interpretation of scores on the ACE-III and the M-ACE relative to the MMSE, which may be helpful for clinical services and research trials.

The Impact of Spatial Orientation Changes on Driving Behavior in Healthy Aging.

OBJECTIVES: Global cognitive changes in older age affect driving behavior and road safety, but how spatial orientation differences affect driving behaviors is unknown on a population level, despite clear implications for driving policy and evaluation during aging. The present study aimed to establish how spatial navigation changes affect driving behavior and road safety within a large cohort of older adults. METHODS: Eight hundred and four participants (mean age: 71.05) were recruited for a prospective cohort study. Participants self-reported driving behavior followed by spatial orientation (allocentric and egocentric) testing and a broader online cognitive battery (visuomotor speed, processing speed, executive functioning, spatial working memory, episodic memory, visuospatial functioning). RESULTS: Spatial orientation performance significantly predicted driving difficulty and frequency. Experiencing more driving difficulty was associated with worse allocentric spatial orientation, processing speed, and source memory performance. Similarly, avoiding challenging driving situations was associated with worse spatial orientation and episodic memory. Allocentric spatial orientation was the only cognitive domain consistently affecting driving behavior in under 70 and over 70 age groups, a common age threshold for driving evaluation in older age. DISCUSSION: We established for the first time that worse spatial orientation performance predicted increased driving difficulty and avoidance of challenging situations within an older adult cohort. Deficits in spatial orientation emerge as a robust indicator of driving performance in older age, which should be considered in future aging driving assessments, as it has clear relevance for road safety within the aging population.

Unravelling phenolic metabotypes in the frame of the COMBAT study, a randomized, controlled trial with cranberry supplementation.

Cranberry (poly)phenols may have potential health benefits. Circulating (poly)phenol metabolites can act as mediators of these effects, but they are subjected to an extensive inter-individual variability. This study aimed to quantify both plasma and urine (poly)phenol metabolites following a 12-week intake of a cranberry powder in healthy older adults, and to investigate inter-individual differences by considering the existence of urinary metabotypes related to dietary (poly)phenols. Up to 13 and 67 metabolites were quantified in plasma and urine respectively. Cranberry consumption led to changes in plasma metabolites, mainly hydroxycinnamates and hippuric acid. Individual variability in urinary metabolites was assessed using different data sets and a combination of statistical models. Three phenolic metabotypes were identified, colonic metabolism being the main driver for subject clustering. Metabotypes were characterized by quali-quantitative differences in the excretion of some metabolites such as phenyl-γ-valerolactones, hydroxycinnamic acids, and phenylpropanoic acids. Metabotypes were further confirmed when applying a model only focused on flavan-3-ol colonic metabolites. 5-(3',4'-dihydroxyphenyl)-γ-valerolactone derivatives were the most relevant metabolites for metabotyping. Metabotype allocation was well preserved after 12-week intervention. This metabotyping approach for cranberry metabolites represents an innovative step to handle the complexity of (poly)phenol metabolism in free-living conditions, deciphering the existence of metabotypes derived from the simultaneous consumption of different classes of (poly)phenols. These results will help contribute to studying the health effects of cranberries and other (poly)phenol-rich foods, mainly considering gut microbiota-driven individual differences.

Examining individual learning patterns using generalised linear mixed models.

Everyone learns differently, but individual performance is often ignored in favour of a group-level analysis. Using data from four different experiments, we show that generalised linear mixed models (GLMMs) and extensions can be used to examine individual learning patterns. Producing ellipsoids and cluster analyses based on predicted random effects, individual learning patterns can be identified, clustered and used for comparisons across various experimental conditions or groups. This analysis can handle a range of datasets including discrete, continuous, censored and non-censored, as well as different experimental conditions, sample sizes and trial numbers. Using this approach, we show that learning a face-named paired associative task produced individuals that can learn quickly, with the performance of some remaining high, but with a drop-off in others, whereas other individuals show poor performance throughout the learning period. We see this more clearly in a virtual navigation spatial learning task (NavWell). Two prominent clusters of learning emerged, one showing individuals who produced a rapid learning and another showing a slow and gradual learning pattern. Using data from another spatial learning task (Sea Hero Quest), we show that individuals' performance generally reflects their age category, but not always. Overall, using this analytical approach may help practitioners in education and medicine to identify those individuals who might need extra help and attention. In addition, identifying learning patterns may enable further investigation of the underlying neural, biological, environmental and other factors associated with these individuals.

