Decline In Multiple Cognitive Domains Research Articles

Associations Between Stroke Type, Ischemic Stroke Subtypes, and Post-Stroke Cognitive Trajectories.

It is unclear how post-stroke cognitive trajectories differ by stroke type and ischemic stroke subtype. We studied associations between stroke types (ischemic, hemorrhagic), ischemic stroke subtypes (cardioembolic, large artery atherosclerotic, lacunar/small vessel, cryptogenic/other determined etiology), and post-stroke cognitive decline. This pooled cohort analysis from four US cohort studies (1971-2019) identified 1,143 dementia-free individuals with acute stroke during follow-up: 1,061 (92.8%) ischemic, 82 (7.2%) hemorrhagic, 49.9% female, 30.8% Black. Median age at stroke was 74.1 (IQR, 68.6, 79.3) years. Outcomes were change in global cognition (primary) and changes in executive function and memory (secondary). Outcomes were standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median follow-up for the primary outcome was 6.0 (IQR, 3.2, 9.2) years. Linear mixed-effects models estimated changes in cognition after stroke. On average, the initial post-stroke global cognition score was 50.78 points (95% CI, 49.52, 52.03) in ischemic stroke survivors and did not differ in hemorrhagic stroke survivors (difference, -0.17 points [95% CI, -1.64, 1.30]; P=0.82) after adjusting for demographics and pre-stroke cognition. On average, ischemic stroke survivors showed declines in global cognition, executive function, and memory. Post-stroke declines in global cognition, executive function, and memory did not differ between hemorrhagic and ischemic stroke survivors. 955 ischemic strokes had subtypes: 200 (20.9%) cardioembolic, 77 (8.1%) large artery atherosclerotic, 207 (21.7%) lacunar/small vessel, 471 (49.3%) cryptogenic/other determined etiology. On average, small vessel stroke survivors showed declines in global cognition and memory, but not executive function. Initial post-stroke cognitive scores and cognitive declines did not differ between small vessel survivors and survivors of other ischemic stroke subtypes. Post-stroke vascular risk factor levels did not attenuate associations. Stroke survivors had cognitive decline in multiple domains. Declines did not differ by stroke type or ischemic stroke subtype.

Neurocognitive Performance Changes with Chimeric Antigen Receptor T-Cell Therapy in Patients with Hematologic Malignancies

Introduction: Chimeric antigen receptor (CAR) T cell therapy is a transformative therapy that has revolutionized the care of patients with hematologic malignancies. However, CAR-T cell therapy is associated with several short-term toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The impact of CAR-T cell therapy on neurocognitive outcomes is unknown. Here, we report on our prospective study examining the changes in neurocognitive performance before and after CAR T cell therapy. Methods: This single-center prospective cohort study recruited consecutive recipients of CAR-T cell therapy enrolled in a prospective study NCT05556928 and a phase II clinical trial NCT04975555. Patients underwent neurocognitive assessment using the NIH Toolbox Cognition Battery (NIHTB-CB). Baseline assessment was done within 3 weeks before receiving CAR-T cell therapy. Follow up assessment was conducted at 90 days of receiving CAR T therapy. Domain specific T-scores adjusted for age, sex, race/ethnicity, and education were calculated. Change in T-scores between pre and post assessments were evaluated, with significant cognitive change defined as +/- 0.5 standard deviations from the mean. Results: Twenty-six eligible patients were identified, of which 9 completed both pre and post assessments. The median age was 66 years (range 45-79) at the time of CAR T cell therapy with 76.9% males and 38.5% being Non-Hispanic Black. Cancer types included diffuse large B-cell lymphoma (46.2%), multiple myeloma (38.5%), and follicular lymphoma (11.5%). Our baseline cognitive assessment showed that our eligible patient cohort had a median total composite T-score of 42 (range 30-64); twelve (46%) patients were one or more standard deviations below the mean. Of the 9 patients that completed a follow up assessment, a decline in one or more cognitive domains was seen in 89% of patients. Largest declines were seen in the cognitive domain of processing speed (66.7%, Figure 1). Conclusion: CAR T cell therapy recipients experienced a short-term cognitive decline in multiple domains. These findings can be used to educate future patients on potential toxicities of CAR T-cell therapy. We continue to enroll participants into our study and updated data will be presented at the meeting.

