Optimal blood tau species for the detection of Alzheimer's disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study.

Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer's disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer's disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195-205, 212-221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (ORp-tau217 = 15.29, ORp-tau205 = 5.05 and ORp-tau231 = 3.86) and Braak staging (ORp-tau217 = 14.29, ORp-tau205 = 5.27 and ORp-tau231 = 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.

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.

Recent advances in understanding Alzheimer's Disease: diagnosis and management strategies.

As the rates of Alzheimer's Disease (AD) increase in the world due to the aging of the population, research has made tremendous advances to target the two hallmark pathologies of AD: amyloid-ß (Aß) plaque deposition and neurofibrillary tangles of hyperphosphorylated tau. Here, we discuss recent advances in the clinical evaluation and management of AD, with a focus on new hypotheses related to the etiology of AD and new evidence related to AD-mimicking neurodegenerative diseases. Though recent clinical studies suggest anti-amyloid disease modifying agents may slow the progression of AD, there is currently no medication that stops it. Moreover, slowing the progression will result in more individuals in the mild cognitive impairment (MCI) and mild dementia stages of AD. Given this reality, we evaluate the development of non-pharmacological strategies to help sustain cognitive function and quality of life.

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.

The Current of Consciousness: Neural Correlates and Clinical Aspects.

PURPOSE OF REVIEW: In this review, we summarize the current understanding of consciousness including its neuroanatomic basis. We discuss major theories of consciousness, physical exam-based and electroencephalographic metrics used to stratify levels of consciousness, and tools used to shed light on the neural correlates of the conscious experience. Lastly, we review an expanded category of 'disorders of consciousness,' which includes disorders that impact either the level or experience of consciousness. RECENT FINDINGS: Recent studies have revealed many of the requisite EEG, ERP, and fMRI signals to predict aspects of the conscious experience. Neurological disorders that disrupt the reticular activating system can affect the level of consciousness, whereas cortical disorders from seizures and migraines to strokes and dementia may disrupt phenomenal consciousness. The recently introduced memory theory of consciousness provides a new explanation of phenomenal consciousness that may explain better than prior theories both experimental studies and the neurologist's clinical experience. Although the complete neurobiological basis of consciousness remains a mystery, recent advances have improved our understanding of the physiology underlying level of consciousness and phenomenal consciousness.

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.

Development and Pilot of a Process for Regularly Sharing Summary Patient Safety Data.

OBJECTIVE: Dissemination of patient safety data is key to understanding safety events and improving the quality of patient care. However, there is limited guidance on how psychiatry residency programs can create a supportive environment in which to disclose and discuss such information. The authors developed and piloted a resident-led Patient Safety Presentation process at an Accreditation Council for Graduate Medical Education-accredited psychiatry residency program, sharing patient safety data while enhancing residents' education and engagement in patient safety. METHODS: From September 2020 through February 2021, the authors convened a workgroup of psychiatry residents and faculty members to devise and conduct the presentation process. The process consisted of an introductory hour-long training of residents in patient safety concepts, followed a week later by the presentation by two psychiatry residents. The authors evaluated the pilot presentation process using pre- and post-presentation resident surveys. RESULTS: The introductory training and the Patient Safety Presentation were included into the didactic schedules of all 32 program residents. Twenty (62.5%) and 17 (53.1%) residents completed the pre- and post-presentation surveys, respectively. Improvements were seen in residents' knowledge regarding the medical center's patient safety practices and perspectives on patient safety practices. On the post-presentation survey, all 17 residents reported overall satisfaction with the presentation. CONCLUSIONS: The piloted Patient Safety Presentation process increased psychiatry residents' knowledge of and engagement in patient safety. The development and pilot of the presentation process serve as an illustrative case study for other residency programs that are aspiring to grow this aspect of their curriculum.

Built Environment Design Interventions at the Exits of Secured Dementia Care Units: A Review of the Empirical Literature.

