Longitudinal Cognitive Performance Research Articles

Cognitive Decline in Parkinson's Disease: A Subgroup of Extreme Decliners Revealed by a Data-Driven Analysis of Longitudinal Progression.

Cognitive impairment is an important symptom of Parkinson’s disease (PD) and predicting future cognitive decline is crucial for clinical practice. Here, we aim to identify latent sub-groups of longitudinal trajectories of cognitive change in PD patients, and explore predictors of differences in cognitive change. Longitudinal cognitive performance data from 349 newly diagnosed PD patients and 145 healthy controls from the Parkinson Progression Marker Initiative were modeled using a multivariate latent class linear mixed model. Resultant latent classes were compared on a number of baseline demographics and clinical variables, as well as cerebrospinal fluid (CSF) biomarkers and striatal dopamine transporter (DAT) density markers of neuropathology. Trajectories of cognitive change in PD were best described by two latent classes. A large subgroup (90%), which showed a subtle impairment in cognitive performance compared to controls but remained stable over the course of the study, and a small subgroup (10%) which rapidly declined in all cognitive performance measures. Rapid decliners did not differ significantly from the larger group in terms of disease duration, severity, or motor symptoms at baseline. However, rapid decliners had lower CSF amyloidß42 levels, a higher prevalence of sleep disorder and pronounced loss of caudate DAT density at baseline. These data suggest the existence of a distinct minority sub-type of PD in which rapid cognitive change in PD can occur uncoupled from motor symptoms or disease severity, likely reflecting early pathological change that extends from motor areas of the striatum into associative compartments and cortex.

Fronto-Parietal Gray Matter Volume Loss Is Associated with Decreased Working Memory Performance in Adolescents with a First Episode of Psychosis.

Cognitive maturation during adolescence is modulated by brain maturation. However, it is unknown how these processes intertwine in early onset psychosis (EOP). Studies examining longitudinal brain changes and cognitive performance in psychosis lend support for an altered development of high-order cognitive functions, which parallels progressive gray matter (GM) loss over time, particularly in fronto-parietal brain regions. We aimed to assess this relationship in a subsample of 33 adolescents with first-episode EOP and 47 matched controls over 2 years. Backwards stepwise regression analyses were conducted to determine the association and predictive value of longitudinal brain changes over cognitive performance within each group. Fronto-parietal GM volume loss was positively associated with decreased working memory in adolescents with psychosis (frontal left (B = 0.096, p = 0.008); right (B = 0.089, p = 0.015); parietal left (B = 0.119, p = 0.007), right (B = 0.125, p = 0.015)) as a function of age. A particular decrease in frontal left GM volume best predicted a significant amount (22.28%) of the variance of decreased working memory performance over time, accounting for variance in age (14.9%). No such association was found in controls. Our results suggest that during adolescence, EOP individuals seem to follow an abnormal neurodevelopmental trajectory, in which fronto-parietal GM volume reduction is associated with the differential age-related working memory dysfunction in this group.

Insomnia Moderates the Relationship Between Amyloid-β and Cognitive Decline in Late-Life Adults without Dementia.

It is suggested that not all individuals with elevated Aβ will develop dementia or cognitive impairment. Environment or lifestyle might modulate the association of amyloid pathology with cognition. Insomnia is a risk factor of cognitive disorders including Alzheimer's disease. To investigate if insomnia moderated the relationship between amyloid-β (Aβ) and longitudinal cognitive performance in non-demented elders. A total of 385 Alzheimer's Disease Neuroimaging Initiative participants (mean age = 73 years, 48% females) who completed 4 + neuropsychological evaluations and a [18F] florbetapir positron emission tomography scan were followed up to 8 years. Linear mixed-effects regression models were used to examine the interactions effect between insomnia and Aβ on longitudinal cognitive sores, including four domains (memory [MEM], executive function [EF], language [LAN], and visuospatial function [VS]). The Aβ-positive status (A+) but not insomnia independently predicted faster cognitive decline in all domains. Furthermore, the relationship between Aβ and cognitive decline was moderated by insomnia (MEM: χ2 = 4.05, p = 0.044, EF: χ2 = 4.38, p = 0.036, LAN: χ2 = 4.56, p = 0.033, and VS: χ2 = 4.12, p = 0.042). Individuals with both elevated Aβ and insomnia experienced faster cognitive decline than those with only elevated Aβ or insomnia. These data reinforced the values of insomnia management in preventing dementia, possibly by interacting Aβ metabolism. Future efforts are warranted to determine whether sleep improvement will postpone the onset of dementia, specifically among populations in stages of preclinical or prodromal AD.

