A category-selective semantic memory deficit for animate objects in semantic variant primary progressive aphasia.

Data are mixed on whether patients with semantic variant primary progressive aphasia exhibit a category-selective semantic deficit for animate objects. Moreover, there is little consensus regarding the neural substrates of this category-selective semantic deficit, though prior literature has suggested that the perirhinal cortex and the lateral posterior fusiform gyrus may support semantic memory functions important for processing animate objects. In this study, we investigated whether patients with semantic variant primary progressive aphasia exhibited a category-selective semantic deficit for animate objects in a word-picture matching task, controlling for psycholinguistic features of the stimuli, including frequency, familiarity, typicality and age of acquisition. We investigated the neural bases of this category selectivity by examining its relationship with cortical atrophy in two primary regions of interest: bilateral perirhinal cortex and lateral posterior fusiform gyri. We analysed data from 20 patients with semantic variant primary progressive aphasia (mean age = 64 years, S.D. = 6.94). For each participant, we calculated an animacy index score to denote the magnitude of the category-selective semantic deficit for animate objects. Multivariate regression analysis revealed a main effect of animacy (ß = 0.52, t = 4.03, P < 0.001) even after including all psycholinguistic variables in the model, such that animate objects were less likely to be identified correctly relative to inanimate objects. Inspection of each individual patient's data indicated the presence of a disproportionate impairment in animate objects in most patients. A linear regression analysis revealed a relationship between the right perirhinal cortex thickness and animacy index scores (ß = -0.57, t = -2.74, P = 0.015) such that patients who were more disproportionally impaired for animate relative to inanimate objects exhibited thinner right perirhinal cortex. A vertex-wise general linear model analysis restricted to the temporal lobes revealed additional associations between positive animacy index scores (i.e. a disproportionately poorer performance on animate objects) and cortical atrophy in the right perirhinal and entorhinal cortex, superior, middle, and inferior temporal gyri, and the anterior fusiform gyrus, as well as the left anterior fusiform gyrus. Taken together, our results indicate that a category-selective semantic deficit for animate objects is a characteristic feature of semantic variant primary progressive aphasia that is detectable in most individuals. Our imaging findings provide further support for the role of the right perirhinal cortex and other temporal lobe regions in the semantic processing of animate objects.

Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.

Neuroimaging in Frontotemporal Lobar Degeneration: Research and Clinical Utility.

Frontotemporal lobar dementia (FTLD) is a clinically and pathologically complex disease. Advances in neuroimaging techniques have provided a specialized set of tools to investigate underlying pathophysiology and identify clinical biomarkers that aid in diagnosis, prognostication, monitoring, and identification of appropriate endpoints in clinical trials. In this chapter, we review data discussing the utility of neuroimaging biomarkers in sporadic FTLD, with an emphasis on current and future clinical applications. Among those modalities readily utilized in clinical settings, T1-weighted structural magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) are best supported in differential diagnosis and as targets for clinical trial endpoints. However, a number of nonclinical neuroimaging modalities, including diffusion tensor imaging and resting-state functional connectivity MRI, show promise as biomarkers to predict progression and as clinical trial endpoints. Other neuroimaging modalities, including amyloid PET, Tau PET, and arterial spin labeling MRI, are also discussed, though more work is required to establish their utility in FTLD in clinical settings.

Aberrant patterns of default-mode network functional connectivity associated with metabolic syndrome: A resting-state study.

INTRODUCTION: Metabolic syndrome (MetS) is a clustering of three or more cardiovascular risk factors (RF), including hypertension, obesity, high cholesterol, or hyperglycemia. MetS and its component RFs are more prevalent in older age, and can be accompanied by alterations in brain structure. Studies have shown altered functional connectivity (FC) in samples with individual RFs as well as in clinical populations that are at higher risk to develop MetS. These studies have indicated that the default mode network (DMN) may be particularly vulnerable, yet little is known about the overall impact of MetS on FC in this network. METHODS: In this study, we evaluated the integrity of FC to the DMN in participants with MetS relative to non-MetS individuals. Using a seed-based connectivity analysis approach, resting-state functional MRI (fMRI) data were analyzed, and the FC measures among the DMN seed (isthmus of the cingulate) and rest of the brain voxels were estimated. RESULTS: Participants with MetS demonstrated reduced positive connectivity between the DMN seed and left superior frontal regions, and reduced negative connectivity between the DMN seed and left superior parietal, left postcentral, right precentral, right superior temporal and right superior parietal regions, after accounting for age- and sex-effects. CONCLUSIONS: Our results suggest that MetS is associated with alterations in FC between the DMN and other regions of the brain. Furthermore, these results indicate that the overall burden of vascular RFs associated with MetS may, in part, contribute to the pathophysiology underlying aberrant FC in the DMN.