PURPOSE: To review evidence around design interventions that influence exiting attempts in dementia care units, informing architectural and clinical practice. BACKGROUND: Built environment design is recognized as important in the care and management of responsive behaviors for those living with Alzheimer's disease and other dementias in secured dementia care units (e.g., exiting attempts, agitation). The repetitious behavior of "walking with purpose" (previously termed wandering) in those with dementia has influenced safety-related architectural design components of dementia care units that decrease exiting attempts. Empirical literature addressing design interventions to prevent exiting for those with dementia is lacking and outdated. METHODS: We sought to describe known design techniques through a topical analysis of experimental studies. A thorough search for empirical studies that assessed interior design interventions at exit doors within dementia care units was undertaken. The review included an extensive search for existing literature and a screening of each study identified for its relevance, quality, and applicability. RESULTS: The experimental studies included in the review collectively assessed five interior design interventions at egress doorways: implementing horizontal and vertical floor grid patterns, mirrors, murals, conditioning responses to color cues, and camouflaging door hardware or vision panels. Why empirical studies have not continued more recently as built environment trends have shifted toward promoting meaningful and purposeful movement through design are considered. Advances in our understanding around the pathophysiology of dementia which might affect future design interventions related to egress are also identified. CONCLUSION: The built environment is an important part of dementia care, and further prospective research is needed on the role of design interventions in the context of exiting attempts within secured units and subsequent behavior outcomes.

Educating students while recruiting underrepresented populations for Alzheimer's disease research: the Student Ambassador Program.

BACKGROUND: Increasing numbers of patients with Alzheimer's Disease and related disorders (ADRD) necessitates increasing numbers of clinicians to care for them. Educational programming related to community outreach with older adults may help inspire interest in future ADRD clinical careers, while increasing awareness of ADRD in the community and aiding recruitment of underrepresented participants into research studies. METHOD: The Boston University Alzheimer's Disease Research Center (BU ADRC) created the BU ADRC Student Ambassador Program, where medical students, graduate students, and undergraduates interested in medicine completed a curriculum during the academic year that included six educational and three outreach events, including monthly dementia-focused didactic meetings and outreach focusing on Black participant recruitment. A pre-post program survey design was implemented to assess changes in students' knowledge of and attitudes toward dementia and related disorders. RESULTS: Between September 2015 and May 2020, thirty-seven students completed the program. Following program completion, students demonstrated increased knowledge of dementia and willingness to work with patients with dementia, as well as more positive attitudes toward patients and the role of empathy in physician practice. In terms of recruitment benefits, the students helped the BU ADRC reach older adults from underrepresented groups who could serve as participants in future research studies. CONCLUSIONS: The BU ADRC Student Ambassador Program can serve as a model for other clinical research programs who wish to encourage students to consider a career in a specific field. In addition, this model has the potential to increase enrollment of participants to research studies. We discuss limitations of our initial efforts and directions for future work to quantify the anticipated benefits for student education and participant recruitment.

Consciousness as a Memory System.

We suggest that there is confusion between why consciousness developed and what additional functions, through continued evolution, it has co-opted. Consider episodic memory. If we believe that episodic memory evolved solely to accurately represent past events, it seems like a terrible system-prone to forgetting and false memories. However, if we believe that episodic memory developed to flexibly and creatively combine and rearrange memories of prior events in order to plan for the future, then it is quite a good system. We argue that consciousness originally developed as part of the episodic memory system-quite likely the part needed to accomplish that flexible recombining of information. We posit further that consciousness was subsequently co-opted to produce other functions that are not directly relevant to memory per se, such as problem-solving, abstract thinking, and language. We suggest that this theory is compatible with many phenomena, such as the slow speed and the after-the-fact order of consciousness, that cannot be explained well by other theories. We believe that our theory may have profound implications for understanding intentional action and consciousness in general. Moreover, we suggest that episodic memory and its associated memory systems of sensory, working, and semantic memory as a whole ought to be considered together as the conscious memory system in that they, together, give rise to the phenomenon of consciousness. Lastly, we suggest that the cerebral cortex is the part of the brain that makes consciousness possible, and that every cortical region contributes to this conscious memory system.

Home-Based Electronic Cognitive Therapy in Patients With Alzheimer Disease: Feasibility Randomized Controlled Trial.

