Battery Of Cognitive Tests Research Articles

A feasibility randomized controlled trial of a community-level physical activity strategy for older adults with motoric cognitive risk syndrome.

The motoric cognitive risk syndrome (MCR) is a syndrome characterized by subjective memory complaints and slow walking speeds that can identify older adults at increased risk for developing Alzheimer's disease or a related dementia (ADRD). To date, the feasibility of community-based physical activity (PA) programs for improving outcomes in MCR have yet to be examined. To address this knowledge gap, we conducted a translational randomized controlled trial (RCT) comparing 24-weeks of PA to a healthy aging education (HE) control intervention delivered within the infrastructure of an urban senior center in Greater Boston (clincaltrials.gov identifier: NCT03750682). An existing senior center employee was trained to administer the multimodal group-based PA program that included moderate-intensity aerobic walking, strength, flexibility and balance training. A total of 79 older adults attended the senior center for a screening visit, of whom 29 met the MCR criteria and 25 were randomized to PA or HE (mean age: 74.4 ± 7years; BMI: 32.4 ± 7kg/m2; 85% female; 3MSE score: 92.4 ± 7; gait speed: 0.52 ± 0.1m/s; SPPB score 4.8 ± 1.9). Due to the Covid-19 pandemic the study was stopped prematurely. Participants could successfully adhere to the study interventions (overall attendance rate: PA: 69% vs. HE:70% at study termination). Participants also successfully completed baseline and follow-up study assessments that included a computerized cognitive testing battery and objective tests of physical performance and functional exercise capacity. No study-related adverse events occurred. Notable trends for improved cognitive performance, gait speed and 6-min walk distance were exhibited in PA compared to HE. Our study provides important preliminary information to aid the design of larger-scale RCTs of PA that may help to preserve the independence of vulnerable older adults at high risk for ADRD in community-based settings.

Vepoloxamer improves functional recovery in rat after traumatic brain injury: A dose-response and therapeutic window study

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. There are no effective therapies available for TBI patients. Vepoloxamer is an amphiphilic polyethylene-polypropylene-polyethylene tri-block copolymer that seals membranes and restores plasma membrane integrity in damaged cells. We previously demonstrated that treatment of TBI rats with Vepoloxamer improves functional recovery. However, additional studies are needed to potentially translate Vepoloxamer treatment from preclinical studies into clinical applications. We thus conducted a study to investigate dose-response and therapeutic window of Vepoloxamer on functional recovery of adult rats after TBI. To identify the most effective dose of Vepoloxamer, male Wistar adult rats with controlled cortical impact (CCI) injury were randomly treated with 0 (vehicle), 100, 300, or 600 mg/kg of Vepoloxamer, administered intravenously (IV) at 2 h after TBI. We then performed a therapeutic window study in which the rats were treated IV with the most effective single dose of Vepoloxamer at different time points of 2 h, 4 h, 1 day, or 3 days after TBI. A battery of cognitive and neurological tests was performed. Animals were killed 35 days after TBI for histopathological analysis. Dose-response experiments showed that Vepoloxamer at all three tested doses (100, 300, 600 mg/kg) administered 2 h post injury significantly improved cognitive functional recovery, whereas Vepoloxamer at doses of 300 and 600 mg/kg, but not the 100 mg/kg dose, significantly reduced lesion volume compared to saline treatment. However, Vepoloxamer at 300 mg/kg showed significantly improved neurological and cognitive outcomes than treatment with a dose of 600 mg/kg.In addition, our data demonstrated that the dose of 300 mg/kg of Vepoloxamer administered at 2 h, 4 h, 1 day, or 3 days post injury significantly improved neurological function compared with vehicle, whereas Vepoloxamer administered at 2 h or 4 h post injury significantly improved cognitive function compared with the 1-day and 3-day treatments, with the most robust effect administered at 2 h post injury. The present study demonstrated that Vepoloxamer improves functional recovery in a dose-and time-dependent manner, with therapeutic efficacy compared with vehicle evident even when the treatment is initiated 3 days post TBI in the rat.

