California Verbal Learning Test-II Research Articles

Life-space mobility and cognition in community-dwelling late-life women: A cross-sectional analysis.

Life-space mobility captures the daily, enacted mobility of older adults. We determined cross-sectional associations between life-space mobility and cognitive impairment (CI) among community-dwelling women in the 9th and 10th decades of life. A total of 1375 (mean age 88 years; 88% White) community-dwelling women enrolled in a prospective cohort of older women. Life-space score was calculated with range 0 (daily restriction to one's bedroom) to 120 (daily trips leaving town without assistance) and categorized (0-20, 21-40, 41-60, 61-80, 81-120). The primary outcome was adjudicated CI defined as mild cognitive impairment or dementia; scores on a 6-test cognitive battery were secondary outcomes. Compared to women with life-space scores of 81-120 and after adjustment for demographics and depressive symptoms, the odds of CI was 1.4-fold (OR 1.36, 95% CI 0.91-2.03) higher for women with life-space scores of 61-80, twofold (OR 1.98, 95% CI 1.33-2.94) higher for women with life-space scores of 41-60, 2.6-fold (OR 2.62, 95% CI 1.71-4.01) higher for women with life-space scores of 21-40, and 2.7-fold (OR 2.71, 95% CI 1.27-5.79) higher for women with life-space scores of 0-20. The association of life-space scores with adjudicated CI was primarily due to higher odds of dementia; the odds of dementia versus normal cognition was eightfold (OR 8.63, 95% CI 3.20-23.26) higher among women with life-space scores of 0-20 compared to women with life-space scores of 81-120. Lower life-space scores were associated in a graded manner with lower mean scores on tests of delayed recall (California Verbal Learning Test-II delayed recall) and language and executive function (phonemic fluency, category fluency, and Trails B). Life-space score was not associated with scores on tests of attention and working memory (forward and backward digit span). Lower life-space mobility is associated in a graded manner with CI among community-dwelling White women in the 9th and 10th decades of life.

B - 107 Is the Flynn Effect Present in a Veteran Outpatient Clinic Sample?

Abstract Objective The Flynn Effect refers to improvement in cognitive scores over time due to advancements in education quality, nutrition, and socioenvironmental variables. Recent studies suggest cognitive scores may plateau or decline over time. Characterization of cohort effects in cognitive performance has implications for normative group selection and identification of brain illness. This study examines cognitive performances of veterans using older and newer versions of normative data to determine if a Flynn effect is present. Method Veterans (N = 189) who passed TOMM and completed the Trail-Making Test (TMT), Animal Naming, and California Verbal Learning Test-II (CVLT-II) were selected for inclusion. The sample was 81% male, racially diverse (49% White/Caucasian, 31% Black/African American, 16% Hispanic/Latino, 4% other), and diagnostically diverse (13% no diagnosis, 33% cognitive disorder, 54% psychiatric diagnosis). Normative scores were calculated from CVLT-II/CVLT-3 manuals for Trial 1, Trial 5, and LDFR; ADC Uniform Data Sets (UDS) were used for TMT-A/B and Animals. Wilcoxon matched-pairs signed rank tests examined differences in z-scores across older and newer normative data. Results Median z-scores were significantly lower using updated UDS norms for TMT-A (z = −11.60, p < 0.001), TMT-B (z = −10.41, p < 0.001), and Animals (z = −11.76, p < 0.001), while CVLT Trial 1 z-scores were significantly higher using CVLT-3 norms (z = 11.24, p < 0.001). CVLT Trial 5 and LDFR medians did not differ. Conclusion Findings demonstrate the need to examine cohort differences in normative reference groups to ensure accurate detection of brain illness. Furthermore, the Flynn Effect may not apply uniformly across domains within a period.

Rationale and methodology for examining the combination of aerobic exercise and cognitive rehabilitation on new learning and memory in persons with multiple sclerosis and mobility disability: Protocol for a randomized controlled trial

BackgroundThis paper describes the protocol for a Phase I/II, parallel-group, single-blind randomized controlled trial (RCT). The RCT investigates the combined effects of 12-weeks of aerobic exercise training (AET) integrated with virtual reality (VR) and cognitive rehabilitation (CR) on new learning and memory in 78 persons with multiple sclerosis (MS) who have mobility disability and objective impairments in learning and memory. MethodsParticipants will undergo baseline assessments consisting of neuropsychological testing, neuroimaging, self-report questionnaires, and cardiorespiratory fitness. Participants will then be randomized into one of two conditions using concealed allocation: aerobic cycling exercise that incorporates VR combined with CR or stretching and toning (i.e., active control; S/T) combined with CR. Participants will be masked regarding the intent of the conditions. After 7-weeks of exercise alone, the 5-week Kessler Foundation modified Story Memory Technique (KF-mSMT®) will be integrated into the training. After the 12-week training period, participants will complete the same measures as at baseline administered by treatment-blinded assessors. Primary study outcomes include new learning and memory (NLM) measured by a small battery of neuropsychological assessments that assess list learning (California Verbal Learning Test-II), prose memory (Memory Assessment Scale), visuospatial memory (Brief Visuospatial Memory Test-Revised), and everyday memory (Ecological Memory Simulations). Secondary study outcomes include neuroimaging outcomes of hippocampal structure, function, and connectivity. ConclusionIf successful, this trial will provide the first Class I evidence supporting the unique combination of aerobic cycling exercise with VR and CR for treating MS-related learning and memory impairments in persons with mobility disability.

