Longitudinal Cognitive Performance Research Articles

Predicting Alzheimer’s disease progression using multi-modal deep learning approach

Alzheimer’s disease (AD) is a progressive neurodegenerative condition marked by a decline in cognitive functions with no validated disease modifying treatment. It is critical for timely treatment to detect AD in its earlier stage before clinical manifestation. Mild cognitive impairment (MCI) is an intermediate stage between cognitively normal older adults and AD. To predict conversion from MCI to probable AD, we applied a deep learning approach, multimodal recurrent neural network. We developed an integrative framework that combines not only cross-sectional neuroimaging biomarkers at baseline but also longitudinal cerebrospinal fluid (CSF) and cognitive performance biomarkers obtained from the Alzheimer’s Disease Neuroimaging Initiative cohort (ADNI). The proposed framework integrated longitudinal multi-domain data. Our results showed that 1) our prediction model for MCI conversion to AD yielded up to 75% accuracy (area under the curve (AUC) = 0.83) when using only single modality of data separately; and 2) our prediction model achieved the best performance with 81% accuracy (AUC = 0.86) when incorporating longitudinal multi-domain data. A multi-modal deep learning approach has potential to identify persons at risk of developing AD who might benefit most from a clinical trial or as a stratification approach within clinical trials.

Self-reported Lifestyle Activities in Relation to Longitudinal Cognitive Trajectories

Few studies have examined the relationship between lifestyle activity engagement and cognitive trajectories among individuals who were cognitively normal at baseline. To examine the relationship of current engagement in lifestyle activities to previous cognitive performance among individuals who were cognitively normal at baseline, and whether this relationship differed for individuals who subsequently developed mild cognitive impairment (MCI), or by APOE-4 genotype, age, and level of cognitive reserve. Participants (N=189) were primarily middle-aged (M=56.6 y) at baseline and have been prospectively followed with annual assessments (M follow-up=14.3 y). Engagement in physical, cognitive, and social activities was measured by the CHAMPS activity questionnaire. Longitudinal cognitive performance was measured by a global composite score. Among individuals who progressed to MCI (n=27), higher lifestyle activity engagement was associated with less decline in prior cognitive performance. In contrast, among individuals who remained cognitively normal, lifestyle activity engagement was not associated with prior cognitive trajectories. These effects were largely independent of APOE-4 genotype, age, and cognitive reserve. Greater engagement in lifestyle activities may modify the rate of cognitive decline among those who develop symptoms of MCI, but these findings need to be confirmed in prospective studies.

Hypertension and obesity moderate the relationship between β-amyloid and cognitive decline in midlife

BackgroundThis study tested if central obesity, hypertension, or depressive symptoms moderated the relationship between β-amyloid (Aβ) and longitudinal cognitive performance in late middle-aged adults enriched for Alzheimer's disease (AD) risk. MethodsParticipants (n = 207; ages = 40–70 years; 73% parental AD) in the Wisconsin Registry for Alzheimer's Prevention study completed 3+ neuropsychological evaluations and a [11C]PiB positron emission tomography scan or lumbar puncture. Linear mixed-effects regression models tested interactions of risk factor × Aβ × visit age on longitudinal Verbal Learning & Memory and Speed & Flexibility factor scores. ResultsThe relationship between Aβ and Verbal Learning & Memory decline was moderated by hypertension (χ2(1) = 3.85, P = .04) and obesity (χ2(1) = 6.12, P = .01); those with both elevated Aβ and the risk factor declined at faster rates than those with only elevated Aβ or elevated risk factors. ConclusionIn this cohort, hypertension and obesity moderated the relationship between Aβ and cognitive decline.

Longitudinal Cognitive Performance in Individuals at Ultrahigh Risk for Psychosis: A 10-year Follow-up.

