Brain age of rhesus macaques over the lifespan.

Through the application of machine learning algorithms to neuroimaging data the brain age methodology was shown to provide a useful individual-level biological age prediction and identify key brain regions responsible for the prediction. In this study, we present the methodology of constructing a rhesus macaque brain age model using a machine learning algorithm and discuss the key predictive brain regions in comparison to the human brain, to shed light on cross-species primate similarities and differences. Structural information of the brain (e.g., parcellated volumes) from brain magnetic resonance imaging of 43 rhesus macaques were used to develop brain atlas-based features to build a brain age model that predicts biological age. The best-performing model used 22 selected features and achieved an R2 of 0.72. We also identified interpretable predictive brain features including Right Fronto-orbital Cortex, Right Frontal Pole, Right Inferior Lateral Parietal Cortex, and Bilateral Posterior Central Operculum. Our findings provide converging evidence of the parallel and comparable brain regions responsible for both non-human primates and human biological age prediction.

Human-to-monkey transfer learning identifies the frontal white matter as a key determinant for predicting monkey brain age.

The application of artificial intelligence (AI) to summarize a whole-brain magnetic resonance image (MRI) into an effective "brain age" metric can provide a holistic, individualized, and objective view of how the brain interacts with various factors (e.g., genetics and lifestyle) during aging. Brain age predictions using deep learning (DL) have been widely used to quantify the developmental status of human brains, but their wider application to serve biomedical purposes is under criticism for requiring large samples and complicated interpretability. Animal models, i.e., rhesus monkeys, have offered a unique lens to understand the human brain - being a species in which aging patterns are similar, for which environmental and lifestyle factors are more readily controlled. However, applying DL methods in animal models suffers from data insufficiency as the availability of animal brain MRIs is limited compared to many thousands of human MRIs. We showed that transfer learning can mitigate the sample size problem, where transferring the pre-trained AI models from 8,859 human brain MRIs improved monkey brain age estimation accuracy and stability. The highest accuracy and stability occurred when transferring the 3D ResNet [mean absolute error (MAE) = 1.83 years] and the 2D global-local transformer (MAE = 1.92 years) models. Our models identified the frontal white matter as the most important feature for monkey brain age predictions, which is consistent with previous histological findings. This first DL-based, anatomically interpretable, and adaptive brain age estimator could broaden the application of AI techniques to various animal or disease samples and widen opportunities for research in non-human primate brains across the lifespan.

Associations between white matter integrity of the cingulum bundle, surrounding gray matter regions, and cognition across the dementia continuum.

INTRODUCTION: Previous Alzheimer's disease and related dementias (AD/ADRD) research studies have illustrated the significance of studying alterations in white matter (WM). Fewer studies have examined how WM integrity, measured with diffusion tensor imaging (DTI), is associated with volume of gray matter (GM) regions and measures of cognitive function in aged participants spanning the dementia continuum. METHODS: Magnetic resonance imaging and cognitive data were collected from 241 Boston University Alzheimer's Disease Research Center participants who spanned from cognitively normal controls to amnestic mild cognitive impairment to having dementia. Primary DTI tracts of interest were the cingulum ventral (CV) and cingulum dorsal (CD) pathways. GM regions of interest (ROIs) were in the medial temporal lobe (MTL), prefrontal cortex, and retrosplenial cortex. Analyses of covariance models were used to assess differences in WM integrity across groups (control, amnestic mild cognitive impairment, and dementia). Multiple linear regression models were used to assess associations between WM integrity and GM volume, and with measures of memory and executive function. RESULTS: Differences in WM integrity were shown in both cingulum pathways in participants across the dementia continuum. Associations between WM integrity of both cingulum pathways and volume of selected GM ROIs were widespread. Functionally significant associations were found between WM of the CV pathway and memory, independent of MTL GM volume. DISCUSSION: Differences in WM integrity of the cingulum bundle and surrounding GM ROI are likely related to the progression of AD/ADRD. Such differences should continue to be studied, particularly in association with memory performance.

Cross-sectional and longitudinal evaluation of plasma glial fibrillary acidic protein to detect and predict clinical syndromes of Alzheimer's disease.