Neuropsychological profile associated with financial exploitation vulnerability in older adults without dementia

Objective: Reports of financial exploitation have steadily increased among older adults. Few studies have examined neuropsychological profiles for individuals vulnerable to financial exploitation, and existing studies have focused on susceptibility to scams, one specific type of financial exploitation. The current study therefore examines whether a general measure of financial exploitation vulnerability is associated with neuropsychological performance in a community sample. Methods: A sample (n = 116) of adults aged 50 or older without dementia completed a laboratory visit that measures physical and psychological functioning and a neuropsychological assessment, the Uniform Data Set-3 (UDS-3) and California Verbal Learning Test-II. Results: After covarying for demographics, current medical problems, financial literacy, and a global cognition screen, financial exploitation vulnerability was negatively associated with scores on the Multilingual Naming Test, Craft Story Recall and Delayed Recall, California Verbal Learning Test-II Delayed Recall and Recognition Discriminability, Phonemic Fluency, and Trails B. Financial exploitation vulnerability was not associated with performance on Digit Span, Semantic Fluency, Benson Complex Figure Recall, or Trails A. Conclusions: Among older adults without dementia, individuals at higher risk for financial exploitation demonstrated worse verbal memory, confrontation naming, phonemic fluency, and set-shifting. These tests are generally sensitive to Default Mode Network functioning and Alzheimer’s Disease neuropathology. Longitudinal studies in more impaired samples are warranted to further corroborate and elucidate these relationships.

The influence of depression and anxiety on cognition in people with multiple sclerosis: a cross-sectional analysis.

There are conflicting findings about the relationships between depression, anxiety, and cognitive dysfunction in people with multiple sclerosis (MS), and a paucity of research has examined the cumulative influence on cognition of depression plus anxiety. This study aimed to determine whether elevated symptoms of depression and anxiety alone or in combination are associated with worse cognition in people with MS. In this cross-sectional analysis, people with MS consecutively seen at a tertiary neuropsychiatry clinic completed the Hospital Anxiety and Depression Scale for symptoms of depression (HADS-D) and anxiety (HADS-A), and the Minimal Assessment of Cognitive Function in MS for cognitive indices. Accounting for covariates, regression models predicted cognitive indices from scores for HADS-D, HADS-A, and the interaction. Of 831 people with MS, 72% were female, mean age was 43.2years, and median Expanded Disability Status Scale score was 2.0. Depressive symptoms were independently predictive of lower verbal fluency (Controlled Oral Word Association Test, p < 0.01), verbal learning (California Verbal Learning Test-II (CVLT-II) total learning, p = 0.02), verbal delayed recall (CVLT-II delayed recall, p < 0.01), and processing speed (Symbol Digit Modalities Test, p < 0.01; three-second Paced Auditory Serial Addition Test (PASAT), p = 0.05; two-second PASAT, p = 0.01). Anxiety in people with depression predicted decreased visuospatial function (Judgment of Line Orientation, p = 0.05), verbal learning (p < 0.01), verbal delayed recall (p < 0.01), visuospatial recall (Brief Visuospatial Memory Test-Revised, p = 0.02), and executive function (Delis-Kaplan Executive Function System, p < 0.01). Anxiety alone was not independently predictive of cognition. In conclusion, depression, especially with comorbid anxiety, is associated with cognitive dysfunction in people with MS.

White matter lesion load and location in relation to cognitive impairment in relapsing–remitting multiple sclerosis