Regional amyloid accumulation predicts memory decline in initially cognitively unimpaired individuals.

IntroductionThe value of quantitative longitudinal and regional amyloid beta (Aβ) measurements in predicting cognitive decline in initially cognitively unimpaired (CU) individuals remains to be determined.MethodsWe selected 133 CU individuals with two or more [11C]Pittsburgh compound B ([11C]PiB) scans and neuropsychological data from Open Access Series of Imaging Studies (OASIS‐3). Baseline and annualized distribution volume ratios were computed for a global composite and four regional clusters. The predictive value of Aβ measurements (baseline, slope, and interaction) on longitudinal cognitive performance was examined.ResultsGlobal performance could only be predicted by Aβ burden in an early cluster (precuneus, lateral orbitofrontal, and insula) and the precuneus region of interest (ROI) by itself significantly improved the model. Precuneal Aβ burden was also predictive of immediate and delayed episodic memory performance. In Aβ subjects at baseline (N = 93), lateral orbitofrontal Aβ burden predicted working and semantic memory performance.DiscussionQuantifying longitudinal and regional changes in Aβ can improve the prediction of cognitive functioning in initially CU individuals.

Longitudinal cognitive performance of Alzheimer's disease neuropathological subtypes.

IntroductionAlzheimer's disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments.MethodsTwo hundred ninety‐two participants with neuropathologically confirmed AD from the Religious Orders Study and Memory and Aging Project were categorized by neuropathological subtype based on previously specified diagnostic criteria using quantitative regional NFT counts. Rates of cognitive decline were compared across subtypes using linear mixed‐effects models that included subtype, time, and a subtype–time interaction as predictors and four cognitive domain factor scores (memory, executive function, language, visuospatial) and a global score as outcomes. To assess if memory was relatively preserved in HpSpAD, non‐memory factor scores were included as covariates in the mixed‐effects model with memory as the outcome.ResultsThere were 57 (20%) with lpAD, 22 (8%) with HpSpAD and 213 (73%) with tAD. LpAD died significantly later than the participants with tAD (2.4 years, P = .01) and with HpSpAD (3.8 years, P = .03). Compared to tAD, HpSpAD, but not lpAD, performed significantly worse in all cognitive domains at the time of initial impairment and declined significantly faster in memory, language, and globally. HpSpAD did not have relatively preserved memory performance at any time point.ConclusionThe relative frequencies of AD neuropathological subtypes in an epidemiological sample were consistent with a previous report in a convenience sample. People with HpSpAD decline rapidly, but may not have a memory‐sparing clinical syndrome. Cohort‐specific differences in regional tau burden and comorbid neuropathology may explain the lack of clinicopathological correlation.

Estimating an individual's placement on a theoretical continuum using longitudinal cognitive trajectories: Relationships with longitudinal amyloid and Tau‐PET

AbstractBackgroundTheoretical models of the Alzheimer’s disease (AD) continuum posit a curvilinear trajectory of declining cognition, with accumulating AD pathology catalyzing an accelerated rate of decline. Assuming this continuum can be modelled, individuals can be placed along the curve based on their longitudinal cognitive performance. In this way, we can reduce multi‐dimensional data to a single parameter (simplification/parsimony) and remove non‐linearity in the cognitive data.Method317 participants from the Harvard Aging Brain Study (72 years (7.6); Female:61.5%) underwent longitudinal neuropsychological assessments (follow‐up: 5.9years (2.1) range:1.7‐9.1) and PIB‐PET imaging. A subset of participants (n=230) also underwent FTP‐PET imaging. Cognition was measured using the Preclinical Alzheimer Cognitive Composite (PACC). Using iterative non‐linear least squares optimization, we defined a curvilinear function (incorporating linear, quadratic and exponential components) that best described the group level PACC trajectory of all participants (Figure 1). Each subject’s longitudinal PACC trajectory was then located on the resulting curve using trust‐region‐reflective non‐linear least squares optimization, solving for an individual’s time offset (toffset). We examined associations between toffset, age, sex, apoe4 status, cross‐sectional PIB‐PET and FTP‐PET. We also examined toffset in relation to changing PIB‐PET and FTP‐PET.ResultIndividuals with a more advanced toffset had higher levels of entorhinal (EC) and inferior temporal (IT) FTP‐PET (r=0.42, p=<<0.001; Figure 2A&B.), and also showed higher PiB‐PET signal (r=0.36, p=<<0.001; Figure 2C.) PIB accumulation appears earlier in toffset followed by EC TAU and finally IT TAU, suggesting that a biomarker cascade is being captured by toffset (Figure 3). FTP‐PET and PIB‐PET did not interact to predict toffset. There was no effect of age or APOE4, or an interaction between the two, on toffset.ConclusionUsing toffset, estimating an individual’s position along a hypothetical clinical continuum can inform the unique contributions of AD biomarkers, and test hypotheses about temporal sequences of events. This data‐reduction approach is superior to that of pulling cognitive slopes, as the tpffest removes complex non‐linearities inherent in the data (Figure 4). We also illustrate that an interaction between FTP‐PET and PIB‐PET does not predict toffset, suggesting a common upstream mechanism that may underlie both Aβ and tau to drive decline, at least during the preclinical stages of disease.

