Preclinical Dementia Research Articles

Differential associations between simple physical performance tests with global and specific cognitive functions in cognitively normal and mild cognitive impairment: a cross-sectional cohort study of Asian community-dwelling older adults

BackgroundPhysical performance declines and executive dysfunctions are predictors of dementia. However, their associations are not well understood in Asian older adults without dementia (cognitively normal [CN] and mild cognitive impairment [MCI]), especially in a single study.ObjectiveExamine the associations between physical performance measures with executive function (EF)-based and non-EF-based neurocognitive tests and whether preclinical dementia cognitive status i.e., CN and MCI, moderated these associations.MethodsWe examined cross-sectional cohort of 716 community-dwelling older adults without dementia (CN = 562 and MCI = 154) using multivariable linear regression models. We associated three simple physical performance measures, namely timed-up-and-go (TUG), fast gait speed (FGS), and 30-s chair stand test (30 s-CST), with a comprehensive neurocognitive test battery measuring EF and non-EF cognitive functions. Moderating effects of cognitive status on the associations were examined. In all models, we controlled for pertinent covariates, including age, education, medical and psychiatric status.ResultsUpon controlling for covariates, TUG was most strongly and positively associated with multiple EF-based neurocognitive tests, followed by FGS, with 30 s-CST having the weakest associations. For all physical performance measures, no significant associations with non-EF-based neurocognitive tests were detected. Cognitive status significantly moderated the associations between all physical measures and several neurocognitive tests, with stronger associations in the MCI than CN.ConclusionCompared to FGS and 30 s-CST, TUG had the most robust associations with multiple EF-based cognitive functions. Given their differential associations with global and detailed neurocognitive tests and significant moderating effects of cognitive status, findings highlight a need to carefully consider the choices of simple physical performance tests when using these tests with a heterogenous group of community-dwelling older adults without dementia.

Longitudinal cognitive change and duration of Alzheimer’s disease stages in relation to cognitive reserve

The relationship of cognitive reserve and measures of reserve with longitudinal cognitive change and the duration of preclinical, prodromal, and mild Alzheimer disease (AD) dementia remains to be fully characterized. In our study, 660 β-amyloid-positive participants staged with preclinical AD, prodromal AD, and dementia due to AD from the Alzheimer’s Disease Neuroimaging Initiative were selected. Cognitive reserve and brain reserve were defined by conventional proxies or the residual method at baseline. We evaluated the utility of these reserves in predicting longitudinal cognitive change by mixed effects models and used a multi-state model to estimate stage duration stratified by reserve groups. Corrected for age, sex, and APOE-ε4 status, reserve was associated with cognitive decline, and the effects changed depending on the specific measures of reserve and the stage of AD. Reserves defined by the residual method were stronger predictors of cognitive change than those defined by conventional proxies. The estimated time from preclinical to mild AD dementia varied from 15–24 years based on the different reserve groups, and we observed a linear trend for the longest duration in individuals with high cognitive reserve/high brain reserve, followed by those with high cognitive reserve/low brain reserve, low cognitive reserve/high brain reserve, and low cognitive reserve/low brain reserve. This study showed a reduced risk of cognitive decline for individuals with higher level of reserve regardless of methods for measuring reserve. Interindividual differences in reserve may be important for clinical practice and trial design.