34 Association Between Subjective Cognitive Decline and Mental Wellbeing in Normal Cognition and MCI Older Adults

Objective:Subjective cognitive decline (SCD, i.e., perceived cognitive decline without neuropsychological deficits) is associated with Alzheimer’s disease pathology and increased risk for cognitive impairment but is heterogenous in etiology and has been linked to other factors including personality and depression. Mental wellbeing (i.e., the perception and functioning of social, emotional, and health-related aspects of one’s life) has been associated with subjective memory complaints, but its relationship with other subjective cognitive domains is poorly understood. Further characterizing the relationship between mental wellbeing and SCD could refine understanding of SCD and inform development of interventions that prevent progression to objective cognitive decline. This study aimed to describe the relationship between mental wellbeing and subjective decline in multiple cognitive domains and examine whether this relationship differs between older adults with normal cognition and those with mild cognitive impairment (MCI).Participants and Methods:Community-dwelling older adults (normal: n = 58, Mage = 73.7±5.6; MCI: n = 43, Mage = 75.9±6.1) completed the Everyday Cognition scale, a validated self-report measure of SCD, and the RAND-36 Health Survey, a validated self-report measure of health-related quality of life which includes a mental wellbeing subscale. Spearman’s rank correlations were conducted between self-reported mental wellbeing and each self-reported cognitive domain (i.e., memory, language, visuospatial, and executive function) for the Normal Cognition and MCI groups.Results:Worse mental wellbeing was associated with worse subjective language and executive function in the normal group, rs(56) = -.42, p =.001; rs(56) = -.37, p =.005, but not for the MCI group, rs(41) = -.23, p =.15; rs(41) = -.12, p =.46. Worse mental wellbeing was associated with worse subjective visuospatial function in the MCI group, rs(41) = -.39, p =.009, but not in the normal group, rs(56) = -.11, p =.39. For both groups, worse mental wellbeing was associated with worse subjective memory, rs(56) = -.45, p < .001; rs(41) = -.37, p =.02. While this correlation was greater in the normal group, the difference was not significant (z = 0.38, p =.71).Conclusions:These results suggest that perceptions of mental wellbeing are related to perceptions of cognitive decline in multiple domains, and that the specific domains involved differ between normal and MCI groups. The differential associations may mean perception of specific cognitive domains more strongly affect mental wellbeing, or mental wellbeing more acutely influences perception of those domains. The overall observed relationship between SCD and mental wellbeing may have several explanations: the impact of broader health perceptions may extend to cognitive perception, behavioral changes associated with poor wellbeing may reduce subjective cognitive function, or worse subjective cognitive function may lead to negative experiences of wellbeing. Future longitudinal investigation could inform causal inferences. The more limited associations between mental wellbeing and SCD among MCI individuals may point to the role of decreased self-awareness (due to cognitive impairment) precluding detection of subtle changes in cognition or wellbeing. This study highlights the importance of better understanding mental wellbeing in experiences of SCD in both normal and MCI older adults to improve cognitive and mental health outcomes.

Brain amyloid-β deposition associated functional connectivity changes of ultra-large structural scale in mild cognitive impairment.

In preclinical Alzheimer's disease, neuro-functional changes due to amyloid-β (Aβ) deposition are not synchronized in different brain lobes and subcortical nuclei. This study aimed to explore the correlation between brain Aβ burden, connectivity changes in an ultra-large structural scale, and cognitive function in mild cognitive impairment. Participants with mild cognitive impairment were recruited and underwent florbetapir (F18-AV45) PET, resting-state functional MRI, and multidomain neuropsychological tests. AV-45 standardized uptake value ratio (SUVR) and functional connectivity of all participants were calculated. Of the total 144 participants, 72 were put in the low Aβ burden group and 72 in the high Aβ burden group. In the low Aβ burden group, all connectivities between lobes and nuclei had no correlation with SUVR. In the high Aβ burden group, SUVR showed negative correlations with the Subcortical-Occipital connectivity (r=-0.36, P = 0.02) and Subcortical-Parietal connectivity (r=-0.26, P = 0.026). Meanwhile, in the high Aβ burden group, SUVR showed positive correlations with the Temporal-Prefrontal connectivity (r = 0.27, P = 0.023), Temporal-Occipital connectivity (r = 0.24, P = 0.038), and Temporal-Parietal connectivity (r = 0.32, P = 0.006). Subcortical to Occipital and Parietal connectivities had positive correlations with general cognition, language, memory, and executive function. Temporal to Prefrontal, Occipital, and Parietal connectivities had negative correlations with memory function, executive function, and visuospatial function, and a positive correlation with language function. In conclusion, Individuals with mild cognitive impairment with high Aβ burden have Aβ-related bidirectional functional connectivity changes between lobes and subcortical nuclei that are associated with cognitive decline in multiple domains. These connectivity changes reflect neurological impairment and failed compensation.