BACKGROUND: Can home-based computerized cognitive training programs be a useful tool to sustain cognition and quality of life in patients with Alzheimer disease (AD)? To date, the progressive nature of the disease has made this question difficult to answer. Computerized platforms provide more accessibility to cognitive trainings; however, the feasibility of long-term, home-based computerized programs for patients with AD dementia remains unclear. OBJECTIVE: We aimed to investigate the feasibility of a 24-week home-based intervention program using the Constant Therapy app and its preliminary efficacy on cognition in patients with AD. Constant Therapy is a program developed for patients with speech and cognitive deficits. We hypothesized that patients with AD would use Constant Therapy daily over the course of the 24-week period. METHODS: Data were collected over a 48-week period. We recruited participants aged between 50 and 90 years with a diagnosis of mild cognitive impairment due to AD or mild AD dementia. Participants were randomly assigned to either the Constant Therapy (n=10) or active control (n=9) group. The Constant Therapy group completed a tablet-based training during the first 24 weeks; the second 24 weeks of computerized training were optional. The active control group completed paper-and-pencil games during the first 24 weeks and were invited to complete an optional Constant Therapy training during the second 24 weeks. Every 6 weeks, the participants completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The participants independently accessed Constant Therapy using an Apple iPad. Our primary feasibility outcomes were the rate of adherence and daily use of Constant Therapy over 24 weeks. Our secondary outcomes were Constant Therapy performance over 24 weeks and change in RBANS scores between the 2 experimental groups. RESULTS: Feasibility analyses were computed for participants who completed 24 weeks of Constant Therapy. We found that long-term use of the Constant Therapy program was feasible in patients with AD over 24 weeks (adherence 80%; program use 121/168 days, for 32 minutes daily). These participants showed an overall improvement in accuracy and latency (P=.005) in the Constant Therapy scores, as well as specific improvements in visual and auditory memory, attention, and arithmetic tasks. The Constant Therapy group showed improvement in the RBANS coding subtest. No unexpected problems or adverse events were observed. CONCLUSIONS: Long-term (eg, 24 weeks) computerized cognitive training using Constant Therapy is feasible in patients with AD in the mild cognitive impairment and mild dementia stages. Patients adhered more to Constant Therapy than to the paper-and-pencil training over 24 weeks and improved their performance over time. These findings support the development of future randomized controlled trials that will investigate the efficacy of Constant Therapy to sustain cognitive function in patients with AD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02521558; https://clinicaltrials.gov/ct2/show/NCT02521558.

Impact of amyloid PET in the clinical care of veterans in a tertiary memory disorders clinic.

Introduction: We aimed to characterize the clinical impact of amyloid PET (APET) in a veteran population with cognitive decline by comparing differences in management between those who did and did not have an APET. Methods: This was a retrospective observational study. Poisson regressions and logistic regression were used for comparisons. Results: Out of 565 veterans, 197 underwent APET; positivity rate was 36.55%. Having an APET was associated with longer follow-up, and increased diagnostic variability; it was not associated with number of additional studies, cholinesterase inhibitors prescription, or referrals to research. A positive APET was associated with less diagnostic variability, fewer additional tests, greater cholinesterase inhibitor prescriptions, and more research referrals. Discussion: In a medically complex, real-world population, APET yielded lower positivity rates and was not associated with classical clinical utility variables when comparing patients with and without an APET. APET may be used more to "rule out" rather than to confirm Alzheimer's disease. Highlights: Amyloid PET was associated with longer follow-up, and higher diagnostic variability.No association was seen with cholinesterase inhibitors prescription, or referrals to research.In complex patients, expected amyloid PET positivity rates are lower than previously described.Amyloid PETs were used to "rule out" AD than to confirm the diagnosis of AD.

Amyloid PET ordering practices in a memory disorders clinic.

Introduction: This study assessed the ordering of amyloid positron emission tomography (PET) scans in a Veterans Affairs (VA) memory disorders clinic as part of routine clinical care, with possible implications for the extent to which ordering may occur outside of the VA in the future if covered by insurance. Methods: Clinical features predictive of ordering amyloid PET scans were retrospectively assessed; the percentage of patients who met appropriate use criteria were evaluated. Results: Among 565 veterans, 34.9% of received an amyloid PET scan and 98.0% of these were consistent with appropriate use criteria. Patients with a PET were younger and more likely to have an initial diagnosis of Alzheimer's disease (AD). Of patients without an amyloid PET scan ordered, 64.4% would have met appropriate use criteria for amyloid PET. Discussion: The majority of scans ordered were consistent with appropriate use criteria and more patients were eligible than received a scan. The current study's findings that approximately one-third of patients in a memory disorders clinic received an amyloid PET scan has implications for memory disorders clinics inside and outside of the US Veterans Health Administration.

Distinguishing Between Genuine and Feigned Dementia Using Event-related Potentials.