Risk Factors and the Assessment Tools for Subjective Memory Complaints in Asia

BACKGROUND: As the aged population is growing worldwide, the topic of subjective memory complaints (SMCs) has become a major interest in the current research on cognitive aging and dementia in Asia. SMC’s relation to dementia is of critical relevance as SMCs were suggested as the first subtle indication of cognitive deterioration before the appearance of preclinical dementia and before actual objective cognitive impairment. AIM: The main questions of this review were to first identify the common risk factors of SMCs in Asia. Second, the assessment tools commonly used in Asia to screen SMCs. METHODS: This systematic review used four databases; Medline, Scopus, PubMed, and Web of Science. The literature searches were conducted from 2010 to 2021. The search terms strategy for all databases was “SMCs” AND “mild cognitive impairment (MCI)” OR “cognitive impairment” OR “MCI.” A total of 861 papers were found and extracted using preferred reporting items for systematic review and meta-analyses guidelines. After screening based on inclusion and exclusion criteria, 15 studies were identified for the purpose of the current review. RESULTS: Of the 15 studies, 14 were cross-sectional and one was longitudinal. The main risk factors of SMCs in Asia were depression and objective cognitive performance. Other risk factors were problems with adaptive daily functioning, self-rated health and pain, sleep, material hardship, childhood socioeconomic status, social and leisure activities, and gender. The majority of tools used to screen SMCs included a close-ended method with questionnaires in their respective country’s first language. To date, there are no SMCs tools that analyze the cultural impact on the SMCs manifestation in Asia. CONCLUSION: SMCs may be linked to changes in mood and cognition performance. Future studies may consider adopting a longitudinal design and explore quantitative studies as they might also help understand how individuals from various backgrounds manifest their memory difficulties. Besides, further research may consider using both open-ended questions and validated questionnaires to measure SMCs.

Association of Enlarged Perivascular Spaces With Amyloid Burden and Cognitive Decline in Alzheimer Disease Continuum.

To investigate the effects of enlarged perivascular space (EPVS) on amyloid burden and cognitive function in Alzheimer disease (AD) continuum. We retrospectively reviewed 208 patients with AD across the cognitive continuum (preclinical, prodromal, and AD dementia) who showed amyloid deposition on 18F-florbetaben PET scans and 82 healthy controls. EPVSs were counted for each patient in the basal ganglia (BG), centrum semiovale (CSO), and hippocampus (HP) on axial T2-weighted images. Patients were then classified according to the number of EPVSs into the EPVS+ (>10 EPVSs) and EPVS- (0-10 EPVSs) groups for the BG and CSO, respectively. In terms of HP-EPVS, equal or more than 7 EPVSs on bilateral hemisphere were regarded as the presence of HP-EPVS. After adjusting for markers of small vessel disease (SVD), multiple linear regression analyses were performed to determine the intergroup differences in global and regional amyloid deposition and cognitive function at the time of diagnosis of AD continuum. A linear mixed model was used to assess the effects of EPVSs on the longitudinal changes in the Mini-Mental State Examination (MMSE) scores. Amyloid burden at the time of diagnosis of AD continuum was not associated with the degree of BG-, CSO-, or HP-EPVS. BG-EPVS affected language and frontal/executive function via SVD markers, and HP-EPVS was associated with general cognition via SVD markers. However, CSO-EPVS was not associated with baseline cognition. A higher number of CSO-EPVS was significantly associated with a more rapid decline in MMSE scores (β = -0.58, standard error = 0.23, p = 0.011) independent of the amyloid burden. In terms of BG and HP, there was no difference between the EPVS+ and EPVS- groups in the rate of longitudinal decreases in MMSE scores. Our findings suggest that BG-, CSO-, and HP-EPVS are not associated with baseline β-amyloid burden or cognitive function independently of SVD at the diagnosis of AD continuum. However, CSO-EPVS appears to be associated with the progression of cognitive decline in an amyloid-independent manner. Further studies are needed to investigate whether CSO-EPVS is a potential therapeutic target in patients with AD continuum.

Greater tau pathology is associated with altered predictive coding.