Cortical thickness and intrinsic activity changes in middle-aged men with alcohol use disorder.

Previous studies reported the alterations of brain structure or function in people with alcohol use disorder (AUD). However, a multi-modal approach combining structural and functional studies is essential to understanding the neural mechanisms of AUD. Hence, we examined regional differences in cortical thickness (CT) and amplitude of low-frequency fluctuation (ALFF) in patients with AUD. Thirty male patients with AUD and thirty age- and education-matched healthy male controls were recruited. High-resolution anatomical and resting-state functional MRI (rs-fMRI) data were collected, and the CT and ALFF were computed. Behaviorally, males with AUD showed a cognitive decline in multiple domains. Structurally, they presented prominent reductions in CT in the bilateral temporal, insular, precentral, and dorsolateral prefrontal gyri (p<0.05, voxel-wise family-wise error [FWE]). Functionally, a significant decrease in ALFF in the bilateral temporal, dorsolateral prefrontal, insular, putamen, cerebellum, right precuneus, mid-cingulate, and precentral gyri were observed (p<0.05, FWE). Our findings demonstrate the dual alterations of alcohol-related brain structure and function in male patients with AUD. These results may be useful in understanding the neural mechanisms in AUD.

A-151 Cognitive Sequelae of “Long COVID-19” in Older Adults with Cerebrovascular Risk Factors: A Case Series

Objective: Cardiovascular risk factors have been associated with increased risk for severe COVID-19 symptoms among older adults (CDC, 2021). Severe symptoms increase the likelihood of persistent symptoms following acute COVID-19 infection (i.e., “Long-COVID-19”) (Garg et al., 2021). Preliminary research has associated Long COVID-19 with psychological disorders and decline in multiple cognitive domains (Pyne & Brickman 2021). Provided the novelty of COVID-19, further research is required to substantiate findings and inform clinical application.Methods: This case series includes three Caucasian geriatric patients with cardiovascular risk factors (e.g., diabetes and hypertension) and unremarkable psychiatric histories. Each was referred for neuropsychological evaluation due to residual cognitive symptoms 6-10 months post-recovery from severe COVID-19 infection. Only Patient A was hospitalized.Results: Patient A’s (82, M) neuropsychological profile reflected deficits in executive functioning, variable processing speed, and mild depression. Patient B (86, F) demonstrated deficits in verbal learning and recall and variable attention, language, and visuospatial abilities. Patient C’s (70, F) results revealed deficits in verbal learning and recall, variable processing speed, and severe depression. All patients reported intact instrumental activities of daily living and were diagnosed with Mild Neurocognitive Disorder.Conclusion: Older adults with cardiovascular risk factors may be at higher risk for persistent changes in cognitive and psychological functioning following COVID-19 infection. Consistent with previous research, the cognitive presentation of Long COVID-19 was heterogeneous among these patients. Future studies should examine the influence of cardiovascular risk factors or neuroimaging-based cerebrovascular burden on long-term recovery from COVID-19 infection among older adults.

Amyloid, cerebrovascular disease, and neurodegeneration biomarkers are associated with cognitive trajectories in a racially and ethnically diverse, community-based sample

We characterized the additive contribution of cerebrovascular biomarkers to amyloid and neurodegeneration biomarkers (AV(N)) when modeling prospective, longitudinal cognitive trajectories within 3 major racial/ethnic groups. Participants (n = 172; age = 69–96 years; 62% women; 31%/49%/20% Non–Hispanic White/Non–Hispanic Black/Hispanic) from the Washington Heights-Inwood Columbia Aging Project were assessed for amyloid (Florbetaben PET), neurodegeneration (cortical thickness, hippocampal volume), and cerebrovascular disease (white matter hyperintensity (WMH), infarcts). Neuropsychological assessments occurred every 2.3 ± 0.6 years for up to 6 visits (follow-up time: 4.2 ± 3.2 years). Linear mixed-effects models were stratified by race/ethnicity groups. Higher amyloid was associated with faster memory decline in all 3 racial/ethnic groups, but was related to faster cognitive decline beyond memory in minoritized racial/ethnic groups. Higher WMH was associated with faster language, processing speed/executive function, and visuospatial ability decline in Non–Hispanic Black participants, while infarcts were associated with faster processing speed/executive function decline in Non–Hispanic White participants. Complementary information from AD, neurodegenerative, and cerebrovascular biomarkers explain decline in multiple cognitive domains, which may differ within each racial/ethnic group. Importantly, treatment strategies exist to minimize vascular contributions to cognitive decline.