BACKGROUND: Individuals with probable Alzheimer disease (AD) may perform below cutoffs on traditional, memory-based performance validity tests. Previous studies have found success using event-related potentials (ERPs) to detect feigned neurocognitive impairment in younger populations. OBJECTIVE: To evaluate the utility of an auditory oddball task in conjunction with the P3b peak amplitude to distinguish probable AD from simulated dementia. METHOD: Twenty individuals with probable AD and 20 older healthy controls (HC) underwent an ERP auditory oddball protocol and the Test of Memory Malingering (TOMM). The HC were asked to perform honestly for one condition and to simulate dementia for the other. The individuals with probable AD were asked to perform honestly. The P3b peak amplitude and button press accuracy were collected from each participant and were analyzed to determine their effectiveness in detecting performance validity. RESULTS: The P3b peak amplitude remained stable regardless of behavioral condition in the HC group. When combined with the TOMM Trial 2 score, the P3b peak amplitude further improved the ability to correctly differentiate individuals with probable AD from HC simulating dementia with 100% sensitivity and 90% specificity. CONCLUSION: The P3b peak amplitude was found to be an effective physiologic measure of cognitive impairment in individuals with probable AD compared with HC simulating dementia. When combined with the TOMM Trial 2 score, the P3b peak amplitude served as a promising performance validity measure for differentiating individuals with probable AD from HC simulating dementia.

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.

Cue-utilization in the imagination inflation effect paradigm in older adults with mild cognitive impairment.

OBJECTIVE: We investigated the imagination inflation effect in healthy older adults and older adults with mild cognitive impairment (MCI) to determine whether an intervention can reduce susceptibility to these distortions, with implications for daily functioning. METHOD: Fifty-seven older adults aged 69-90 participated. In Session 1, participants either: listened to an action statement being read, performed the action, or imagined performing the action. Actions were either functional (encountered actions of daily life; e.g., "fill the pillbox") or nonfunctional (not routinely encountered; e.g., "put the toy duck on a plate"). During Session 2, participants imagined action statements from the first session. In Session 3, participants were asked to determine whether action statements were performed during the first session. Intervention participants were instructed before the first and third sessions to attend various sensory aspects of their experience using a cue-utilization technique. RESULTS: Memory was worse for functional compared to nonfunctional actions. For older adults with MCI, the intervention increased correct identifications of functional actions that were performed. For healthy older adults, the intervention increased source memory of functional actions that were imagined. The intervention did not impact the accuracy of nonfunctional actions or the rates of misremembering an action as having been performed. CONCLUSIONS: These initial findings supported the efficacy of a cue-utilization intervention to improve memory for functional actions in an imagination inflation effect paradigm in community-dwelling older adults. The use of such strategies represents an important first step in designing interventions that are applicable to daily life. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A comparison between tau and amyloid-ß cerebrospinal fluid biomarkers in chronic traumatic encephalopathy and Alzheimer disease.

BACKGROUND: Cerebrospinal fluid (CSF) tau and beta-amyloid levels in chronic traumatic encephalopathy (CTE), a disease which can be clinically indistinguishable from Alzheimer's disease (AD), are largely unknown. We examined postmortem CSF analytes among participants with autopsy confirmed CTE and AD. METHODS: In this cross-sectional study 192 participants from the Boston University AD Research Center, VA-BU-CLF Center, and Framingham Heart Study (FHS) had post-mortem CSF collected at autopsy. Participants were divided into pathological groups based on AD and CTE criteria, with 61 CTE participants (18 low, 43 high stage), 79 AD participants (23 low, 56 intermediate to high), 11 participants with CTE combined with AD, and 41 participants lacking both CTE and AD neuropathology. The Meso Scale Discovery immunoassay system was utilized to measure amyloid-beta (Aß1-40, Aß1-42), total tau (t-tau), and phosphorylated tau (p-tau181 and p-tau231). CSF analytes were then compared across the pathological groups: no CTE/no AD (control), Low CTE, Low AD, High CTE, Intermediate/High AD, and AD+CTE. RESULTS: Among the Low disease state groups, the Low CTE group had significantly higher levels of p-tau231 versus the control group and compared to the Low AD group. The Low CTE group was also found to have significantly lower levels of Aß1-42 compared to the control group. The high CTE group had higher levels of p-tau231 and lower levels of Aß1-42 compared to Intermediate/High AD group. CONCLUSIONS: Importantly, p-tau231 and Aß1-42 were predictors of diagnosis of CTE vs. control and CTE vs. AD. Increased CSF p-tau231 is a promising potentially sensitive biomarker of CTE, and CSF Aß1-42 needs further investigation in CTE.