Disruptions in resting state functional connectivity in euthymic bipolar patients with insomnia symptoms.

Insomnia is prevalent in bipolar disorder (BD) even during periods of euthymic mood. We compared resting state brain activity and cognitive function between euthymic BD with and without insomnia, and secondarily to healthy individuals. BD patients with insomnia symptoms showed a significantly lower functional connectivity within the task-positive network, compared to those without insomnia. They also showed significantly slower cognitive processing speed. These two features of BD with insomnia appeared relatively independent of each other. Preliminary findings suggest that exploration of the mechanisms of sleep disturbance in BD could lead to improved understanding and treatment of inattention in BD.

Abnormal levels of vascular endothelial biomarkers in schizophrenia.

Schizophrenia is associated with chronic low-grade inflammation, which has been linked to increased vascular risk and rates of cardiovascular disease. Levels of vascular endothelial growth factor (VEGF), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) have been related to aging and neurodegeneration, but their role in schizophrenia remains uncertain. Using a cross-sectional, case-control design, this study included 99 outpatients with schizophrenia and 99 healthy comparison subjects (HCs). Sociodemographic and clinical data were collected, and plasma levels of VEGF, ICAM-1, and VCAM-1 were assayed. A "vascular endothelial index" (VEI) was computed using logistic regression to create a composite measure that maximally differed between groups. General linear models were conducted to examine the possible role of demographic, physical, and lifestyle factors. A linear combination of ICAM-1 and VCAM-1 levels best distinguished the groups, with significantly higher levels of this composite VEI in persons with schizophrenia than HCs. Group differences in the VEI persisted after adjustment for BMI and cigarette smoking. Neither age nor gender was significantly related to the VEI. Schizophrenia patients with higher VEI had earlier age of disease onset, higher systolic and diastolic blood pressure, lower high-density lipoprotein cholesterol, higher insulin resistance, lower levels of mental well-being, and higher Framingham Coronary Heart Disease Risk scores. Schizophrenia is characterized by an elevation of vascular endothelial biomarkers, specifically cell adhesion molecules poised at the intersection between inflammatory response and vascular risk. Interventions aimed at reducing vascular risk may help reduce vascular endothelial abnormalities and prevent cardiovascular morbidity and mortality in schizophrenia.

Faulty Adaptation to Repeated Face-Name Associative Pairs in Mild Cognitive Impairment is Predictive of Cognitive Decline.

OBJECTIVE: We examined BOLD (Blood-Oxygen-Level Dependent) activity reduction upon stimuli repetition of face-name pairs in older adults with amnestic (aMCI) and non-amnestic (naMCI) mild cognitive impairment diagnosed using a comprehensive actuarial method, and relationships between activity reduction and behavioral indices. METHOD: Twenty-nine cognitively healthy older adults (CHs) and 20 with MCI (n = 12 aMCI; n = 8 naMCI) underwent functional MRI event-related imaging, a comprehensive neuropsychological battery, and 1-year follow-up exam. During scanning, participants were shown face-name pairs 1-3 times and administered a post-scan recognition task. RESULTS: The MCI group demonstrated less activity reduction upon repetition of face-name pairs within the MTL and other regions compared to CHs. Less activity reduction was associated with poorer Time 1 neuropsychological performance for the CH group and poorer post-scan recognition performance for the MCI group. Less activity reduction was related to poorer neuropsychological performance at Time 2 in the MCI group. Within MCIs, those with aMCI demonstrated less activity reduction upon repetition of face-name pairs than those with naMCI. CONCLUSIONS: Distinct patterns of brain activity were identified in the MCI group compared to CHs, and aMCI compared to naMCI. Activated regions were not restricted to traditional memory circuitry, implicating a wider network of regions involved in the encoding of associative tasks. Findings add support to the hypothesis that lack of reduced BOLD activity reflects "faulty adaptation" to repeated stimuli and that reduction in activity represents successful encoding processes. They also provide further support for use of the face-name paradigm as a marker of prodromal Alzheimer's disease, and method to distinguish between MCI subtypes.

