Neural correlates of the revised reinforcement sensitivity theory: A cross-sectional structural neuroimaging study in middle-aged adults.

The revised reinforcement sensitivity theory (RST) proposes that neurobiological systems control behavior: the fight-flight-freeze (FFFS) for avoidance of threat; behavioral approach/activation (BAS) for approach to rewards; and behavioral inhibition (BIS) for conflict resolution when avoidance and approach are possible. Neuroimaging studies have confirmed some theoretical associations between brain structures and the BAS and BIS; however, little representative population data are available for the FFFS. We investigated the neural correlates of the revised RST in a sample of 404 middle-aged adults (Mage = 47.18 (SD = 1.38); 54.5% female). Participants underwent structural magnetic resonance imaging and completed health questionnaires and the BIS/BAS/FFFS scales. We used multiple regression analyses to investigate the association between scale scores and volumes of a priori theoretically linked regions of interest while controlling for sex, age, intracranial volume, and cardio-metabolic variables; and conducted exploratory analyses on cortical thickness. The BIS was negatively associated with hippocampus laterality. At standard significance levels, the fear component of the FFFS was positively associated with anterior cingulate cortex; the BAS was positively associated with bilateral caudate; and the BIS was positively associated with posterior cingulate cortex volume. Furthermore, these neurobiological systems showed distinct patterns of association with cortical thickness though future work is needed. Our results showed that the neurobiological systems of the revised RST characterized in rodents can also be identified in the human brain.

A role for retro-splenial cortex in the task-related P3 network.

OBJECTIVE: The P3 is an event-related response observed in relation to task-relevant sensory events. Despite its ubiquitous presence, the neural generators of the P3 are controversial and not well identified. METHODS: We compared source analysis of combined magneto- and electroencephalography (M/EEG) data with functional magnetic resonance imaging (fMRI) and simulation studies to better understand the sources of the P3 in an auditory oddball paradigm. RESULTS: Our results suggest that the dominant source of the classical, postero-central P3 lies in the retro-splenial cortex of the ventral cingulate gyrus. A second P3 source in the anterior insular cortex contributes little to the postero-central maximum. Multiple other sources in the auditory, somatosensory, and anterior midcingulate cortex are active in an overlapping time window but can be functionally dissociated based on their activation time courses. CONCLUSIONS: The retro-splenial cortex is a dominant source of the parietal P3 maximum in EEG. SIGNIFICANCE: These results provide a new perspective for the interpretation of the extensive research based on the P3 response.

A role for retro-splenial cortex in the task-related P3 network.

Objective: The P3 is an event-related response observed in relation to task-relevant sensory events. Despite its ubiquitous presence, the neural generators of the P3 are controversial and not well identified. Methods: We compared source analysis of combined magneto- and electroencephalography (M/EEG) data with functional magnetic resonance imaging (fMRI) and simulation studies to better understand the sources of the P3 in an auditory oddball paradigm. Results: Our results suggest that the dominant source of the classical, postero-central P3 lies in the retro-splenial cortex of the ventral cingulate gyrus. A second P3 source in the anterior insular cortex contributes little to the postero-central maximum. Multiple other sources in the auditory, somatosensory, and anterior midcingulate cortex are active in an overlapping time window but can be functionally dissociated based on their activation time courses. Conclusion: The retro-splenial cortex is a dominant source of the parietal P3 maximum in EEG. Significance: These results provide a new perspective for the interpretation of the extensive research based on the P3 response.

Longitudinal Effects of Physical Activity Change on Hippocampal Volumes over up to 12 Years in Middle and Older Age Community-Dwelling Individuals.

The objectives of this study were to investigate the long-term associations between changes in physical activity levels and hippocampal volumes over time, while considering the influence of age, sex, and APOE-ε4 genotype. We investigated the effects of change in physical activity on hippocampal volumes in 411 middle age (mean age = 47.2 years) and 375 older age (mean age = 63.1 years) adults followed up to 12 years. An annual volume decrease was observed in the left (middle age: 0.46%; older age: 0.51%) but not in the right hippocampus. Each additional 10 metabolic equivalents (METs, ~2 h of moderate exercise) increase in weekly physical activity was associated with 0.33% larger hippocampal volume in middle age (equivalent to ~1 year of typical aging). In older age, each additional MET was associated with 0.05% larger hippocampal volume; however, the effects declined with time by 0.005% per year. For older age APOE-ε4 carriers, each additional MET was associated with a 0.10% increase in hippocampal volume. No sex effects of physical activity change were found. Increasing physical activity has long-term positive effects on hippocampal volumes and appears especially beneficial for older APOE-ε4 carriers. To optimize healthy brain aging, physical activity programs should focus on creating long-term exercise habits.