Thalamic nuclei changes in early and late onset Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia worldwide. Increasing evidence points to the thalamus as an important hub in the clinical symptomatology of the disease, with the 'limbic thalamus' been described as especially vulnerable. In this work, we examined thalamic atrophy in early-onset AD (EOAD) and late-onset AD (LOAD) compared to young and old healthy controls (YHC and OHC, respectively) using a recently developed cutting-edge thalamic nuclei segmentation method. A deep learning variant of Thalamus Optimized Multi Atlas Segmentation (THOMAS) was used to parcellate 11 thalamic nuclei per hemisphere from T1-weighted MRI in 88 biomarker-confirmed AD patients (49 EOAD and 39 LOAD) and 58 healthy controls (41 YHC and 17 OHC) with normal AD biomarkers. Nuclei volumes were compared among groups using MANCOVA. Further, Pearson's correlation coefficient was computed between thalamic nuclear volume and cortical-subcortical regions, CSF tau levels, and neuropsychological scores. The results showed widespread thalamic nuclei atrophy in EOAD and LOAD compared to their respective healthy control groups, with EOAD showing additional atrophy in the centromedian and ventral lateral posterior nuclei compared to YHC. In EOAD, increased thalamic nuclei atrophy was associated with posterior parietal atrophy and worse visuospatial abilities, while LOAD thalamic nuclei atrophy was preferentially associated with medial temporal atrophy and worse episodic memory and executive function. Our findings suggest that thalamic nuclei may be differentially affected in AD according to the age at symptoms onset, associated with specific cortical-subcortical regions, CSF total tau and cognition.

Spatial cognition is associated with levels of phosphorylated-tau and ß-amyloid in clinically normal older adults.

Spatial cognition is associated with Alzheimer's disease (AD) biomarkers in the symptomatic stages of the disease. We investigated whether cerebrospinal fluid (CSF) biomarkers (phosphorylated-tau [p-tau] and ß-amyloid) are associated with poorer spatial cognition in clinically normal older adults. Participants were 1875 clinically normal adults (age 67.8 [8.5] years) from the European Prevention of Alzheimer's Dementia Consortium. Mixed effect models assessed the cross-sectional association between p-tau181, ß-amyloid1-42 (Aß1-42) and p-tau181/Aß1-42 ratio and spatial cognition measured using semi-automated Supermarket Task and the 4 Mountains Task. Levels of p-tau181, Aß1-42, and p-tau181/Aß1-42 ratio were significantly associated with spatial cognition scores on both tasks. The p-tau181/Aß1-42 ratio showed the largest effect sizes (ß = -0.04/0.05, p < 0.001). Lower entorhinal cortical volume was associated with poorer outcomes on both tasks (ß = 0.06, p < 0.002) and accounted for 18%-22% of the direct association between p-tau181 and spatial cognition scores. In conclusion, degeneration of the entorhinal cortex mediates a significant proportion of the association between p-tau181 and spatial assessments in cognitively normal adults. Future studies should focus on increasing the sensitivity of digital spatial assessments.

Heterogeneous factors influence social cognition across diverse settings in brain health and age-related diseases.

Aging may diminish social cognition, which is crucial for interaction with others, and significant changes in this capacity can indicate pathological processes like dementia. However, the extent to which non-specific factors explain variability in social cognition performance, especially among older adults and in global settings, remains unknown. A computational approach assessed combined heterogeneous contributors to social cognition in a diverse sample of 1063 older adults from 9 countries. Support vector regressions predicted the performance in emotion recognition, mentalizing, and a total social cognition score from a combination of disparate factors, including clinical diagnosis (healthy controls, subjective cognitive complaints, mild cognitive impairment, Alzheimer's disease, behavioral variant frontotemporal dementia), demographics (sex, age, education, and country income as a proxy of socioeconomic status), cognition (cognitive and executive functions), structural brain reserve, and in-scanner motion artifacts. Cognitive and executive functions and educational level consistently emerged among the top predictors of social cognition across models. Such non-specific factors showed more substantial influence than diagnosis (dementia or cognitive decline) and brain reserve. Notably, age did not make a significant contribution when considering all predictors. While fMRI brain networks did not show predictive value, head movements significantly contributed to emotion recognition. Models explained between 28-44% of the variance in social cognition performance. Results challenge traditional interpretations of age-related decline, patient-control differences, and brain signatures of social cognition, emphasizing the role of heterogeneous factors. Findings advance our understanding of social cognition in brain health and disease, with implications for predictive models, assessments, and interventions.