It remains unclear whether the onset of psychosis is associated with deterioration in cognitive performance. The aim of this study was to examine the course of cognitive performance in an ultrahigh risk (UHR) cohort, and whether change in cognition is associated with transition to psychosis and change in functioning. Consecutive admissions to Personal Assessment and Crisis Evaluation (PACE) Clinic between May 1994 and July 2000 who had completed a comprehensive cognitive assessment at baseline and follow-up were eligible (N = 80). Follow-up ranged from 7.3 to 13.4 years (M = 10.4 years; SD = 1.5). In the whole sample, significant improvements were observed on the Similarities (P = .03), Information (P < .01), Digit Symbol Coding (P < .01), and Trail Making Test-B (P = .01) tasks, whereas performance on the Rey Auditory Verbal Learning Test (Trials 1-3) declined significantly (P < .01) over the follow-up period. Change in performance on cognitive measures was not significantly associated with transition status. Taking time to transition into account, those who transitioned after 1 year showed significant decline on Digit Symbol Coding, whereas those who did not transition improved on this measure (P = .01; effect size [ES] = 0.85). Small positive correlations were observed between improvements in functioning and improvements in performance on Digit Symbol Coding and Arithmetic (0.24, P = .03 and 0.28, P = .01, respectively). In summary, the onset of psychosis was not associated with deterioration in cognitive ability. However, specific findings suggest that immediate verbal learning and memory, and processing speed may be relevant domains for future risk models and early intervention research in UHR individuals.

Systemic Inflammation Is Associated With Longitudinal Changes in Cognitive Performance Among Urban Adults.

Objectives/Background: Systemic inflammation can affect cognitive performance over time. The current study examined associations between systemic inflammation and cognitive performance among African Americans and Whites urban adults, stratifying by sex, and age group and by race.Patients/Methods: Among 1,555–1,719 White and African-American urban adults [Agebase: 30–64y, 2004-2013, mean±SD follow-up time(y): 4.64 ± 0.93y], conducted linear mixed-effects regression models were conducted to test associations of inflammatory markers [C-reactive protein, Erythrocyte Sedimentation Rate (ESR), albumin, iron, and an inflammation composite score (ICS)] with longitudinal cognitive performance.Results: Among key findings, CRP was linked to poorer baseline mental status among younger women (≤50y, γ01 = –0.03 ± 0.01, p = 0.002) and poorer attention in older women (>50y, γ01 = −0.024 ± 0.007, p < 0.004) and African-Americans (γ01 = −0.029 ± 0.008, p < 0.001). ESR was related to faster decline on verbal memory among older men (>50y, γ11 = −0.008 ± 0.003, P = 0.009); with poorer performance on attention tests overall (γ01 = −0.010 ± 0.003, P = 0.003) and among African-Americans (γ01 = −0.013 ± 0.004, P = 0.002); on verbal fluency among older women (>50y,γ01 = −0.037 ± 0.013, P = 0.004) and on executive function: overall (γ01 = +0.62 ± 0.21, P = 0.004), older men (>50y, γ01 = +1.69 ± 0.53, P = 0.001) and African-Americans (γ01 = +0.84 ± 0.28, P = 0.002). Albumin was linked to slower attention decline among older men (>50y, γ11 = +0.329 ± 0.103, P = 0.009), over-time improvement in executive function overall (γ11 = −6.00 ± 2.26, P = 0.008), and better baseline psychomotor speed among African-Americans (γ01 = +0.56 ± 0.19, P = 0.003). Finally, ICS predicted faster decline on visual memory/visuo-constructive abilities among older men (>50y, γ11 = +0.17 ± 0.06, p = 0.003).Conclusion: In sum, strong associations between systemic inflammation and longitudinal cognitive performance were detected, largely among older individuals (>50y) and African-Americans. Randomized trials targeting inflammation are warranted.

