Neuropsychological Changes Research Articles

Disfunções cognitivas em pacientes com hipotireoidismo subclínico

Evaluate neuropsychological changes in patients with subclinical hypothyroidism (SH). Cross-sectional study comparing the results of the neuropsychological evaluation of 89 SH patients and 178 individuals without thyroid disease. The participants underwent the following neuropsychological assessment: Conner's Continuous Performance Test (CPT-II), Iowa Gambling Task, Stroop Test, Wisconsin Card Sorting Test (WCST), Verbal Fluency Test (semantic and phonologic categories) and Rey Auditory Verbal Learning Test. Among the neuropsychological tests, patients showed worse performance only in cognitive flexibility (WCST) and the ability to maintain sustained attention (omission errors on the CPT-II). These losses can cause detriments in the daily lives of patients, constituting potential treatment indications.

Mapping the brain in younger and older asymptomatic HIV-1 men: Frontal volume changes in the absence of other cortical or diffusion tensor abnormalities

IntroductionOver the past decade the developments made in treating people with human immune deficiency virus (HIV) have greatly improved quality of life and life expectancy. However, the nature of asymptomatic HIV-associated minor neurocognitive disorder (HAND) remains unclear. In this study we explored the occurrence of neuropsychological and neuroimaging changes in medically and psychiatrically stable HIV-1 infected patients on highly active antiretroviral treatment (HAART) from two separate age groups. MethodsParticipants included 20 HIV-1 infected younger (aged 20–40) and 20 HIV-1 older patients (aged 50–75). Comparisons were made with 20 age- and education-matched younger and 22 matched older healthy seronegative males. Participants were stable on treatment and asymptomatic at study onset with undetectable HIV-1 viral loads, and free of medical or psychiatric co-morbidity, alcohol or substance misuse. A detailed neuropsychological assessment was used and volumetric-magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) performed to assess grey and white-matter integrity. ResultsWe found significant effects of ageing on memory, grey and white matter measures. Comparison of the HIV-positive and HIV-negative groups did not show significant differences on the neuropsychological tests after Bonferroni correction, and there were no significant age by HIV status interactions. However, we did find reduced grey matter volume on MRI in our HIV-positive participants within the medial and superior frontal gyri. We also found significant ageing effects in fronto-temporal grey and white matter, independent of the effect of HIV. ConclusionsThe results from this study suggest that HIV-1 disease by itself does not significantly impair cognitive function when patients are otherwise asymptomatic. Nevertheless, the imaging techniques were sensitive enough to detect subtle grey matter changes not normally evident until much later in the disease. If confirmed in a longitudinal study this frontal grey matter change could represent an important biomarker for trials in HIV disease.

Effects of acute relapses on neuropsychological status in multiple sclerosis patients

Little is known about neuropsychological status changes in multiple sclerosis (MS) patients experiencing a relapse. The Symbol Digit Modalities Test (SDMT) and MS Neuropsychological Screening Questionnaire (MSNQ) are brief measures of cognitive performance and self-reported status, respectively. We retrospectively identified relapses in subjects participating in the 48-week open-label, safety-extension study of natalizumab (STRATA) to determine if changes in cognitive ability occurred during acute relapses. SDMT and MSNQ were administered prior to infusions. We analyzed SDMT and MSNQ scores pre- and post-relapse in 53 MS patients with relapses (cases) and 115 MS patients without relapses (controls) matched on age, gender, baseline SDMT and time from study initiation. ANOVA and GLM were used to compare cases versus controls overall, and stratified by EDSS cerebral functional status (cFS) scores. SDMT change pre- to post-relapse in cases was significantly lower than difference between similar time points in controls (p = 0.003). When comparing visit 2 (two visits pre-relapse) to visit 1 (first visit post-relapse), MSNQ change was significantly different between cases and controls (p = 0.012). For cFS ≤ 1, the change in SDMT was significantly different between cases and controls but not for cFS ≥ 2. These results confirm the involvement of cognitive function during some MS relapses suggesting the SDMT or MSNQ can be used to identify transitory neuropsychological status changes and cognitive relapses.