Introduction: This study examined plasma glial fibrillary acidic protein (GFAP) as a biomarker of cognitive impairment due to Alzheimer's disease (AD) with and against plasma neurofilament light chain (NfL), and phosphorylated tau (p-tau)181+231. Methods: Plasma samples were analyzed using Simoa platform for 567 participants spanning the AD continuum. Cognitive diagnosis, neuropsychological testing, and dementia severity were examined for cross-sectional and longitudinal outcomes. Results: Plasma GFAP discriminated AD dementia from normal cognition (adjusted mean difference = 0.90 standard deviation [SD]) and mild cognitive impairment (adjusted mean difference = 0.72 SD), and demonstrated superior discrimination compared to alternative plasma biomarkers. Higher GFAP was associated with worse dementia severity and worse performance on 11 of 12 neuropsychological tests. Longitudinally, GFAP predicted decline in memory, but did not predict conversion to mild cognitive impairment or dementia. Discussion: Plasma GFAP was associated with clinical outcomes related to suspected AD and could be of assistance in a plasma biomarker panel to detect in vivo AD.

Identification of an APOE ε4-specific blood-based molecular pathway for Alzheimer's disease risk.

INTRODUCTION: The precise apolipoprotein E (APOE) ε4-specific molecular pathway(s) for Alzheimer's disease (AD) risk are unclear. METHODS: Plasma protein modules/cascades were analyzed using weighted gene co-expression network analysis (WGCNA) in the Alzheimer's Disease Neuroimaging Initiative study. Multivariable regression analyses were used to examine the associations among protein modules, AD diagnoses, cerebrospinal fluid (CSF) phosphorylated tau (p-tau), and brain glucose metabolism, stratified by APOE genotype. RESULTS: The Green Module was associated with AD diagnosis in APOE ε4 homozygotes. Three proteins from this module, C-reactive protein (CRP), complement C3, and complement factor H (CFH), had dose-dependent associations with CSF p-tau and cognitive impairment only in APOE ε4 homozygotes. The link among these three proteins and glucose hypometabolism was observed in brain regions of the default mode network (DMN) in APOE ε4 homozygotes. A Framingham Heart Study validation study supported the findings for AD. DISCUSSION: The study identifies the APOE ε4-specific CRP-C3-CFH inflammation pathway for AD, suggesting potential drug targets for the disease.Highlights: Identification of an APOE ε4 specific molecular pathway involving blood CRP, C3, and CFH for the risk of AD.CRP, C3, and CFH had dose-dependent associations with CSF p-Tau and brain glucose hypometabolism as well as with cognitive impairment only in APOE ε4 homozygotes.Targeting CRP, C3, and CFH may be protective and therapeutic for AD onset in APOE ε4 carriers.

Biomarkers of Alzheimer's disease in Black and/or African American Alzheimer's Disease Neuroimaging Initiative (ADNI) participants.

Majority of dementia research is conducted in non-Hispanic White participants despite a greater prevalence of dementia in other racial groups. To obtain a better understanding of biomarker presentation of Alzheimer's disease (AD) in the non-Hispanic White population, this study exclusively examined AD biomarker abnormalities in 85 Black and/or African American participants within the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants were classified by the ADNI into 3 clinical groups: cognitively normal, mild cognitive impairment, or dementia. Data examined included demographics, apolipoprotein E (APOE) ε4, cerebrospinal fluid (CSF) Aß1-42, CSF total tau (t-tau), CSF phosphorylated tau (p-tau), 3T magnetic resonance imaging (MRI), and measures of cognition and function. Analyses of variance and covariance showed lower cortical thickness in 5 of 7 selected MRI regions, lower hippocampal volume, greater volume of white matter hyperintensities, lower measures of cognition and function, lower measures of CSF Aß1-42, and greater measures of CSF t-tau and p-tau between clinical groups. Our findings confirmed greater AD biomarker abnormalities between clinical groups in this sample.

Event-related Potentials Corresponding to Decision-making Under Uncertain Conditions.