Associations between lifestyle risk, β‐amyloid, tau, and cognition in late mid‐life

AbstractBackgroundModifiable lifestyle risk (LR) factors are increasingly viewed as preventive strategies for AD and dementia; however, the impact of LR factors on AD biomarkers or AD biomarker‐related cognitive decline remains unknown. We utilized the Lifestyle for BRAin health (LIBRA) index 1)to investigate whether baseline LR predicts incident cognitive impairment and/or β‐amyloid onset; 2)to examine the effect of longitudinal LR on cognitive decline in the presence of β‐amyloid; 3)to preliminarily examine the cross‐sectional relationship between late‐midlife LR and β‐amyloid and tau biomarker groups.MethodParticipants (n=1244, Table 1) from the Wisconsin Registry for Alzheimer’s Prevention completed serial health and neuropsychological assessments with a subset undergoing PiB PET imaging (n=238) and MK‐6240 (n=186) PET imaging. Cox regressions assessed the predictive utility of baseline LIBRA for incident cognitive impairment (1.5 SD below covariate adjusted 3‐test Preclinical Alzheimer’s Cognitive Composite, PACC‐3) and β‐amyloid duration (i.e. age at assessment – estimated age PiB(+)). Linear mixed models examined the main effects and age interactions of LIBRA and β‐amyloid duration on longitudinal cognitive performance. Group differences in LIBRA were assessed across biomarker groups, where amyloid (A+) and tau (T+) positivity were defined as a global PiB DVR>1.19 and entorhinal cortex MK‐6240 SUVR>1.27, respectively.ResultIn the survival analysis, baseline LIBRA predicted risk for incident cognitive impairment of subjects unimpaired at baseline (HR=1.18; Figure 1). In the amyloid imaging subset, baseline LIBRA did not predict β‐amyloid onset (HR=0.85; Figure 1). Linear mixed effects models indicated a significant main effect of LIBRA (higher LIBRA risk = worse PACC‐3) and a significant interaction of β‐amyloid duration×age on PACC‐3 (longer β‐amyloid duration = faster PACC‐3 decline; Figure 2). In the combined imaging subset (n=186), there were no differences in LIBRA across biomarker groups (Kruskal‐Wallis H: 5.08, p=.166; Figure 3).ConclusionThese findings suggest that a healthy lifestyle is associated with overall cognitive performance but not the rate of cognitive decline or biomarker status. In this sample, LR did not influence the onset of β‐amyloid or hasten AD‐related cognitive decline. Replication of this finding and future work is necessary to better understand the relationships between LR factors, cognitive decline and AD.