Multimorbidity pattern and risk of dementia in later life: an 11-year follow-up study using a large community cohort and linked electronic health records.

BACKGROUND: Several long-term chronic illnesses are known to be associated with an increased risk of dementia independently, but little is known how combinations or clusters of potentially interacting chronic conditions may influence the risk of developing dementia. METHODS: 447 888 dementia-free participants of the UK Biobank cohort at baseline (2006-2010) were followed-up until 31 May 2020 with a median follow-up duration of 11.3 years to identify incident cases of dementia. Latent class analysis (LCA) was used to identify multimorbidity patterns at baseline and covariate adjusted Cox regression was used to investigate their predictive effects on the risk of developing dementia. Potential effect moderations by C reactive protein (CRP) and Apolipoprotein E (APOE) genotype were assessed via statistical interaction. RESULTS: LCA identified four multimorbidity clusters representing Mental health, Cardiometabolic, Inflammatory/autoimmune and Cancer-related pathophysiology, respectively. Estimated HRs suggest that multimorbidity clusters dominated by Mental health (HR=2.12, p<0.001, 95% CI 1.88 to 2.39) and Cardiometabolic conditions (2.02, p<0.001, 1.87 to 2.19) have the highest risk of developing dementia. Risk level for the Inflammatory/autoimmune cluster was intermediate (1.56, p<0.001, 1.37 to 1.78) and that for the Cancer cluster was least pronounced (1.36, p<0.001, 1.17 to 1.57). Contrary to expectation, neither CRP nor APOE genotype was found to moderate the effects of multimorbidity clusters on the risk of dementia. CONCLUSIONS: Early identification of older adults at higher risk of accumulating multimorbidity of specific pathophysiology and tailored interventions to prevent or delay the onset of such multimorbidity may help prevention of dementia.

Wayfinding and path integration deficits detected using a virtual reality mobile app in patients with traumatic brain injury.

The ability to navigate is supported by a wide network of brain areas which are particularly vulnerable to disruption brain injury, including traumatic brain injury (TBI). Wayfinding and the ability to orient back to the direction you have recently come (path integration) may likely be impacted in daily life but have so far not been tested with patients with TBI. Here, we assessed spatial navigation in thirty-eight participants, fifteen of whom had a history of TBI, and twenty-three control participants. Self-estimated spatial navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. No significant difference between TBI patients and a control group was identified. Rather, results indicated that both participant groups demonstrated 'good' self-inferred spatial navigational ability on the SBSOD scale. Objective navigation ability was tested via the virtual mobile app test Sea Hero Quest (SHQ), which has been shown to predict real-world navigation difficulties and assesses (a) wayfinding across several environments and (b) path integration. Compared to a sub-sample of 13 control participants, a matched subsample of 10 TBI patients demonstrated generally poorer performance on all wayfinding environments tested. Further analysis revealed that TBI participants consistently spent a shorter duration viewing a map prior to navigating to goals. Patients showed mixed performance on the path integration task, with poor performance evident when proximal cues were absent. Our results provide preliminary evidence that TBI impacts both wayfinding and, to some extent, path integration. The findings suggest long-lasting clinical difficulties experienced in TBI patients affect both wayfinding and to some degree path integration ability.

Vestibular contribution to path integration deficits in 'at-genetic-risk' for Alzheimer's disease.

Path integration changes may precede a clinical presentation of Alzheimer's disease by several years. Studies to date have focused on how spatial cell changes affect path integration in preclinical AD. However, vestibular input is also critical for intact path integration. Here, we developed the vestibular rotation task that requires individuals to manually point an iPad device in the direction of their starting point following rotational movement, without any visual cues. Vestibular features were derived from the sensor data using feature selection. Machine learning models illustrate that the vestibular features accurately classified Apolipoprotein E ε3ε4 carriers and ε3ε3 carrier controls (mean age 62.7 years), with 65% to 79% accuracy depending on task trial. All machine learning models produced a similar classification accuracy. Our results demonstrate the cross-sectional role of the vestibular system in Alzheimer's disease risk carriers. Future investigations should examine if vestibular functions explain individual phenotypic heterogeneity in path integration among Alzheimer's disease risk carriers.

Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer's Disease (EPAD) cohort.

BACKGROUND: The risk of dementia is higher in women than men. The metabolic consequences of estrogen decline during menopause accelerate neuropathology in women. The use of hormone replacement therapy (HRT) in the prevention of cognitive decline has shown conflicting results. Here we investigate the modulating role of APOE genotype and age at HRT initiation on the heterogeneity in cognitive response to HRT. METHODS: The analysis used baseline data from participants in the European Prevention of Alzheimer's Dementia (EPAD) cohort (total n= 1906, women= 1178, 61.8%). Analysis of covariate (ANCOVA) models were employed to test the independent and interactive impact of APOE genotype and HRT on select cognitive tests, such as MMSE, RBANS, dot counting, Four Mountain Test (FMT), and the supermarket trolley test (SMT), together with volumes of the medial temporal lobe (MTL) regions by MRI. Multiple linear regression models were used to examine the impact of age of HRT initiation according to APOE4 carrier status on these cognitive and MRI outcomes. RESULTS: APOE4 HRT users had the highest RBANS delayed memory index score (P-APOE*HRT interaction = 0.009) compared to APOE4 non-users and to non-APOE4 carriers, with 6-10% larger entorhinal (left) and amygdala (right and left) volumes (P-interaction= 0.002, 0.003, and 0.005 respectively). Earlier introduction of HRT was associated with larger right (standardized ß= -0.555, p=0.035) and left hippocampal volumes (standardized ß= -0.577, p=0.028) only in APOE4 carriers. CONCLUSION: HRT introduction is associated with improved delayed memory and larger entorhinal and amygdala volumes in APOE4 carriers only. This may represent an effective targeted strategy to mitigate the higher life-time risk of AD in this large at-risk population subgroup. Confirmation of findings in a fit for purpose RCT with prospective recruitment based on APOE genotype is needed to establish causality.

Landmark-dependent Navigation Strategy Declines across the Human Life-Span: Evidence from Over 37,000 Participants.

Humans show a remarkable capacity to navigate various environments using different navigation strategies, and we know that strategy changes across the life span. However, this observation has been based on studies of small sample sizes. To this end, we used a mobile app-based video game (Sea Hero Quest) to test virtual navigation strategies and memory performance within a distinct radial arm maze level in over 37,000 participants. Players were presented with six pathways (three open and three closed) and were required to navigate to the three open pathways to collect a target. Next, all six pathways were made available and the player was required to visit the pathways that were previously unavailable. Both reference memory and working memory errors were calculated. Crucially, at the end of the level, the player was asked a multiple-choice question about how they found the targets (i.e., a counting-dependent strategy vs. a landmark-dependent strategy). As predicted from previous laboratory studies, we found the use of landmarks declined linearly with age. Those using landmark-based strategies also performed better on reference memory than those using a counting-based strategy. These results extend previous observations in the laboratory showing a decreased use of landmark-dependent strategies with age.

Spatial orientation - a stable marker for vascular cognitive impairment?

Vascular cognitive impairment (VCI) is the second most prevalent form of dementia, but little is known about the early cognitive and neuroimaging markers. Spatial navigation deficits are an emerging marker for Alzheimer's disease (AD), yet less is known about spatial orientation deficits sensitive to VCI. This case report follows up on the first VCI patient identified to have an egocentric orientation deficit. The study aimed to examine the patient's spatial deficits three years on and gain insights from the addition of the patient's MRI brain scan. A battery of spatial navigation tasks were administered following neuropsychological assessment. Results continue to show spatial orientation deficits. Critically, these changes appear stable and are sensitive to novel spatial tests. Whereas conventional screening tools demonstrate patient recovery. MRI DTI analysis indicates a non-significant trend towards loss of structural integrity to the posterior tracts of the longitudinal superior fasciculus (SLF), while the medial temporal lobe, typically implicated in spatial navigation, is unaffected. This finding potentially reflects reduced network connectivity in posterior to anterior white matter tracts co-existing with spatial orientation deficits. Findings have clinical utility and show spatial orientation as a potential sensitive cognitive marker for VCI.

Explaining World-Wide Variation in Navigation Ability from Millions of People: Citizen Science Project Sea Hero Quest.