Development and Pilot Randomized Control Trial of a Drama Program to Enhance Well-being Among Older Adults.

OBJECTIVE: Develop a novel theatre-based program and test its feasibility, tolerability, and preliminary efficacy for improving empathy/compassion and well-being among older adults. METHOD: Thirteen older adults were randomized to a 6-week Drama Workshop (DW) program or time-equivalent Backstage Pass (BP) control condition. Pre- and post-treatment measures included empathy, compassion, and mood scales. Additional post-treatment measures included self-rated change in empathy/compassion, confidence, and affect. Participants also rated their mood/affect after each session. RESULTS: The program was successfully completed and well-liked. No pre-to-post-treatment changes in empathy/compassion or mood symptoms were found in either group. Compared to BP, DW weekly ratings indicated higher levels of anxiety and lower happiness; however, the DW program had higher self-ratings of positive change in self-esteem, confidence, and happiness post-treatment. DISCUSSION: While the DW may not promote empathy/compassion and was personally challenging during the program, engagement in dramatic exercises and rehearsing and performing a dramatic piece was seen by participants as a positive growth experience, as indicated by the post-treatment ratings of enhanced self-esteem, confidence and happiness. Thus, such a program might be useful for counteracting some of the potential negative aspects of aging, including reduced self-efficacy due to physical limitations and negative affect due to losses.

Steeper Slope of Age-Related Changes in White Matter Microstructure and Processing Speed in Bipolar Disorder.

OBJECTIVES: Bipolar disorder (BD) is associated with compromised white matter (WM) integrity and deficits in processing speed (PS). Few studies, however, have investigated age relationships with WM structure and cognition to understand possible changes in brain health over the lifespan. This investigation explored whether BD and healthy counterpart (HC) participants exhibited differential age-related associations with WM and cognition, which may be suggestive of accelerated brain and cognitive aging. DESIGN: Cross-sectional study. SETTING: University of California San Diego and the Veterans Administration San Diego Healthcare System. PARTICIPANTS: 33 euthymic BD and 38 HC participants. MEASUREMENTS: Diffusion tensor imaging was acquired as a measure of WM integrity, and tract-specific fractional anisotropy (FA) was extracted utilizing the Johns Hopkins University probability atlas. PS was assessed with the Number and Letter Sequencing conditions of the Delis-Kaplan Executive Function System Trail Making Test. RESULTS: BD participants demonstrated slower PS compared with the HC group, but no group differences were found in FA across tracts. Multiple linear regressions revealed a significant group-by-age interaction for the right uncinate fasciculus, the left hippocampal portion of the cingulum, and for PS, such that older age was associated with lower FA values and slower PS in the BD group only. The relationship between age and PS did not significantly change after accounting for uncinate FA, suggesting that the observed age associations occur independently. CONCLUSIONS: Results provide support for future study of the accelerated aging hypothesis by identifying markers of brain health that demonstrate a differential age association in BD.

Bipolar Patients with Vascular Risk Display a Steeper Age-Related Negative Slope in Inhibitory Performance but Not Processing Speed: A Preliminary Study.

OBJECTIVE: Bipolar disorder (BD) is associated with cognitive deficits, yet little is known about associations between cognition, vascular risk (VR), and age in this population. This study investigated whether BD patients with VR demonstrate stronger apparent age-related decline in inhibitory performance and processing speed (PS). METHODS: A full medical history was obtained for 34 euthymic BD and 41 healthy comparison (HC) individuals. The Delis-Kaplan Executive Functions Color Word Interference Subtests were administered to all participants to assess for inhibitory performance (condition 3) and PS (conditions 1 and 2). VR positive (VRPos) and VR negative (VRNeg) groups were created based on the presence of one or more VR factors. RESULTS: VRPos-BD participants demonstrated significantly worse inhibitory performance with older age, whereas age and inhibition were not significantly related in the VRPos-HC group or in those who were VRNeg. The same was not true for PS. CONCLUSION: BD patients with VR may also be at risk for greater decline in inhibitory performance, but not PS, with age. Longitudinal studies are needed to further investigate the contributions of VR to cognitive decline among older BD patients.