BACKGROUND: Decision-making is essential to human functioning, and resolving uncertainty is an essential part of decision-making. Impaired decision-making is present in many pathological conditions, and identifying markers of decision-making under uncertainty will provide a measure of clinical impact in future studies of therapeutic intervention for impaired decision-making. OBJECTIVE: To describe EEG event-related potentials (ERPs) correlating with decision-making under uncertain conditions when compared with certain conditions. METHOD: We used a novel card-matching task based on the Wisconsin Card Sorting Test to describe the neural correlates of uncertainty, as measured by EEG, in a group of 27 neurotypical individuals. We evaluated 500-ms intervals in the 2 seconds after card presentation to identify ERPs that are associated with maximal uncertainty compared with maximal certainty. RESULTS: After correcting for multiple comparisons, we identified an ERP in the 500-1000-ms time frame (certain > uncertain, max amplitude 12.73 µV, latency 914 ms) in the left posterior inferior region of the scalp. We also found a P300-like ERP in the left frontal and parietal regions in the 0-500-ms time frame when the individuals received correct versus incorrect feedback (incorrect feedback > correct feedback, max amplitude 1.625 µV, latency 339 ms). CONCLUSION: We identified an ERP in the 500-1000-ms time frame (certain > uncertain) that may reflect the resolution of uncertainty, as well as a P300-like ERP when feedback is presented (incorrect feedback > correct feedback). These findings can be used in future studies to improve decision-making and resolve uncertainty on the described markers.

Neuronal properties of pyramidal cells in lateral prefrontal cortex of the aging rhesus monkey brain are associated with performance deficits on spatial working memory but not executive function.

Age-related declines in cognitive abilities occur as early as middle-age in humans and rhesus monkeys. Specifically, performance by aged individuals on tasks of executive function (EF) and working memory (WM) is characterized by greater frequency of errors, shorter memory spans, increased frequency of perseverative responses, impaired use of feedback and reduced speed of processing. However, how aging precisely differentially impacts specific aspects of these cognitive functions and the distinct brain areas mediating cognition are not well understood. The prefrontal cortex (PFC) is known to mediate EF and WM and is an area that shows a vulnerability to age-related alterations in neuronal morphology. In the current study, we show that performance on EF and WM tasks exhibited significant changes with age, and these impairments correlate with changes in biophysical properties of layer 3 (L3) pyramidal neurons in lateral LPFC (LPFC). Specifically, there was a significant age-related increase in excitability of L3 LPFC pyramidal neurons, consistent with previous studies. Further, this age-related hyperexcitability of LPFC neurons was significantly correlated with age-related decline on a task of WM, but not an EF task. The current study characterizes age-related performance on tasks of WM and EF and provides insight into the neural substrates that may underlie changes in both WM and EF with age.

Annualized changes in rate of amyloid deposition and neurodegeneration are greater in participants who become amyloid positive than those who remain amyloid negative.

This study longitudinally examined participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who underwent a conversion in amyloid-beta (Aß) status in comparison to a group of ADNI participants who did not show a change in amyloid status over the same follow-up period. Participants included 136 ADNI dementia-free participants with 2 florbetapir positron emission tomography (PET) scans. Of these participants, 68 showed amyloid conversion as measured on florbetapir PET, and the other 68 did not. Amyloid converters and non-converters were chosen to have representative demographic data (age, education, sex, diagnostic status, and race). The amyloid converter group showed increased prevalence of APOE ε4 (p < 0.001), greater annualized percent volume loss in selected magnetic resonance imaging (MRI) regions (p < 0.05), lower cerebrospinal fluid Aß1-42 (p < 0.001), and greater amyloid retention (as measured by standard uptake value ratios) on florbetapir PET scans (p < 0.001) in comparison to the non-converter group. These results provide compelling evidence that important neuropathological changes are occurring alongside amyloid conversion.

Prefrontal and medial temporal interactions in memory functions in the rhesus monkey.