Normative data and validation of a regression based summary score for assessing meaningful neuropsychological change

Reliable detection and quantification of longitudinal cognitive change are of considerable importance in many neurological disorders, particularly to monitor central nervous system effects of disease progression and treatment. In the current study, we developed normative data for repeated neuropsychological (NP) assessments (6 testings) using a modified standard regression-based (SRB) approach in a sample that includes both HIV-uninfected (HIV–, N = 172) and neuromedically stable HIV-infected (HIV+, N = 124) individuals. Prior analyses indicated no differences in NP change between the infected and uninfected participants. The norms for change included correction for factors found to significantly affect follow-up performance, using hierarchical regression. The most robust and consistent predictors of follow-up performance were the prior performance on the same test (which contributed in all models) and a measure of prior overall NP competence (predictor in 97% of all models). Demographic variables were predictors in 10–46% of all models and in small amounts; while test–retest interval contributed in only 6% of all models. Based on the regression equations, standardized change scores (z scores) were computed for each test measure at each interval; these z scores were then averaged to create a total battery change score. An independent sample of HIV– participants who had completed 8 of the 15 tests was used to validate an abridged summary change score. The normative data are available in an electronic format by e-mail request to the first author. Correction for practice effects based on normative data improved the consistency of NP impairment classification in a clinically stable longitudinal cohort after baseline.

Impact of side of lesion, seizure outcome and interictal epileptiform discharges on attention and memory after surgery in temporal lobe epilepsy

To determine the impact of side of surgery, seizure outcome and interictal epileptiform discharges (IEDs) on attention and memory in a cohort of patients with temporal lobe epilepsy who had undergone unilateral mesial temporal lobe resection. Ninety-four patients were investigated pre- and postoperatively by means of a standardised neuropsychological battery measuring subcomponents of attention, as well as short-term, working and long-term memory. The side of epilepsy surgery, seizure outcome and the presence of postoperative IEDs, as well as their possible relationship to the neuropsychological changes, were assessed. Statistical data were analysed using a repeated-measures MANOVA. The absence of seizures following surgery had a positive effect on short-term memory and attentional control. The occurrence of IEDs was found in patients with impaired figural learning. In terms of attentional control and working memory, patients who continued to present IEDs had also scored lower in these domains prior to surgery. IEDs had an effect independent of seizure presence, but were found to have a "supplementary negative effect" when the two variables were combined.

Kognitive Störungen nach kardiochirurgischen Eingriffen

Over 100,000 heart surgeries are performed in Germany annually. Although severe neurological complications like ischaemic strokes have meanwhile become rare occurrences, subtle neuropsychological changes are still frequently recognized after major heart surgeries. The hitherto unsolved problem of postoperative cognitive decline (POCD) is portrayed in this article. Multifactorial aetiologies including microembolism and preoperative risk factors are supposed to play a significant role in POCD. A variety of neuroprotective strategies such as intraoperative microemboli filtration have been suggested to minimize cerebral risks. The utility of neuroprotective methods has recently been verified in randomized studies.

Neuropsychological changes and treatment response in severe depression

Impaired neuropsychological function and differences in facial emotion processing are features of major depression. Some aspects of these functions may change during treatment and may be useful in assessing treatment response, even at an early stage of treatment. To examine early and later changes in neuropsychological functioning and facial emotion processing as potential markers of treatment response in major depression. In total, 68 newly admitted in-patients with a primary diagnosis of major depression and 50 healthy controls completed an assessment, including mood ratings, neuropsychological measures and facial emotion processing measures at three time points (baseline, 10-14 days and 6 weeks). Pervasive neuropsychological impairment was evident at baseline in patients with depression compared with healthy controls. During 6 weeks of treatment, only simple reaction time, verbal working memory and the recognition of angry facial expressions showed differential change in those whose depression responded to treatment compared with treatment non-responders in the depression group. None of the measures showed a significant difference between treatment responders and non-responders at 10-14 days. Despite significant impairment in neuropsychological functioning in the depression group, most measures failed to differentiate between treatment responders and non-responders at 10-14 days or at 6 weeks. Simple reaction time, verbal working memory and recognition of angry facial expressions may be useful in assessing response in severe depression but probably not at an early stage.