Altered predictive coding may underlie the reduced auditory mismatch negativity amplitude observed in patients with dementia. We hypothesized that accumulating dementia-associated pathologies, including amyloid and tau, lead to disturbed predictions of our sensory environment. This would manifest as increased reliance on ‘observed’ sensory information with an associated increase in feedforward, and decrease in feedback, signalling. To test this hypothesis, we studied a cross-sectional cohort of participants who underwent PET imaging and high-density EEG during an oddball paradigm, and used dynamic casual modelling and Bayesian statistics to make inferences about the neuronal architectures (generators) and mechanisms (effective connectivity) underlying the observed auditory-evoked responses. Amyloid-β imaging with [C-11] Pittsburgh Compound-B PET was qualitatively rated using established criteria. Tau-positive PET scans, with [F-18]MK-6240, were defined by an MK-6240 standardized uptake value ratio positivity threshold at 2 standard deviations above the mean of the Amyloid(–) group in the entorhinal cortex (entorhinal MK-6240 standardized uptake value ratio > 1.27). The cross-sectional cohort included a total of 56 participants [9 and 13 participants in the Tau(+) and Amyloid(+) subgroups, respectively: age interquartile range of (73.50–75.34) and (70.5–75.34) years, 56 and 69% females, respectively; 46 and 43 participants in the Tau(−) and Amyloid(−) subgroups, respectively: age interquartile range of (62.72–72.5) and (62.64–72.48) years, 67 and 65% females, respectively]. Mismatch negativity amplitudes were significantly smaller in Tau+ subgroup than Tau− subgroup (cluster statistics corrected for multiple comparisons: P = 0.028). Dynamic causal modelling showed that tau pathology was associated with increased feedforward connectivity and decreased feedback connectivity, with increased excitability of superior temporal gyrus but not inferior frontal regions. This effect on superior temporal gyrus was consistent with the distribution of tau disease on PET in these participants, indicating that the observed differences in mismatch negativity reflect pathological changes evolving in preclinical dementia. Exclusion of participants with diagnosed mild cognitive impairment or dementia did not affect the results. These observational data provide proof of concept that abnormalities in predictive coding may be detected in the preclinical phase of Alzheimer’s disease. This framework also provides a construct to understand how progressive impairments lead to loss of orientation to the sensory world in dementia. Based on our modelling results, plus animal models indicating that Alzheimer’s disease pathologies produce hyperexcitability of higher cortical regions through local disinhibition, mismatch negativity might be a useful monitor to deploy as strategies that target interneuron dysfunction are developed.

Functional Connectivity Dynamics Altered of the Resting Brain in Subjective Cognitive Decline.

BackgroundSubjective cognitive decline (SCD) appears in the preclinical stage of the Alzheimer's disease continuum. In this stage, dynamic features are more sensitive than static features to reflect early subtle changes in functional brain connectivity. Therefore, we studied local and extended dynamic connectivity of the resting brain of people with SCD to determine their intrinsic brain changes.MethodsWe enrolled cognitively normal older adults from the communities and divided them into SCD and normal control (NC) groups. We used mean dynamic amplitude of low-frequency fluctuation (mdALFF) to evaluate region of interest (ROI)-wise local dynamic connectivity of resting-state functional MRI. The dynamic functional connectivity (dFC) between ROIs was tested by whole-brain-based statistics.ResultsWhen comparing SCD (N = 40) with NC (N = 45), mdALFFmean decreased at right inferior parietal lobule (IPL) of the frontoparietal network (FPN). Still, it increased at the right middle temporal gyrus (MTG) of the ventral attention network (VAN) and right calcarine of the visual network (VIS). Also, the mdALFFvar (variance) increased at the left superior temporal gyrus of AUD, right MTG of VAN, right globus pallidum of the cingulo-opercular network (CON), and right lingual gyrus of VIS. Furthermore, mdALFFmean at right IPL of FPN are correlated negatively with subjective complaints and positively with objective cognitive performance. In the dFC seeded from the ROIs with local mdALFF group differences, SCD showed a generally lower dFCmean and higher dFCvar (variance) to other regions of the brain. These weakened and unstable functional connectivity appeared among FPN, CON, the default mode network, and the salience network, the large-scale networks of the triple network model for organizing neural resource allocations.ConclusionThe local dynamic connectivity of SCD decreased in brain regions of cognitive executive control. Meanwhile, compensatory visual efforts and bottom-up attention rose. Mixed decrease and compensatory increase of dynamics of intrinsic brain activity suggest the transitional nature of SCD. The FPN local dynamics balance subjective and objective cognition and maintain cognitive preservation in preclinical dementia. Aberrant triple network model features the dFC alternations of SCD. Finally, the right lateralization phenomenon emerged early in the dementia continuum and affected local dynamic connectivity.