Abstract Background In relapsing–remitting multiple sclerosis (RRMS) the connection between cognitive impairment (CI) and white matter lesion load (WM-LL) and location is still unclear. This study aimed to identify the relationship between CI in RRMS patients and WM-LL and locations using a fully automated platform. CI and WM-LL were evaluated in 90 patients with RRMS using the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and Automated MRI volumetric measures of WM-LL and lesion distribution. Regression analysis of BICAMS as a dependent variable with different clinical and radiological parameters was performed. Results Data were obtained from 90 patients with RRMS who had a mean age of 32.74 ± 8.43 years and a female-to-male ratio of 3:1. The mean (± SD) cognitive rating scores for the BICAMS subtests were 28.07 ± 11.78 for the Symbol Digit Modalities Test (SDMT), 42.32 ± 12.46 for the California Verbal Learning Test-II (CVLT-II), and 16.13 ± 8.17 for the Brief Visuospatial Memory Test-Revised (BVMT-R). According to the BICAMS criteria, 29 cases (32.2%) had CI. BICAMS scores were significantly correlated with age, education level, relapse frequency, disease duration, and time to start disease-modifying therapies. Whole WM-LL and periventricular lesion load were significantly associated with CI. After controlling for age, sex, and education, logistic regression analysis revealed that total WM-LL was the best predictor for CI together with duration of illness and years of education. The cut-off value of 12.85 cc for total WM-LL predicted CI. Conclusions Whole WM-LL and periventricular lesion load are the best anatomical predictors for CI probably due to the effect on the anterior commissural fibers while years of education and duration of disease are the best demographic predictors for CI.

Use of perceptual memory as a performance validity indicator: initial validation with simulated mild traumatic brain injury

ABSTRACT Introduction Many commonly employed performance validity tests (PVTs) are several decades old and vulnerable to compromise, leading to a need for novel instruments. Because implicit/non-declarative memory may be robust to brain damage, tasks that rely upon such memory may serve as an effective PVT. Using a simulation design, this experiment evaluated whether novel tasks that rely upon perceptual memory hold promise as PVTs. Method Sixty healthy participants were provided instructions to simulate symptoms of mild traumatic brain injury (TBI), and they were compared to a group of 20 honest responding individuals. Simulator groups received varying levels of information concerning TBI symptoms, resulting in naïve, sophisticated, and test-coached groups. The Word Memory Test, Test of Memory Malingering, and California Verbal Learning Test-II Forced Choice Recognition Test were administered. To assess perceptual memory, selected images from the Gollin Incomplete Figures and Mooney Closure Test were presented as visual perception tasks. After brief delays, memory for the images was assessed. Results No group differences emerged on the perception trials of the Gollin and Mooney figures, but simulators remembered fewer images than the honest responders. Simulator groups differed on the standard PVTs, but they performed equivalently on the Gollin and Mooney figures, implying robustness to coaching. Relying upon a criterion of 90% specificity, the Gollin and Mooney figures achieved at least 90% sensitivity, comparing favorably to the standard PVTs. Conclusions The Gollin and Mooney figures hold promise as novel PVTs. As perceptual memory tests, they may be relatively robust to brain damage, but future research involving clinical samples is necessary to substantiate this assertion.

Internet-delivered lifestyle physical activity intervention for cognitive processing speed in multiple sclerosis

BackgroundWe propose a randomized controlled trial(RCT) of a Social Cognitive Theory-based(SCT), Internet-delivered behavioral intervention targeting lifestyle physical activity(LPA) for yielding improvements in cognitive processing speed(CPS), learning and memory(L/M), symptoms, and quality of life(QOL) among persons with mild multiple sclerosis(MS)-related ambulatory impairment who have impaired CPS. Methods/designThe study involves a Phase-II, parallel group, RCT design. Participants with MS(N = 300) will be randomly assigned on an equal basis(1:1) into behavioral intervention(n = 150) or attention and social contact control(n = 150) conditions. The conditions will be administered over 6-months by trained behavior coaches who will be uninvolved in screening, recruitment, random assignment, and outcome assessment. We will collect outcome data remotely every 6-months over the 12-month period(baseline, immediate follow-up, and 6-month follow-up) using a treatment blinded assessor. The primary outcome is the raw, oral Symbol Digit Modalities Test as a neuropsychological measure of CPS. The secondary outcomes include the California Verbal Learning Test-II as an objective measure of L/M, and patient-reported outcomes of fatigue, depressive symptoms, anxiety, pain, and QOL. The tertiary outcome is accelerometry as an objective, device-based measure of steps/day for generating a minimal clinically important difference(MCID) value that guides the prescription of LPA for improving CPS in clinical practice. The primary data analyses will involve intent-to-treat principles, and mixed-effects models and logistic regression. DiscussionIf successful, the proposed study will provide Class I evidence for the efficacy of a theory-based, Internet-delivered behavioral intervention focusing on LPA for improving CPS and mitigating its negative impact on other outcomes in persons with MS.Clinicaltrials.gov: NCT04518657

The impact of race and other demographic factors on the false positive rates of five embedded Performance Validity Tests (PVTs) in a Veteran sample