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

To determine the relationship between glycemic status and cognitive performance in men living with HIV (MLWH) and without HIV infection. A prospective HIV/AIDS cohort study in four US cities between 1999 and 2016. Glycemic status was categorized as normal glucose, impaired fasting glucose, controlled diabetes mellitus and uncontrolled diabetes mellitus at each semiannual visit. Cognitive performance was evaluated using nine neuropsychological tests which measure attention, constructional ability, verbal learning, executive functioning, memory and psychomotor speed. Linear mixed models were used to assess the association between glycemic status and cognition. Overall, 900 MLWH and 1149 men without HIV were included. MLWH had significantly more person-visits with impaired fasting glucose (52.1 vs. 47.9%) and controlled diabetes mellitus (58.2 vs. 41.8%) than men without HIV (P < 0.05). Compared with men with normal glucose, men with diabetes mellitus had significantly poorer performance on psychomotor speed, executive function and verbal learning (all P < 0.05). There was no difference in cognition by HIV serostatus. The largest effect was observed in individuals with uncontrolled diabetes mellitus throughout the study period, equivalent to 16.5 and 13.4 years of aging on psychomotor speed and executive function, respectively, the effect of which remained significant after adjusting for HIV-related risk factors. Lower CD4+ nadir was also associated with worse cognitive performance. Abnormalities in glucose metabolism were more common among MLWH than men without HIV and were related to impaired cognitive performance. Metabolic status, along with advanced age and previous immunosuppression, may be important predictors of cognition in the modern antiretroviral therapy era.

Neurogranin as a predictor of memory and executive function decline in MCI patients.

To determine whether high CSF levels of neurogranin (Ng) predict longitudinal decline in memory and executive function during early-stage Alzheimer disease (AD). Baseline levels of CSF Ng were studied in relation to cross-sectional and longitudinal cognitive performance over 8 years. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database, and participants with normal cognition (n = 111) and mild cognitive impairment (MCI) (n = 193) were included. High levels of CSF Ng were associated with poor baseline memory scores (β = -0.21, p < 0.0001). CSF Ng predicted both memory and executive function decline over time (β = -0.0313, p = 0.0068 and β = -0.0346, p = 0.0169, respectively) independently of age, sex, education, and APOE ε4 status. When the rate of decline by tertiles was examined, CSF Ng was a level-dependent predictor of memory function, whereby the group with highest levels of Ng showed the fastest rates of decline in both memory and executive function. When examined separately, elevated Ng was associated with cognitive decline in participants with MCI but not in those with normal cognition. The levels of CSF Ng were not associated with cognitive measures when tau and amyloid 42 (Aβ42) were controlled for in these analyses. High CSF Ng associates with poor memory scores in participants with MCI cross-sectionally and with poor memory and executive function longitudinally. The association of Ng with cognitive measures disappears when tau and Aβ42 are included in the statistical models. Our findings suggest that CSF Ng may serve as a biomarker of cognition. Synaptic dysfunction contributes to cognitive impairment in early-stage AD.

Association of Peripheral Interleukin-6 with Global Cognitive Decline in Non-demented Adults: A Meta-Analysis of Prospective Studies.

Background: Elevated biomarkers of systemic inflammation have been reported in individuals with cognitive decline, however, most of the literature concerns cross-sectional analyses that have produced mixed results. This study investigates the etiology of this association by performing meta-analyses on prospective studies investigating the relationship between baseline interleukin-6 (IL-6), an established marker of peripheral inflammation, with cognitive decline risk in non-demented adults at follow-up.Methods: We reviewed studies reporting peripheral IL-6 with future cognitive decline, up to February 2017 by searching the PubMed, Science Direct, Scopus and Google Scholar databases. Studies which contained odds ratios (ORs) for the association between circulating baseline IL-6 and longitudinal cognitive performance in non-demented community dwelling older adults were pooled in random-effects models.Results: The literature search retrieved 5,642 potential articles, of which 7 articles containing 8 independent aging cohorts were eligible for review. Collectively, these studies included 15,828 participants at baseline. Those with high circulating IL-6 were 1.42 times more likely to experience global cognitive decline at follow-up, over a 2–7-year period, compared to those with low IL-6 (OR 1.42, 95% CI 1.18–1.70; p < 0.001). Subgroup and sensitivity analyses suggests that this association is independent of the study sample size, duration of follow-up and cognitive assessments used.Conclusions: These results add further evidence for the association between high peripheral inflammation, as measured by blood IL-6, and global cognitive decline. Measuring circulating IL-6 may be a useful indication for future cognitive health.