Both the medial temporal lobe and the dorsolateral prefrontal cortex have been implicated in learning and memory. However, it has been difficult to ascertain the degree to which the two structures are dependent on each other or interact in subserving these cognitive functions. To investigate this question directly, we prepared two group of monkeys. First, the contralateral frontal-hippocampal split group (CFHS) received a unilateral lesion of the hippocampus and surrounding posterior parahippocampal cortices (H +), combined with a contralateral lesion of the dorsolateral prefrontal cortex (DLPFC) plus transection of the corpus callosum and anterior commissure. This preparation functionally "disconnects" the remaining intact H + from the sole intact DLPFC in the opposite hemisphere. As a surgical control group, a second set of animals, the ipsilateral frontal-hippocampal split group, was prepared with a unilateral lesion of the DLPFC and an ipsilateral H + lesion together plus transection of the corpus callosum and anterior commissure. This preparation matches the locus and extent of damage in the cross-lesion group but allows the intact H + and intact DLPFC to interact ipsilaterally. Following recovery from surgery, all animals were then tested on the delayed nonmatching to sample task (DNMS), a test of recognition memory. The crossed-lesion split-brain group (CFHS) was markedly impaired on DNMS in both acquisition (rule learning) and performance over delays (recognition memory). The results provide evidence of a functionally dependent interaction between the medial temporal lobe and the dorsolateral prefrontal cortex in learning and memory. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neuronal properties of pyramidal cells in lateral prefrontal cortex of the aging rhesus monkey brain are associated with performance deficits on spatial working memory but not executive function.

Age-related declines in cognitive abilities occur as early as middle-age in humans and rhesus monkeys. Specifically, performance by aged individuals on tasks of executive function (EF) and working memory (WM) is characterized by greater frequency of errors, shorter memory spans, increased frequency of perseverative responses, impaired use of feedback and reduced speed of processing. However, how aging precisely differentially impacts specific aspects of these cognitive functions and the distinct brain areas mediating cognition are not well understood. The prefrontal cortex (PFC) is known to mediate EF and WM and is an area that shows a vulnerability to age-related alterations in neuronal morphology. In the current study, we show that performance on EF and WM tasks exhibited significant changes with age and these impairments correlate with changes in biophysical properties of L3 pyramidal neurons in lateral LPFC (LPFC). Specifically, there was a significant age-related increase in excitability of Layer 3 LPFC pyramidal neurons, consistent with previous studies. Further, this age-related hyperexcitability of LPFC neurons was significantly correlated with age-related decline on a task of WM, but not an EF task. The current study characterizes age-related performance on tasks of WM and EF and provides insight into the neural substrates that may underlie changes in both WM and EF with age.

The prevalence of mild cognitive impairment in Gulf War veterans: a follow-up study.

Introduction: Gulf War Illness (GWI), also called Chronic Multisymptom Illness (CMI), is a multi-faceted condition that plagues an estimated 250,000 Gulf War (GW) veterans. Symptoms of GWI/CMI include fatigue, pain, and cognitive dysfunction. We previously reported that 12% of a convenience sample of middle aged (median age 52 years) GW veterans met criteria for mild cognitive impairment (MCI), a clinical syndrome most prevalent in older adults (e.g., ≥70 years). The current study sought to replicate and extend this finding. Methods: We used the actuarial neuropsychological criteria and the Montreal Cognitive Assessment (MoCA) to assess the cognitive status of 952 GW veterans. We also examined regional brain volumes in a subset of GW veterans (n = 368) who had three Tesla magnetic resonance images (MRIs). Results: We replicated our previous finding of a greater than 10% rate of MCI in four additional cohorts of GW veterans. In the combined sample of 952 GW veterans (median age 51 years at time of cognitive testing), 17% met criteria for MCI. Veterans classified as MCI were more likely to have CMI, history of depression, and prolonged (≥31 days) deployment-related exposures to smoke from oil well fires and chemical nerve agents compared to veterans with unimpaired and intermediate cognitive status. We also replicated our previous finding of hippocampal atrophy in veterans with MCI, and found significant group differences in lateral ventricle volumes. Discussion: Because MCI increases the risk for late-life dementia and impacts quality of life, it may be prudent to counsel GW veterans with cognitive dysfunction, CMI, history of depression, and high levels of exposures to deployment-related toxicants to adopt lifestyle habits that have been associated with lowering dementia risk. With the Food and Drug Administration's recent approval of and the VA's decision to cover the cost for anti-amyloid ß (Aß) therapies, a logical next step for this research is to determine if GW veterans with MCI have elevated Aß in their brains.

Different loneliness types, cognitive function, and brain structure in midlife: Findings from the Framingham Heart Study.