Structural brain and neuropsychometric changes associated with pediatric bipolar disorder with psychosis

To identify neuropsychological and structural brain changes using a combination of high-resolution structural and diffusion tensor imaging in pediatric bipolar disorder (PBD) with psychosis (presence of delusions and or hallucinations). We recruited 15 patients and 20 euthymic age- and gender-matched healthy controls. All subjects underwent high-resolution structural and diffusion tensor imaging. Voxel-based morphometry (VBM), tract-based spatial statistics (TBSS), and probabilistic tractography were used to analyse magnetic resonance imaging data. The PBD subjects had normal overall intelligence with specific impairments in working memory, executive function, language function, and verbal memory. Reduced gray matter (GM) density was found in the left orbitofrontal cortex, left pars triangularis, right premotor cortex, occipital cortex, right occipital fusiform gyrus, and right crus of the cerebellum. TBSS analysis showed reduced fractional anisotropy (FA) in the anterior corpus callosum. Probabilistic tractography from this cluster showed that this region of the corpus callosum is connected with the prefrontal cortices, including those regions whose density is decreased in PBD. In addition, FA change was correlated with verbal memory and working memory, while more widespread reductions in GM density correlated with working memory, executive function, language function, and verbal memory. The findings suggest widespread cortical changes as well as specific involvement of interhemispheric prefrontal tracts in PBD, which may reflect delayed myelination in these tracts.

Neuropsychological Clustering Highlights Cognitive Differences In Young People Presenting With Depressive Symptoms

Early stages of affective or psychotic disorders may be accompanied by neuropsychological changes that help to predict risk of developing more severe disorders. A comprehensive set of neuropsychological measures was collected in 109 help-seeking young people (16 to 30 years; 54 females), recently diagnosed with an affective or psychotic disorder and presenting with current depression. Hierarchical cluster analysis determined three clusters: one deemed to have a "poor memory" profile (n = 40); another with a "poor mental flexibility" profile (n = 38) and a third with widespread difficulties plus "impaired attention and memory" (n = 31). In general, the three clusters were comparable in demographic, functional and clinical factors suggesting some unique role for neurocognitive impairments. A discriminant function analysis confirmed that the clusters were best characterized by performance in "attentional" versus "learning/memory" measures. Furthermore, profiles of independent neuropsychological variables validated the original solution for two of the clusters, distinguishing all cluster-groups on an attentional measure. The findings of this study suggest that despite presenting with very similar levels of current depressive symptomatology, young help-seeking individuals in the early stages of illness have underlying neuropsychological heterogeneity. Distinct neuropsychological profiling may help to predict later psychiatric outcomes and enhance individually-tailored early intervention strategies.

Topiramate dose effects on cognition

Topiramate (TPM), a broad-spectrum antiepileptic drug, has been associated with neuropsychological impairment in patients with epilepsy and in healthy volunteers. To establish whether TPM-induced neuropsychological impairment emerges in a dose-dependent fashion and whether early cognitive response (6-week) predicts later performance (24-week). Computerized neuropsychological assessment was performed on 188 cognitively normal adults who completed a double-blind, placebo-controlled, parallel-group, 24-week, dose-ranging study which was designed primarily to assess TPM effects on weight. Target doses were 64, 96, 192, or 384 mg per day. The Computerized Neuropsychological Test Battery was administered at baseline and 6, 12, and 24 weeks. Individual cognitive change was established using reliable change index (RCI) analysis. Neuropsychological effects emerged in a dose-dependent fashion in group analyses (p < 0.0001). RCI analyses showed a dose-related effect that emerged only at the higher dosing, with 12% (64 mg), 8% (96 mg), 15% (192 mg), and 35% (384 mg) of subjects demonstrating neuropsychological decline relative to 5% declining in the placebo group. Neuropsychological change assessed at 6 weeks significantly predicted individual RCI outcome at 24 weeks. Neuropsychological impairment associated with TPM emerges in a dose-dependent fashion. Subjects more likely to demonstrate cognitive impairment after 24 weeks of treatment can be identified early on during treatment (i.e., within 6 weeks). RCI analysis provides a valuable approach to quantify individual neuropsychological risk.

Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy

Traumatic brain injury (TBI) has been recently recognized as a risk factor for cognitive impairment and hypopituitarism, presented most frequently with GH deficiency (GHD). GHD is associated not only with changes in body composition, but also with impaired quality of life, cognitive dysfunctions and some psychiatric sequelae, usually classified as "depression" or "atypical depression". The impact of GH therapy on mental status in TBI patients is still unknown. Psychiatric and cognitive functions were tested in 6 GHD patients at baseline (minimum 3 yr after TBI), reassessed after 6 months of GH therapy as well as 12 months after discontinuation of GH therapy. Psychiatric and cognitive examinations included semi-structured interviews and 3 instruments: Symptom-checklist (SCL-90-R), Zung Depression Inventory, and standard composite neuropsychological battery. Six months of GH therapy in GHD TBI patients improved cognitive abilities (particularly verbal and non-verbal memory) and significantly improved psychiatric functioning. Severity of depression decreased, as well as intensity of interpersonal sensitivity, hostility, paranoid ideation, anxiety, and psychoticism. Somatization, obsessive-compulsive symptoms and phobic anxiety decreased in all except in one patient. In 3 GHD patients who stopped GH therapy for 12 months we registered worsening of the verbal and non-verbal memory, as well symptoms in 3 SCL dimensions: inter-personal sensitivity, anxiety, and paranoid ideation. GH-deficient TBI patients are depressed and have cognitive impairment. GH therapy induced reduction of depression, social dysfunction, and certain cognitive domains. Our preliminary data support the necessity of conducting randomized placebo-controlled trials on the effects of GH therapy on neuropsychological and psychiatric status in GHD TBI patients.

Cognitive deficits in patients with mild to moderate traumatic brain injury

Traumatic brain injury (TBI) is one of the most frequent causes of brain damage. Cognitive deficits reported in the literature after moderate to severe TBI include memory, language, executive functions, attention and information processing speed impairments. However, systematic studies on patients with mild TBI are scarce although neuropsychological changes are present. To investigate the cognitive functioning of patients with mild to moderate TBI. We evaluated 12 patients with mild to moderate TBI using a comprehensive protocol (PN01) of neuropsychological tests. There were significant deficits of episodic memory including immediate and delayed verbal memory recall, verbal recognition, immediate and delayed visual memory recall, naming, verbal fluency and information processing speed. These results emphasize the importance of comprehensive neuropsychological assessments even in cases of mild TBI in order to identify impaired and preserved functions providing adequate managing including rehabilitation programs for each case.

Altered functional adaptation to attention and working memory tasks with increasing complexity in relapsing‐remitting multiple sclerosis patients

As attention, processing speed, and working memory seem to be fundamental for a broad range of cognitive performance, the present study on patients with mild forms of relapsing-remitting multiple sclerosis (RR-MS) focused on these domains. To explore subtle neuropsychological changes in either the clinical or fMRI domain, we applied a multistep experimental design with increasing task complexity to investigate global brain activity, functional adaptation, and behavioral responses to typical cognitive processes related to attention and working memory. Fifteen patients with RR-MS (mean age 38 years, 22-49 years, 9 females, mean disease duration 5.9 years (SD = 3.6 years), mean Expanded Disability Status Scale score, 2.3 (SD = 1.3) but without reported cognitive impairment), and 15 age-matched healthy controls (HC; mean age, 34 years, 23-50 years, 6 women) participated. After a comprehensive neuropsychological assessment, participants performed different fMRI experiments testing attention and working memory. In the neuropsychological assessment, patients showed only subtle reduction in learning and memory abilities. In the fMRI experiments, both groups activated the brain areas typically involved in attention and working memory. HC showed a linear in- or decrease in activation paralleling the changing task complexity. Patients showed stronger activation change at the level of the simple tasks and a subsequent saturation effect of (de-)activation at the highest task load. These group/task interaction differences were found in the right parahippocampal cortex and in the middle and medial frontal regions. Our results indicate that, in MS, functional adaptation patterns can be found which precede clinical evidence of apparent cognitive decline.