A variant in PPP4R3A protects against alzheimer-related metabolic decline.

A reduction in glucose metabolism in the posterior cingulate cortex (PCC) predicts conversion to Alzheimer's disease (AD) and tracks disease progression, signifying its importance in AD. We aimed to use decline in PCC glucose metabolism as a proxy for the development and progression of AD to discover common genetic variants associated with disease vulnerability. We performed a genome-wide association study (GWAS) of decline in PCC fludeoxyglucose F 18 ([18 F] FDG) positron emission tomography measured in Alzheimer's Disease Neuroimaging Initiative participants (n = 606). We then performed follow-up analyses to assess the impact of significant single-nucleotide polymorphisms (SNPs) on disease risk and longitudinal cognitive performance in a large independent data set (n = 870). Last, we assessed whether significant SNP influence gene expression using two RNA sequencing data sets (n = 210 and n = 159). We demonstrate a novel genome-wide significant association between rs2273647-T in the gene, PPP4R3A, and reduced [18 F] FDG decline (p = 4.44 × 10-8 ). In a follow-up analysis using an independent data set, we demonstrate a protective effect of this variant against risk of conversion to MCI or AD (p = 0.038) and against cognitive decline in individuals who develop dementia (p = 3.41 × 10-15 ). Furthermore, this variant is associated with altered gene expression in peripheral blood and altered PPPP4R3A transcript expression in temporal cortex, suggesting a role at the molecular level. PPP4R3A is a gene involved in AD risk and progression. Given the protective effect of this variant, PPP4R3A should be further investigated as a gene of interest in neurodegenerative diseases and as a potential target for AD therapies. Ann Neurol 2017;82:900-911.

Statins and Cognition in Parkinson's Disease.

The relationship between statins and cognition in Parkinson's disease (PD) is poorly understood. Analyses were performed to determine associations between statin use and cross-sectional and longitudinal cognitive performance in PD. Neuropsychological tests, medication logs, and ratings of functional abilities were collected from 313 PD participants longitudinally. At baseline, statin users (SU; N = 129) were older, more likely male, and had shorter PD duration than non-statin users (NSU; N = 184). In Cross-sectional analysis, SU performed better on global cognition, Trails B, semantic fluency, and phonemic fluency tasks. Rate of long-term global cognitive (Dementia Rating Scale-2 and MoCA) decline was significantly less in SU.

Higher Adiposity Is Associated With Slower Cognitive Decline in Hypertensive Patients: Secondary Analysis of the China Stroke Primary Prevention Trial.

BackgroundObesity is a risk factor for many diseases. However, the potential association between adiposity and cognitive decline in hypertensive patients is inconclusive. We performed a secondary data analysis of the CSPPT (China Stroke Primary Prevention Trial) to examine whether adiposity is correlated with longitudinal cognitive performance in hypertensive adults.Methods and ResultsThe analysis included 16 791 patients in the CSPPT who received at least 2 cognitive assessments by the Mini‐Mental State Examination (MMSE) during the follow‐up (median, 4.5 years; interquartile range, 4.2–4.8 years). Outcomes included changes in MMSE scores and cognitive impairment (defined as MMSE score less than education‐specific cutoff point). A marked reduction in MMSE scores at the final (compared with at the 1‐year) follow‐up was apparent in both men (n=4838; mean [SD] score, 0.41 [3.62]) and women (n=7190; mean [SD] score, 1.07 [4.61]; both P<0.001). Analysis using a mixed‐effects model revealed an association between higher body mass index with less MMSE decline, even after controlling for demographics and comorbidities (men, β=0.0134 [SE, 0.0036]; women, β=0.0133 [SE, 0.0034]; both P<0.001). A total of 1037 men (15.3%) and 3317 women (33.1%) developed cognitive impairment. In multivariable Cox regression analyses, being obese in men (11.3% versus 18.0%; hazard ratio, 0.75; 95% confidence interval, 0.60–0.94) and women (30.1% versus 36.5%; hazard ratio, 0.82; 95% confidence interval, 0.74–0.91) was a protective factor against cognitive impairment compared with normal body mass index.ConclusionsHigher adiposity is independently associated with slower cognitive decline in Chinese hypertensive adults.Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885 CSPPT.