BLOOD PRESSURE MEASURES ARE NOT CORRELATED WITH NIH TOOLBOX COGNITIVE BATTERY PERFORMANCE IN BLACK OLDER ADULTS

Abstract Elevated blood pressure has been inconsistently associated with cognitive performance in older adults. Black adults experience higher rates of elevated blood pressure and cognitive impairment than White adults. This study investigated whether blood pressure measurements were associated with cognitive performance on the NIH Toolbox Cognition Battery (NIHTB-CB) in older Black adults. 77 older Black adults 65+ years of age (M=72.6, SD=4.9) with subjective cognitive decline were administered the NIHTB-CB, a battery of computer-based cognitive tests. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured before and after cognitive testing and a cognitive task-based EEG/ERP. Average SBP, DBP, and pulse pressure (PP) were calculated. Difference scores from pre- to post-EEG/ERP served as a reactivity index following cognitive task engagement. A ratio of the difference scores to the baseline measures controlled for resting blood pressure. Bayesian correlations examined the relations between blood pressure measurements and NIHTB-CB performance. Data analysis used fully corrected T scores from the NIHTB-CB subtests. Average SBP, SBP difference scores, and baseline SBP were not associated with NIHTB-CB performance on any measurement (all BF10 < 3.0). Similarly, DBP and PP were unrelated to NIHTB-CB performance. Systolic and diastolic blood pressure were not associated with any NIHTB-CB measure. Additionally, blood pressure reactivity was not related to cognitive performance. Future research may investigate the relationship between SBP reactivity and cognitive performance across multiple measurement periods. Antihypertensive medication and duration of hypertension among hypertensive individuals may also be an important consideration in future studies.

THE RELATIONSHIP BETWEEN SEDENTARY BEHAVIOR AND COGNITIVE DOMAINS AMONG PEOPLE LIVING WITH DEMENTIA

Abstract Greater sedentary behavior negatively impacts cognition among older adults without dementia; however, the relationship between sedentary behavior and cognitive domains among people living with dementia (PWD) is unclear. Our aim was to explore the association between sedentary behavior and cognitive domains in PWD in residential care facilities. The testing took place at one nursing home (n=15/23), one memory care unit (n=4/23), and one assisted living facility (n=4/23). Participants completed a battery of cognitive tests (global cognition: Montreal Cognitive Assessment; executive function: Trail Making test, Digit Span Backwards Test; perception and orientation: Benton Judgment of Line Orientation Test; language: Boston Naming Test; learning and memory: Rey Auditory Verbal Learning Test; complex attention: Digit Symbol Substitution Test). We used the Morse Fall Scale to measure fall risk. Participants wore an actigraphy monitor on their wrist over seven days to measure sedentary behavior. Most participants were male (74%), white (87%), and had unspecified dementia (48%). Participants were sedentary for 8.0±2.7 hours/day. The regression model for sedentary behavior was significant (R2=0.82, F(10, 12)=5.39, RMSE=92.47, p< 0.05). Greater sedentary behavior was associated with poorer language function (β=-0.82, p=0.02), poorer learning and memory (β=-0.82, p=0.002), and greater fall risk (β=-0.43, p=0.03). Sedentary behavior was not associated with the other cognitive domains. Greater sedentary behavior may indicate a decline in language function, learning and memory, and increase fall risk in PWD. Sedentary behavior should be considered in routine assessments, as it may play an important role in monitoring cognitive decline in PWD in residential care facilities.

EXPLORING THE ASSOCIATION OF SLEEP WITH COGNITIVE DOMAINS AMONG PEOPLE LIVING WITH DEMENTIA

Abstract People living with dementia (PWD) commonly experience sleep disruptions, which impacts mental alertness, increases daytime sleepiness, and results in poorer quality of life. While sleep preserves cognitive function among PWD, the relationship between sleep and different cognitive domains is unclear. Our objective was to explore the association between sleep and cognition domains among PWD. Twenty-three PWD completed a battery of cognitive tests (global cognition: Montreal Cognitive Assessment; executive function: Trail-Making Test (TMT), Digit Span Forward Test; perception and orientation: Benton Judgement of Line Orientation Test (BJLO); language: Boston Naming Test; learning and memory: Rey Auditory Verbal Learning Test; complex attention: Digit Symbol Substitution Test) at two residential care facilities. Participants wore a motion watch on their wrist for 7 days to monitor sleep. Participants were primarily male (74%), white (87%), and 48% had unspecified dementia. The average number of hours of sleep per night was 4.6±1.2 hours. The overall regression model for sleep was significant (R2=0.80, F(10,12)=4.68, RMSE=42.32, p< 0.05). More sleep was associated with better perception and orientation (BJLO:β=0.57, p=0.03), greater sleep efficiency (β=0.93, p=0.01), longer wake after sleep onset (β=1.19, p 0.002), and there was a trend for better executive function (TMT:β=-0.34, p=0.09). PWD have inadequate sleep. Greater amounts of sleep seem to preserve perception and orientation and may play a protective role for executive function, but more evidence is needed. Regularly assessing sleep may be useful in screening and monitoring cognitive changes among PWD in residential care facilities.