ABSTRACT Introduction It is common to use normative adjustments based on race to maintain accuracy when interpreting cognitive test results during neuropsychological assessment. However, embedded performance validity tests (PVTs) do not adjust for these racial differences and may result in elevated rates of false positives in African American/Black (AA) samples compared to European American/White (EA) samples. Methods Veterans without Major Neurocognitive Disorder completed an outpatient neuropsychological assessment and were deemed to be performing in a valid manner (e.g., passing both the Test of Memory Malingering Trial 1 (TOMM1) and the Medical Symptom Validity Test (MSVT), (n = 531, EA = 473, AA = 58). Five embedded PVTs were administered to all patients: WAIS-III/IV Processing Speed Index (PSI), Brief Visuospatial Memory Test-Revised: Discrimination Index (BVMT-R), TMT-A (secs), California Verbal Learning Test-II (CVLT-II) Forced Choice, and WAIS-III/IV Digit Span Scaled Score. Individual PVT false positive rates, as well as the rate of failing two or more embedded PVTs, were calculated. Results Failure rates of two embedded PVTs (PSI, TMT-A), and the total number of PVTs failed, were higher in the AA sample. The PSI and TMT-A remained significantly impacted by race after accounting for age, education, sex, and presence of Mild Neurocognitive Disorder. There were PVT failure rates greater than 10% (and considered false positives) in both groups (AA: PSI, TMT-A, and BVMT-R, 12–24%; EA: BVMT-R, 17%). Failing 2 or more PVTs (AA = 9%, EA = 4%) was impacted by education and Mild Neurocognitive Disorder but not by race. Conclusions Individual (timed) PVTs showed higher false positive rates in the AA sample even after accounting for demographic factors and diagnosis of Mild Neurocognitive Disorder. Requiring failure on 2 or more embedded PVTs reduced false positive rates to acceptable levels across both groups (10% or less) and was not significantly influenced by race.

Speed of processing training to improve cognition in moderate to severe TBI: a randomized clinical trial.

Moderate to severe traumatic brain injury (TBI) often results in cognitive deficits. Processing speed (PS) deficits are common, exerting a significant impact on daily life. Few studies have examined the efficacy of cognitive rehabilitation specifically for PS deficits in moderate to severe TBI. Examine the efficacy of Speed of Processing Training (SOPT) in moderate to severe TBI. This protocol is a 10-session behavioral intervention for PS deficits that has been successfully used with other cognitively impaired populations. This double-blind, placebo-controlled, randomized clinical trial included 46 participants with moderate to severe TBI, 22 randomly assigned to the treatment group and 24 to the placebo-control group. Baseline and follow-up measures included a task similar to the training task (UFOV), measures of near transfer (neuropsychological measures of processing speed: Symbol Digit Modalities Test (SDMT), Wechsler Adult Intelligence Scale-IV (WAIS-IV) Symbol Search, WAIS-IV Coding) and measures of far transfer [neuropsychological measures of learning and memory: the California Verbal Learning Test-II (CVLT-II), Memory Assessment Scales - Prose Memory (MAS-PM)]. Significant improvement from pre-to post-SOPT was observed on all subtests of the UFOV, which is similar to the training task. There was no significant difference on neuropsychological measures of PS or new learning and memory post-treatment. Neuropsychological assessment 6-months post-treatment showed no significant change in PS ability over time. Monthly booster sessions did not impact performance at the 6-month follow-up. Consistent with the SOPT literature, SOPT improves PS ability as measured by the UFOV, a task similar to the training task, in moderate to severe TBI. However, neither near nor far transfer was noted. That is, no improvement was noted on neuropsychological measures of PS.

Frequency of cognitive impairment in patients with neuromyelitis optica spectrum disorder in Mexico.

Between 29% and 67% of neuromyelitis optica spectrum disorder patients have cognitive alterations. To assess the frequency of cognitive impairment in patients with neuromyelitis optica spectrum disorder in Mexico using the Brief International Cognitive Assessment for Multiple Sclerosis. We evaluated 40 neuromyelitis optica spectrum disorder patients and 40 healthy controls from Mexico. 28 (70.0%) patients with neuromyelitis optica spectrum disorder had cognitive impairment in two or more cognitive domains. Student´s T test showed statistically poor performance by neuromyelitis optica spectrum disorder patients compared to healthy controls on all three neuropsychological test scores. This significant difference was observed on the Symbols Digit Modalities Test (t = 8.875; p ≤ 0.001); California Verbal Learning Test-II memory (t = 10.418; p ≤ 0.001); and Brief Visuospatial Memory Test Revised (t = 6.123; p ≤ 0.001). This study showed that 70% of neuromyelitis optica spectrum disorder patients exhibited cognitive impairment in two or more cognitive domains. Determining the frequency of cognitive impairment will guide the decision of Neuropsychologists in planning cognitive rehabilitation across various domains.

Cognitive function and brain magnetic resonance imaging profiles in neuromyelitis optica spectrum disorder and multiple sclerosis.

