Neuromark PET: A multivariate method for Estimating and comparing whole brain functional networks and connectomes from fMRI and PET data.

Positron emission tomography (PET) and magnetic resonance imaging (MRI) are both widely used neuroimaging techniques to study brain function. Although whole brain resting functional MRI (fMRI) connectomes are widely used, the integration or association of whole brain functional connectomes with PET data are rarely done. This likely stems from the fact that PET data is typically analyzed by using a regions of interest approach, while whole brain spatial networks and their connectivity (covariation) receive much less attention. As a result, to date, there have been no direct comparisons between whole brain PET and fMRI connectomes. In this study, we present a method that uses spatially constrained independent component analysis (scICA) to estimate corresponding PET and fMRI connectomes and examine the relationship between them using mild cognitive impairment (MCI) datasets. Our results demonstrate highly modularized PET connectome patterns that complement those identified from resting fMRI. In particular, fMRI showed strong intra-domain connectivity with interdomain anticorrelation in sensorimotor and visual domains as well as default mode network. PET amyloid data showed similar strong intra-domain effects, but showed much higher correlations within cognitive control and default mode domains, as well as anticorrelation between cerebellum and other domains. The estimated PET networks have similar, but not identical, network spatial patterns to the resting fMRI networks, with the PET networks being slightly smoother and, in some cases, showing variations in subnodes. We also analyzed the differences between individuals with MCI receiving medication versus a placebo. Results show both common and modality specific treatment effects on fMRI and PET connectomes. From our fMRI analysis, we observed higher activation differences in various regions, such as the connection between the thalamus and middle occipital gyrus, as well as the insula and right middle occipital gyrus. Meanwhile, the PET analysis revealed increased activation between the anterior cingulate cortex and the left inferior parietal lobe, along with other regions, in individuals who received medication versus placebo. In sum, our novel approach identifies corresponding whole-brain PET and fMRI networks and connectomes. While we observed common patterns of network connectivity, our analysis of the MCI treatment and placebo groups revealed that each modality identifies a unique set of networks, highlighting differences between the two groups.

Anti-Amyloid Therapy, AD, and ARIA: Untangling the Role of CAA.

Anti-amyloid therapies (AATs), such as anti-amyloid monoclonal antibodies, are emerging treatments for people with early Alzheimer's disease (AD). AATs target amyloid ß plaques in the brain. Amyloid-related imaging abnormalities (ARIA), abnormal signals seen on magnetic resonance imaging (MRI) of the brain in patients with AD, may occur spontaneously but occur more frequently as side effects of AATs. Cerebral amyloid angiopathy (CAA) is a major risk factor for ARIA. Amyloid ß plays a key role in the pathogenesis of AD and of CAA. Amyloid ß accumulation in the brain parenchyma as plaques is a pathological hallmark of AD, whereas amyloid ß accumulation in cerebral vessels leads to CAA. A better understanding of the pathophysiology of ARIA is necessary for early detection of those at highest risk. This could lead to improved risk stratification and the ultimate reduction of symptomatic ARIA. Histopathological confirmation of CAA by brain biopsy or autopsy is the gold standard but is not clinically feasible. MRI is an available in vivo tool for detecting CAA. Cerebrospinal fluid amyloid ß level testing and amyloid PET imaging are available but do not offer specificity for CAA vs amyloid plaques in AD. Thus, developing and testing biomarkers as reliable and sensitive screening tools for the presence and severity of CAA is a priority to minimize ARIA complications.

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment.

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-ß42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-ß42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.

Recognition Memory Performance as a Cognitive Marker of Prodromal Alzheimer's Disease.