Analysis of Morphological Brain Change of Alzheimer Disease (AD) Patients

A growing body of evidence suggests that a preclinical phase of Alzheimer’s disease (AD) exists several years or more prior to the overt manifestation of clinical symptoms and is characterized by subtle neuropsychological and brain changes. Identification of individuals prior to the development of significant clinical symptoms is imperative in order to have the greatest treatment impact by maintaining cognitive abilities and preserving quality of life. Functional magnetic resonance imaging (fMRI) offers considerable promise as a non-invasive tool for detecting morphological brain changes in Alzheimer disease affected patients. In fact, evidence to date indicates that functional brain decline precedes structural decline in preclinical samples. Therefore, fMRI may offer the unique ability to capture the dynamic state of change in the degenerating brain. This analysis examines morphological change in brain structure in those at risk for AD as well as in early AD. fMRI data analysis and findings is done on at-risk groups by collecting data from fMRI data centre which is gathered according to the virtue of genetic susceptibility or mild cognitive decline followed by an appraisal of the methodological issues concerning the diagnostic usefulness of fMRI in early AD. A total number of 28 subjects data, including 16 young Subjects data (18 and 30 year’s of age) and 12 Alzheimer disease affected subjects data (65 and 92 year’s of age) from fMRI data centre (www.fmridc.org) were analyzed in this paper. The analysis result shows that the cortex, hippocampus, and ventricle area of the Alzheimer diseased patients have shrunk dramatically than the normal subjects and other changes of brain are distinguishable. A discussion of data analyzing procedure has been given that will improve the ability to reliably detect early brain changes and will help for early identification of Alzheimer (AD) disease and to cure the disease.

Academic problems in children with seizures: Relationships with neuropsychological functioning and family variables during the 3 years after onset

Objectives Children with long-standing epilepsy have a significantly increased risk of academic underachievement compared with healthy controls. We prospectively followed children from seizure onset to assess the relationship between change in neuropsychological functioning and change in academic achievement and to explore the risk and protective moderating effects of demographic, seizure, and family variables. Methods As part of a larger study, neuropsychological and academic data were collected at both baseline and 36 months for 219 children 6–14 years of age with seizures. Prior factor analysis of results from a battery of well-standardized neuropsychological tests yielded four factors: language, processing speed, attention/executive/construction, and verbal memory/learning. Academic achievement was measured with the Woodcock–Johnson Revised Achievement Test Battery. Correlation coefficients and linear mixed models were used for analysis. Results The reading and math scores of children with seizures and siblings did not differ at baseline, but children with seizures had lower scores than siblings at 36 months. Writing scores were significantly lower for affected children than siblings at both times. Among children with seizures, there were positive correlations between neuropsychological functioning and academic achievement at baseline and 36 months. Changes in language and in verbal memory/learning were positively correlated with change in reading achievement ( r = 0.25 and r = 0.17, respectively). Age at onset moderated the association between change in neuropsychological functioning and change in reading and writing achievement ( P ≤ 0.006), with stronger relationships among younger children (β = 0.25–0.44). The association between change in language and change in writing achievement was moderated by caregiver anxiety ( P = 0.04; stronger for more anxious parents, β = 0.40), and the association between change in processing speed and change in math achievement was moderated by etiology ( P = 0.02; stronger for symptomatic/cryptogenic vs idiopathic, β = 0.29). Gender and other family variables did not have significant moderating effects. Conclusions Changes in neuropsychological function were associated with changes in academic achievement following onset of seizures, with risk factors being younger age at onset, lower caregiver education, high parental anxiety, and symptomatic/cryptogenic etiology. Academic performance should be closely monitored in children with early-onset seizures.

TCT-20: Neuropsychological Changes Following Carotid Artery Stenting in Asymptomatic Patients

TCT-20: Neuropsychological Changes Following Carotid Artery Stenting in Asymptomatic Patients

Self-reported symptoms and neuropsychological function among tunnel workers previously exposed to acrylamide and N-methylolacryl­amide

The aim of this study was to examine possible exposure-related symptoms and neuropsychological changes among tunnel workers previously exposed to grout containing acrylamide and N-methylolacrylamide. In a cross sectional study, 44 male tunnel workers previously exposed to acrylamide and N-methylolacrylamide during grouting operations were exam-in-ed with neuropsychological tests, 2-10 years after last exposure. The control group consisted of 49 male tunnel workers with no history of acrylamide exposure. Questionnaires were used to assess retrospectively recalled symptoms during work and current symptoms at the time of the examination. The prevalence of paresthesia in hands and legs, and leg cramps during work peri-ods were higher in the exposed than control group. Self-reported prevalence of skin irritation, peeling of skin on the hands, white-finger attacks, headache, and breathlessness was also higher among the exposed workers. The Q-16 questionnaire on current symptoms indicated higher symptom prevalence among the exposed of impaired memory and concentration, emotional change, sleep disturbances, tiredness, headache, and sensory or motor changes. In contrast, no association was found between neuropsychological test results and acrylamide exposure, adjusting for relevant confounders. However, selected motor symptoms were associated with the corresponding results on tests for motor function. Despite higher prevalences of self-reported current symptoms among the acrylamide-exposed compared to the control group, we did not find an association between occupational acrylamide exposure and health out-comes as measured by the chosen neuropsychological tests. Observed associations between chemical exposure and self-reported symptoms should be interpreted with great caution.