Neuroimaging and Neuropsychological Performance in Parkinson's Disease Patients with Mild Cognitive Impairment: A Systematic Review

Introduction: One of the most common non motor symptoms of Parkinson's disease (PD) is cognitive decline. Scientific evidence has demonstrated that patients with PD experience rapid cognitive decline in multiple cognitive domains, specifically executive functions, attention, visuospatial, language and memory. However, the extent of cognitive decline with its correlation to brain regions on neuroimaging have not been reviewed extensively in the literature.&#x0D; Objective: The objective of this review is to summarize the existing literature that explores cognitive performance in patients with PD with mild cognitive impairment (MCI) using different neuroimaging techniques.&#x0D; Methods: A comprehensive search was conducted on PubMed and Web of Science databases. This review is focused on articles that explored neuroimaging and neuropsychological performance in patients with Parkinson’s disease. We screened articles and excluded those that did not fit the criteria of this study, and a total of 13 articles have met the criteria.&#x0D; Results: Overall, PD-MCI patients experienced more cognitive decline than PD patients without MCI. Global cognitive ability was associated with frontal lobe, basal ganglia, para-hippocampal gyrus, occipital lobe, and the cerebellum. In addition, some specific cognitive domains were associated with specific brain regions. Attention and executive functions were associated with insula network and the parietal and frontal regions. Learning and memory were associated with grey matter atrophy and right cingulate gyrus and the limbic lobe. Language was associated with frontal cortex, precuneus, and anterior cingulate gyrus. Visuospatial ability was associated with Salience network (SN) and White Matter Hyperintensity (WMH).&#x0D; Conclusion: This review of the literature showed that PD-MCI patients display different cognitive impairment as well as different neuroanatomical changes when compared to PD-Normal Cognition (NC). These findings may suggest that cognitive impairment in PD-MCI patients require different clinical treatment and care. This review also can have diagnostic and treatment implications for this group of patients.

Alzheimer's Disease Classification Accuracy is Improved by MRI Harmonization based on Attention-Guided Generative Adversarial Networks.

Alzheimer's disease (AD) accounts for 60% of dementia cases worldwide; patients with the disease typically suffer from irreversible memory loss and progressive decline in multiple cognitive domains. With brain imaging techniques such as magnetic resonance imaging (MRI), microscopic brain changes are detectable even before abnormal memory loss is detected clinically. Patterns of brain atrophy can be measured using MRI, which gives us an opportunity to facilitate AD detection using image classification techniques. Even so, MRI scanning protocols and scanners differ across studies. The resulting differences in image contrast and signal to noise make it important to train and test classification models on multiple datasets, and to handle shifts in image characteristics across protocols (also known as domain transfer or domain adaptation). Here, we examined whether adversarial domain adaptation can boost the performance of a Convolutional Neural Network (CNN) model designed to classify AD. To test this, we used an Attention-Guided Generative Adversarial Network (GAN) to harmonize images from three publicly available brain MRI datasets - ADNI, AIBL and OASIS - adjusting for scanner-dependent effects. Our AG-GAN optimized a joint objective function that included attention loss, pixel loss, cycle-consistency loss and adversarial loss; the model was trained bidirectionally in an end-to-end fashion. For AD classification, we adapted the popular 2D AlexNet CNN to handle 3D images. Classification based on harmonized MR images significantly outperformed classification based on the three datasets in non-harmonized form, motivating further work on image harmonization using adversarial techniques.

Shift or night shift work and dementia risk: a systematic review.