Dynamic functional connectivity in bipolar disorder is associated with executive function and processing speed: A preliminary study.

OBJECTIVE: Disturbances in functional connectivity have been suggested to contribute to cognitive and emotion processing deficits observed in bipolar disorder (BD). Functional connectivity between medial prefrontal cortex (mPFC) and other brain regions may be particularly abnormal. The goal of the present study was to characterize the temporal dynamics of the default mode network (DMN) connectivity in BD and examine its association with cognition. METHOD: In a preliminary study, euthymic BD (n = 15) and healthy comparison (HC, n = 19) participants underwent resting-state functional MRI, using high-resolution sequences adapted from the Human Connectome Project, and completed neuropsychological measures of processing speed and executive function. A seed-based approach was used to measure DMN correlations in each participant, with regions of interest in the mPFC, posterior cingulate cortex (PCC), and lateral parietal cortex. Subsequently, to characterize temporal dynamics, correlational analyses between the mPFC and other DMN nodes were repeated using a sliding-window correlational analysis with subsets of the time series. RESULTS: When averaged across the entire scan, there were no group differences in overall connectivity strength between the mPFC and other regions of the DMN. However, dynamic connectivity between the mPFC and PCC was altered in BD, such that connectivity was less variable (i.e., more rigid) over time. Decreased connectivity variability was associated with slower processing speed and reduced cognitive set-shifting in BD patients. CONCLUSIONS: Variability in resting-state functional connectivity may be an index of internetwork flexibility that is reduced in BD and a correlate of ongoing cognitive impairment during periods of euthymia. (PsycINFO Database Record

Peripheral inflammation related to lower fMRI activation during a working memory task and resting functional connectivity among older adults: a preliminary study.

OBJECTIVE: Peripheral inflammation has been associated with adverse effects on cognition and brain structure in late life, a process called 'inflammaging.' Identifying biomarkers of preclinical cognitive decline is critical in the development of preventative therapies, and peripheral inflammation may be able to serve as an indicator of cognitive decline. However, little is known regarding the relationship between peripheral inflammation and brain structure and function among older adults. METHODS: Twenty-four older adults (mean age = 78) underwent a functional magnetic resonance imaging (fMRI) resting state functional connectivity scan, and a subset (n = 14) completed the n-Back working memory task in the scanner. All participants completed a blood draw, and inflammation was measured with interleukin 6 (IL-6) and C-Reactive Protein (CRP). RESULTS: Surprisingly, age was unrelated to measures of inflammation (IL-6, CRP) or brain function (default mode network (DMN) connectivity; working memory performance; blood oxygenation level dependent (BOLD) activation with higher working memory load). However, lower functional connectivity between the left parietal seed and all other DMN regions was associated with higher levels of IL-6 and CRP. Additionally, greater plasma concentration of IL-6 was associated with lower BOLD activation in the left middle frontal gyrus in response to increased working memory load. CONCLUSIONS: These preliminary findings support the importance of IL-6 and CRP in brain function among older adults. Frontal and parietal regions may be particularly sensitive to the effects of inflammation. Additionally, these findings provide preliminary evidence of inflammatory contributions to level of neural activity, even after accounting for vascular risk factors.

The temporal course and clinical correlates of subjective impulsivity in bipolar disorder as revealed through ecological momentary assessment.