Longitudinal trajectories of hippocampal volume in middle to older age community dwelling individuals.

Understanding heterogeneity in brain aging trajectories is important to estimate the extent to which aging outcomes can be optimized. Although brain changes in late life are well-characterized, brain changes in middle age are not well understood. In this study, we investigated hippocampal change in a generally healthy community-living population of middle (n = 421, mean age 47.2 years) and older age (n = 411, mean age 63.0 years) individuals, over a follow-up of up to 12 years. Manually traced hippocampal volumes were analyzed using multilevel models and latent class analysis to investigate longitudinal aging trajectories and laterality and sex effects, and to identify subgroups that follow different aging trajectories. Hippocampal volumes decreased on average by 0.18%/year in middle age and 0.3%/year in older age. Men tended to experience steeper declines than women in middle age only. Three subgroups of individuals following different trajectories were identified in middle age and 2 in older age. Contrary to expectations, the subgroup containing two-thirds of older age participants maintained stable hippocampal volumes across the follow-up.

Objectively measured physical activity is associated with dorsolateral prefrontal cortex volume in older adults.

BACKGROUND: Epidemiological studies suggest physical activity (PA) can slow or prevent both cognitive decline and age-related atrophy in frontal and hippocampal gray matter volumes. However, much of this evidence is based on self-reported measures of PA. METHODS: PA was measured objectively with a SenseWear™ Armband to examine the cross-sectional associations between the duration of light, moderate and vigorous intensity PA with gray matter volume in the dorsolateral prefrontal cortex (DLPFC) and hippocampus in 167 (female: 43%) cognitively healthy older adults aged 73 to 78. RESULTS: The duration of objective moderate to vigorous intensity physical activity (MVPA) was associated with a greater volume of the right DLPFC (ߠ​= â€‹0.16; p â€‹= â€‹0.04). In addition, objective moderate-intensity PA alone was also associated with greater volume of the left (ߠ​= â€‹0.17; p â€‹= â€‹0.03) and right (ߠ​= â€‹0.19; p â€‹= â€‹0.01) DLPFC after controlling for covariates and adjustment for multiple comparisons. In contrast, there were no significant associations between light- or vigorous-intensity PA and gray matter volumes (all p â€‹> â€‹0.05). No associations between PA and cognitive performance were detected, and self-reported PA was not associated with any of the outcomes investigated. CONCLUSIONS: These findings suggest that an intensity-dependent relationship may exist, whereby a greater duration of MVPA, perhaps driven by moderate-intensity PA, is associated with preserved gray matter volume in frontal regions of the brain. Future research should investigate the mechanisms of this dose-effect and determine whether greater brain volumes associated with objective PA convey protective effects against cognitive decline.

Volumetric brain differences in clinical depression in association with anxiety: a systematic review with meta-analysis.

Background: Structural differences associated with depression have not been confirmed in brain regions apart from the hippocampus. Comorbid anxiety has been inconsistently assessed, and may explain discrepancies in previous findings. We investigated the link between depression, comorbid anxiety and brain structure. Methods: We followed Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines (PROSPERO CRD42018089286). We searched the Cochrane Library, MEDLINE, PsycInfo, PubMed and Scopus, from database inception to Sept. 13, 2018, for MRI case-control studies that reported brain volumes in healthy adults and adults with clinical depression. We summarized mean volumetric differences using meta-analyses, and we assessed demographics, depression factors and segmentation procedure as moderators using meta-regressions. Results: We included 112 studies in the meta-analyses, assessing 4911 healthy participants and 5934 participants with depression (mean age 49.8 yr, 68.2% female). Volume effects were greater in late-onset depression and in multiple episodes of depression. Adults with depression and no comorbidity showed significantly lower volumes in the putamen, pallidum and thalamus, as well as significantly lower grey matter volume and intracranial volume; the largest effects were in the hippocampus (6.8%, p < 0.001). Adults with depression and comorbid anxiety showed significantly higher volumes in the amygdala (3.6%, p < 0.001). Comorbid anxiety lowered depression effects by 3% on average. Sex moderated reductions in intracranial volume. Limitations: High heterogeneity in hippocampus effects could not be accounted for by any moderator. Data on symptom severity and medication were sparse, but other factors likely made significant contributions. Conclusion: Depression-related differences in brain structure were modulated by comorbid anxiety, chronicity of symptoms and onset of illness. Early diagnosis of anxiety symptomatology will prove crucial to ensuring effective, tailored treatments for improving long-term mental health and mitigating cognitive problems, given the effects in the hippocampus.