The objective of this study was to investigate cognitive performance and brain volume profile in patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). In a historical cohort study, 29 MS patients, 31 NMOSD patients, and 20 healthy controls (HCs) underwent neuropsychological assessment using the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS). Patients with MS and NMOSD also underwent a 1.5-tesla magnetic resonance imaging scan and high-resolution three-dimensional T1-weighted MPRAGE sequence. The Symbol Digit Modalities Test scores were significantly lower in MS (mean [standard deviation (SD)] =44.1 [14]) and NMOSD (mean [SD] =45.5 [14.3]) patients compared to HCs (mean [SD] =57 [9.5], P < 0.001). Scores of the Controlled Oral Word Association Test were also lower in MS (mean [SD] =25.9 [9.8]) and NMOSD (mean [SD] =24.6 [10.2]) patients compared to HCs (mean [SD] =36.6 [9.8], P < 0.001). Additionally, the MS group performed worse on the Brief Visuospatial Memory Test (BVMT) compared to the NMOSD group (9.4 ± 3.4 vs. 7.1 ± 3.7 P < 0.001). In MS patients, there was a significant correlation between all cognition scores and total brain lesions, as well as between every test except BVMT-Revised with thalamic volumes. In NMOSD patients, a correlation was found between gray matter volume and the learning phase of the California Verbal Learning Test-II as well as between total lesion percentage and verbal memory and information processing speed. Both NMOSD and MS patients experienced impairment of information processing speed, working memory, and verbal fluency, whereas visuospatial memory impairment was only observed in MS patients. Despite lower total brain lesion and less thalamic atrophy, patients with NMOSD are at risk of cognitive impairment. Microscopic structural abnormalities may be a possible cause.

Effects of healthy aging and mnemonic strategies on verbal memory performance across the adult lifespan: Mediating role of posterior hippocampus.

In this study, we aimed to understand the contributions of hippocampal anteroposterior subregions (head, body, tail) and subfields (cornu ammonis 1-3 [CA1-3], dentate gyrus [DG], and subiculum [Sub]) and encoding strategies to the age-related verbal memory decline. Healthy participants were administered the California Verbal Learning Test-II to evaluate verbal memory performance and encoding strategies and underwent 4.7 T magnetic resonance imaging brain scan with subsequent hippocampal subregions and subfields manual segmentation. While total hippocampal volume was not associated with verbal memory performance, we found the volumes of the posterior hippocampus (body) and Sub showed significant effects on verbal memory performance. Additionally, the age-related volume decline in hippocampal body volume contributed to lower use of semantic clustering, resulting in lower verbal memory performance. The effect of Sub on verbal memory was statistically independent of encoding strategies. While total CA1-3 and DG volumes did not show direct or indirect effects on verbal memory, exploratory analyses with DG and CA1-3 volumes within the hippocampal body subregion suggested an indirect effect of age-related volumetric reduction on verbal memory performance through semantic clustering. As semantic clustering is sensitive to age-related hippocampal volumetric decline but not to the direct effect of age, further investigation of mechanisms supporting semantic clustering can have implications for early detection of cognitive impairments and decline.

When Failing One Performance Validity Test Matters

There appears to be a lack of consensus regarding how best to interpret cognitive test findings when there is a failure on only one Performance Validity Test (PVT). The current study examined the impact of failing one freestanding, forced-choice, memory-based (Fr-FC-MB) PVT across two memory measures in a large sample of veterans (N = 1,353). The impact of failing zero, one, or two Fr-FC-MB PVTs (Test of Memory Malingering Trial 1 or the Medical Symptom Validity Test) on subsequent memory measures was examined (California Verbal Learning Test-II [CVLT-II], Brief Visuospatial Memory Test-R [BVMT-R]). Compared to those failing zero PVTs, those failing one PVT showed significant declines across all memory indices with large average effect sizes (BVMT-R, d = −0.9, CVLT-II, d = −1.0). Those failing one PVT had memory scores more similar to those failing two PVTs. There is a need for greater nuance and flexibility when determining invalid test performance. The current findings, along with a brief review of the literature, find that failing even one Fr-FC-MB PVT dramatically (negatively) impacts memory performance. Results suggest that including individuals failing one Fr-FC-MB PVT into a credible group should be more closely scrutinized.

Larger hippocampal and temporal lobe volume may associate with early rapid forgetting in cognitively healthy individuals with a predisposition to Alzheimer’s disease