EVIDENCE FOR EARLY DETECTION OF CSF BETA-AMYLOID AND TAU AND EFFECT ON LONGITUDINAL COGNITIVE PERFORMANCE IN INDIVIDUALS AT RISK FOR ALZHEIMER’S DISEASE

This study provides a comprehensive analysis of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in a large cohort of late middle-aged adults. Recent studies using NIA-AA criteria to define preclinical AD suggest that cognitively healthy older adults with abnormal markers of beta-amyloid (Aβ) and tau exhibit greater rates of decline, but whether similar patterns occur across memory and non-memory domains in late middle-aged adults remains unknown. N=396 adults enrolled in longitudinal studies (Wisconsin Registry for Alzheimer's Prevention; Wisconsin Alzheimer's Disease Research Center) were included (Table 1). Participants completed a lumbar puncture and at least two neuropsychological evaluations. Seventy-eight participants (n=38 dementia and n=40 cognitively healthy) were included in receiver operating curve analyses to develop cut-points for positive or negative CSF Aβ42 and tau (Table 2). n=318 cognitively healthy participants were included in linear mixed effects regression analyses to test for interactions between biomarker group and time on longitudinal cognitive performance. 70% were biomarker negative (Stage 0), 16% were Aβ+ only (Stage 1), 7% were Aβ+ and tau+ (Stage 2), and 7% were tau+ only (Table 3). There were no group differences in baseline cognitive performance; however, Stages 1 and 2 exhibited steeper memory decline compared to Stage 0 (Figure 1). Only Stage 2 exhibited steeper executive functioning decline (p < .01; Figure 2). The tau+ only group did not differ significantly from Stage 0 on 6 of 7 measures. Baseline age moderated the relationship between biomarker group and time; older age at study entry was associated with steeper rates of decline for Stage 1 only.

Evaluation of a research diagnostic algorithm for DSM-5 neurocognitive disorders in a population-based cohort of older adults

BackgroundThere is little information on the application and impact of revised criteria for diagnosing dementia and mild cognitive impairment (MCI), now termed major and mild neurocognitive disorders (NCDs) in the DSM-5. We evaluate a psychometric algorithm for diagnosing DSM-5 NCDs in a community-dwelling sample, and characterize the neuropsychological and functional profile of expert-diagnosed DSM-5 NCDs relative to DSM-IV dementia and International Working Group criteria for MCI.MethodsA population-based sample of 1644 adults aged 72–78 years was assessed. Algorithmic diagnostic criteria used detailed neuropsychological data, medical history, longitudinal cognitive performance, and informant interview. Those meeting all criteria for at least one diagnosis had data reviewed by a neurologist (expert diagnosis) who achieved consensus with a psychiatrist for complex cases.ResultsThe algorithm accurately classified DSM-5 major NCD (area under the curve (AUC) = 0.95, 95% confidence interval (CI) 0.92–0.97), DSM-IV dementia (AUC = 0.91, 95% CI 0.85–0.97), DSM-5 mild NCD (AUC = 0.75, 95% CI 0.70–0.80), and MCI (AUC = 0.76, 95% CI 0.72–0.81) when compared to expert diagnosis. Expert diagnosis of dementia using DSM-5 criteria overlapped with 90% of DSM-IV dementia cases, but resulted in a 127% increase in diagnosis relative to DSM-IV. Additional cases had less severe memory, language impairment, and instrumental activities of daily living (IADL) impairments compared to cases meeting DSM-IV criteria for dementia. DSM-5 mild NCD overlapped with 83% of MCI cases and resulted in a 19% increase in diagnosis. These additional cases had a subtly different neurocognitive profile to MCI cases, including poorer social cognition.ConclusionDSM-5 NCD criteria can be operationalized in a psychometric algorithm in a population setting. Expert diagnosis using DSM-5 NCD criteria captured most cases with DSM-IV dementia and MCI in our sample, but included many additional cases suggesting that DSM-5 criteria are broader in their categorization.