Dementia is a neurodegenerative disorder characterized by a progressive decline in multiple cognitive domains. Individual and/or environmental risk factors, i.e., aging, are involved in its pathogenesis. It is possible that shift and night works, affecting circadian rhythms, may contribute to the occurrence/progression of the disease. Therefore, aim of this review was to provide an overview on the possible association between shift or night work and cognitive decline. A systematic review of literature studies available in PubMed, Scopus, and ISI Web of Science databases, addressing the possible relationship between shift or night work and dementia was performed. Not-homogeneous findings emerged from the revised studies. Some results supported a positive association between shift work and increased risk of dementia, although with a not unique evidence concerning the role of night work schedules and the consequent circadian misalignment in disease pathogenesis. Cardiometabolic disorders, underlying lifestyles, and additional occupational risk factors, including, psychosocial stress, may act as mediators in the shift work-dementia relationship, that may be overall affected by the individual genetic susceptibility too. Length of employment in shift works was also suggested to be responsible for cognitive damaging effects. The limited number of available studies, the several and different work schedules analyzed, together with the possible co-exposure to other occupational risk factors prevent to draw conclusions on shift work-dementia relationship. Further research should confirm such association and the causal relation with early cognitive alterations in order to guide suitable occupational risk assessment, as well as to promote healthy lifestyle and occupational management strategies, with the ultimate goal of preventing cognitive decline of shift workers. This may overall support the active aging of the workforce while providing benefits for the public health system.

Posterior Cingulate Cortex Network Predicts Alzheimer's Disease Progression.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of toxic misfolded proteins, which are believed to have propagated from disease-specific epicenters through their corresponding large-scale structural networks in the brain. Although previous cross-sectional studies have identified potential AD-associated epicenters and corresponding brain networks, it is unclear whether these networks are associated with disease progression. Hence, this study aims to identify the most vulnerable epicenters and corresponding large-scale structural networks involved in the early stages of AD and to evaluate its associations with multiple cognitive domains using longitudinal study design. Annual neuropsychological and MRI assessments were obtained from 23 patients with AD, 37 patients with amnestic mild cognitive impairment (MCI), and 33 healthy controls (HC) for 3 years. Candidate epicenters were identified as regions with faster decline rate in the gray matter volume (GMV) in patients with MCI who progressed to AD as compared to those regions in patients without progression. These epicenters were then further used as pre-defined regions of interest to map the synchronized degeneration network (SDN) in HCs. Spatial similarity, network preference and clinical association analyses were used to evaluate the specific roles of the identified SDNs. Our results demonstrated that the hippocampus and posterior cingulate cortex (PCC) were the most vulnerable AD-associated epicenters. The corresponding PCC-SDN showed significant spatial association with the patterns of GMV atrophy rate in each patient group and the overlap of these patterns was more evident in the advanced stages of the disease. Furthermore, individuals with a higher GMV atrophy rate of the PCC-SDN also showed faster decline in multiple cognitive domains. In conclusion, our findings suggest the PCC and hippocampus are two vulnerable regions involved early in AD pathophysiology. However, the PCC-SDN, but not hippocampus-SDN, was more closely associated with AD progression. These results may provide insight into the pathophysiology of AD from large-scale network perspective.

The Role of Basement Membranes in Cerebral Amyloid Angiopathy.

Dementia is a neuropsychiatric syndrome characterized by cognitive decline in multiple domains, often leading to functional impairment in activities of daily living, disability, and death. The most common causes of age-related progressive dementia include Alzheimer’s disease (AD) and vascular cognitive impairment (VCI), however, mixed disease pathologies commonly occur, as epitomized by a type of small vessel pathology called cerebral amyloid angiopathy (CAA). In CAA patients, the small vessels of the brain become hardened and vulnerable to rupture, leading to impaired neurovascular coupling, multiple microhemorrhage, microinfarction, neurological emergencies, and cognitive decline across multiple functional domains. While the pathogenesis of CAA is not well understood, it has long been thought to be initiated in thickened basement membrane (BM) segments, which contain abnormal protein deposits and amyloid-β (Aβ). Recent advances in our understanding of CAA pathogenesis link BM remodeling to functional impairment of perivascular transport pathways that are key to removing Aβ from the brain. Dysregulation of this process may drive CAA pathogenesis and provides an important link between vascular risk factors and disease phenotype. The present review summarizes how the structure and composition of the BM allows for perivascular transport pathways to operate in the healthy brain, and then outlines multiple mechanisms by which specific dementia risk factors may promote dysfunction of perivascular transport pathways and increase Aβ deposition during CAA pathogenesis. A better understanding of how BM remodeling alters perivascular transport could lead to novel diagnostic and therapeutic strategies for CAA patients.