Trajectories of cognitive decline and dementia development: A 12-year longitudinal study.

Mapping the preclinical dementia phase is important for early detection and evaluation of interventions. We assessed the trajectories of cognitive decline in preclinical dementia over 12 years and investigated whether being a fast decliner across 6 years is associated with increased risk of dementia the following 6 years. Rates of cognitive decline were determined using mixed-effects models for 1646 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) cohort. Cox regression was used to assess the future likelihood of dementia for fast decliners (declining ≥1.5 standard deviations [SDs] faster than the age-specific rates). Participants in a preclinical phase of dementia showed increased rates of decline in all cognitive tests compared to the no-dementia group, particularly closer (0-6 years) to diagnosis. Participants declining fast in three or more cognitive tests 12-6 years before diagnosis demonstrated a high risk of dementia 6 years later (hazard ratio [HR] 3.90, 95% confidence interval [CI] 2.28-6.69). Being a fast decliner is linked to increased risk of future dementia.

Overall and sex-specific risk factors for subjective cognitive decline: findings from the 2015\u20132018 Behavioral Risk Factor Surveillance System Survey

BackgroundPrior research indicates that at least 35% of Alzheimer’s disease and related dementia risk may be amenable to prevention. Subjective cognitive decline is often the first indication of preclinical dementia, with the risk of subsequent Alzheimer’s disease in such individuals being greater in women than men. We wished to understand how modifiable factors are associated with subjective cognitive decline, and whether differences exist by sex.MethodsData were collected from men and women (45 years and older) who completed the U.S. Behavioral Risk Factor Surveillance System Cognitive Decline Module (2015–2018), n = 216,838. We calculated population-attributable fractions for subjective cognitive decline, stratified by sex, of the following factors: limited education, deafness, social isolation, depression, smoking, physical inactivity, obesity, hypertension, and diabetes. Our models were adjusted for age, race, income, employment, marital and Veteran status, and accounted for communality among risk factors.ResultsThe final study sample included more women (53.7%) than men, but both had a similar prevalence of subjective cognitive decline (10.6% of women versus 11.2% of men). Women and men had nearly equivalent overall population-attributable fractions to explain subjective cognitive decline (39.7% for women versus 41.3% for men). The top three contributing risk factors were social isolation, depression, and hypertension, which explained three-quarters of the overall population-attributable fraction.ConclusionsWhile we did not identify any differences in modifiable factors between men and women contributing to subjective cognitive decline, other factors including reproductive or endocrinological health history or biological factors that interact with sex to modify risk warrant further research.

Impact of clinical symptoms and diagnosis: the electronic Person-Specific Outcome Measure (ePSOM) development programme