INVESTIGATING THE RELATIONSHIP BETWEEN HABITUAL ACTIVITY AND COGNITIVE DOMAINS AMONG PEOPLE LIVING WITH DEMENTIA

Abstract Habitual activity preserves cognitive function in people without dementia, but the relationship between habitual activity and cognitive domains among people living with dementia is unclear. The purpose of this study was to explore the association between habitual activity and cognition domains among people living with dementia. Participants living with dementia in residential care facilities (complete case analysis: n=24/42) completed a battery of cognitive tests (global cognition: Montreal Cognitive Assessment; executive function: Trail-Making Test, Digit Span Forward Test; perception and orientation: Benton Judgement of Line Orientation Test; language: Boston Naming Test; learning and memory: Rey Auditory Verbal Learning Test; complex attention: Digit Symbol Substitution Test). Participants wore an actigraphy monitor on their non-dominant wrist over seven days. We conducted a linear regression for total habitual activity (independent variable) with race (white/black), fall risk (Morse Fall Scale), and the number of comorbidities (Functional Comorbidities Index) as covariates, and cognitive tests as variables of interest. Participants were primarily male (75%), white (87.5%), and 50% had unspecified dementia (Alzheimer’s disease: 33%). Greater habitual activity was associated with poorer global cognition, better executive function, and better learning and memory (ps< 0.05). Habitual activity was not related to visuospatial perception, language, or complex attention. Habitual activity may preserve executive function and learning and memory among people living with dementia. Wandering is more common in later stages of dementia, which may explain greater habitual activity observed with lower global cognition. Regularly assessing habitual activity may be useful in screening and monitoring cognitive changes.

IN-VEHICLE SENSORS TO DETECT CHANGES IN DRIVING BEHAVIORS WITH EMERGENCE OF MCI

Abstract Driving is a complex behavior requiring attention, judgment, orientation, memory, processing speed, visual acuity, adequate limb strength, and other functional abilities. It has been suggested that a change in driving behavior may be an early indicator of cognitive decline in the aging brain. The literature suggests that older drivers will drive less and more slowly as their cognitive skills begin to decline. In the “In-Vehicle Sensors to Detect Cognitive Change in Older Drivers” study, sensors are installed in participant vehicles and data is downloaded every three months at which time a carefully curated battery of cognitive tests is also administered. Records of those suggesting mild cognitive impairment (MCI) are reviewed by a Consensus Diagnostic Panel for confirmation. In the first 100 participants who have been followed over a year, nine participants evidenced existing or emerging MCI. Of these, six have experienced a decline in cognition in the last year. A comparison of driving behaviors over the year evidenced the previously reported slower, less frequent driving but also a previously unreported increase in hard braking and hard turns. The uniqueness of our longitudinal study is the continuous tracking of vehicle acceleration patterns over time, revealing significant relationships between g-force acceleration and cognition.

FEASIBILITY OF A COMMUNITY-LEVEL PHYSICAL ACTIVITY STRATEGY FOR OLDER ADULTS WITH MOTORIC COGNITIVE RISK SYNDROME

Abstract The motoric cognitive risk syndrome (MCR) is a pre-dementia syndrome characterized by slow walking speeds and subjective memory complaints. To date, the feasibility of a community-based physical activity (PA) program for improving outcomes in MCR has not been examined. To address this knowledge gap, we conducted a translational randomized controlled trial (RCT) of 24-weeks of PA or a healthy aging education (HE) control intervention delivered within the existing infrastructure of an urban senior center in Greater Boston. A senior center employee was trained to administer the multimodal group-based PA program that included moderate-intensity aerobic walking, strength, flexibility and balance training. A total of 79 older adults attended the senior center for a screening visit of whom 25 met the MCR criteria and were randomized to PA or HE (mean age: 74.4 ± 7 yrs; BMI: 32.4 ± 7 kg/m2; 85% female; 3MSE score: 92.4 ± 7; gait speed: 0.52 ± 0.1 m/sec; SPPB score 4.8 ± 1.9). Due to COVID-19 the study was terminated early, however participants successfully completed baseline and follow-up study assessments that included objective tests of physical function and an iPad-based cognitive testing battery. Participants could appropriately adhere to the study interventions (overall attendance rate: PA: 69.3% vs. HE:70.1% at study termination). No study-related adverse events occurred. Trends for improved executive cognitive performance were exhibited in PA compared to HE. Our study provides important preliminary information to aid the design of larger-scale RCTs to preserve the independence of vulnerable older adults with MCR in community-based settings.