Background: It remains unclear whether persistent loneliness is related to brain structures that are associated with cognitive decline and development of Alzheimer's disease (AD). This study aimed to investigate the relationships between different loneliness types, cognitive functioning, and regional brain volumes. Methods: Loneliness was measured longitudinally, using the item from the Center for Epidemiologic Studies Depression Scale in the Framingham Heart Study, Generation 3, with participants' average age of 46·3 ± 8·6 years. Robust regression models tested the association between different loneliness types with longitudinal neuropsychological performance (n = 2,609) and regional magnetic resonance imaging brain data (n = 1,829) (2002-2019). Results were stratified for sex, depression, and Apolipoprotein E4 (ApoE4). Findings: Persistent loneliness, but not transient loneliness, was strongly associated with cognitive decline, especially memory and executive function. Persistent loneliness was negatively associated with temporal lobe volume (ß = -0.18, 95%CI [-0.32, -0.04], P = 0·01). Among women, persistent loneliness was associated with smaller frontal lobe (ß = -0.19, 95%CI [-0.38, -0.01], P = 0·04), temporal lobe (ß = -0.20, 95%CI [-0.37, -0.03], P = 0·02), and hippocampus volumes (ß = -0.23, 95%CI [-0.40, -0.06], P = 0·007), and larger lateral ventricle volume (ß = 0.15, 95%CI [0.02, 0.28], P = 0·03). The higher cumulative loneliness scores across three exams, the smaller parietal, temporal, and hippocampus volumes and larger lateral ventricle were evident, especially in the presence of ApoE4. Interpretation: Persistent loneliness in midlife was associated with atrophy in brain regions responsible for memory and executive dysfunction. Interventions to reduce the chronicity of loneliness may mitigate the risk of age-related cognitive decline and AD. Funding: US National Institute on Aging.

Association of Carotid Intima Media Thickening with Future Brain Region Specific Amyloid-ß Burden.

BACKGROUND: Carotid atherosclerosis is associated with cognitive impairment and dementia, though there is limited evidence of a direct link between carotid disease and amyloid-ß (Aß) burden. OBJECTIVE: We studied the association of baseline and progressive carotid intima media thickness (CIMT) with Aß on 11C-Pittsburgh Compound B (PiB) to determine if those with carotid atherosclerosis would have higher Aß burden. METHODS: We studied 47 participants from the Framingham Offspring cohort with carotid ultrasounds measuring CIMT at their 6th clinic examination (aged 49.5±5.7 years) and an average of 9.6 years later, and PiB imaging measuring Aß on average 22.1 years post baseline. We used multivariate linear regression analyses to relate baseline, follow-up, mean, and progression of internal carotid artery (ICA) and common carotid artery (CCA) CIMT to Aß in brain regions associated with Alzheimer's disease (AD) and related dementias (ADRD), adjusting for age, sex, and other vascular risk factors. RESULTS: Participants with higher mean ICA IMT had more Aß in the precuneus (beta±standard error [ß±SE]: 0.466±0.171 mm, p = 0.01) and the frontal, lateral, and retrosplenial regions (ß±SE: 0.392±0.164 mm, p = 0.022) after adjusting for age, sex, vascular risk factors, and medication use. We did not find an association between any CCA IMT measures and Aß or progression of ICA or CCA IMT and Aß. CONCLUSION: Carotid atherosclerosis, as measured by ICA IMT, is associated with increased Aß burden later in life. These findings support a link between vascular disease and AD/ADRD pathophysiology.

Ante-mortem plasma phosphorylated tau (181) predicts Alzheimer's disease neuropathology and regional tau at autopsy.