Prescription medications and co‐morbidities in late middle‐age are associated with lower executive function: Results from WRAP

AbstractBackgroundAging is often accompanied by the accumulation of chronic illnesses such as diabetes, cardiovascular disease or hypertension and a corresponding increase in use of medications to manage these conditions. Polypharmacy (use of multiple prescription medications) is a growing health concern and has been associated with poorer clinical outcomes in older adults. This study investigates associations between comorbidities, polypharmacy and longitudinal cognitive performance in an Alzheimer’s disease (AD) risk‐enriched cohort, the Wisconsin Registry for Alzheimer’s Prevention (WRAP).MethodEligible WRAP participants included 1039 (free of dementia or clinical impairment not due to mild cognitive impairment (MCI) and with >=2 visits with cognitive composites, self‐reported health history, and concurrent medication records. Sums of prescribed medications and self‐reported co‐morbidities (include self‐ report over the lifetime) (Table 1) were calculated for each visit and converted to z‐scores for use in mixed effects models of cognition (covariates: age, gender, education, WRAT III reading recognition, practice and study site). Linear mixed effects analyses first examined whether associations between medications, comorbidities and cognitive z‐scores varied across cognitive domains of working memory, immediate recall, delayed recall, executive function, and a preclinical Alzheimer’s cognitive composite (PACC3) before examining associations with each cognitive composite. In secondary analyses, we examined whether number of medications and comorbidities interacted with each other or modified age trajectories.ResultSample characteristics are shown in Table 2 overall and by gender (mean(sd) baseline age=58.99(6.60)). More comorbidities were associated with more prescription medications (Figure 1). More comorbidities and medications were associated with lower executive function (β = ‐0.11, p=.002; β = ‐0.07, p = 0.047; Table 3); using z‐scores of 10th and 90th centile with model parameters, those with low co‐morbidities and medications performed an average of 0.39 SD higher than those elevated on both (Figure 2).ConclusionAssociations between medications, comorbidities, and executive function suggest that persons with more comorbidities and medications may be either at increased risk of reaching clinical levels of impairment earlier than healthier, less medicated peers, or may have potentially reversible clinical impairment. Researchers should be aware of the possibility that medication use and comorbidity may impact cognitive performance (and by extension, adjudicated cognitive status).

Cognitive performance among participants with Alzheimer’s disease and cerebral amyloid angiopathy

AbstractBackgroundBeta‐amyloid found in Alzheimer’s disease (AD) plaques can also be present in the brain’s blood vessels as cerebral amyloid angiopathy (CAA). Co‐occurrence of AD and CAA is common. We examined the relationship between AD and CAA, and cognitive performance.MethodData were obtained from the National Alzheimer’s Coordinating Center. The sample was restricted to those with an autopsy ≤2 years of their last clinic visit and non‐missing data on Braak neurofibrillary tangle stage, neuritic plaque score, and CAA at autopsy. We excluded participants who had autopsy evidence of rare neuropathological diseases. Linear regression models with generalized estimating equations were run comparing CDR® Dementia Staging Instrument sum of boxes (CDR‐SB) and cognitive domain z‐scores across four groups (AD+/CAA+, AD+/CAA‐, AD‐/CAA+, AD‐/CAA‐). AD+ included those with Braak III‐VI and moderate/frequent neuritic plaques. Overall neocortical amyloid angiopathy was assessed for presence of CAA. Models accounted for clustering by center and adjusted for covariates. We also examined the mean differences in CDR‐SB by CAA severity (absent, mild, moderate, severe), stratifying by AD+/‐ and APOE ε4+/‐.ResultWe identified 1723 AD+/CAA+, 547 AD+/CAA‐, 443 AD‐/CAA+, and 741 AD‐/CAA‐ participants. All groups were more likely to be APOE ε4 carriers compared to AD‐/CAA‐. CAA+ participants, regardless if they had AD, were more likely to have arteriolosclerosis. After adjusting for covariates, AD+/CAA+ and AD+/CAA‐ participants had worse CDR‐SB scores compared to AD‐/CAA‐. There was no significant difference in CDR‐SB scores among AD‐ participants with or without CAA. Similar results were seen when examining differences in cognitive domain z‐scores, where AD+ participants performed worse regardless of the presences of CAA when compared to AD‐/CAA‐ participants. We did not observe significant differences in CDR‐SB scores by CAA severity after adjusting for covariates.ConclusionThese results demonstrate that the presence of AD neuropathologic features appears to be driving the cognitive performance irrespective of the presence or severity of CAA. Our observation that arteriolosclerosis was more likely to be present among those with CAA even in the absence of AD is of note and something to investigate further. Future work should also examine if these differences hold true when examining longitudinal cognitive performance.