IntroductionRegulatory bodies recommend that outcome measures used in Alzheimer’s disease (AD) clinical trials capture clinically meaningful changes for the trial participant. However, commonly used outcome measures do not reflect the individual’s views on what matters to them individually. The aim of the electronic Person-Specific Outcome Measure (ePSOM) programme is to better understand what outcomes matter to patients in early Alzheimer’s disease.MethodsAs part of the ePSOM programme, we designed and ran an online study to understand what matters to individuals when developing new treatments for AD. The ePSOM survey ran Aug 2019–Dec 2019 (UK) and collected primarily free text responses which were analysed using Natural Language Processing (NLP) techniques. In this paper, we focus our analyses on individuals who reported having a neurodegenerative disease diagnosis (primarily Mild Cognitive Impairment (MCI) or AD), reporting the most frequent and most important brain health priorities for this group. Due to a small sample size, the Diagnosis group was analysed as a whole. Finally, we compared the Diagnosis group to an age and gender matched control group using chi-squared tests to look for any differences between the Diagnosis and control groups’ priorities.ResultsThe survey was completed by 5808 respondents, of whom 167 (2.9%) (women n = 91, men n = 69, other n = 7) had received one of our pre-defined neurodegenerative disease diagnosis: most commonly MCI n = 52, 1.1% (mean age 69.42, SD = 10.8); or Alzheimer’s disease n = 48, 1.0% (mean age 71.24, SD = 9.79). Several thematic clusters were significantly more important for the target diagnostic group, e.g.: Expressing opinions; and less important, e.g., Cognitive Games.ConclusionWe conclude there are a range of outcomes which individuals consider important and what potential new treatments should help maintain or improve, suggesting that outcomes that matter shift along the preclinical, prodromal and overt dementia continuum. This has important implications for the development of outcome measures in long term prevention studies that last several years where participants may pass through different stages of disease. In the final stage of our project, we will design an electronic outcomes app which will employ the methodology tested in the large-scale survey to capture what matters to individuals about their brain health at an individual level.

Associations of plasma soluble CD22 levels with brain amyloid burden and cognitive decline in Alzheimer's disease.

CD22 has been suggested to contribute to Alzheimer's disease (AD) pathogenesis by inhibiting microglial amyloid β (Aβ) phagocytosis. Soluble CD22 (sCD22) generated by cleavage from cell membranes may be a marker of inflammation and microglial dysfunction; but alterations of sCD22 levels in AD and their correlation with AD biomarkers remain unclear. Plasma sCD22 levels were measured in cognitively normal non-AD participants and patients with preclinical AD and AD dementia from a Chinese cohort and the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. Plasma sCD22 levels were elevated in patients with preclinical and dementia AD. Plasma sCD22 levels were negatively correlated with cerebrospinal fluid (CSF) Aβ42 levels and Aβ42/Aβ40, and positively correlated with CSF phosphorylated tau levels and brain Aβ burden, but negatively correlated with cognitive function. Moreover, higher plasma sCD22 levels were associated with faster cognitive decline during follow-up. These findings suggest that CD22 plays important roles in AD development, and that sCD22 is a potential biomarker for AD.

Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease

BackgroundIncreased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer’s disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels.MethodsWe performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer’s Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study.ResultsWe found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood–brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins.ConclusionsCSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood–brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.

Psychological Impact of Predictive Genetic Testing for Inherited Alzheimer Disease and Frontotemporal Dementia: The IT-DIAfN Protocol.

Aim:Our aim was to evaluate the psychological impact of predictive genetic testing in individuals at-risk for inherited dementia who underwent a structured counseling and testing protocol.Methods:Participants were healthy at-risk relatives from families with at least one affected patient, in whom a disease-associated genetic variant had been ascertained. A comprehensive psychological assessment (personality, anxiety and depression, quality of life, coping strategies, resilience and health-related beliefs) was administered at baseline, at 6 months and 12 months follow-up.Results:Twenty-four participants from 13 families were included. Sixteen participants underwent blood sampling and genetic analysis; 6 resulted to be carriers of pathogenic variants (1 in PSEN1, 1 in PSEN2, 4 in GRN). Carriers showed higher score on the Resilience Scale for Adults (RSA) – social competence, and on Multidimensional Health Locus of Control – internal, than noncarriers (P=0.03 for both). Ten at-risk relatives who completed the follow-up showed improvement in RSA – planned future (P=0.01) with respect to baseline.Discussion:Our case series showed that at-risk individuals undergoing predictive testing showed benefit on personal life and no detrimental impact on a broad range of psychological outcomes. Higher social skills and lower internal health locus of control in carriers may be an early psychological correlate of preclinical dementia.

