Hemodynamic latency is associated with reduced intelligence across the lifespan: an fMRI DCM study of aging, cerebrovascular integrity, and cognitive ability

Changes in neurovascular coupling are associated with both Alzheimer’s disease and vascular dementia in later life, but this may be confounded by cerebrovascular risk. We hypothesized that hemodynamic latency would be associated with reduced cognitive functioning across the lifespan, holding constant demographic and cerebrovascular risk. In 387 adults aged 18–85 (mean = 48.82), dynamic causal modeling was used to estimate the hemodynamic response function in the left and right V1 and V3-ventral regions of the visual cortex in response to a simple checkerboard block design stimulus with minimal cognitive demands. The hemodynamic latency (transit time) in the visual cortex was used to predict general cognitive ability (Full-Scale IQ), controlling for demographic variables (age, race, education, socioeconomic status) and cerebrovascular risk factors (hypertension, alcohol use, smoking, high cholesterol, BMI, type 2 diabetes, cardiac disorders). Increased hemodynamic latency in the visual cortex predicted reduced cognitive function (p < 0.05), holding constant demographic and cerebrovascular risk. Increased alcohol use was associated with reduced overall cognitive function (Full Scale IQ 2.8 pts, p < 0.05), while cardiac disorders (Full Scale IQ 3.3 IQ pts; p < 0.05), high cholesterol (Full Scale IQ 3.9 pts; p < 0.05), and years of education (2 IQ pts/year; p < 0.001) were associated with higher general cognitive ability. Increased hemodynamic latency was associated with reduced executive functioning (p < 0.05) as well as reductions in verbal concept formation (p < 0.05) and the ability to synthesize and analyze abstract visual information (p < 0.01). Hemodynamic latency is associated with reduced cognitive ability across the lifespan, independently of other demographic and cerebrovascular risk factors. Vascular health may predict cognitive ability long before the onset of dementias

The Lifespan Human Connectome Project in Development: A large-scale study of brain connectivity development in 5-21 year olds

Recent technological and analytical progress in brain imaging has enabled the examination of brain organization and connectivity at unprecedented levels of detail. The Human Connectome Project in Development (HCP-D) is exploiting these tools to chart developmental changes in brain connectivity. When complete, the HCP-D will comprise approximately ∼1750 open access datasets from 1300 + healthy human participants, ages 5–21 years, acquired at four sites across the USA. The participants are from diverse geographical, ethnic, and socioeconomic backgrounds. While most participants are tested once, others take part in a three-wave longitudinal component focused on the pubertal period (ages 9–17 years). Brain imaging sessions are acquired on a 3 T Siemens Prisma platform and include structural, functional (resting state and task-based), diffusion, and perfusion imaging, physiological monitoring, and a battery of cognitive tasks and self-reports. For minors, parents additionally complete a battery of instruments to characterize cognitive and emotional development, and environmental variables relevant to development. Participants provide biological samples of blood, saliva, and hair, enabling assays of pubertal hormones, health markers, and banked DNA samples. This paper outlines the overarching aims of the project, the approach taken to acquire maximally informative data while minimizing participant burden, preliminary analyses, and discussion of the intended uses and limitations of the dataset

The Lifespan Human Connectome Project in Aging: An overview.

The original Human Connectome Project yielded a rich data set on structural and functional connectivity in a large sample of healthy young adults using improved methods of data acquisition, analysis, and sharing. More recent efforts are extending this approach to include infants, children, older adults, and brain disorders. This paper introduces and describes the Human Connectome Project in Aging (HCP-A), which is currently recruiting 1200 + healthy adults aged 36 to 100+, with a subset of 600 + participants returning for longitudinal assessment. Four acquisition sites using matched Siemens Prisma 3T MRI scanners with centralized quality control and data analysis are enrolling participants. Data are acquired across multimodal imaging and behavioral domains with a focus on factors known to be altered in advanced aging. MRI acquisitions include structural (whole brain and high resolution hippocampal) plus multiband resting state functional (rfMRI), task fMRI (tfMRI), diffusion MRI (dMRI), and arterial spin labeling (ASL). Behavioral characterization includes cognitive (such as processing speed and episodic memory), psychiatric, metabolic, and socioeconomic measures as well as assessment of systemic health (with a focus on menopause via hormonal assays). This dataset will provide a unique resource for examining how brain organization and connectivity changes across typical aging, and how these differences relate to key characteristics of aging including alterations in hormonal status and declining memory and general cognition. A primary goal of the HCP-A is to make these data freely available to the scientific community, supported by the Connectome Coordination Facility (CCF) platform for data quality assurance, preprocessing and basic analysis, and shared via the NIMH Data Archive (NDA). Here we provide the rationale for our study design and sufficient details of the resource for scientists to plan future analyses of these data. A companion paper describes the related Human Connectome Project in Development (HCP-D, Somerville et al., 2018), and the image acquisition protocol common to both studies (Harms et al., 2018)

Extending the human connectome project across ages: imaging protocols for the lifespan development and aging projects