Language skills as a predictor of cognitive decline in adults with Down syndrome.

IntroductionAdults with Down syndrome (DS) are at high risk for early onset Alzheimer's disease (AD), characterized by a progressive decline in multiple cognitive domains including language, which can impact social interactions, behavior, and quality of life. This cross‐sectional study examined the relationship between language skills and dementia.MethodsA total of 168 adults with DS (mean age = 51.4 years) received neuropsychological assessments, including Vineland Communication Domain, McCarthy Verbal Fluency, and Boston Naming Test, and were categorized in one of three clinical groups: cognitively stable (CS, 57.8%); mild cognitive impairment (MCI‐DS, 22.6%); and probable/definite dementia (AD‐DS, 19.6%). Logistic regression was used to determine how well language measures predict group status.ResultsVineland Communication, particularly receptive language, was a significant predictor of MCI‐DS. Semantic verbal fluency was the strongest predictor of AD‐DS.DiscussionAssessment of language skills can aid in the identification of dementia in adults with DS. Clinically, indications of emerging language problems should warrant further evaluation and monitoring.

Cingulate Cortex Atrophy Is Associated With Hearing Loss in Presbycusis With Cochlear Amplifier Dysfunction.

Age-related hearing loss is associated with cognitive decline and has been proposed as a risk factor for dementia. However, the mechanisms that relate hearing loss to cognitive decline remain elusive. Here, we propose that the impairment of the cochlear amplifier mechanism is associated with structural brain changes and cognitive impairment. Ninety-six subjects aged over 65 years old (63 female and 33 male) were evaluated using brain magnetic resonance imaging, neuropsychological and audiological assessments, including distortion product otoacoustic emissions as a measure of the cochlear amplifier function. All the analyses were adjusted by age, gender and education. The group with cochlear amplifier dysfunction showed greater brain atrophy in the cingulate cortex and in the parahippocampus. In addition, the atrophy of the cingulate cortex was associated with cognitive impairment in episodic and working memories and in language and visuoconstructive abilities. We conclude that the neural abnormalities observed in presbycusis subjects with cochlear amplifier dysfunction extend beyond core auditory network and are associated with cognitive decline in multiple domains. These results suggest that a cochlear amplifier dysfunction in presbycusis is an important mechanism relating hearing impairments to brain atrophy in the extended network of effortful hearing.

Clinical significance of amyloid β positivity in patients with probable cerebral amyloid angiopathy markers.

We investigated the frequency and clinical significance of amyloid β (Aβ) positivity on PET in patients with cerebral amyloid angiopathy (CAA). We recruited 65 patients who met the modified Boston criteria for probable CAA. All underwent amyloid PET, MRI, APOE genotyping and neuropsychological testing, and we obtained information on MRI markers of CAA and ischemic cerebral small-vessel disease (CSVD). We investigated the CAA/ischemic CSVD burden and APOE genotypes in relation to Aβ positivity and investigated the effect of Aβ positivity on longitudinal cognitive decline. Among the 65 CAA patients, 43 (66.2%) showed Aβ PET positivity (Aβ+). Patients with Aβ+ CAA had more lobar microbleeds (median 9, interquartile range 2-41, vs. 3, 2-8; P = 0.045) and a higher frequency of cortical superficial siderosis (34.9% vs. 9.1%; P = 0.025), while patients with Aβ- CAA had more lacunes (1, 0-2, vs. 0, 0-1; P = 0.029) and a higher frequency of severe white matter hyperintensities (45.5% vs. 20.9%; P = 0.040). The frequency of ε4 carriers was higher in Aβ+ patients (57.1%) than in Aβ- patients (18.2%; P = 0.003), while the frequency of ε2 carriers did not differ between the two groups. Finally, Aβ positivity was associated with faster decline in multiple cognitive domains including language (P < 0.001), visuospatial function (P < 0.001), and verbal memory (P < 0.001) in linear mixed effects models. Our findings suggest that a significant proportion of patients with probable CAA in a memory clinic are Aβ- on PET. Aβ positivity in CAA patients is associated with a distinct pattern of CSVD biomarker expression, and a worse cognitive trajectory. Aβ positivity has clinical relevance in CAA and might represent either advanced CAA or additional Alzheimer's disease neuropathological changes.