Defining longitudinal change on the auditory verbal learning test using a conditional normative model to account for practice effects: Preliminary validation in preclinical Alzheimer’s disease

AbstractBackgroundPractice effects can obscure interpretation of longitudinal cognitive performance. Reliable change indices (RCIs) provide data for determining a significant change, typically for a single repeat assessment, but multiple follow‐up visits are common clinically and in research cohorts. Further, regression‐based or linear mixed effects models improve prediction of future cognitive decline and have higher correlations with neuroimaging biomarkers than RCI approaches. We present norms for change for the Auditory Verbal Learning Tests (AVLT) with conditional normative z‐scores for up to 7 repeat assessments, and demonstrate application of this method to individuals with preclinical Alzheimer’s disease (AD).MethodNormative Sample: Robust conditional norms were derived from 1001 adults ages 50‐90 from the Mayo Clinic Study of Aging (MCSA) who completed the AVLT across 4‐8 visits approximately 15 months apart and remained cognitively unimpaired (CU) across all available visits. Linear mixed effects models were used to compute a conditional normative z‐score for AVLT 30‐minute recall and sum of trials. Models included adjustment for baseline performance, number of prior test exposures, demographic factors (age, sex, education), and interactions (baseline*time; sex*time). Test Sample: We used a preclinical AD sample with positive amyloid and tau imaging (n= 27 CU A+T+; Jack et al. 2017) expected to have a higher rate of intra‐individual cognitive decline relative to CU A‐T‐ individuals (n = 268) to compare mean performances of conditional normative z‐scores to typical age‐corrected Mayo’s Older Americans Normative Studies (MOANS) norms. Participants had at least 1 and up to 4 follow‐up visits, with their most recent AT data used for classification.ResultAVLT performance based on typical norms did not differ across A+T+ and A‐T‐ groups. Specifically, across 2‐4 follow‐up visits, the typical norms mean z‐score was similar across groups (p=0.945; see Table 1). However, the conditional norms mean z‐score that accounts for practice effects and typical trajectories of AVLT performance was lower in the A+T+ relative to the A‐T‐ group for 30‐minute recall (p=0.055) and sum of trials (p=0.060).ConclusionConditional normative methods that account for practice effects are more sensitive to preclinical AD than typical norms, and show promise for identifying transitional cognitive decline.

Utility of Plasma Neurofilament Light in the 1Florida Alzheimer's Disease Research Center (ADRC).

Background:Plasma NfL (pNfL) levels are elevated in many neurological disorders. However, the utility of pNfL in a clinical setting has not been established.Objective:In a cohort of diverse older participants, we examined: 1) the association of pNfL to age, sex, Hispanic ethnicity, diagnosis, and structural and amyloid imaging biomarkers; and 2) its association to baseline and longitudinal cognitive and functional performance.Methods:309 subjects were classified at baseline as cognitively normal (CN) or with cognitive impairment. Most subjects had structural MRI and amyloid PET scans. The most frequent etiological diagnosis was Alzheimer’s disease (AD), but other neurological and neuropsychiatric disorders were also represented. We assessed the relationship of pNfL to cognitive and functional status, primary etiology, imaging biomarkers, and to cognitive and functional decline.Results:pNfL increased with age, degree of hippocampal atrophy, and amyloid load, and was higher in females among CN subjects, but was not associated with Hispanic ethnicity. Compared to CN subjects, pNfL was elevated among those with AD or FTLD, but not those with neuropsychiatric or other disorders. Hippocampal atrophy, amyloid positivity and higher pNfL levels each added unique variance in predicting greater functional impairment on the CDR-SB at baseline. Higher baseline pNfL levels also predicted greater cognitive and functional decline after accounting for hippocampal atrophy and memory scores at baseline.Conclusion:pNfL may have a complementary and supportive role to brain imaging and cognitive testing in a memory disorder evaluation, although its diagnostic sensitivity and specificity as a stand-alone measure is modest. In the absence of expensive neuroimaging tests, pNfL could be used for differentiating neurodegenerative disease from neuropsychiatric disorders.

Individual changes in visual performance in non-demented Parkinson's disease patients: a 1-year follow-up study.