AbstractBackgroundGrowing need exists to link volumetric brain analysis to functional cognitive performance in early prediction of Alzheimer’s disease.MethodIn cognitively healthy older adults (N = 40; M age = 71.7±7.7 years), we established amyloid/tau ratios from cerebrospinal fluid, thus finding a small group with pathological amyloid/tau ratios (PAT, n = 11) and normal ratio (NAT, n = 29). Approximately 40% of the PAT group were expected to convert to mild cognitive impairment within 4 years. It was hypothesized that reduced performance on the California Verbal Learning Test‐II (CVLT‐II) Short Delay Free (SDFR) and Cued Recall (SDCR) task would be associated with smaller hippocampal and temporal lobe volume (obtained via NeuroQuant).ResultHippocampal total, left, and right percentiles were found to be negatively associated with SDFR in the PAT group, r(38) = ‐.67*, ‐.66*, and ‐.63*, but not in the NAT group, r(38) = ‐.21, ‐.04, and ‐.35, such that a larger hippocampus was associated with fewer remembered words after a short delay on a list learning task in those with pathological amyloid/tau ratios. Temporal lobe volume was also found to be negatively associated with SDFR and SDCR in the PAT group, r(38) = ‐.67* and ‐.69*, but not in the NAT group, r(38) = ‐.36 and ‐.34, such that a larger temporal lobe was associated with fewer remembered words after a short delay on a list learning task (even when cued) in those with smaller amyloid/tau ratios. Two hierarchical multiple regression analyses, one including amyloid/tau ratio and the other including amyloid only, found that age and sex associate with ∼20.4% variance of the performance on the CVLT‐II SDFR task while temporal lobe volume increased associative value by 16.1% in the former [F (1, 35) = 8.871, p &lt; .05] and by 15.4% in the latter [F (1, 35) = 8.430, p &lt; .05].ConclusionOur findings suggest there may be early compensation in brain structures among cognitively healthy individuals whose CSF biomarker suggest increased risk for the development of symptomatic Alzheimer’s disease, such that hippocampi and temporal lobes increase in size during early pre‐Alzheimer’s stages despite reduced performance on memory tasks.

6 The Moderating Role of Physical Activity on Hippocampal Iron Deposition and Memory Outcomes in Typically Aging Older Adults

Objective:Quantitative Susceptibility Mapping (QSM) is an MRI-based technique that sensitively measures in-vivo iron deposition via relaxation and magnetic susceptibility of brain tissue. Iron is essential for brain homeostasis, including oxidative metabolism, formation and maintenance of neural networks, and myelin synthesis. While increased levels of iron deposition occur during normal aging, high levels may have detrimental effects. Previous work has linked excessive brain iron accumulation to oxidative stress, beta-amyloid and tau toxicity, neurodegeneration, and cognitive dysfunction, particularly memory loss. Physical activity, on the other hand, correlates with higher synaptic integrity and memory performance, even in the presence of neuropathology. To date, it is unknown how physical activity may affect iron deposition-related cognition changes. We examined the moderating role of physical activity on the relationship between QSM hippocampal iron deposition and verbal memory in typically aging adults.Participants and Methods:62 cognitively unimpaired older adults from the UCSF Memory and Aging Center (age mean(SD) = 78.34(7.28) years; 56% women; education mean(SD) = 17.94(1.72) years; 85% non-Hispanic White) completed neuropsychological testing and brain MRI during annual research visits, followed by Fitbit™ physical activity monitoring for 30 days. Average total daily steps were aggregated. Participants completed 3T Prisma neuroimaging with QSM, and regional iron deposition levels were quantified. All subjects also underwent diffusion tensor imaging (fractional anisotropy). Verbal memory was assessed via long delay free recall scores from the California Verbal Learning Test II (CVLT-II). Linear regression examined verbal memory as a function of hippocampal QSM (bilateral), physical activity, and their interaction. Models covaried for age, sex, and education. Additional models separately examined left and right hippocampal QSM, as well as subcortical QSM to determine lateralization and specificity of verbal memory effects to hippocampal iron deposition, respectively.Results:Univariably, higher bilateral hippocampal QSM correlated with worse verbal memory (r= 0.35; p= 0.015). Adjusting for demographics, physical activity moderated the relationship between bilateral hippocampal QSM and verbal memory (ß= 0.41, p= 0.011), such that at higher levels of physical activity, the negative relationship between hippocampal QSM and verbal memory was significantly attenuated. Results persisted when adjusting for DTI integrity of the uncinate fasciculus and fornix white matter tracts. Lateralization models were both significant, suggesting that results were not dominantly driven by either left (ß= 0.34, p= 0.048), or right (ß=0.31, p= 0.035) hippocampal QSM. In contrast, subcortical QSM did not correlate with memory performance (r= 0.13, p &gt; 0.05) or interact with physical activity on verbal memory outcomes (p &gt; 0.05).Conclusions:Physical activity significantly moderated the negative relationship between hippocampal QSM and verbal memory performance. Higher exercise engagement may buffer the adverse effect of hippocampal iron deposition on memory, potentially through its role in maintenance of myelin and synaptic integrity and/or protecting against other neurotoxic events (e.g., oxidative stress, neuronal cell death). Our results support that physical activity continues to be a modifiable risk factor that may offer a protective role in neurobiological pathways of memory and cognitive decline.