Cognitive/Functional Measures Predict Alzheimer's Disease, Dependent on Hippocampal Volume.

OBJECTIVES: This study aimed to investigate the predictive value of cognitive/functional measures in combination with hippocampal volume (HCV) on the probability of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: The Rey Auditory Verbal Learning Test for immediate memory, Mini-Mental State Examination, a functional assessment for independent daily activities and Alzheimer's Disease Assessment Scale were used as cognitive/functional measures and HCV as neuroimaging measure. Logistic regression and Cox proportional hazard analyses were used to explore the measures' predictive values for AD conversion and time to conversion. RESULTS: The probability of conversion from MCI to AD was associated with cognitive function, but this was moderated by HCV: higher at lower HCV and lower at higher HCV. General cognitive/functional measures were less predictive than immediate memory in predicting time to conversion to AD at small HCVs. CONCLUSION: Effectiveness of cognitive measures and subtle functional abnormality in predicting conversion from MCI to AD is dependent on HCV, thus combined evaluation should be considered. A combination of HCV and immediate memory appear to perform best in predicting time to conversion.

Regional brain atrophy predicts time to conversion to Alzheimer's disease, dependent on baseline volume.

A key question for the design of clinical trials for Alzheimer's disease (AD) is whether the timing of conversion from mild cognitive impairment (MCI) to AD can be predicted. This is also an important question for the clinical management of MCI. This study aims to address this question by exploring the contribution of baseline brain volume and annual volume change, using Cox regression, in predicting the time to conversion. Individuals with MCI, who converted to AD (n = 198), reverted to normal (n = 38), or remained stable (n = 96) for at least five years, were included in this study. The results revealed that the volumes of all the brain areas considered were predictive of the time to conversion from MCI to AD. Annual change in volume was also predictive of the time to conversion but only when initial volumes were above a certain threshold. This is important because it suggests that reduction in atrophy rate, which is the outcome of some clinical trials, is not inevitably associated with delay in conversion from MCI to AD.

Validated Alzheimer's Disease Risk Index (ANU-ADRI) is associated with smaller volumes in the default mode network in the early 60s.

Strong evidence is available suggesting that effective reduction of exposure to demonstrated modifiable risk factors in mid-life or before could significantly decrease the incidence of Alzheimer's disease (AD) and delay its onset. A key ingredient to achieving this goal is the reliable identification of individuals at risk well before they develop clinical symptoms. The aim of this study was to provide further neuroimaging evidence of the effectiveness of a validated tool, the ANU Alzheimer's Disease Risk Index, for the assessment of future risk of cognitive decline. Participants were 461 (60-64 years, 48% female) community-living individuals free of dementia at baseline. Associations between risk estimates obtained with the ANU-ADRI, total and regional brain volumes including in the default mode network (DMN) measured at the same assessment and diagnosis of MCI/dementia over a 12-year follow-up were tested in a large sample of community-living individuals free of dementia at baseline. Higher risk estimates on the ANU-ADRI were associated with lower cortical gray matter and particularly in the DMN. Importantly, difference in participants with high and low risk scores explained 7-9% of the observed difference in gray matter volume. In this sample, every one additional risk point on the ANU-ADRI was associated with an 8% increased risk of developing MCI/dementia over a 12-year follow-up and this association was partly mediated by a sub-region of the DMN. Risk of cognitive decline assessed with a validated instrument is associated with gray matter volume, particularly in the DMN, a region known to be implicated in the pathological process of the disease.

Longitudinal Assessment of Hippocampal Atrophy in Midlife and Early Old Age: Contrasting Manual Tracing and Semi-automated Segmentation (FreeSurfer).