Clinical and cognitive characteristics of subjects with schizophrenia and childhood attention-deficit/hyperactivity disorder: Results from the multicentric FACE-SZ cross-sectional dataset

BackgroundChildhood Attention-deficit/hyperactivity disorder (C-ADHD) is a neurodevelopmental disorder, associated with an increased risk of subsequent schizophrenia. The objective of the present study was to determine the prevalence of C-ADHD in schizophrenia and the clinical and cognitive characteristics associated with C-ADHD history in schizophrenia. Methods569 subjects with schizophrenia (74 % men, mean age 30.8) were included in ten expert centers at a national level and tested with a comprehensive battery of clinician-rated, patient-reported scales and cognitive tests. C-ADHD was assessed with the WURS (Wender Utah Rating Scale) self-report questionnaire. Multivariate, correlation, and principal component analyses (PCA) were conducted. ResultsThirty-nine subjects (N = 39, 6.9 %) were classified in the C-ADHD group. Compared to those without C-ADHD, subjects with C-ADHD were more frequently male, had lower education levels, more severe positive clinical symptoms, more subjective cognitive deficits complaints, and lower medication adherence with small to medium effect sizes. Two cognitive components emerged from the PCA, one component including perceptual reasoning and working memory, and another component including visuospatial search and graphomotor speed, cognitive inhibition/flexibility and central executive functioning. Both components were associated with lower performances in the C-ADHD group. ConclusionsC-ADHD is frequent in schizophrenia and associated with more severe positive symptoms and impaired cognitive performances compared to those without C-ADHD. This suggests that the pathophysiological mechanisms contributing to these disorders may lead to the worsening of the cognitive functioning in patients with both disorders. C-ADHD is a relevant clinical marker to discriminate subgroups of schizophrenia with different profiles for a precision-psychiatry approach.

Association of Neurofilament Light Chain, [18F]PI-2620 Tau-PET, TSPO-PET, and Clinical Progression in Patients With β-Amyloid-Negative CBS.

Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in β-amyloid (Aβ)-negative CBS. We included patients with clinically diagnosed Aβ-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [18F]PI-2620-PET for assessing tau pathology, [18F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction). Overall, 21 patients with Aβ-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [18F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model. [18F]PI-2620 tau-PET, [18F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aβ-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.

Cognitive dysfunction in systemic lupus erythematosus is associated with disease activity and oxidative stress: a comparative study with rheumatoid arthritis for identifying biomarkers

BackgroundThe prevalence and pathophysiological mechanisms of cognitive deficits (CD) Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA) are very heterogeneous and poorly understood. We characterized CD in patients with SLE compared with RA patients and healthy controls. We compared the neuropsychological profile of SLE and RA with patients’ oxidative/inflammatory biomarkers for CD.MethodsWe performed a cross-sectional study, including 50 SLE patients, 29 RA patients, and 32 healthy controls. SLEDAI and DAS28 assessed disease activity. SF-36 questionnaire and a battery of cognitive tests were applied to all participants. Blood samples were collected to determine IL-6, S100ß, myeloperoxidase (MPO), malondialdehyde and reduced glutathione (GSH) alterations.ResultsIn the SLE group, higher GSH was associated with the absence of CD (With CD = 69 ± 49, Without CD = 112 ± 81, p = 0.030), while higher IL-6 was associated with the presence of CD in the RA group (With CD = 603 ± 173, Without CD = 431 ± 162, p = 0.032). Regarding specific cognitive domains, in SLE higher MPO was associated with poor performance in reasoning and abstraction (p = 0.039), higher IL-6 was associated with poor performance in inhibitory control and attention (p = 0.031), and higher GSH was associated with better performance in memory(p = 0.021). Higher SLEDAI was associated with poor performance in semantic fluency(p = 0.031), inhibitory control, and attention in the SLE group(p = 0.037). In the RA group, higher DAS-28 was associated with poor performance in executive functions(p = 0.016) and phonemic fluency (p = 0.003).ConclusionSLE patients’ disease activity, inflammatory state, and oxidative stress were associated with CD. In RA patients, CD was associated with disease activity and inflammatory state. These results encourage further studies with larger samples aiming to confirm oxidative stress parameters as biomarkers of CD in SLE patients.

Sensitivity of Individual and Composite Test Scores from the Cogstate Brief Battery to Mild Cognitive Impairment and Dementia Due to Alzheimer's Disease.

The Cogstate Brief Battery (CBB) is a computerized cognitive test battery used commonly to identify cognitive deficits related to Alzheimer's disease (AD). However, AD and normative samples used to understand the sensitivity of the CBB to AD in the clinic have been limited, as have the outcome measures studied. This study investigated the sensitivity of CBB outcomes, including potential composite scores, to cognitive impairment in mild cognitive impairment (MCI) and dementia due to AD, in carefully selected samples. Samples consisted of 4,871 cognitively unimpaired adults and 184 adults who met clinical criteria for MCI (Clinical Dementia Rating (CDR) = 0.5) or dementia (CDR > 0.5) due to AD and CBB naive. Speed and accuracy measures from each test were examined, and theoretically- and statistically-derived composites were created. Sensitivity and specificity of classification of cognitive impairment were compared between outcomes. Individual CBB measures of learning and working memory showed high discriminability for AD-related cognitive impairment for CDR 0.5 (AUCs ∼ 0.79-0.88), and CDR > 0.5 (AUCs ∼ 0.89-0.96) groups. Discrimination ability for theoretically derived CBB composite measures was high, particularly for the Learning and Working Memory (LWM) composite (CDR 0.5 AUC = 0.90, CDR > 0.5 AUC = 0.97). As expected, statistically optimized linear composite measures showed strong discrimination abilities albeit similar to the LWM composite. In older adults, the CBB is effective for discriminating cognitive impairment due to MCI or AD-dementia from unimpaired cognition with the LWM composite providing the strongest sensitivity.