Cognitive deficits in Parkinson's disease (PD) are heterogeneous entities, and the cognitive status fluctuates over time. However, individual changes in longitudinal cognitive performance in PD are not fully understood. We evaluated three visual indices (visuoperception, visuoconstruction, and visuospatial ability) and four cognitive domains (attention/working memory, executive function, memory, and language) at baseline (Time1) and at 1-year follow-up (Time2) in 36 patients with PD and 32 healthy controls (HCs). To explore the magnitude and frequency of cognitive changes, we analyzed data using the simple difference method and the standardized regression-based method. We also explored the correlations between changes in test scores and several clinical predictors, using logistic regression analysis. At 1 year, patients with PD showed higher rates of change in scores on several cognitive tests, especially the Incomplete Letters test of visuoperception, compared to HCs. After adjusting for demographic variables, the visuoperceptual change was 61.1% overall, with the largest effect size. The changes in scores of visuoperception correlated with those of memory (r = 0.672, p < 0.001), language (r = 0.389, p < 0.05), and visuospatial ability (r = 0.379, p < 0.05). The severity of olfactory disturbance, the MDS-UPDRS Part I score, and younger PD onset predicted the significant changes observed in the Incomplete Letters test scores. Visuoperception changed more in non-demented PD patients than in HCs at 1-year follow-up. The changes in visuoperception could relate to involvement of the ventral occipitotemporal pathway, the more widespread temporal lobe, and brain reserve in PD.

Examining Cognitive Decline Across Black and White Participants in the Harvard Aging Brain Study.

Black Americans are approximately twice as likely to develop dementia as compared to White Americans and the magnitude of this disparity is often attributed to a variety of factors that include psychosocial and vascular risk factors. However, less is known about the potential contribution of Alzheimer's disease pathological differences. To examine potential differences incross-sectional and longitudinal cognitive performance in black and white participants who were clinically normal at baseline. 296 participants (48 African-American/black participants) underwent MRI and amyloid PET at baseline. Linear mixed models were used to examine the main effects of race, years of education, reading ability, Framingham Heart Study cardiovascular risk score (FHS-CVD), white matter hyperintensities (WMH), and amyloid (Aβ) burden on the Preclinical Alzheimer Cognitive Composite-5 (PACC5). Lower levels of educationalattainment and reading ability were found for blacks compared to whites. By contrast, no differences in FHS-CVD, WMH, or Aβ were found by racial group. Baseline differences in PACC5 score were attenuated after adjusting for educationalfactors, vascular factors, and Aβ, but remained lower for blacks compared to whites (β= -0.24, p = 0.014). Further, blacks demonstrated a faster rate of PACC5 decline longitudinally compared to whites (β = -0.055, p = 0.025) after adjusting for covariates. Accounting for educationalfactors, vascular factors, and Aβ burden diminished, but did not eliminate, racial differences in PACC5 performance longitudinally. Understanding potential differences in longitudinal cognitive outcomes by race may be important for upcoming secondary prevention trials.

Disease-modifying treatments and cognition in relapsing-remitting multiple sclerosis: A meta-analysis.

Disease-modifying treatments (DMTs) are the gold standard for slowing disability progression in multiple sclerosis (MS), but their effects on cognitive impairment, a key symptom of the disease, are mostly unknown. We conducted a systematic review and meta-analysis to evaluate the differential effects of DMTs on cognitive test performance in relapsing-remitting MS (RRMS). PubMed, Scopus, and Cochrane Library were searched for studies reporting longitudinal cognitive performance data related to all major DMTs. The standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used as the main effect size measure. Forty-four studies, including 55 distinct MS patient samples, were found eligible for the systematic review. Twenty-five studies were related to platform therapies (mainly β-interferon [n = 17] and glatiramer acetate [n = 4]), whereas 22 studies were related to escalation therapies (mainly natalizumab [n = 14] and fingolimod [n = 6]). Reported data were mostly confined to the cognitive domain processing speed. A meta-analysis including 41 studies and 7,131 patients revealed a small to moderate positive effect on cognitive test performance of DMTs in general (g = 0.27, 95% confidence interval [CI] = [0.21-0.33]), but no statistically significant differences between platform (g = 0.27, 95% CI = [0.18-0.35]) and escalation therapies (g = 0.28, 95% CI = [0.19-0.37]) or between any single DMT and β-interferon. DMTs are effective in improving cognitive test performance in RRMS, but a treatment escalation mainly to amend cognition is not supported by the current evidence. Given the multitude of DMTs and their widespread use, the available data regarding differential treatment effects on cognitive impairment are remarkably scant. Clinical drug trials that use more extensive cognitive outcome measures are urgently needed.

Self-reported health behaviors and longitudinal cognitive performance in late middle age: Results from the Wisconsin Registry for Alzheimer's Prevention.