It is important to have accurate estimates of normal age-related brain structure changes and to understand how the choice of measurement technique may bias those estimates. We compared longitudinal change in hippocampal volume, laterality and atrophy measured by manual tracing and FreeSurfer (version 5.3) in middle age (n = 244, 47.2[1.4] years) and older age (n = 199, 67.0[1.4] years) individuals over 8 years. The proportion of overlap (Dice coefficient) between the segmented hippocampi was calculated and we hypothesised that the proportion of overlap would be higher for older individuals as a consequence of higher atrophy. Hippocampal volumes produced by FreeSurfer were larger than manually traced volumes. Both methods produced a left less than right volume laterality difference. Over time this laterality difference increased for manual tracing and decreased for FreeSurfer leading to laterality differences in left and right estimated atrophy rates. The overlap proportion between methods was not significantly different for older individuals, but was greater for the right hippocampus. Estimated middle age annualised atrophy rates were - 0.39(1.0) left, 0.07(1.01) right, - 0.17(0.88) total for manual tracing and - 0.15(0.69) left, - 0.20(0.63) right, - 0.18(0.57) total for FreeSurfer. Older age atrophy rates were - 0.43(1.32) left, - 0.15(1.41) right, - 0.30 (1.23) total for manual tracing and - 0.34(0.79) left, - 0.68(0.78) right, - 0.51(0.65) total for FreeSurfer. FreeSurfer reliably segments the hippocampus producing atrophy rates that are comparable to manual tracing with some biases that need to be considered in study design. FreeSurfer is suited for use in large longitudinal studies where it is not cost effective to use manual tracing.

Higher fasting plasma glucose is associated with smaller striatal volume and poorer fine motor skills in a longitudinal cohort.

Previous studies have demonstrated associations between higher blood glucose and brain atrophy and functional deficits, however, little is known about the association between blood glucose, striatal volume and striatal function despite sensori-motor deficits being reported in diabetes. This study investigated the relationship between blood glucose levels, striatal volume and fine motor skills in a longitudinal cohort of cognitively healthy individuals living in the community with normal or impaired fasting glucose or type 2 diabetes. Participants were 271 cognitively healthy individuals (mean age 63 years at inclusion) with normal fasting glucose levels (<5.6 mmol/L) (n=173), impaired fasting glucose (5.6-6.9 mmol/L) (n=57), or with type 2 diabetes (≥7.0 mmol/L) (n=41). Fasting glucose, Purdue Pegboard scores as measurement of fine motor skills, and brain scans were collected at wave 1, 2 and 4, over a total follow-up of twelve years. Striatal volumes were measured using FreeSurfer after controlling for age, sex and intracranial volume. Results showed that type 2 diabetes was associated with smaller right putamen volume and lower Purdue Pegboard scores after controlling for age, sex and intracranial volume. These findings add to the evidence suggesting that higher blood glucose levels, especially type 2 diabetes, may impair brain structure and function.

A simple and clinically relevant combination of neuroimaging and functional indexes for the identification of those at highest risk of Alzheimer's disease.

The current challenge in clinical practice is to identify those with mild cognitive impairment (MCI), who are at greater risk of Alzheimer's disease (AD) conversion in the near future. The aim of this study was to assess a clinically practical new hippocampal index-hippocampal volume normalized by cerebellar volume (hippocampus to cerebellum volume ratio) used alone or in combination with scores on the Mini-Mental State Examination, as a predictor of conversion from MCI to AD. The predictive value of the HCCR was also contrasted to that of the hippocampal volume to intracranial volume ratio. The findings revealed that the performance of the combination of measures was significantly better than that of each measure used individually. The combination of Mini-Mental State Examination and hippocampal volume, normalized by the cerebellum or by intracranial volume, accurately discriminated individuals with MCI who progress to AD within 5 years from other MCI types (stable, reverters) and those with intact cognition (area under receiver operating curve of 0.88 and 0.89, respectively). Normalization by cerebellar volume was as accurate as normalization by intracranial volume with the advantage of being more practical, particularly for serial assessments.

Increasing Body Mass Index at Midlife is Associated with Increased Cortical Thinning in Alzheimer's Disease-Vulnerable Regions.

Higher body mass index (BMI) at midlife is associated with greater decreases in cognitive function at older age as well as increased Alzheimer's disease (AD) risk, compared to those with normal BMI. Here, we tested whether BMI at midlife was associated with cortical thinning in brain regions known to be affected in early AD. We examined a large sample (n = 404) of midlife individuals (44-49 years) from the PATH population-based study. Individuals were scanned with magnetic resonance imaging (1.5T) on up to three occasions over eight years. Change in cortical thickness was modeled as a linear function of BMI and change in BMI longitudinally. Being obese was associated with thinner right frontal cortex at baseline (44-49 years). Across all individuals, increasing BMI over the 8-year study period was associated with increased cortical thinning in posterior cingulate bilaterally, as well as right lingual gyrus, anterior cingulate, and the peri-calcarine sulcus. Accelerated age-related cortical atrophy at midlife, particularly in posterior cingulate, is consistent with increased risk of AD in individuals with high BMI at this age. The findings suggest that management of body weight at midlife could reduce the risk of AD.

