Jeffrey A. James

Frequent Amyloid Deposition Without Significant Cognitive Impairment Among the Elderly

OBJECTIVE To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests. DESIGN Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs). SETTING University medical center. PARTICIPANTS From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included. MAIN OUTCOME MEASURES Regional PiB retention and cognitive test performance. RESULTS Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. CONCLUSIONS Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.

Amyloid Imaging in Mild Cognitive Impairment Subtypes

We utilized the amyloid imaging ligand Pittsburgh Compound B (PiB) to determine the presence of Alzheimers disease (AD) pathology in different mild cognitive impairment (MCI) subtypes and to relate increased PiB binding to other markers of early AD and longitudinal outcome.

Basal Cerebral Metabolism May Modulate the Cognitive Effects of Aβ in Mild Cognitive Impairment: An Example of Brain Reserve

Inverse correlations between amyloid-β (Aβ) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [18F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimers disease (AD) patients, suggest local Aβ-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Aβ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Aβ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer periods of time does Aβ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

Abnormally Reduced Dorsomedial Prefrontal Cortical Activity and Effective Connectivity With Amygdala in Response to Negative Emotional Faces in Postpartum Depression

OBJECTIVE Postpartum major depression is a significant public health problem that strikes 15% of new mothers and confers adverse consequences for mothers, children, and families. The neural mechanisms involved in postpartum depression remain unknown, but brain processing of affective stimuli appears to be involved in other affective disorders. The authors examined activity in response to negative emotional faces in the dorsomedial pre-frontal cortex and amygdala, key emotion regulatory neural regions of importance to both mothering and depression. METHOD Postpartum healthy mothers (N=16) and unmedicated depressed mothers (N=14) underwent functional magnetic resonance imaging blood-oxygen-level-dependent acquisition during a block-designed face versus shape matching task. A two-way analysis of variance was performed examining main effects of condition and group and group-by-condition interaction on activity in bilateral dorsomedial prefrontal cortical and amygdala regions of interest. RESULTS Depressed mothers relative to healthy mothers had significantly reduced left dorsomedial prefrontal cortical face-related activity. In depressed mothers, there was also a significant negative correlation between left amygdala activity and postpartum depression severity and a significant positive correlation between right amygdala activity and absence of infant-related hostility. There was reliable top-down connectivity from the left dorsomedial prefrontal cortex to the left amygdala in healthy, but not depressed, mothers. CONCLUSIONS Significantly diminished dorsomedial prefrontal cortex activity and dorsomedial prefrontal cortical-amygdala effective connectivity in response to negative emotional faces may represent an important neural mechanism, or effect, of postpartum depression. Reduced amygdala activity in response to negative emotional faces is associated with greater postpartum depression severity and more impaired maternal attachment processes in postpartum depressed mothers.

Rapid Habituation of Ventral Striatal Response to Reward Receipt in Postpartum Depression

BACKGROUND Little is known about neural mechanisms of postpartum depression (PPD). Previous research notes ventral striatal activity and dopamine release increases with maternal attachment but decreases in major depressive disorder. This study tests the hypothesis that striatal response to reward is altered in PPD. METHODS Subjects underwent functional magnetic resonance imaging blood oxygenation level-dependent acquisition during a fast event-related card-guessing, monetary reward task. Time series data from an independent sample of 10 healthy mothers were used to establish the ventral striatal region of interest (ROI). Repeated-measures analysis of variance of time series data in the established ROI was then conducted for a discrete group of healthy (n = 12) and depressed, unmedicated mothers (n = 12). RESULTS Data from the independent sample of 10 healthy mothers established an ROI in the left ventral striatum (-13, 12, -4, 477 mm(3)), with cluster significance p < .01, corrected. There was a significant quadratic interaction of time × group [F(1,22) = 5.22, p = .032] in this ROI in the healthy (n = 12) and depressed mothers (n = 12). This effect represents a nonlinear attenuation of ventral striatal response with time that was greater in depressed than healthy mothers. CONCLUSIONS Rapid attenuation of ventral striatal response to reward receipt in postpartum depression might represent an important neural mechanism of postpartum depression. Additional study with infant stimuli and in relationship to mother-infant behavior is needed.