Blood-based biomarkers such as tau phosphorylated at threonine 181 (phosphorylated-tau181) represent an accessible, cost-effective and scalable approach for the in vivo detection of Alzheimer's disease pathophysiology. Plasma-pathological correlation studies are needed to validate plasma phosphorylated-tau181 as an accurate and reliable biomarker of Alzheimer's disease neuropathological changes. This plasma-to-autopsy correlation study included participants from the Boston University Alzheimer's Disease Research Center who had a plasma sample analysed for phosphorylated-tau181 between 2008 and 2018 and donated their brain for neuropathological examination. Plasma phosphorelated-tau181 was measured with single molecule array technology. Of 103 participants, 62 (60.2%) had autopsy-confirmed Alzheimer's disease. Average time between blood draw and death was 5.6 years (standard deviation = 3.1 years). Multivariable analyses showed higher plasma phosphorylated-tau181 concentrations were associated with increased odds for having autopsy-confirmed Alzheimer's disease [AUC = 0.82, OR = 1.07, 95% CI = 1.03-1.11, P < 0.01; phosphorylated-tau standardized (z-transformed): OR = 2.98, 95% CI = 1.50-5.93, P < 0.01]. Higher plasma phosphorylated-tau181 levels were associated with increased odds for having a higher Braak stage (OR = 1.06, 95% CI = 1.02-1.09, P < 0.01) and more severe phosphorylated-tau across six cortical and subcortical brain regions (ORs = 1.03-1.06, P < 0.05). The association between plasma phosphorylated-tau181 and Alzheimer's disease was strongest in those who were demented at time of blood draw (OR = 1.25, 95%CI = 1.02-1.53), but an effect existed among the non-demented (OR = 1.05, 95% CI = 1.01-1.10). There was higher discrimination accuracy for Alzheimer's disease when blood draw occurred in years closer to death; however, higher plasma phosphorylated-tau181 levels were associated with Alzheimer's disease even when blood draw occurred >5 years from death. Ante-mortem plasma phosphorylated-tau181 concentrations were associated with Alzheimer's disease neuropathology and accurately differentiated brain donors with and without autopsy-confirmed Alzheimer's disease. These findings support plasma phosphorylated-tau181 as a scalable biomarker for the detection of Alzheimer's disease.

Trajectories of Cognitive Decline in Brain Donors With Autopsy-Confirmed Alzheimer Disease and Cerebrovascular Disease.

BACKGROUND AND OBJECTIVES: Cerebrovascular disease (CBVD) is frequently comorbid with autopsy-confirmed Alzheimer disease (AD), but its contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer's Coordinating Center (NACC) uniform and neuropathology datasets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD- brain donors. METHODS: The sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3, Consortium to Establish a Registry for Alzheimer's Disease score ≥2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, with the most recent UDS evaluation within 2 years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We used propensity score weighting to isolate the effects of comorbid AD and CBVD. This method improved the balance of covariates between the AD+/CBVD+ and AD+/CBVD- groups. Longitudinal mixed-effects models were assessed with robust bayesian estimation. UDS neuropsychological test and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores were primary outcomes. RESULTS: Of 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD- donors, the AD+/CBVD+ group had accelerated decline (i.e., group × time effects) on measures of processing speed (ß = -0.93, 95% CI -1.35, -0.51, Bayes factor [BF] 130.75), working memory (ß = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (ß = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (ß = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (ß = -0.08, 95% CI -0.12, -0.05, BF 18.11). Effects ranged from weak (BFs <3.0) to strong (BFs <150). We also found worse performance in the AD+/CBVD+ group across time on naming (ß = -1.04, 95% CI -1.83, -0.25, BF 2.52) and verbal fluency (ß = -0.73, 95% CI -1.30, -0.15, BF 1.34) and more impaired CDR-SB scores (ß = 0.45, 95% CI 0.01, 0.89, BF 0.33). DISCUSSION: In brain donors with autopsy-confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for comorbid CBVD neuropathology in AD.

Curcumin improves reversal learning in middle-aged rhesus monkeys.

Age-related impairments in cognitive function occur in multiple animal species including humans and nonhuman primates. Humans and rhesus monkeys exhibit a similar pattern of cognitive decline beginning in middle age, particularly within the domain of executive function. The prefrontal cortex is the brain region most closely associated with mediating executive function. Previous studies in rhesus monkeys have demonstrated that normal aging leads to an increase in myelin degradation in the prefrontal regions that correlates with cognitive decline. This myelin deterioration is thought to result, at least in part, from the age-related emergence of chronic low levels of inflammation. One therapeutic that may arrest the deleterious effects of neuroinflammation is curcumin (CUR), the primary component of the spice turmeric. CUR has been shown to be a potent anti-inflammatory and antioxidant and improves performance on tasks for working memory and motor function. In the present study, middle-aged monkeys (12-21 years old) were given daily dietary supplementation of 500 mg of curcumin or vehicle over a period of 3-4 years. Here, we present data from a series of both object and spatial reversal tasks. Compared to vehicle, the CUR group showed enhanced performance on object, but not spatial reversal learning. These findings suggest that curcumin may improve specific aspects of executive function. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Association Between Antemortem FLAIR White Matter Hyperintensities and Neuropathology in Brain Donors Exposed to Repetitive Head Impacts.