BACKGROUND: Impulsivity is frequently linked with bipolar disorder and is associated with mania and negative outcomes. The temporal dynamics of subjective impulsivity are unclear, in particular whether impulsivity precedes or follows changes in positive or negative affect. METHODS: A total of 41 outpatients with bipolar disorder (I or II) were provided with mobile devices for 11 weeks and completed twice-daily surveys about affective states and subjective impulsivity. We examined the association between aggregate subjective impulsivity with baseline global cognitive function, suicide risk ratings, and medication adherence, as well as concurrent and lagged associations with momentary positive and negative affect ratings. RESULTS: A total of 2902 ratings were available across study subjects. Higher aggregate mean ratings of impulsivity were associated with worse baseline global cognitive function, prior suicide attempts, and self-reported problems with medication adherence, as well as more severe manic (but not depressive) symptoms. Time-lagged models indicated that greater negative affect, but not positive affect, predicted subsequent increases in subjective impulsivity, which, in turn, predicted diminished positive affect. LIMITATIONS: Other measures of impulsivity with which to validate subjective ratings were unavailable and the sample was restricted to generally clinically stable outpatients. CONCLUSIONS: Subjective impulsivity as measured by daily monitoring was associated with worse cognitive function and self-rated medication adherence, and higher suicide risk ratings. Impulsivity may be a maladaptive strategy to regulate negative affect in bipolar disorder.

Distinct neural correlates of emotional and cognitive empathy in older adults.

Empathy is thought to be a mechanism underlying prosocial behavior across the lifespan, yet little is known about how levels of empathy relate to individual differences in brain functioning among older adults. In this exploratory study, we examined the neural correlates of affective and cognitive empathy in older adults. Thirty older adults (M=79 years) underwent fMRI scanning and neuropsychological testing and completed a test of affective and cognitive empathy. Brain response during processing of cognitive and emotional stimuli was measured by fMRI in a priori and task-related regions and was correlated with levels of empathy. Older adults with higher levels of affective empathy showed more deactivation in the amygdala and insula during a working memory task, whereas those with higher cognitive empathy showed greater insula activation during a response inhibition task. Our preliminary findings suggest that brain systems linked to emotional and social processing respond differently among older adults with more or less affective and cognitive empathy. That these relationships can be seen both during affective and non-emotional tasks of "cold" cognitive abilities suggests that empathy may impact social behavior through both emotional and cognitive mechanisms.

Increased cerebral blood flow associated with better response inhibition in bipolar disorder.

Impairment on inhibitory tasks has been well documented in bipolar disorder (BD). Differences in cerebral blood flow (CBF) between BD patients and healthy comparison (HC) participants have also been reported. Few studies have examined the relationship between cognitive performance and regional CBF in this patient population. We hypothesized that group differences on an inhibitory task (the Delis-Kaplan Executive Function Scale's Color-Word Inhibition task) would be associated with differential CBF in bilateral anterior cingulate cortex (ACC), inferior parietal lobule (IPL) and dorsolateral prefrontal cortex (DLPFC) regions. Whole brain resting CBF was measured using Multiphase Pseudocontinuous Arterial Spin Labeling MR imaging for 28 euthymic BD and 36 HC participants. Total gray matter (GM) CBF was measured, and regional CBF values were extracted for each region of interest (ROI) using Freesurfer-based individual parcellations. Group, CBF, and group-by-CBF interaction were examined as predictors of inhibition performance. Groups did not differ in age, gender or education. BD patients performed significantly worse on Color-Word inhibition. There were no significant group differences in CBF in either total GM or in any ROI. There was a group by CBF interaction in the bilateral ACC, right IPL and right DLPFC such that better inhibitory performance was generally associated with higher resting state CBF in BD subjects, but not HC participants. Although CBF was not abnormal in this euthymic BD sample, results confirm previous reports of inter-episode inhibitory deficits and indicate that the perfusion-cognition relationship is different in BD compared to HC individuals.

Elevated cerebrovascular resistance index is associated with cognitive dysfunction in the very-old.

INTRODUCTION: Age-related vascular changes, including blood pressure elevation and cerebral blood flow (CBF) reduction, are associated with cognitive decline and Alzheimer's disease (AD). Evidence suggests that the relationship between blood pressure and dementia risk varies between younger and older samples within the elderly population. METHODS: We examined the relationship between mean arterial pressure (MAP), CBF, and cognition in young-old (60 to 75 years of age) versus very-old (80+ years of age) adults. Fifty-eight non-demented older adults completed an arterial spin labeling MRI scan, and an index of cerebrovascular resistance (CVRi) was estimated for each participant by calculating the ratio of MAP and CBF. RESULTS: Results demonstrated a similar negative relationship between MAP and CBF across both age groups. However, very-old participants exhibited elevated CVRi and reduced CBF compared to young-old participants in regions implicated in AD and cerebral small vessel disease. Furthermore, significant age by CVRi interactions revealed that elevated CVRi in the thalamus was inversely related to verbal fluency performance in the very-old group. CONCLUSIONS: Findings support CVRi as a potential vascular biomarker and suggest that regionally-specific vascular changes may contribute to cognitive decline, particularly in the very-old.