The cerebellum shrinks faster than normal ageing in Alzheimer's disease but not in mild cognitive impairment.

BACKGROUND: While acceleration in age-related cerebral atrophy has been well documented in Alzheimer's disease, the cerebellar contributions to this effect have not been thoroughly investigated. OBJECTIVE: This study investigated cerebellar volume and atrophy rate using magnetic resonance imaging in individuals with normal cognition (CN), mild cognitive impairment (MCI), and Alzheimer's disease (AD). METHODS: Two hundred twenty-nine CN, 398 MCI and 191 AD participants of stage I ADNI database with screening scans were evaluated for cerebellar volume. Of those, 758 individuals with two or more follow-up scans were categorized into stable, converted, and reverted CN, MCI and AD and evaluated for cerebellar atrophy rate. RESULTS: Cerebellar volume was 2.5% larger in CN than in those with AD but there were no differences between CN and MCI and MCI and AD in cross-sectional analysis. Similarly, the atrophy rate was 49% larger in AD and 64% larger in MCI who converted to AD but no difference was detected between CN and MCI. There were no association between education and APOEe4 and cerebellar volume or cerebellar atrophy across the diagnostic groups. CONCLUSION: Cerebellar atrophy contributes to Alzheimer's clinical progression but mostly at the late stage of the disease. However, even in the late stage shrinkage rate is less than the average of the shrinkage in the cerebrum and is not associated with AD moderators. This suggests that cerebellar involvement is secondary to cerebral involvement and can be due to network connection spread regardless of the primary pathology. Hum Brain Mapp, 2017. © 2017 Wiley Periodicals, Inc. Hum Brain Mapp 38:3141-3150, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. Hum Brain Mapp 38:3141-3150, 2017. © 2017 Wiley Periodicals, Inc.

Higher Fasting Plasma Glucose is Associated with Increased Cortical Thinning Over 12 Years: The PATH Through Life Study.

Recent evidence suggests that type 2 diabetes (T2D) is associated with accelerated brain ageing, consistent with the observation of increased risk of cognitive impairment and dementia in affected individuals. Even non-diabetic individuals with impaired fasting plasma glucose (IFG) levels have shown increased cerebral atrophy, compared to individuals with normal glucose levels. We tested whether longitudinal rates of age-related cortical thinning were associated with fasting plasma glucose levels in a large sample (n = 322) of early-old age individuals (60-66 years) who were scanned with magnetic resonance imaging (1.5 T) on up to four occasions over 12 years. Higher plasma glucose levels (measured on up to three occasions) were associated with increased cortical thinning in individuals with T2D as well as those with IFG, with a similar trend for individuals with normal fasting glucose (NFG) levels. Across groups, a 1 mmol/l increase in plasma glucose (above 5 mmol/l in NFG and IFG and above 6.1 mmol/l in T2D) resulted in a 10-13% increase in annual cortical thinning. Increased cortical thinning was detected in insular cortex, as well as posterior cingulate, parahippocampus and medial orbitofrontal cortex. Our results provide support for the idea that raised plasma glucose levels, even in the normal range, are associated with accelerated age-related cortical atrophy.

Associations between corpus callosum size and ADHD symptoms in older adults: The PATH through life study.

Neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) have revealed deviations of the corpus callosum in children and adolescents. However, little is known about the link between callosal morphology and symptoms of inattention or hyperactivity in adulthood, especially later in life. Here, we investigated in a large population-based sample of 280 adults (150 males, 130 females) in their late sixties and early seventies whether ADHD symptoms correlate with callosal thickness. In addition, we tested for significant sex interactions, which were followed by correlation analyses stratified by sex. Within males, there were significant negative correlations with respect to inattention and hyperactivity in various callosal regions, including the anterior third, anterior and posterior midbody, isthmus, and splenium. A thinner corpus callosum may be associated with fewer fibers or less myelination of fibers. Thus, the observed negative correlations suggest impaired inter-hemispheric communication channels necessary to sustain motor control and attention, which may contribute to symptoms of hyperactivity, impulsivity and/or inattention. Interestingly, within females, callosal thickness was positively related to hyperactivity in a small area within the rostral body, suggesting a sexually dimorphic neurobiology of ADHD symptoms. Altogether, the present results may reflect a lasting relationship between callosal morphology and ADHD symptoms throughout life.