BackgroundStudies have suggested associations between self-reported engagement in health behaviors and reduced risk of cognitive decline. Most studies explore these relationships using one health behavior, often cross-sectionally or with dementia as the outcome. In this study, we explored whether several individual self-reported health behaviors were associated with cognitive decline when considered simultaneously, using data from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), an Alzheimer’s disease risk-enriched cohort who were non-demented and in late midlife at baseline.MethodWe analyzed longitudinal cognitive data from 828 participants in WRAP, with a mean age at baseline cognitive assessment of 57 (range = 36–78, sd = 6.8) and an average of 6.3 years (standard deviation = 1.9, range = 2–10) of follow-up. The primary outcome was a multi-domain cognitive composite, and secondary outcomes were immediate/delayed memory and executive function composites. Predictors of interest were self-reported measures of physical activity, cognitive activity, adherence to a Mediterranean-style diet (MIND), and interactions with each other and age. We conducted linear mixed effects analyses within an Information-theoretic (IT) model averaging (MA) approach on a set of models including covariates and combinations of these 2- and 3-way interactions. The IT approach was selected due to the large number of interactions of interest and to avoid pitfalls of traditional model selection approaches.ResultsModel-averaged results identified no significant self-reported health behavior*age interactions in relationship to the primary composite outcome. In secondary outcomes, higher MIND diet scores associated with slower decline in executive function. Men showed faster decline than women on delayed memory, independent of health behaviors. There were no other significant interactions among any other health behaviors and cognitive trajectories.ConclusionsWhen multiple covariates and health behaviors were considered simultaneously, there were limited weak associations with cognitive decline in this age range. These results may be explained alone or in combination by three alternative explanations: 1) the range of cognitive decline is in middle age is too small to observe relationships with health behaviors, 2) the putative associations of these health behaviors on cognition may not be robust in this age range, or 3) the self-reported measures of the health behaviors may not be optimal for predicting cognitive decline. More study may be needed that incorporates sensitive measures of health behaviors, AD biomarker profiles, and/or other disease comorbidities.

The complexities of understanding cognitive trajectory in bipolar disorder.

The recent systematic review and meta-analysis by Szmulewicz, Valerio (1) addresses an issue of current debate in the field - that of whether cognition in bipolar disorder (BD) is neuroprogressive or stable(2). Based on a synthesis of studies of longitudinal cognitive performance in recent-onset (8 studies) and late-life BD (4 studies), this review provides evidence against this hypothesis and is consistent with an earlier meta-analysis in predominantly mid-life adults with established BD(3).

P1‐448: GAMECHANGER: CAN DIGITAL BIOMARKERS TRANSFORM THE DETECTION OF PRECLINICAL ALZHEIMER'S DISEASE?

Smartphone-based digital biomarkers provide a low-burden opportunity for remote, high frequency cognitive assessment. As such, these tools may enable earlier detection of cognitive decline than achievable via traditional memory clinic routes. The GameChanger study, supported by Alzheimer's Society, tests the feasibility of conducting longitudinal, smartphone-based cognitive assessment in a general population. Individual differences in ‘heathy’ cognitive ageing will be assessed as a function of demographic characteristics and risk of Alzheimer's disease (AD). GameChanger is open to ‘healthy’ UK-based adults as part of a citizen science initiative. Participants download the Mezurio smartphone ‘App’, through which they are prompted to complete 5 minutes of novel, AD-targeted cognitive tasks every day for a month. In addition, frequent reports of subjective sleep, mood and cognitive errors in everyday life are collected. Although data collection for the baseline wave of GameChanger is ongoing, by the end of the first month the study has more than 10,000 participants (age range 18–93 years). Qualitative feedback from 1708 participants confirms the acceptability of this ‘little and often’ approach to measuring cognition remotely, with an average score of 4.02 out of 5 for participant enjoyment. Ongoing analyses will explore individual differences in longitudinal cognitive performance according to demographic characteristics (e.g. age, education) and dementia risk (family history, subjective cognitive change). The response to GameChanger to date demonstrates the enormous potential for digital biomarkers to explore ‘healthy’ ageing and preclinical AD at scale in a general population. Qualitative feedback was positive in the majority; however, several key steps were highlighted to maintain long-term engagement in the e-cohort. In addition to longitudinal follow-up at 12- and 24-months, organized collaborations with existing UK-based cohorts will enable medical records, genetics and standardised neuropsychological test scores to be analysed alongside GameChanger performance.