Navigation ability varies widely across humans. Prior studies have reported that being younger and a male has an advantage for navigation ability. However, these studies have generally involved small numbers of participants from a handful of western countries. Here, we review findings from our project Sea Hero Quest, which used a video game for mobile and tablet devices to test 3.9 million people on their navigation ability, sampling across every nation-state and from 18 to 99 years of age. Results revealed that the task has good ecological validity and across all countries sufficiently sampled (N = 63), age is linked to a near-linear decline in navigation ability from the early 20s. All countries showed a male advantage, but this varied considerably and could be partly predicted by gender inequality. We found that those who reported growing up in a city were on average worse at navigating than those who grew up outside cities and that navigation performance helped identify those at greater genetic risk of Alzheimer's disease. We discuss the advantages and challenges of using a mobile app to study cognition and the future avenues for understanding individual differences in navigation ability arising from this research.

Cognitive impairment in the immune-mediated inflammatory diseases compared with age-matched controls: Systematic review and meta-regression.

OBJECTIVES: To compare the magnitude of cognitive impairment against age-expected levels across the immune mediated inflammatory diseases (IMIDs: systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], axial spondyloarthritis [axSpA], psoriatic arthritis [PsA], psoriasis [PsO]). METHODS: A pre-defined search strategy was implemented in Medline, Embase and Psychinfo on 29/05/2021. Inclusion criteria were: (i) observational studies of an IMID, (ii) healthy control comparison, (iii) measuring cognitive ability (overall, memory, complex attention/executive function, language/verbal fluency), and (iv) sufficient data for meta-analysis. Standardised mean differences (SMD) in cognitive assessments between IMIDs and controls were pooled using random-effects meta-analysis. IMIDs were compared using meta-regression. RESULTS: In total, 65 IMID groups were included (SLE: 39, RA: 19, axSpA: 1, PsA: 2 PsO: 4), comprising 3141 people with IMIDs and 9333 controls. People with IMIDs had impairments in overall cognition (SMD: -0.57 [95% CI -0.70, -0.43]), complex attention/executive function (SMD -0.57 [95% CI -0.69, -0.44]), memory (SMD -0.55 [95% CI -0.68, -0.43]) and language/verbal fluency (SMD -0.51 [95% CI -0.68, -0.34]). People with RA and people with SLE had similar magnitudes of cognitive impairment in relation to age-expected levels. People with neuropsychiatric SLE had larger impairment in overall cognition compared with RA. CONCLUSIONS: People with IMIDs have moderate impairments across a range of cognitive domains. People with RA and SLE have similar magnitudes of impairment against their respective age-expected levels, calling for greater recognition of cognitive impairment in both conditions. To further understand cognition in the IMIDs, more large-scale, longitudinal studies are needed.

The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset.

BACKGROUND AND PURPOSE: How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed. METHOD: Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (-EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (-LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. RESULTS: Significantly more mammillary body atrophy in +EOAD compared to -EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to -LOAD. Medial temporal GM volume loss was also found in +EOAD compared to -LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in -LOAD. CONCLUSIONS: Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to -LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.

The Utility of Arterial Spin Labeling MRI in Medial Temporal Lobe as a Vascular Biomarker in Alzheimer's Disease Spectrum: A Systematic Review and Meta-Analysis.

We sought to systematically review and meta-analy the role of cerebral blood flow (CBF) in the medial temporal lobe (MTL) using arterial spin labeling magnetic resonance imaging (ASL-MRI) and compare this in patients with Alzheimer's disease (AD), individuals with mild cognitive impairment (MCI), and cognitively normal adults (CN). The prevalence of AD is increasing and leading to high healthcare costs. A potential biomarker that can identify people at risk of developing AD, whilst cognition is normal or only mildly affected, will enable risk-stratification and potential therapeutic interventions in the future. All studies investigated the role of CBF in the MTL and compared this among AD, MCI, and CN participants. A total of 26 studies were included in the systematic review and 11 in the meta-analysis. Three separate meta-analyses were conducted. Four studies compared CBF in the hippocampus of AD compared with the CN group and showed that AD participants had 2.8 mL/min/100 g lower perfusion compared with the CN group. Eight studies compared perfusion in the hippocampus of MCI vs. CN group, which showed no difference. Three studies compared perfusion in the MTL of MCI vs. CN participants and showed no statistically significant differences. CBF measured via ASL-MRI showed impairment in AD compared with the CN group in subregions of the MTL. CBF difference was significant in hippocampus between the AD and CN groups. However, MCI and CN group showed no significant difference in subregions of MTL.