Amyloid pathology in the progression to mild cognitive impairment

The objective of this study was to determine the cognitive and functional decline and development of brain injury in individuals progressing from preclinical (β-amyloid positive cognitively normal) to prodromal Alzheimer's disease (AD) (β-amyloid positive mild cognitive impairment [MCI]), and compare this with individuals who progress to MCI in the absence of significant amyloid pathology. Seventy-five cognitively healthy participants who progressed to MCI were followed for 4 years on average and up to 10 years. We tested effects of β-amyloid (Aβ) on measures of cognition, functional status, depressive symptoms, and brain structure and metabolism. Preclinical AD subjects showed greater cognitive decline in multiple domains and increased cerebrospinal fluid phosphorylated tau levels at baseline while Aβ-negative progressors showed increased rates of white matter hyperintensity accumulation and had a greater frequency of depressive symptoms at baseline. Aβ status did not influence patterns of brain atrophy, but preclinical AD subjects showed greater decline of brain metabolism than Aβ-negative progressors. Several unique features separate the transition from preclinical to prodromal AD from other causes of cognitive decline. These features may facilitate early diagnosis and treatment of AD, especially in clinical trials aimed at halting the progression from preclinical to prodromal AD.

Amyloid β Deposition and Suspected Non-Alzheimer Pathophysiology and Cognitive Decline Patterns for 12 Years in Oldest Old Participants Without Dementia

ImportanceThe prevalence of pathologic conditions of the brain associated with Alzheimer disease increases strongly with age. Little is known about the distribution and clinical significance of preclinical biomarker staging in the oldest old, when most individuals without dementia are likely to have positive biomarkers.ObjectiveTo compare the patterns of long-term cognitive decline in multiple domains by preclinical biomarker status in the oldest old without dementia.Design, Setting, and ParticipantsA longitudinal observational study with a mean (SD) of 12.2 (2.2) years (range 7.2-15.1 years) of follow-up was conducted in an academic medical center from August 24, 2000, to January 14, 2016, including and extending observations from the Ginkgo Evaluation of Memory study. A total of 197 adults who had completed the Ginkgo Evaluation of Memory study, were free of dementia, and were able to undergo magnetic resonance imaging were eligible for a neuroimaging study in 2009. Of these patients, 175 were included in the present analyses; 140 (80%) were cognitively normal and 35 (20%) had mild cognitive impairment.Main Outcomes and MeasuresBiomarker groups included amyloid β negative (Aβ−)/neurodegeneration negative (ND−), amyloid β positive (Aβ+)/ND−, Aβ−/neurodegeneration positive (ND+), and Aβ+/ND+ based on Pittsburgh Compound B retention and hippocampal volume in 2009. Participants completed baseline neuropsychological testing from 2000 to 2002 and annual testing from 2004 to 2016. Domains included memory, executive function, language, visual-spatial reasoning, and attention and psychomotor speed. Slopes of decline were evaluated with linear mixed models adjusted for age, sex, and years of education.ResultsOf the 175 participants (71 women and 104 men), at imaging, mean (SD) age was 86.0 (2.9) years (range, 82-95 years). A total of 42 participants (24.0%) were Aβ−/ND−, 32 (18.3%) were Aβ+/ND−, 35 (20.0%) were Aβ−/ND+, and 66 (37.7%) were Aβ+/ND+. On all cognitive measures, the Aβ+/ND+ group showed the steepest decline. Compared with the Aβ−/ND− group, the amyloid deposition alone (Aβ+/ND−) group showed faster decline on tests of verbal and visual memory (–0.3513; 95% CI, –0.5269 to –0.1756), executive function (0.0158; 95% CI, 0.0013-0.0303), and language (–0.1934; 95% CI, –0.3520 to –0.0348). The Aβ−/ND+ group showed faster visual memory decline than the Aβ−/ND− reference group (–0.3007; 95% CI, –0.4736 to –0.1279).Conclusions and RelevanceIn the oldest old without dementia, presence of either or both Aβ and hippocampal atrophy is typical (>75%). Isolated hippocampal volume atrophy is associated only with greater decline in memory. However, isolated Aβ is associated with decline in memory plus language and executive functions. These findings suggest different underlying pathophysiologic processes in the Aβ+/ND− and Aβ−/ND+ groups.