Feasibility and acceptability of automated cognitive assessment over the telephone in the SpeAK study

AbstractBackgroundThere is growing interest in the development of speech markers as novel, non‐invasive biomarkers of early Alzheimer’s disease (AD). Before including such speech assessments in clinical trials, the technology must be tested to confirm feasibility of administration and acceptability with the target population to ensure future engagement. This study aimed to assess feasibility and acceptability in an at‐risk population receiving automated administration of cognitive tasks over the telephone during the Speech on the Phone Assessment (SPeAk) study [35]. A second goal of the study was to assess participant acceptability of receiving cognitive test results ‐ an important consideration for psychological safety.MethodParticipants (n = 68, mean age 70.43 years, 52.9% male) completed a baseline – administered by a trained researcher ‐ and three month follow up visit – administered by an automated phonebot. Tasks included a spontaneous speech assessment and cognitive battery (immediate and delayed recall, digit span and verbal fluency). Participants were randomized to receive their cognitive test results after the final or after each study visit. Participants completed acceptability questionnaires electronically after each study visit.ResultRetention was high (98.5%), with few technical issues (n = 6.7%), there was good inter rater reliability, and test scores were similar when administered by phonebot compared to human administrator in most subtests. A significant lower mean score in digit span was noted at follow up. These findings indicate general feasibility of the assessment. Participants preferred a human tester but rated the automated assessments as acceptable and would be happy to complete a phonebot assessment again, confirming the ease of use of the technology and comfort of completing cognitive tasks on the phone. Participants generally reported feeling happy to receive their cognitive tests results, and this disclosure did not cause participants to feel worried.ConclusionThe results from this usability and acceptability analysis suggests that completing this brief battery of cognitive tests via a telephone call is both acceptable and feasible in a midlife‐to‐older adult population in the UK, living at risk for AD.

Prognostic value of Neurofilament light chain, [18F]‐PI2620 PET and [18F]GE‐180‐PET in amyloid‐negative Corticobasal Syndrome

AbstractBackgroundCorticobasal syndrome (CBS) with underlying 4‐repeat tauopathy is a progressive neurodegenerative disorder characterized by declining cognitive and motor functions. Biomarkers for assessing pathological brain changes in CBS including tau‐ and microglia‐PET or neurofilament light chain (NfL) have recently been evaluated for differential diagnosis and disease staging, yet the prognostic accuracy of these biomarkers for predicting disease trajectories remains unclear. To address this, we performed a head‐to‐head comparison of neuroimaging (tau‐PET, microglia‐PET) and plasma biomarker NfL as prognostic tools for future clinical trajectories in 21 CBS patients with longitudinal clinical data.MethodWe included 21 clinically diagnosed CBS patients with ∼2‐year clinical follow‐up data who underwent baseline [18F]PI‐2620‐PET for assessing tau pathology, [18F]GE‐180‐PET for microglia activation and plasma‐NfL for neurodegeneration. All patients were negative on amyloid biomarkers. To quantify tau and microglia load we assessed summary scores of whole‐brain, cortical and subcortical tracer signal. NfL was assessed using immunoassays on the Simoa platform. Symptom progression was determined using a battery of cognitive and motor tests. Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster progression of symptoms over time (i.e. time x biomarker interaction).ResultOverall, there was on average a rapid decline over time on the assessed clinical scores. For tau‐PET, CBS patients with higher global tau load showed faster clinical progression. This time x tau‐PET interaction was driven by cortical rather than subcortical tau‐PET load. Patients with higher [18F]GE‐180‐PET whole‐brain load showed slower clinical progression. Concerning plasma biomarker NfL, higher plasma‐NfL was prognostic of faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau‐PET, microglia‐PET as well as plasma‐NfL showed significant (i.e. p&lt;0.05) interaction effects with time on clinical trajectories when tested in the same model, suggesting that these biomarkers explain unique variability in future disease trajectories.Conclusion[18F]PI‐2620 tau‐PET, [18F]GE‐180 microglia‐PET and plasma‐NfL show prognostic potential for clinical progression in CBS patients with probable 4‐repeat tauopathy, which can be useful for clinical decision making as well as stratifying patients in clinical trials.