5 Rejuvenating Blood Factor TIMP2 Relates to Physical Activity and Cognitive Functioning in Older Adults on The Alzheimer’s Disease Continuum

Objective:Tissue inhibitor of metalloproteinases 2 (TIMP2) is produced peripherally, crosses the blood-brain barrier, and improves synaptic plasticity and hippocampal-dependent cognition in aged mice; however, the role of TIMP2 in human cognitive aging is unclear. We examined associations of circulating TIMP2 levels in blood with a known plasticity-inducing behavior, physical activity, and cognitive functioning among older adults along the Alzheimer’s disease continuum.Participants and Methods:Participants included 84 community-dwelling older adults (meanage = 78.8; 57% female; 82% cognitively normal; 14% MCI; 4% mild dementia; 35% PET Aß+) enrolled in the UC San Francisco Memory and Aging Center. All participants completed 30 days of observational FitbitTM monitoring to quantify physical activity (average daily steps), as well as a comprehensive in-person visit including blood draw (proteins assayed on SOMAscan platform), [18F]AV-45 positron emission tomography (PET) to quantify brain beta-amyloid (centiloids), and neuropsychological assessment. Composite cognitive z-scores were calculated for memory (California Verbal Learning Test-II [CVLT-II] and Benson Figure Recall), semantic processing (animal fluency and Boston Naming Test), and executive functioning (digits backwards span, Stroop inhibition, modified trail making test, lexical fluency, and design fluency). Multiple linear regression examined TIMP2 as a function of physical activity, covarying for age and PET centiloids. Additional regression models separately examined cognitive z-scores as a function of TIMP2, covarying for age, sex, education, PET centiloids, and body mass index (BMI).Results:TIMP2 was not significantly correlated with age, sex, education, or PET centiloids (ps &gt; 0.05); however, TIMP2 was negatively correlated with BMI (r = -0.23, p = 0.036). Greater average daily steps related to higher levels of TIMP2 (b = 0.30, 95%CI = 0.04-0.55, p = 0.022). TIMP2 also related to better semantic processing (b = 0.28, 95%CI = 0.04-0.51, p = 0.021) and executive functioning (b = 0.26, 95%CI = 0.03-0.49, p = 0.028). TIMP2 did not significantly relate to memory (p &gt; 0.05).Conclusions:Greater physical activity was associated with higher concentrations of blood factor TIMP2, which in turn related to better cognitive functioning independent of Alzheimer’s disease pathology burden. These results support previous mouse models by broadly replicating relationships between TIMP2 and cognition in humans, while also uniquely demonstrating an association between TIMP2 and physical activity, a modifiable protective factor in both typical and diseased cognitive aging. Our domain-specific results, however, suggest that benefits of TIMP2 in humans may involve a broader neuroanatomical network than the hippocampal-specific effects previously shown in mice. Although exact mechanisms of TIMP2 need further examination, TIMP2 is known to be enriched in human umbilical cord plasma, has been shown to be involved in cell-growth promoting activities, and may relate to increased neural plasticity in older age. Further examination of TIMP2 and other novel blood-based proteins as potential therapeutic targets for improved cognitive aging, including in the presence of Alzheimer’s disease, is warranted.

47 Amyloid/Tau Ratio and Early Predictors of Alzheimer's Disease

Objective:Early cognitive signs of Alzheimer's disease are often subtle and go unnoticed until they become more prominent and debilitating. Thus, symptoms begin long before an actual Alzheimer's diagnosis is given. However, it is known that cognitively healthy older individuals with lower amyloid/tau ratios (PAT) are more likely to develop Alzheimer's disease than those with higher amyloid/tau ratios (NAT). Therefore, we explored whether this ratio can be used in conjunction with neuropsychological tests to isolate cognitive predictors of Alzheimer's disease amongst cognitively healthy older adults. We were interested in potential group differences on the California Verbal Learning Test, Second Edition (CVLT-II) Long Delay Free Recall scores and Cued Recall scores. We hypothesized that: (a) individuals in the PAT group would have weaker CVLT-II Long Delay Free Recall scores than individuals in the NAT group; and (b) individuals in the PAT group would recall fewer words on the CVLT-II Long Delay Cued Recall trial than individuals in the NAT group.Participants and Methods:There were 115 older individuals recruited via Huntington Medical Research Institutes and the University of Southern California who had their cerebral spinal fluid extracted to measure amyloid/tau ratios. They completed the California Verbal Learning Test-II as part of a larger neuropsychological battery and were determined to be cognitively healthy. The mean age of these participants was 74.5 years (SD = 8.3), and there were 36 who met the threshold for the amyloid/tau ratio associated with Alzheimer's disease (PAT) while the other 79 did not (NAT). A hierarchical linear regression tested the hypotheses, with two blocks used for the analyses. Block 1 for both analyses contained variables to control for the potential effects of various factors in performance on the Long Delay tasks. Block 2 consisted of the amyloid groups (NAT vs. PAT).Results:After controlling for age, sex, education, body mass index, Montreal Cognitive Assessment scores, and depression, we found no significant difference between CVLT-II Long Delay Free Recall scores or Long Delay Cued Recall scores for the two groups.Conclusions:While no significant difference was found on the long delay trials of the CVLT-II, it is important to note that it is unclear at what stage Alzheimer's related decline begins or can be detected using cognitive testing. Longitudinal studies would help to better understand if this lack of association holds true over time. Other aspects of the CVLT-II, such as intrusions and repetitions, would also help to better understand the different ways that symptoms of Alzheimer's disease can manifest early on.