Adiposity, Change in Adiposity, and Cognitive Decline in Mid- and Late Life.

To examine associations between adiposity and adiposity change (loss, stable, gain) and subsequent longitudinal cognitive performance in African Americans in mid and late life. Cohort study using linear mixed models. Genetic Epidemiology Network of Arteriopathy. African-American sibships with hypertension in Jackson, Mississippi (N=1,108). Waist circumference and body mass index (BMI) were measured at two examinations 5years apart. Stable adiposity was defined as values within 5% of the first measure. A composite cognitive Z-score was derived from individual cognitive test Z-scores at two study visits 6years apart. Larger waist circumference was associated with greater rate of cognitive decline during follow-up (beta=-0.0009 per year, P=.001); BMI, change in waist circumference, and change in BMI were not associated with rate of decline. Loss of adiposity in midlife was associated with higher cognitive Z-scores in middle-aged individuals, and loss of adiposity in late life was associated with lower Z-scores in older adults (P=.01 for interaction between waist circumference and age; P=.04 for interaction between BMI and age). Simultaneous inclusion of waist circumference and BMI in the cross-sectional model suggested an association between larger waist circumference and poorer cognitive performance (beta=-0.009, P=.006) and between higher BMI and better cognitive performance (beta=0.014, P=.06). The results suggested a differential pattern of the relationship between adiposity and cognition according to age (mid- or late life) and regional distribution of adiposity.

Impact of Personality on Cognitive Aging: A Prospective Cohort Study

The aim of this study was to assess the association between personality factors and age-related longitudinal cognitive performance, and explore interactions of stress-proneness with apolipoprotein E (APOE) ɛ4, a prevalent risk factor for Alzheimer's disease (AD). A total of 510 neuropsychiatrically healthy residents of Maricopa County recruited through media ads (mean age 57.6±10.6 years; 70% women; mean education 15.8±2.4 years; 213 APOE ɛ4 carriers) had neuropsychological testing every 2 years (mean duration follow-up 9.1±4.4 years), and the complete Neuroticism Extraversion Openness Personality Inventory-Revised. Several tests were administered within each of the following cognitive domains: memory, executive skills, language, visuospatial skills, and general cognition. Primary effects on cognitive trajectories and APOE ɛ4 interactions were ascertained with quadratic models. With personality factors treated as continuous variables, Neuroticism was associated with greater decline, and Conscientiousness associated with reduced decline consistently across tests in memory and executive domains. With personality factors trichotomized, the associations of Neuroticism and Conscientiousness were again highly consistent across tests within memory and to a lesser degree executive domains. While age-related memory decline was greater in APOE ɛ4 carriers as a group than ɛ4 noncarriers, verbal memory decline was mitigated in ɛ4 carriers with higher Conscientiousness, and visuospatial perception and memory decline was mitigated in ɛ4 carriers with higher Openness. Neuroticism and Conscientiousness were associated with changes in longitudinal performances on tests sensitive to memory and executive skills. APOE interactions were less consistent. Our findings are consistent with previous studies that have suggested that personality factors, particularly Neuroticism and Conscientiousness are associated with cognitive aging patterns. (JINS, 2016, 22, 765-776).