136 Long-term Supratentorial Radiographic Effects of Surgery and Local Radiation in Children with Infratenorial Ependymoma

Abstract INTRODUCTION Current standard of care for children with an infratentorial ependymoma includes maximal safe resection with local radiation of 54–59gy. High-dose local radiation has been associated with decline in multiple cognitive domains. The anatomic correlates of this cognitive decline remain undefined and there have been no radiographic studies on the long-term effects of this treatment paradigm. METHODS A comprehensive database of pediatric brain tumor patients treated at Stanford Children's from 2004–2016 was queried. 7 patients with posterior fossa ependymoma were identified who were treated with surgery and local radiation alone, who had no evidence of recurrent disease, and had imaging suitable for analysis. Diffusion-weighted MRI (DWI) datasets were used to calculate apparent diffusion coefficient (ADC) maps for each subject, while arterial spin labeling (ASL) datasets were used to calculated maps of cerebral blood flow (CBF). Using an atlas-based approach, the following brain structures were automatically segmented: cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, and accumbens. Furthermore, DWI and ASL datasets of 52 age-matched healthy children were available and analyzed in the same fashion to enable group comparisons. Binomial logistic regression models were developed for CBF and ADC measurements with disease status as a binary response variable and a significance threshold of P &lt; 0.05. RESULTS &gt;Several statistically significant differences were detected between the two groups. CBF was lower in the caudate (OR = .424 95%CI.142-.838 p = .05) and pallidum (OR = .479 95%CI = .204-.808 p = .029) and higher in the accumbens (OR = 1.917 95%CI = 1.182-4.472 p = .046) in the ependymoma cohort compared to controls. ADC was increased in the thalamus (OR = 1.168 95%CI = 1.040-1.407 p = .027) and trended towards decreased in the amygdala (OR = .93 95%CI = .846-.996 P = 0.068). CONCLUSION Surgery and local radiation for posterior fossa ependymoma are associated with supratentorial ADC and CBF alterations which may represent an anatomical and physiologic correlate to the previously published decline in neurocognitive outcomes in this population.

Association of financial and health literacy with cognitive health in old age

ABSTRACTWe tested the hypothesis that higher financial and health literacy is associated with better cognitive health in 755 older persons who completed a literacy measure (M = 67.9, SD = 14.5) and then had annual clinical evaluations for a mean of 3.4 years. In proportional hazards models, higher literacy was associated with decreased risk of developing incident Alzheimer’s disease (n = 68) and results were similar for financial and health literacy subscales and after adjustment for potential confounders. In mixed-effects models, higher literacy was related to higher baseline level of cognition and reduced cognitive decline in multiple domains. Among the 602 persons without any cognitive impairment at baseline, higher literacy was associated with a reduced rate of cognitive decline and risk of developing incident mild cognitive impairment (n = 142). The results suggest that higher levels of financial and health literacy are associated with maintenance of cognitive health in old age.

APOE ε4 and the associations of seafood and long-chain omega-3 fatty acids with cognitive decline.

To examine the association between consumption of seafood and long-chain n-3 fatty acids with change in 5 cognitive domains over an average of 4.9 years. From an ongoing longitudinal, community-based epidemiologic study of aging and dementia (the Rush Memory and Aging Project), we included 915 participants (age 81.4 ± 7.2 years, 25% men) who had completed at least one follow-up cognitive assessment and dietary data. Diet was assessed by semiquantitative food frequency questionnaire. Scores for global cognitive function and 5 cognitive domains (episodic, semantic, and working memory, perceptual speed, and visuospatial ability) were assessed using 19 cognitive tests. Mixed models adjusted for multiple risk factors of cognitive change were used to assess the associations. Consumption of seafood was associated with slower decline in semantic memory (β = 0.024; p = 0.03) and perceptual speed (β = 0.020; p = 0.05) in separate models adjusted for age, sex, education, participation in cognitive activities, physical activity, alcohol consumption, smoking, and total energy intake. In secondary analyses, APOE ε4 carriers demonstrated slower rates of decline in global cognition and in multiple cognitive domains with weekly seafood consumption and with moderate to high long-chain n-3 fatty acid intake from food. These associations were not present in APOE ε4 noncarriers. Higher intake levels of α-linolenic acid were associated with slower global cognitive decline, but also only in APOE ε4 carriers. These results suggest protective relations of one meal per week of seafood and long-chain n-3 fatty acids against decline in multiple cognitive domains. The role of APOE ε4 in this association needs further study.