Discrimination between dementia with Lewy bodies and Alzheimer’s disease based on biofluid monoamines, biomarker values and cognitive parameters

AbstractBackgroundDespite disease‐specific symptoms, differentiation between Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) remains challenging, especially in early, prodromal stages. This is fueled by overlapping pathology in both diseases (Slaets et al., 2013). Monoamine neurotransmitters are significantly altered between DLB and AD and are capable of distinguishing DLB from AD, when added to the panel of cerebrospinal fluid (CSF) dementia biomarkers (Aβ1‐40, Aβ1‐42, T‐tau, P‐tau) and as standalone biomarkers (Janssens et al., 2018). Additionally, cognitive and behavioral differences linked to monoaminergic changes between DLB, AD patients and non‐demented control individuals, have been previously described (Engelborghs et al., 2006, Vermeiren et al., 2015).This study aimed to further explore these dissimilarities for improving discrimination between prodromal and advanced DLB and AD stages.MethodMonoamine neurotransmitter levels were measured in CSF and plasma of 160 prodromal AD (proAD), prodromal DLB (proDLB), AD and DLB patients and 40 non‐demented individuals, using ultra‐high‐performance liquid chromatography. CSF biomarker levels were determined through ELISA. A battery of cognitive and behavioral tests was performed. Monoaminergic, biomarker, cognitive and demographic data were integrated in stepwise regression models to discriminate between (prodromal) DLB and AD.ResultSignificant serotonergic differences in CSF between DLB and AD, as well as noradrenergic, dopaminergic and serotonergic differences in plasma between DLB and AD and with non‐demented individuals were noted. CSF dementia biomarkers levels differed significantly between proAD, proDLB, DLB and AD stages and with non‐demented individuals. There were no CSF, plasma monoamines or CSF biomarker changes between proDLB versus DLB, and proAD versus AD stages. Cognitive functioning differed significantly between prodromal and advanced DLB and AD stages and with non‐demented individuals. Stepwise regression identified that models including plasma and CSF serotonergic components, as well as cognitive tests were the most accurate at discriminating between proDLB versus DLB, proAD versus AD, proDLB versus proAD and DLB versus AD, with area under the curve (AUC), sensitivity and specificity values &gt; 0.9.ConclusionThese findings support differentially affected monoaminergic, pathological biomarker levels and cognitive abilities between (prodromal) AD and DLB, and with non‐demented individuals. In addition, this study provides robust models for discrimination between (prodromal) DLB and AD.

Electrophysiological correlates of objective memory impairments in community‐dwelling older adults at risk of dementia

AbstractBackgroundThe electrophysiological correlates of Short‐Term Memory Binding (STMB) have been previously investigated in older adults at risk of dementia (i.e., Mild Cognitive Impairment ‐MCI). Pietto et al. (2016) reported reduced early electrophysiological activity (100‐250 ms) over fronto‐central (FC) and parieto‐occipital (PO) regions in MCI patients recruited from clinic. We investigated if such an electrophysiological pattern is also observed in a larger sample of community‐dwelling older adults with MCI who had not sought medical advice.MethodsA sample of 215 community‐dwelling older adults were recruited into the study. They were assessed with a battery of cognitive tests including CERAD (Aguirre‐Acevedo et al., 2016), the Addenbrooke’s Cognitive Examination (ACE‐R), the STMB Task, clinical, and functional scales. The STMB task assesses the ability to detect changes between two consecutive visual arrays of coloured shapes. Changes consisted of shapes swapping colours (the binding condition). Time‐locked EEG signals were collected while participants performed the STMB task. Monte Carlo tests and non‐parametric bootstrapping running 1000 permutations revealed electrodes and time windows of relevance.ResultsA group of 108 participants met classical criteria for MCI (Petersen, 2004; Winblad et al., 2004). They showed impaired STMB abilities. ERP analyses revealed significant Group x Time Windows interactions (p&lt;0.01). Early ERP showed reduced neural recruitment (MCI&lt;HC) on the left PO and right centro‐parietal (CP) (300‐500ms) regions during shape‐colour encoding, and on PO bilaterally and left FC during retrieval (150‐450ms). Late ERP showed increased neural recruitment (MCI&gt;HC) on right fronto‐central (FC) regions (900‐1200ms) during shape‐colour encoding, and on left FC and PO regions (872‐1200ms) during retrieval.ConclusionAltered spatio‐temporal dynamics underpinning STMB deficits in MCI patients followed a pattern similar to that described by Pietto et al. (2016). Of note, we observed hyper‐recruitment for late ERP linked to encoding and retrieval over anterior and posterior regions of the STMB network. Such hyper‐recruitment may reflect compensatory changes in the early stages of MCI. These results confirm the usefulness of EEG‐based cognitive biomarkers to screen community‐dwelling older adults at risk of dementia.Aguirre‐Acevedo et al. (2016). Int. Psychogeriatr, 28(3), 503‐510.Pietto et al. (2016). Journal of Alzheimer’s Disease, 53(4), 1325‐1340.