Neuropsychological decline after catheter ablation of atrial fibrillation

Cerebral embolic events represent recognized side effects after catheter ablation in the treatment of recurrent atrial fibrillation (AF). The study was performed to analyze the neuropsychological outcome and to detect new embolic ischemic brain lesions after therapeutic left atrial catheter ablation of AF. We enrolled 23 patients with recurrent AF who underwent elective circumferential pulmonary vein isolation. The primary endpoint was the neuropsychological outcome 3 months after intervention in contrast to the results of non-AF controls (n = 23) without ablation and in covariance of baseline performance. Cerebral diffusion-weighted magnetic resonance imaging (DWI) was performed in 21 AF patients at baseline, 2-4 days, and 3 months after intervention. In 3/21 patients (14.3%), new ischemic lesions were detected on DWI shortly after intervention. In one patient, a territorial middle cerebral artery infarct occurred with severe clinical symptoms. The other two patients represented clinically silent small lesions. In contrast to the control group and in covariance of baseline performance, the ablation group showed worse neuropsychological outcome in verbal memory (one of five cognitive domains) with an effect size of d = 0.93[t (.05; 42) = -3.53; P < .001; false discovery rate (FDR)(crit) ≤ .01]. Adverse neuropsychological changes after left atrial catheter ablation are verifiable in verbal memory and, conjoined with ischemic brain lesions on DWI, might represent cerebral side effects of this procedure.

Cardiac Index Is Associated With Brain Aging

Cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults with prevalent cardiovascular disease, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to subclinical brain injury. We hypothesized that cardiac function, as measured by cardiac index, would be associated with preclinical brain magnetic resonance imaging (MRI) and neuropsychological markers of ischemia and Alzheimer disease in the community. Brain MRI, cardiac MRI, neuropsychological, and laboratory data were collected on 1504 Framingham Offspring Cohort participants free of clinical stroke, transient ischemic attack, or dementia (age, 61+/-9 years; 54% women). Neuropsychological and brain MRI variables were related to cardiac MRI-assessed cardiac index (cardiac output/body surface area). In multivariable-adjusted models, cardiac index was positively related to total brain volume (P=0.03) and information processing speed (P=0.02) and inversely related to lateral ventricular volume (P=0.048). When participants with clinically prevalent cardiovascular disease were excluded, the relation between cardiac index and total brain volume remained (P=0.02). Post hoc comparisons revealed that participants in the bottom cardiac index tertile (values <2.54) and middle cardiac index tertile (values between 2.54 and 2.92) had significantly lower brain volumes (P=0.04) than participants in the top cardiac index tertile (values >2.92). Although observational data cannot establish causality, our findings are consistent with the hypothesis that decreasing cardiac function, even at normal cardiac index levels, is associated with accelerated brain aging.

Cardiac Output as a Potential Risk Factor for Abnormal Brain Aging

Heart failure has served as a clinically useful model for understanding how cardiac dysfunction is associated with neuroanatomic and neuropsychological changes in aging adults, theoretically because systemic hypoperfusion disrupts cerebral perfusion, contributing to clinical brain injury. This review summarizes more recent data suggesting that subtle cardiac dysfunction or low normal levels of cardiac function, as quantified by cardiac output, are related to cognitive and neuroimaging markers of abnormal brain aging in the absence of heart failure or severe cardiomyopathy. Additional work is required, but such associations suggest that reduced cardiac output may be a risk factor for Alzheimer's disease (AD) and abnormal brain aging through the propagation or exacerbation of neurovascular processes, microembolism due to thrombosis, and AD neuropathological processes. Such mechanistic pathways are discussed in the context of a theoretical model that posits a direct pathway of injury between cardiac output and abnormal brain aging (i.e., reduced systemic blood flow disrupts cerebral blood flow homeostasis), contributing to clinical brain injury, independent of shared risk factors for both cardiac dysfunction and abnormal brain aging.