BACKGROUND: The utility of recognition memory for identifying persons with biomarker evidence of Alzheimer's disease (AD) is unclear since prior studies of mild cognitive impairment (MCI) relied only on clinical diagnosis and did not include simultaneous measures of central amyloidosis and tauopathy. OBJECTIVE: We evaluated whether recognition memory and associated indices, including discriminability and response bias from signal detection theory, differentiate persons with amnestic MCI (aMCI) due to prodromal AD from non-prodromal AD. METHOD: Sixty older adults with aMCI were classified as prodromal AD (n = 28) or non-prodromal AD (n = 32) based upon cerebrospinal fluid levels of amyloid-ß and tau. Memory was assessed using the Hopkins Verbal Learning Test-Revised which includes free recall and recognition. RESULTS: ANCOVAs adjusting for age indicated comparable (all p > 0.05) performances between prodromal and non-prodromal MCI groups respectively on traditional HVLT-R recognition measures of hits (mean±SD: 9.5±3.0 versus 10.9±1.7), false alarms (1.8±1.8 versus 1.5±1.5), and hits minus false alarms (7.7±3.0 versus 9.2±2.6). In contrast, discriminability (d'), which reflects how easily targets and distractors are distinguished, was significantly (p = 0.009) poorer in the prodromal versus non-prodromal groups (3.1±1.9 versus 4.8±2.0, effect size = 0.87). In addition, only d' significantly predicted group membership (OR = 0.66, CI = 0.48-0.92, p = 0.04). Response bias, the tendency to report that a target did or did not appear, was comparable between groups (0.08±1.1 versus -0.04±1.3). CONCLUSION: Recognition discriminability is significantly poorer in aMCI with biomarker evidence of prodromal AD. In contrast to traditional recognition indices, discriminability from signal detection theory may be superior in identifying aMCI due to AD versus non-AD etiologies.

Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study.

BACKGROUND: Redox signaling, which can be assessed by circulating aminothiols, reflects oxidative stress (OS) status and has been linked to clinical cardiovascular disease and its risk factors. These, in turn, are related to executive function decline. OS may precede the pro-inflammatory state seen in vascular disease. The objective of this study is to investigate the association between aminothiol markers of OS and inflammation in cognitive decline, especially in the executive cognitive domain which is highly susceptible to cardiovascular risk factors and is an important predictor of cognitive disability. METHODS: The study design is that of a longitudinal cohort study within the setting of a large academic institution with participants being university employees (n = 511), mean age 49 years, 68% women, and 23% African-American. These participants were followed for four consecutive years with a yearly cognitive assessment conducted using computerized versions of 15 cognitive tests. Peripheral cystine, glutathione, their disulfide derivatives, and C-reactive protein (CRP) were measured. RESULTS: Lower levels of glutathione at baseline was associated with a decline in the executive domain over 4 years (covariate-adjusted relative risk (RR) for glutathione = 1.70 (95% CI = 1.02-2.85), p = 0.04). Furthermore, a longitudinal decline in glutathione level was associated with a faster decline in the executive domain (p = 0.03). None of the other OS markers or CRP were linked to cognitive decline over 4 years. CONCLUSION: Increased OS reflected by decreased glutathione was associated with a decline in executive function in a healthy population. In contrast, inflammation was not linked to cognitive decline. OS may be an earlier biomarker that precedes the inflammatory phase of executive decline with aging.

The impact of lifestyle behavior on hypertension awareness, treatment, and control in a southeastern population.

BACKGROUND: We were interested in determining the rates of hypertension awareness, treatment, and control in individuals living in the southeastern United States and evaluating the impact of lifestyle behaviors on these rates. METHODS: This is a cross-sectional survey of a sample of community dwellers in the greater Columbia, South Carolina area. The survey was developed from validated community-based survey questionnaires to evaluate demographic and social history (age, gender, race-ethnicity, income, and education), hypertension history (diagnosis and treatment), and lifestyle behavior (servings of fruits and vegetables [FV] and physical activity [PA] duration and frequency), as well as blood pressure measurement. RESULTS: A total of 763 people (mean +/- standard error age 52.4 +/- 0.7 years; 68% women, 53% African American) agreed to be screened. Of all participants with hypertension (438 [58%]), 82% were aware of their illness and 79% were on treatment. Of all hypertensive participants, 39% had their hypertension controlled below 140/90 mm Hg at the time of the survey. Only 11% reported consuming five or more FV per day and 18% reported PA five or more times per week. African-Americans consumed less FV (P < 0.001) and performed less PA (P < 0.001). Those consuming more FV and exercising more frequently had lower hypertension prevalence and tended to have better control rates. CONCLUSIONS: In a sample of southeastern residents, the control rate was suboptimal despite a relatively high rate of treatment. Low levels of FV consumption and PA were noted especially in African-American patients and may explain this rate.