MICROGLIAL ACTIVATION AND TAU BURDEN PREDICT COGNITIVE DECLINE IN ALZHEIMER’S DISEASE

Neurodegeneration, tau pathology, and neuroinflammation are key etiopathogenic processes of Alzheimer's disease (AD). Understanding whether these features predict cognitive decline in AD is crucial to developing prognostic measures. We studied the independent prognostic value of atrophy (structural MRI), tau burden ([18F]AV-1451 PET), and neuroinflammation ([11C]PK-11195 PET) in predicting longitudinal cognitive decline in patients with AD dementia, and amyloid positive Mild Cognitive Impairment (MCI+). 29 healthy controls (HC) and 26 patients with AD pathology (12 AD and 14 MCI+) underwent a cross-sectional assessment with structural MRI, dynamic [11C]PK-11195, and [18F]AV-1451 PET imaging as part of the NIMROD study (NeuroImaging of MemoRy and Other related Disorders). An annual cognitive follow-up (using the Revised Addenbrooke's Cognitive Examination (ACE-R)) was performed for two years. Regional grey matter volumes were derived from structural MRI in AD-specific regions, while [18F]AV-1451 and [11C]PK-11195 non-displaceable specific binding were calculated for these volumes to quantify tau pathology and neuroinflammation. To reduce dimensionality of the data, we used a Principal Component Analysis (PCA) on each imaging method. A Latent Growth Curve model (LGCM) was used to test for the independent predictive value of the PCA-derived neuroimaging measures on longitudinal cognitive decline (Figure 1). PCA identified a global component for grey matter volumes, and two components for each PET ligand: one in anterior temporal regions, and another in posterior temporo-parietal regions (Figure 2). The LGCM using MRI (χ2(4)=2.82, p=0.59, RMSEA=0.00, CFI=1.00) showed a positive association between grey-matter volumes and longitudinal ACE-R scores (Std all=0.56, p<0.001). LGCM with [11C]PK-11195 (χ2(6)=1.50, p=0.96, RMSEA=0.00, CFI=1.00) indicated a positive association with 2-year cognitive decline in both anterior (Std all=−0.42, p<0.001) and posterior (Std all=−0.35, p=0.016) components. Furthermore, in LGCM with [18F]AV-1451 (χ2(6)=10.63, p=0.10, RMSEA=0.12, CFI=0.98), longitudinal cognitive performance correlated negatively with values in the posterior (Std all=−0.61, p=0.01) and anterior (Std all=−0.43, p<0.001) components.

Impact of glycemic status on longitudinal cognitive performance in men with and without HIV infection: Erratum.

Impact of glycemic status on longitudinal cognitive performance in men with and without HIV infection: Erratum.

Amyloid PET and cognitive decline in cognitively normal individuals: the SCIENCe project

We examined the relationships between amyloid-β PET and concurrent and longitudinal cognitive performance in 107 cognitively normal individuals with subjective cognitive decline (age: 64 ± 8 years, 44% female, Mini-Mental State Examination score 29 ± 1). All underwent 90-minute dynamic [18F]florbetapir PET scanning and longitudinal neuropsychological tests with a mean follow-up of 3.4 ± 3.0 years. Receptor parametric mapping was used to calculate [18F]florbetapir binding potential (BPND), and we performed linear mixed models to assess the relationships between global [18F]florbetapir BPND and neuropsychological performance. Higher [18F]florbetapir BPND was related to lower concurrent Mini-Mental State Examination (β ± SE: −1.69 ± 0.63 p < 0.01) and to steeper rate of decline on tasks capturing memory (Rey Auditory Verbal Learning Task immediate [β ± SE −1.81 ± 0.81, p < 0.05] and delayed recall [β ± SE −1.19 ± 0.34, p < 0.01]), attention/executive functions (Stroop II [color] [β ± SE −0.02 ± 0.01, p < 0.05], Stroop III [word-color] [β ± SE −0.03 ± 0.02, p < 0.05]), and language (category fluency [β ± SE −0.04 ± 0.01, p < 0.01]). These findings suggest that higher amyloid-β load in cognitively normal individuals with subjective cognitive decline from a memory clinic is associated with lower concurrent global cognition and with faster rate of decline in a variety of cognitive domains.