Interactive effects of vascular risk burden and advanced age on cerebral blood flow.

Vascular risk factors and cerebral blood flow (CBF) reduction have been linked to increased risk of cognitive impairment and Alzheimer's disease (AD); however the possible moderating effects of age and vascular risk burden on CBF in late life remain understudied. We examined the relationships among elevated vascular risk burden, age, CBF, and cognition. Seventy-one non-demented older adults completed an arterial spin labeling MR scan, neuropsychological assessment, and medical history interview. Relationships among vascular risk burden, age, and CBF were examined in a priori regions of interest (ROIs) previously implicated in aging and AD. Interaction effects indicated that, among older adults with elevated vascular risk burden (i.e., multiple vascular risk factors), advancing age was significantly associated with reduced cortical CBF whereas there was no such relationship for those with low vascular risk burden (i.e., no or one vascular risk factor). This pattern was observed in cortical ROIs including medial temporal (hippocampus, parahippocampal gyrus, uncus), inferior parietal (supramarginal gyrus, inferior parietal lobule, angular gyrus), and frontal (anterior cingulate, middle frontal gyrus, medial frontal gyrus) cortices. Furthermore, among those with elevated vascular risk, reduced CBF was associated with poorer cognitive performance. Such findings suggest that older adults with elevated vascular risk burden may be particularly vulnerable to cognitive change as a function of CBF reductions. Findings support the use of CBF as a potential biomarker in preclinical AD and suggest that vascular risk burden and regionally-specific CBF changes may contribute to differential age-related cognitive declines.

Cortical and subcortical cerebrovascular resistance index in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer's disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease. OBJECTIVE: To compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF. METHODS: Eighty-one participants (12 AD, 23 MCI, 46 NC) were compared on CVRi using voxel-wise analyses. Region-of-interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume. RESULTS: Voxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior cingulate). MCI participants exhibited intermediate CVRi values within cortical and medial temporal areas. Significant CVRi clusters were larger and more widespread than those of parallel CBF analyses. Among MCI and AD participants, subcortical CVRi elevation was associated with lower Dementia Rating Scale score (r = -0.52, p = 0.001, for both thalamus and caudate), and caudate CVRi correlated with WML volume (r = 0.45, p = 0.001). CONCLUSIONS: Cortical and subcortical CVRi is elevated in AD, particularly within the caudate and thalamus, where it is associated with decreased cognitive performance and increased WMLs. Findings suggest CVRi may play a role in cognitive decline and cerebrovascular disease in MCI and AD.

Interaction of age and APOE genotype on cerebral blood flow at rest.

We investigated the impact of APOE genotype on cerebral blood flow (CBF) in older and younger adults. Forty cognitively normal older adults (16 ε4 carriers, 24 non-ε4 carriers) and 30 younger adults (15 ε4 carriers, 15 non-ε4 carriers) completed a resting-state whole-brain pulsed arterial spin labeling magnetic resonance scan. Main effects of aging were demonstrated wherein older adults had decreased gray matter CBF corrected for partial volume effects compared to younger adults in widespread brain regions. Main effects of APOE genotype were also observed wherein ε4 carriers displayed greater CBF in the left lingual gyrus and precuneus than non-carriers. An interaction between age and APOE genotype in the left anterior cingulate cortex (ACC) was characterized by reduced CBF in older ε4 carriers and increased CBF in young ε4 carriers. Increased CBF in the left ACC resulting from the interaction of age group and APOE genotype was positively correlated with executive functioning in young ε4 adults (r = 0.61, p = 0.04). Results demonstrate APOE genotype differentially impacts cerebrovascular function across the lifespan and may modify the relationship between CBF and cognition. Findings may partially support suggestions that the gene exerts antagonistic pleiotropic effects.