Cortical Thinning at Midlife: The PATH Through Life Study.

Cortical thinning is a part of normal ageing. Recent studies suggest that accelerated cortical thinning in vulnerable regions may be a useful biomarker for neuropathologies including Alzheimer's disease (AD). Longitudinal studies, which have largely focused on older adults, have provided estimates of normative rates and patterns of age-related cortical thinning. Very little, however, is known about healthy cortical thinning at midlife. Here we provide longitudinal estimates of age-related cortical thinning observed over 8 years, in a large (n = 404) group of healthy individuals aged 44-49 years at baseline, who were scanned with MRI (1.5T) on up to three occasions. Age-related cortical thinning was assessed across the whole cortex. We measured a mean annual decrease in cortical thickness of 0.26 % on the left and 0.17 % on the right hemisphere, and largely affecting frontal and cingulate cortices. Medial and lateral temporal regions were generally spared. Studying regions that are specifically vulnerable to-or spared from-healthy age-related cortical thinning at midlife may be important for the early identification of neurodegeneration, including AD.

Age-related cortical thinning in cognitively healthy individuals in their 60s: the PATH Through Life study.

Although it is recognized that the human cortex thins with age, longitudinal estimates of thinning patterns specific to healthy young-old age (<75 years) individuals are lacking. Importantly, many neurodegenerative disorders first manifest between midlife and old age, and normative estimates may provide a reference for differential change associated with such disorders. Here, we provide longitudinal estimates of cortical thinning observed over 12 years in a large group (n = 396) of healthy individuals, aged 60-66 years at baseline scan, who were scanned with magnetic resonance imaging (1.5T) on 4 occasions. Longitudinal age-related thinning was observed across most of the cortices, with a mean change of -0.3% per year. We measured significant thinning in heteromodal association cortex, with less thinning in regions expected to atrophy later in life (e.g., primary sensory cortex). Men showed more extensive thinning than women. Our comparison of cross-sectional and longitudinal estimates adds to growing evidence that cross-sectional designs may underestimate age-related changes in cortical thickness.

A systematic review and meta-analysis of longitudinal hippocampal atrophy in healthy human ageing.

INTRODUCTION: This review aimed to produce hippocampal atrophy rate estimates from healthy ageing studies as well as control samples from observational studies across the adult lifespan which can be used as benchmarks to evaluate abnormal changes in pathological conditions. METHODS: The review followed PRISMA guidelines. PUBMED (to February 2014) was searched for longitudinal MRI studies reporting hippocampal atrophy or volume change in cognitively healthy individuals. Titles were screened and non-English, duplicate or irrelevant entries were excluded. Remaining record abstracts were reviewed to identify studies for full text retrieval. Full text was retrieved and screened against inclusion/exclusion criteria. Bibliographies and previous reviews were examined to identify additional studies. Data were summarised using meta-analysis and age, segmentation technique and study type were tested as potential moderators using meta-regression. It was hypothesised that population studies would produce higher atrophy rates than clinical observational studies. RESULTS: The systematic search identified 4410 entries and 119 studies were retrieved with 58 failing selection or quality criteria, 30 were excluded as multiple reports and 3 studies were unsuitable for meta-analysis. The remaining 28 studies were included in the meta-analysis, n=3422, 44.65% male, 11,735 person-years of follow-up, mean age was 24.50 to 83 years. Mean total hippocampal atrophy for the entire sample was 0.85% per year (95% CI 0.63, 1.07). Age based atrophy rates were 0.38% per year (CI 0.14, 0.62) for studies with mean age <55 years (n=413), 0.98% (CI 0.27, 1.70) for 55 to <70 years (n=426), and 1.12% (CI 0.86, 1.38) for ≥70 years (n=2583). Meta-regression indicated age was associated with increased atrophy rates of 0.0263% (CI 0.0146, 0.0379) per year and automated segmentation approaches were associated with a reduced atrophy rate of -0.466% (CI -0.841, -0.090). Population studies were not associated with a significant effect on atrophy. Analyses of 11 studies separately measuring left and right hippocampal atrophy (n=1142) provided little evidence of laterality effects. While no study separately reported atrophy by gender, a number tested for gender effects and 2 studies reported higher atrophy in males. CONCLUSIONS: Hippocampal atrophy rates increase with age with the largest increases occurring from midlife onwards. Manual segmentation approaches result in higher measured atrophy rates.