Low serum 25‑hydroxy-vitamin D levels are associated with cognitive impairment in multiple sclerosis

BackgroundCognitive impairment frequently affects people with multiple sclerosis (MS). Low vitamin D has been associated with cognitive dysfunction in different neurodegenerative diseases, and, in MS, with motor disability and disease activity. We aim to investigate associations between vitamin D and cognitive status in MS. MethodsIn this cross-sectional study, we included 181 MS patients, recruited consecutively at the MS Unit of the Policlinico Federico II University Hospital of Naples, Italy, between January and April 2022, with serum 25‑hydroxy (25-OH) vitamin D measurements using Chemiluminescence-ImmunoAssay, and cognitive assessment using the Brief International Cognitive Assessment for MS (BICAMS), which includes Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II) and Brief Visuospatial Memory Test-Revised (BVMT-R). We collected demographics (age, sex, education), and clinical variables (disease duration, disease subtype, expanded disability status scale (EDSS), disease modifying treatment, relapses in previous 12 months, vitamin D supplementation, comorbidities). For a subset of patients (n = 41, 23.2% of the total sample), we collected Beck Depression Inventory-II, Beck Anxiety Inventory, and Modified Fatigue Impact Scale. ResultsAt univariable linear regression models, serum 25-OH-vitamin D levels were 0.9 ng/mL higher for each unit increase of SDMT adjusted scores (Coeff=0.93; 95%CI=0.81, 1.04; p<0.01), 0.7 ng/mL higher for each unit increase of CVLT-II adjusted scores (Coeff=0.68; 95%CI=0.53, 0.83; p<0. 01), 0.6 ng/mL higher for each unit increase of BVMT-R adjusted scores (Coeff=0.58; 95%CI=0.43, 0.73; p<0.01), -9.63 ng/mL lower for each impaired BICAMS test (Coeff=-9.63; 95%CI=-11.48, -7.79; p<0.01), and -2.2 ng/mL lower for each unit increase of EDSS (Coeff=-2.16; 95%CI=-3.57, -0.75; p<0.01). At multivariable linear regression models, we confirmed associations between 25-OH-vitamin D and EDSS (Coeff=-2.09; 95%CI=-4.45, -0.43; p<0.01), SDMT (Coeff=0.75; 95%CI=0.60, 0.90; p<0.01), and CVLT-II (Coeff=0.14; 95%CI=0.01, 0.28; p = 0. 04). Results remained unchanged when including depression, anxiety and fatigue scores. ConclusionsLower serum 25-OH-vitamin D was associated with worse cognitive function in MS. Future studies should consider longitudinal variations in cognitive function in relation to vitamin D supplementation.

Patterns of proactive interference in CVLT-II: evidence of a low-organized, disorganized, and highly organized learning style

ABSTRACT Objective Previous studies have interpreted proactive interference (PI) either as indicating executive dysfunction or a normal process indicating deep level encoding. We investigated these competing models of PI in a large clinical sample using cluster analyses. We expected to find clusters defined by high PI but otherwise characterized by either EF impairment or of good memory performance. Method File records of 731 patients with neurological or psychiatric disorders were analyzed. PI-scores, false positive recognition errors, and semantic organization scores on the California Verbal Learning Test-II (CVLT-II) were subjected to cluster analyses. Clusters were compared regarding buildup and release from PI, memory performance and strategy measures, measures of intelligence, EF, and processing speed. Results The analyses revealed six analyzable clusters. Two clusters showed no buildup of PI and normal release from PI. Discriminability was impaired both in List A and B. Learning acquisition and speeded measures of EF were reduced. One cluster showed both buildup of PI and problems with releasing from PI, and particularly impaired discriminability of List B. Semantic organization was low. Learning consolidation and EF speeded measures were impaired. Two other clusters showed buildup of PI, but no problem with release. Learning was highly organized, and they showed good memory and normal neuropsychological performance. Conclusions Results shows differentiation between a low organized EF dysfunction pattern with no PI, a disorganized PI pattern also indicating EF dysfunction and a highly organized pattern where PI seems to be the price to pay for high effort put into the learning process.