Chronotype and Diurnal Patterns of Positive Affect and Affective Neural Circuitry in Primary Insomnia

While insomnia is a well‐established risk factor for the initial onset, recurrence or relapse of affective disorders, the specific characteristics of insomnia that confer risk remain unclear. Patients with insomnia with an evening chronotype may be one particularly high‐risk group, perhaps due to alterations in positive affect and its related affective circuitry. We explored this possibility by comparing diurnal patterns of positive affect and the activity of positive affect‐related brain regions in morning‐ and evening‐types with insomnia. We assessed diurnal variation in brain activity via the relative regional cerebral metabolic rate of glucose uptake by using [18F]fluorodeoxyglucose‐positron emission tomography during morning and evening wakefulness. We focused on regions in the medial prefrontal cortex and striatum, which have been consistently linked with positive affect and reward processing. As predicted, chronotypes differed in their daily patterns in both self‐reported positive affect and associated brain regions. Evening‐types displayed diurnal patterns of positive affect characterized by phase delay and smaller amplitude compared with those of morning‐types with insomnia. In parallel, evening‐types showed a reduced degree of diurnal variation in the metabolism of both the medial prefrontal cortex and the striatum, as well as lower overall metabolism in these regions across both morning and evening wakefulness. Taken together, these preliminary findings suggest that alterations in the diurnal activity of positive affect‐related neural structures may underlie differences in the phase and amplitude of self‐reported positive affect between morning and evening chronotypes, and may constitute one mechanism for increased risk of mood disorders among evening‐type insomniacs.

Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort study

BACKGROUND The biomarker model of Alzheimers disease postulates a dynamic sequence of amyloidosis, neurodegeneration, and cognitive decline as an individual progresses from preclinical Alzheimers disease to dementia. Despite supportive evidence from cross-sectional studies, verification with long-term within-individual data is needed. METHODS For this prospective cohort study, carriers of autosomal dominant Alzheimers disease mutations (aged ≥21 years) were recruited from across the USA through referrals by physicians or from affected families. People with mutations in PSEN1, PSEN2, or APP were assessed at the University of Pittsburgh Alzheimers Disease Research Center every 1-2 years, between March 23, 2003, and Aug 1, 2014. We measured global cerebral amyloid β (Aβ) load using (11)C-Pittsburgh Compound-B PET, posterior cortical metabolism with (18)F-fluorodeoxyglucose PET, hippocampal volume (age and sex corrected) with T1-weighted MRI, verbal memory with the ten-item Consortium to Establish a Registry for Alzheimers Disease Word List Learning Delayed Recall Test, and general cognition with the Mini Mental State Examination. We estimated overall biomarker trajectories across estimated years from symptom onset using linear mixed models, and compared these estimates with cross-sectional data from cognitively normal control individuals (age 65-89 years) who were negative for amyloidosis, hypometabolism, and hippocampal atrophy. In the mutation carriers who had the longest follow-up, we examined the within-individual progression of amyloidosis, metabolism, hippocampal volume, and cognition to identify progressive within-individual changes (a significant change was defined as an increase or decrease of more than two Z scores standardised to controls). FINDINGS 16 people with mutations in PSEN1, PSEN2, or APP, aged 28-56 years, completed between two and eight assessments (a total of 83 assessments) over 2-11 years. Significant differences in mutation carriers compared with controls (p<0·01) were detected in the following order: increased amyloidosis (7·5 years before expected onset), decreased metabolism (at time of expected onset), decreased hippocampal volume and verbal memory (7·5 years after expected onset), and decreased general cognition (10 years after expected onset). Among the seven participants with longest follow-up (seven or eight assessments spanning 6-11 years), three individuals had active amyloidosis without progressive neurodegeneration or cognitive decline, two amyloid-positive individuals showed progressive neurodegeneration and cognitive decline without further progressive amyloidosis, and two amyloid-positive individuals showed neither active amyloidosis nor progressive neurodegeneration or cognitive decline. INTERPRETATION Our results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimers disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimers disease-active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline-indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimers disease. FUNDING National Institutes of Health and Howard Hughes Medical Institute.