BACKGROUND AND OBJECTIVES: Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathologic correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH and repetitive head impact exposure and informant-reported cognitive and daily function were tested. METHODS: This imaging-pathologic correlation study included symptomatic male decedents exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathologic assessments included semiquantitative ratings of white matter rarefaction, cerebrovascular disease, hyperphosphorylated tau (p-tau) severity (CTE stage, dorsolateral frontal cortex), and ß-amyloid (Aß). Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p ≤ 0.05. RESULTS: The sample included 75 donors: 67 football players and 8 nonfootball contact sport athletes or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log TLV was associated with white matter rarefaction (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.03, 5.24; p = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; p = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; p = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; p = 0.01). There was no association with Aß. More years of football play was associated with log TLV (unstandardized ß 0.04, 95% CI 0.01, 0.06; p = 0.01). Greater log TLV correlated with higher FAQ (unstandardized ß 4.94, 95% CI 0.42, 8.57; p = 0.03) and CDS scores (unstandardized ß 15.35, 95% CI -0.27, 30.97; p = 0.05). DISCUSSION: WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging-pathologic correlation studies are needed. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence of associations between FLAIR white matter hyperintensities and neuropathologic changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.

Plasma p-tau181 shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau.

INTRODUCTION: We examined the ability of plasma hyperphosphorylated tau (p-tau)181 to detect cognitive impairment due to Alzheimer's disease (AD) independently and in combination with plasma total tau (t-tau) and neurofilament light (NfL). METHODS: Plasma samples were analyzed using the Simoa platform for 235 participants with normal cognition (NC), 181 with mild cognitive impairment due to AD (MCI), and 153 with AD dementia. Statistical approaches included multinomial regression and Gaussian graphical models (GGMs) to assess a network of plasma biomarkers, neuropsychological tests, and demographic variables. RESULTS: Plasma p-tau181 discriminated AD dementia from NC, but not MCI, and correlated with dementia severity and worse neuropsychological test performance. Plasma NfL similarly discriminated diagnostic groups. Unlike plasma NfL or t-tau, p-tau181 had a direct association with cognitive diagnosis in a bootstrapped GGM. DISCUSSION: These results support plasma p-tau181 for the detection of AD dementia and the use of blood-based biomarkers for optimal disease detection.

The Effects of a Novel Non-catechol Dopamine Partial Agonist on Working Memory in the Aged Rhesus Monkey.

Aged-related declines in cognition, especially working memory and executive function, begin in middle-age and these abilities are known to be mediated by the prefrontal cortex (PFC) and more specifically the dopamine (DA) system within the PFC. In both humans and monkeys, there is significant evidence that the PFC is the first cortical region to change with age and the PFC appears to be particularly vulnerable to age-related loss of dopamine (DA). Therefore, the DA system is a strong candidate for therapeutic intervention to slow or reverse age related declines in cognition. In the present study, we administered a novel selective, potent, non-catechol DA D1 R agonist PF-6294 (Pfizer, Inc.) to aged female rhesus monkeys and assessed their performance on two benchmark tasks of working memory - the Delayed Non-match to Sample Task (DNMS) and Delayed Recognition Span Task (DRST). The DNMS task was administered first with the standard 10 s delay and then with 5 min delays, with and without distractors. The DRST was administered each day with four trials with unique sequences and one trial of a repeated sequence to assess evidence learning and retention. Overall, there was no significant effect of drug on performance on any aspect of the DNMS task. In contrast, we demonstrated that a middle range dose of PF-6294 significantly increased memory span on the DRST on the first and last days of testing and by the last day of testing the increased memory span was driven by the performance on the repeated trials.