The Human Connectome Projects in Development (HCP-D) and Aging (HCP-A) are two large-scale brain imaging studies that will extend the recently completed HCP Young-Adult (HCP-YA) project to nearly the full lifespan, collecting structural, resting-state fMRI, task-fMRI, diffusion, and perfusion MRI in participants from 5 to 100 + years of age. HCP-D is enrolling 1300 + healthy children, adolescents, and young adults (ages 5-21), and HCP-A is enrolling 1200 + healthy adults (ages 36-100+), with each study collecting longitudinal data in a subset of individuals at particular age ranges. The imaging protocols of the HCP-D and HCP-A studies are very similar, differing primarily in the selection of different task-fMRI paradigms. We strove to harmonize the imaging protocol to the greatest extent feasible with the completed HCP-YA (1200 + participants, aged 22-35), but some imaging-related changes were motivated or necessitated by hardware changes, the need to reduce the total amount of scanning per participant, and/or the additional challenges of working with young and elderly populations. Here, we provide an overview of the common HCP-D/A imaging protocol including data and rationales for protocol decisions and changes relative to HCP-YA. The result will be a large, rich, multi-modal, and freely available set of consistently acquired data for use by the scientific community to investigate and define normative developmental and aging related changes in the healthy human brain

Visual Personal Familiarity in Amnestic Mild Cognitive Impairment

BACKGROUND: Patients with amnestic mild cognitive impairment are at high risk for developing Alzheimer's disease. Besides episodic memory dysfunction they show deficits in accessing contextual knowledge that further specifies a general concept or helps to identify an object or a person. METHODOLOGY/PRINCIPAL FINDINGS: Using functional magnetic resonance imaging, we investigated the neural networks associated with the perception of personal familiar faces and places in patients with amnestic mild cognitive impairment and healthy control subjects. Irrespective of stimulus type, patients compared to control subjects showed lower activity in right prefrontal brain regions when perceiving personally familiar versus unfamiliar faces and places. Both groups did not show different neural activity when perceiving faces or places irrespective of familiarity. CONCLUSIONS/SIGNIFICANCE: Our data highlight changes in a frontal cortical network associated with knowledge-based personal familiarity among patients with amnestic mild cognitive impairment. These changes could contribute to deficits in social cognition and may reduce the patients' ability to transition from basic to complex situations and tasks

Spatial Language Processing in the Blind: Evidence for a Supramodal Representation and Cortical Reorganization

Neuropsychological and imaging studies have shown that the left supramarginal gyrus (SMG) is specifically involved in processing spatial terms (e.g. above, left of), which locate places and objects in the world. The current fMRI study focused on the nature and specificity of representing spatial language in the left SMG by combining behavioral and neuronal activation data in blind and sighted individuals. Data from the blind provide an elegant way to test the supramodal representation hypothesis, i.e. abstract codes representing spatial relations yielding no activation differences between blind and sighted. Indeed, the left SMG was activated during spatial language processing in both blind and sighted individuals implying a supramodal representation of spatial and other dimensional relations which does not require visual experience to develop. However, in the absence of vision functional reorganization of the visual cortex is known to take place. An important consideration with respect to our finding is the amount of functional reorganization during language processing in our blind participants. Therefore, the participants also performed a verb generation task. We observed that only in the blind occipital areas were activated during covert language generation. Additionally, in the first task there was functional reorganization observed for processing language with a high linguistic load. As the visual cortex was not specifically active for spatial contents in the first task, and no reorganization was observed in the SMG, the latter finding further supports the notion that the left SMG is the main node for a supramodal representation of verbal spatial relations

Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's Disease: a cross-sectional study

BACKGROUND: The presence of the apolipoprotein E (APOE) ε4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the ε4 allele on hippocampal activation has not been firmly established. METHODS: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD. RESULTS: We found that ε3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to ε3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in ε3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the ε3/3 homozygotes, but not in the ε3/4 heterozygotes. CONCLUSION: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE ε4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline

Functional connectivity and microstructural white matter changes in phenocopy frontotemporal dementia

Objectives: Phenocopy frontotemporal dementia (phFTD) is a rare and poorly understood clinical syndrome. PhFTD shows core behavioural variant FTD (bvFTD) symptoms without associated cognitive deficits and brain abnormalities on conventional MRI and without progression. In contrast to phFTD, functional connectivity and white matter (WM) microstructural abnormalities have been observed in bvFTD. We hypothesise that phFTD belongs to the same disease spectrum as bvFTD and investigated whether functional connectivity and microstructural WM changes similar to bvFTD are present in phFTD. Methods: Seven phFTD patients without progression or alternative psychiatric diagnosis, 12 bvFTD patients and 17 controls underwent resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Default mode network (DMN) connectivity and WM measures were compared between groups. Results: PhFTD showed subtly increased DMN connectivity and subtle microstructural changes in frontal WM tracts. BvFTD showed abnormalities in similar regions as phFTD, but had lower increased DMN connectivity and more extensive microstructural WM changes. Conclusions: Our findings can be interpreted as neuropathological changes in phFTD and are in support of the hypothesis that phFTD and bvFTD may belong to the same disease spectrum. Advanced MRI techniques, objectively identifying brain abnormalities, would therefore be potentially suited to improve the diagnosis of phFTD. Key points: • PhFTD shows brain abnormalities that are similar to bvFTD.• PhFTD shows increased functional connectivity in the parietal default mode network.• PhFTD shows microstructural white matter abnormalities in the frontal lobe.• We hypothesise phFTD and bvFTD may belong to the same disease spectrum