Inter-rater reliability of manual and automated region-of-interest delineation for PiB PET

A major challenge in positron emission tomography (PET) amyloid imaging studies of Alzheimers disease (AD) is the reliable detection of early amyloid deposition in human brain. Manual region-of-interest (ROI) delineation on structural magnetic resonance (MR) images is generally the reference standard for the extraction of count-rate data from PET images, as compared to automated MR-template(s) methods that utilize spatial normalization and a single set of ROIs. The goal of this work was to assess the inter-rater reliability of manual ROI delineation for PiB PET amyloid retention measures and the impact of CSF dilution correction (CSF) on this reliability for data acquired in elderly control (n=5) and AD (n=5) subjects. The intraclass correlation coefficient (ICC) was used to measure reliability. As a secondary goal, ICC scores were also computed for PiB outcome measures obtained by an automated MR-template ROI method and one manual rater; to assess the level of reliability that could be achieved using different processing methods. Fourteen ROIs were evaluated that included anterior cingulate (ACG), precuneus (PRC) and cerebellum (CER). The PiB outcome measures were the volume of distribution (V(T)), summed tissue uptake (SUV), and corresponding ratios that were computed using CER as reference (DVR and SUVR). Substantial reliability (ICC≥0.932) was obtained across 3 manual raters for V(T) and SUV measures when CSF correction was applied across all outcomes and regions and was similar in the absence of CSF correction. The secondary analysis revealed substantial reliability in primary cortical areas between the automated and manual SUV [ICC≥0.979 (ACG/PRC)] and SUVR [ICC≥0.977/0.952 (ACG/PRC)] outcomes. The current study indicates the following rank order among the various reliability results in primary cortical areas and cerebellum (high to low): 1) V(T) or SUV manual delineation, with or without CSF correction; 2) DVR or SUVR manual delineation, with or without CSF correction; 3) SUV automated delineation, with CSF correction; and 4) SUVR automated delineation, with or without CSF correction. The high inter-rater reliability of PiB outcome measures in primary cortical areas (ACG/PRC) is important as reliable methodology is needed for the detection of low levels of amyloid deposition on a cross-sectional basis and small changes in amyloid deposition on a longitudinal basis.

A window into the invisible wound of war: Functional neuroimaging of REM sleep in returning combat veterans with PTSD

Relative regional cerebral metabolic rate of glucose in rapid eye movement (REM) sleep and wakefulness was explored in combat veterans with and without posttraumatic stress disorder PTSD, using positron emission tomography. Hypermetabolism in brain regions involved in arousal regulation, fear responses, and reward processing persist during REM sleep in combat veterans with PTSD.

Incidental Cerebral Microbleeds and Cerebral Blood Flow in Elderly Individuals

IMPORTANCE Cerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs. OBJECTIVE To evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, β-amyloid (Aβ), and cognition. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional study of 55 cognitively normal individuals with a mean (SD) age of 86.8 (2.7) years was conducted from May 1, 2010, to May 1, 2013, in an academic medical center in Pittsburgh; data analysis was performed between June 10, 2013, and April 9, 2015. INTERVENTIONS 3-Tesla magnetic resonance imaging was performed with susceptibility-weighted imaging or gradient-recalled echo to assess CMBs, arterial spin labeling for CBF, and T1- and T2-weighted imaging for atrophy, white matter hyperintensities, and infarcts. Positron emission tomography was conducted with fluorodeoxyglucose to measure cerebral metabolism and Pittsburgh compound B for fibrillar Aβ. Neuropsychological evaluation, including the Clinical Dementia Rating scale, was performed. MAIN OUTCOMES AND MEASURES Magnetic resonance images were rated for the presence and location of CMBs. Lobar CMBs were subclassified as cortical or subcortical. Measurements of CBF, metabolism, and Aβ were compared with the presence and number of CMBs with voxelwise and region-of-interest analyses. RESULTS The presence of cortical CMBs was associated with significantly reduced CBF in multiple regions on voxelwise and region-of-interest analyses (percentage difference in global CBF, -25.3%; P = .0003), with the largest reductions in the parietal cortex (-37.6%; P < .0001) and precuneus (-31.8%; P = .0006). Participants with any CMBs showed a nonsignificant trend toward reduced CBF. Participants with cortical CMBs had a significant association with greater prevalence of infarcts (24% vs 6%; P = .047) and demonstrated a trend to greater prevalence of deficits demonstrated on the Clinical Dementia Rating scale (45% vs 19%; P = .12). There was no difference in cortical amyloid (measured by Pittsburgh compound B positron emission tomography) between participants with and without CMBs (P = .60). CONCLUSIONS AND RELEVANCE In cognitively normal elderly individuals, incidental CMBs in cortical locations are associated with widespread reductions in resting-state CBF. Chronic hypoperfusion may put these people at risk for neuronal injury and neurodegeneration. Our results suggest that resting-state CBF is a marker of CMB-related small-vessel disease.