Longitudinal change in neurocognition and its relation to symptomatic and functional changes over 2 years in individuals at clinical high-risk for psychosis

BackgroundNegative symptoms and functional disability represent the core of schizophrenia and both are associated with cognitive impairments. We explored the course of cognitive change and its relation to symptomatic and functional changes in individuals at clinical high-risk (CHR) for psychosis to identify cognitive indicators of long-term course. Such attempts may offer insight into the pathological changes associated with the development of illness in the prodromal state. MethodsForty-seven CHR individuals completed neurocognitive, clinical, and functional assessments at baseline and 2-year follow-up; twenty-eight healthy controls were assessed for neurocognitive and functional measures at baseline and 2-year follow-up. The delta values of CHR individuals in neurocognitive, clinical, and functional domains were determined from differences between baseline and follow-up scores to estimate the degree of change. ResultsAlthough overall longitudinal cognitive performance of CHR individuals improved, the magnitude of improvement was not statistically different from that of normal controls at the group level. However, the individual data yielded two groups of CHR subjects showing opposite trajectories of cognitive change in semantic fluency (i.e., improvement or decline), which was significantly associated with changes in negative symptoms and functioning. Moreover, the relationships between negative symptoms and functioning were more strengthened over time than baseline. ConclusionsOur findings show that semantic fluency seems to be a neurocognitive indicator reflecting clinical courses in CHR individuals. The longitudinal relationship of negative symptoms and functioning with semantic fluency may represent ongoing pathological processes in neural systems involving aberrant fronto–temporal interaction in the early phase of schizophrenia.

Amyloid negativity in patients with clinically diagnosed Alzheimer disease and MCI.

To examine the clinical and biomarker characteristics of patients with amyloid-negative Alzheimer disease (AD) and mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a prospective cohort study. We first investigated the reliability of florbetapir- PET in patients with AD and patients with MCI using CSF-Aβ1-42 as a comparison amyloid measurement. We then compared florbetapir- vs florbetapir+ patients with respect to several AD-specific biomarkers, baseline and longitudinal cognitive measurements, and demographic and clinician report data. Florbetapir and CSF-Aβ1-42 +/- status agreed for 98% of ADs (89% of MCIs), indicating that most florbetapir- scans were a reliable representation of amyloid status. Florbetapir- AD (n = 27/177; 15%) and MCI (n = 74/217, 34%) were more likely to be APOE4-negative (MCI 83%, AD 96%) than their florbetapir+ counterparts (MCI 30%, AD 24%). Florbetapir- patients also had less AD-specific hypometabolism, lower CSF p-tau and t-tau, and better longitudinal cognitive performance, and were more likely to be taking medication for depression. In MCI only, florbetapir- participants had less hippocampal atrophy and hypometabolism and lower functional activity questionnaire scores compared to florbetapir+ participants. Overall, image analysis problems do not appear to be a primary explanation of amyloid negativity. Florbetapir- ADNI patients have a variety of clinical and biomarker features that differ from their florbetapir+ counterparts, suggesting that one or more non-AD etiologies (which may include vascular disease and depression) account for their AD-like phenotype.

What is a normal change in memory? n=1 classification of clinically relevant cognitive decline

Background: Clinicians often have to decide whether a person’s reported or measured change in cognition reflects normal aging or clinically-relevant cognitive decline. For most cognitive tests, there is no evidence-based guidance for how much change is ‘normal’ over a given timeframe. This study aimed to statistically determine the limits of clinically-significant memory change among healthy older adults and those with mild cognitive impairment (MCI). Methods: Longitudinal cognitive performance was examined in 21 healthy older adults and 81 individuals with clinically-defined MCI. Participants were assessed on Cantab Paired Associate Learning (PAL), a non-verbal episodic memory test, at baseline, 10 months and 20 months as part of a comprehensive neuropsychological assessment. They were classified as amnestic-MCI if there was a deficit (performance <10th percentile relative to norms) in memory tests (with our without impairment in other cognitive tests), and nonamnestic MCI if deficits were limited to non-memory domains. Over the three assessments, MCI was stable, resolved or progressed to dementia. The performance of control participants was used to determine the normal limits for initial and longitudinal change in performance, against which participants with stable or resolved MCI and those who progressed to dementia could be compared on an individual basis. Results: In healthy controls, PAL showed good stability using Bland-Altmann analysis. Na-MCI, and those with resolved MCI performed at a level comparable to healthy controls on each occasion. Patients with stable a-MCI or AD patients were significantly impaired relative to other groups. This persisted even when controlling for age, education, gender and baseline level of performance. Individual estimates of clinically significant impairment and change were able to reliably detect patients who would subsequently develop dementia, or had stable a-MCI. Conclusions: Repeated assessments with the Cantab PAL test are feasible, show good psychometric properties, and can characterise typical and atypical patterns of change in episodic memory. A repeat assessment of memory at <1 year can reliably inform clinical decisions about the presence or absence of pathological cognitive decline.