Pesticides and cognitive impairment in older adults: evidence from southern Colombia

AbstractBackgroundEnvironmental exposure to specific chemical groups of pesticides (Carbamates, Organophosphates, Pyrethroids, and Organochlorines), as well as the non or inadequate use of personal protective equipment during pest management, have been associated to cognitive decline and increased risk of dementia (Hayden et al., 2010). This study investigated cognitive functioning in older adults exposed to pesticides in southern Colombia.MethodsA sample of 353 older adults was recruited. Of these, 279 had not been exposed to pesticides (n‐Exp) and 74 had (Exp). They were matched according to age [n‐Ex: 63.80 (3.25), Ex: 63.30 (6.96), t = 0.618, p = 0.538] and years of education [n‐Ex: 9.29 (6.28), Ex: 8.95(6.35), t = 0.418, p = 0.676]. They were assessed with a battery of cognitive tests including CERAD (Aguirre‐Acevedo et al., 2016), The Addenbrooke’s Cognitive Examination (ACE‐R), the Free and Cued Selective Reminding Test (FCSRT) and questionnaires.ResultsFDR corrected comparisons revealed overall lower cognitive abilities in the Exp group (ACE‐R, q = 0.027). They also displayed Memory (FCSRT, q = 0.020; World List Learning q = 0.014) and Constructional Praxis (q = 0.007) impairments. Of those exposed, 73% reported no use of personal protective equipment, and neither the participants nor their family members reported concerns about cognitive decline [Self‐reported: n‐Exp: 14.27 (7.44), Exp: 14.92 (7.98), t = ‐0.654, p = 0.513; Family‐reported: n‐Exp: 10.43 (7.12), Exp: 10.26 (7.45), t = ‐0.182, p = 0.856].ConclusionOlder adults from southern Colombia who have been exposed to pesticides show significant cognitive impairments, which have gone unnoticed by both the affected individuals and their family. Cognitive abilities found to be affected have been associated with risk of dementia caused by Alzheimer’s Disease or Parkinson’s Disease (FCSRT and Constructional Praxis). These types of dementia have been previously associated with this environmental risk factor (Chin‐Chan et al., 2015). More awareness about environmental factors and actions to mitigate their risk are urgently needed, and should be considered by future recommendations (e.g., Livingston et al., 2020).Aguirre‐Acevedo et al. (2016). Int. Psychogeriatr, 28(3), 503‐510. https://doi.org/S1041610215001660.Chin‐Chan et al. (2015). Frontiers in Cellular Neuroscience, 9. https://www.frontiersin.org/articles/10.3389/fncel.2015.00124Hayden et al. (2010). Neurology, 74(19), 1524‐1530. https://doi.org/10.1212/WNL.0b013e3181dd4423Livingston et al. (2020). Lancet, 396(10248), 413‐446. https://doi.org/10.1016/S0140‐6736(20)30367‐6

Sensitivity of individual and composite test scores from the Cogstate Brief Battery to mild cognitive impairment and dementia due to Alzheimer’s disease

AbstractBackgroundThe Cogstate Brief Battery (CBB) is a computerized cognitive test battery found to detect and confirm cognitive deficits related to Alzheimer’s Disease (AD). As the clinical AD and normative samples used to understand the sensitivity of the CBB to AD have been relatively small and varied in terms of selection criteria, it is important to examine the ability of all CBB measures, and potential composites, to discriminate adults with mild cognitive impairment (MCI) and dementia due to AD from carefully selected cognitively unimpaired (CU) adults.MethodAll speed and accuracy measures from the CBB were examined and both theoretically and statistically derived composites were created, from a sample of 4969 CU adults and 185 adults who met clinical criteria for MCI (clinical dementia rating, CDR = 0.5) or dementia (CDR &gt; 0.5) due to AD.ResultIndividual CBB measures of learning and working memory showed high discriminability for AD‐related cognitive impairment for CDR 0.5 (AUCs ∼ 82‐.85), and CDR &gt; 0.5 (AUCs ∼ .90‐.95). There was also high discrimination ability for theoretically derived CBB composite measures, particularly for the Learning and Working Memory (LWM) composite measure (CDR 0.5 AUC = .83, CDR &gt; 0.5 AUC = .97). Various statistically derived linear composite measures showed discrimination abilities similar to the LWM composite.ConclusionIn older adults, the CBB is an effective instrument for objectively discriminating cognitive impairment due to MCI or AD‐dementia from unimpaired cognition, with the LWM composite being a near‐optimal linear CBB composite for that purpose.

Topline results of INTERCEPT‐AD: A phase I trial of Aβ oligomer‐targeting ACU193 in early Alzheimer’s disease

AbstractBackgroundACU193 is a humanized IgG2 subclass monoclonal antibody targeting soluble amyloid‐beta oligomers (sAβOs). Growing evidence supports the view that sAβOs may be the most toxic and pathogenic form of Aβ relative to Aβ monomers and amyloid plaques and are one of the primary drivers of Alzheimer’s disease (AD) neurodegeneration. Thus, blocking the toxicity of sAβOs with ACU193 is a promising approach for treating AD.MethodINTERCEPT‐AD is a phase 1 randomized, placebo‐controlled, single‐ and multiple‐ ascending dose (SAD/MAD) study of the safety, tolerability, and pharmacokinetics (PK) of intravenous ACU193 in participants with early AD, i.e., mild cognitive impairment or mild dementia due to AD. Key inclusion criteria are 55‐90 years of age, confirmation of amyloid pathology with a PET scan, MMSE score of 18‐30, and CDR‐Global score (CDR‐GS) of 0.5 or 1.0. The MAD portion of the study includes three administrations of ACU193 at doses of 10, 25, or 60 mg/kg. In addition to standard safety measures, MRI is assessed periodically. Cerebrospinal fluid is collected to assess PK and evidence of target engagement. The study also includes exploratory measures such as standard cognitive and functional assessments, a computerized cognitive test battery, measures of cerebral blood flow via arterial spin labeling on MRI, and various plasma biomarkers.ResultSixty‐five participants from 17 U.S. study sites were randomized to INTERCEPT‐AD, with 53% female and baseline age of 72.1 ± 7.8 years (mean ± SD). The baseline MMSE was 24.2 ± 3.6, CDR‐GS was 0.64 ± 0.27, and CDR‐Sum of Boxes was 3.5 ± 1.8. In addition to baseline characteristics, the presentation will provide topline safety results, frequency of amyloid‐related imaging abnormalities (ARIA), PK assessments, and evidence of target engagement. Some exploratory measures including cognitive and functional assessments, computerized cognitive testing, and endpoint florbetapir PET results will also be presented.ConclusionWe will present topline results, along with key baseline demographic, clinical, and cognitive characteristics of participants in the INTERCEPT‐AD trial. The data generated from this trial will guide further development of ACU193 in a subsequent trial to test the novel mechanism of action of ACU193 in the treatment of early AD.

Development of a selective estrogen β‐receptor phytoestrogen formulation – PhytoSERM – for the reduction of Alzheimer’s risk and relief of menopausal symptoms in women: a phase 2 randomized clinical trial framework

AbstractBackgroundThe greatest risk factors for Alzheimer’s disease (AD) are age, APOɛ4 allele and female sex. The estimated lifetime risk for AD is 19.5% for women compared to 10.3% in men. Accumulating evidence points to life‐time estrogen exposure as a protective factor against cognitive decline and AD in women, and to the menopause transition as a trigger for an existing AD predisposition. Estrogen replacement therapy (ERT) is effective for sustaining neurological health, but fear of breast cancer is the principal reason menopausal women reject it. Instead, women utilize over the counter products labeled as natural and considered to be safer. Thus, to attain brain protection and address breast protection we developed a rationally designed combination of select ERβ‐selective phytoestrogens that promote brain health to reduce AD risk without increasing breast cell proliferation.MethodA total of 100 participants, 50 per treatment arm, will be enrolled. Eligible participants are woman, 45‐60 years, peri or post‐menopausal (last menstrual period completed ≥ 60 days and ≤ 4 years), MoCA≥22, and experiencing ≥7 hot flashes per day. Participants will be randomized to 50 mg of PhytoSERM or placebo (orally, once‐per‐day) for a 24‐week period. FDG‐PET scans will be conducted at baseline and 24 weeks. Cognitive measures and clinical ratings will be assessed. Hot flashes will be measured both subjectively with a diary and objectively with a digital wristband measuring electrodermal activity.ResultPrimary endpoint is change from baseline to 24 weeks in regional brain glucose metabolism standardized uptake value ratio (SUVR). Secondary outcome measures include cognitive test battery scores, hot flash score and clinical ratings scores. Exploratory measures will include MRI brain volumes, fractional anisotropy, quantitative anisotropy, functional connectivity, and cerebral blood perfusion.ConclusionHerein we present a phase 2 proof‐of‐concept framework to assess the efficacy of PhytoSERM as a potential non‐pharmacologic therapeutic to improve cognitive health and reduce menopausal symptoms. Results from this study will validate previous findings that indicate that PhytoSERM is a safe alternative to hormone therapy and has the potential to sustain neurological health during the menopausal transition.