Subjective cognitive complaints are associated with longitudinal changes in episodic memory

Older adults with subjective cognitive complaints (SCCs) and no objective impairment may be in a preclinical stage of Alzheimer's disease (AD), based on research linking SCCs to in vivo AD biomarkers, post-mortem AD neuropathology, and elevated incidence of mild cognitive impairment and dementia. Thus, SCCs may reflect a true deterioration in cognitive abilities too subtle to be detected by most standard measures. The present study sought to determine if adults with SCCs showed greater decline in cognitive performance compared to those without SCCs in a large, longitudinal dataset. This retrospective analysis utilized data from the National Alzheimer Coordinating Center on 4,945 normal control participants who received at least one annual follow-up cognitive evaluation. Baseline SCCs were determined by participants’ response to a question about their subjective report of cognitive decline (yes = 3987, no = 958). Annualized mean change was calculated for scores on tests measuring attention, episodic memory, executive function, language, processing speed, and working memory. An ANOVA with Tukey post-hoc comparisons identified differences in mean change as a function of SCCs. An additional analysis explored if the presence of an APOE e4 allele, a genetic risk factor for AD, modulated the relationship between SCCs and longitudinal cognitive performance. The average age at baseline evaluation was 70.2 years and the average follow-up was 4.5 visits. The annualized mean change score differed as a function of SCCs for one test of episodic memory, which involves the immediate, but not delayed, recall of a short story (Logical Memory I, p=0.0047). The group without SCCs demonstrated an annual improvement in immediate recall score [mean(SE)=0.162(0.028)] that was significantly greater than improvement in the group with SCCs [mean(SE)=-0.029(0.061)]. Annualized change scores did not differ as a function of APOE status. Results show that SCCs predict longitudinal performance on a neuropsychological test of immediate recall. Participants without SCCs demonstrated an improvement in scores over repeated administrations, a “practice effect,” which was not observed in the participants with SCCs. Findings suggest that presence/absence of a practice effect may be a sensitive metric for quantifying subtle cognitive changes in individuals with SCCs.

Stroke risk interacts with Alzheimer's disease biomarkers on brain aging outcomes

Alzheimer's disease (AD) biomarkers and stroke risk factors independently predict cognitive impairment, likely through independent disease pathways. However, limited work has sought to describe the dynamic interplay between these important risk factors. This article evaluated the interaction between stroke risk and AD biomarkers on hippocampal volume and cognitive performance. We first evaluated the interaction between stroke risk factors and AD biomarkers using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 1202). We then extended our findings to an independent autopsy data set from the National Alzheimer's Coordinating Center (NACC, n = 1122) using measures of AD pathology. Stroke risk was quantified using the Framingham Stroke Risk Profile. In ADNI, stroke risk interacted with tau and amyloid levels in relation to baseline and longitudinal cognitive performance. Similarly, in NACC, stroke risk interacted with amyloid and tau positivity on cognitive performance. The effect of stroke risk factors on cognition was strongest in the absence of AD biomarkers or neuropathology, providing additional evidence that AD biomarkers and stroke risk factors relate to cognition through independent pathways.