Ten years of image analysis and machine learning competitions in dementia

Machine learning methods exploiting multi-parametric biomarkers, especially based on neuroimaging, have huge potential to improve early diagnosis of dementia and to predict which individuals are at-risk of developing dementia. To benchmark algorithms in the field of machine learning and neuroimaging in dementia and assess their potential for use in clinical practice and clinical trials, seven grand challenges have been organized in the last decade: MIRIAD (2012), Alzheimer’s Disease Big Data DREAM (2014), CADDementia (2014), Machine Learning Challenge (2014), MCI Neuroimaging (2017), TADPOLE (2017), and the Predictive Analytics Competition (2019). Based on two challenge evaluation frameworks, we analyzed how these grand challenges are complementing each other regarding research questions, datasets, validation approaches, results and impact.The seven grand challenges addressed questions related to screening, clinical status estimation, prediction and monitoring in (pre-clinical) dementia. There was little overlap in clinical questions, tasks and performance metrics. Whereas this aids providing insight on a broad range of questions, it also limits the validation of results across challenges. The validation process itself was mostly comparable between challenges, using similar methods for ensuring objective comparison, uncertainty estimation and statistical testing. In general, winning algorithms performed rigorous data pre-processing and combined a wide range of input features.Despite high state-of-the-art performances, most of the methods evaluated by the challenges are not clinically used. To increase impact, future challenges could pay more attention to statistical analysis of which factors (i.e., features, models) relate to higher performance, to clinical questions beyond Alzheimer’s disease, and to using testing data beyond the Alzheimer’s Disease Neuroimaging Initiative. Grand challenges would be an ideal venue for assessing the generalizability of algorithm performance to unseen data of other cohorts. Key for increasing impact in this way are larger testing data sizes, which could be reached by sharing algorithms rather than data to exploit data that cannot be shared. Given the potential and lessons learned in the past ten years, we are excited by the prospects of grand challenges in machine learning and neuroimaging for the next ten years and beyond.

Accelerated decline in white matter microstructure in subsequently impaired older adults and its relationship with cognitive decline.

Little is known about a longitudinal decline in white matter microstructure and its associations with cognition in preclinical dementia. Longitudinal diffusion tensor imaging and neuropsychological testing were performed in 50 older adults who subsequently developed mild cognitive impairment or dementia (subsequently impaired) and 200 cognitively normal controls. Rates of white matter microstructural decline were compared between groups using voxel-wise linear mixed-effects models. Associations between change in white matter microstructure and cognition were examined. Subsequently impaired individuals had a faster decline in fractional anisotropy in the right inferior fronto-occipital fasciculus and bilateral splenium of the corpus callosum. A decline in right inferior fronto-occipital fasciculus fractional anisotropy was related to a decline in verbal memory, visuospatial ability, processing speed and mini-mental state examination. A decline in bilateral splenium fractional anisotropy was related to a decline in verbal fluency, processing speed and mini-mental state examination. Accelerated regional white matter microstructural decline is evident during the preclinical phase of mild cognitive impairment/dementia and is related to domain-specific cognitive decline.

Weight loss in a cardiovascular trial population identifies people at future risk of dementia.

IntroductionPopulations at increased risk of dementia need to be identified for well‐powered trials of preventive interventions. Weight loss, which often occurs in pre‐clinical dementia, could identify a population at sufficiently high dementia risk.MethodsIn 12,975 survivors in the Heart Protection Study statin trial of people with, or at high risk of, cardiovascular disease, the association of weight change over 5 years during the trial with post‐trial dementia recorded in electronic hospital admission and death records (n = 784) was assessed, after adjustment for age, sex, treatment allocation, and deprivation measures.ResultsAmong the 60% without substantial weight gain (≤2 kg weight gain), each 1 kg weight loss was associated with a risk ratio for dementia of 1.04 (95% confidence interval, 1.02–1.07). Weight loss ≥4 kg and cognitive function below the mean identified participants aged ≥67 years with a 13% 10‐year dementia risk.DiscussionThe combination of weight loss and high vascular risk identified individuals at high risk of dementia who could be recruited to dementia prevention trials.

Grip Strength, Gait Speed and Plasma Markers of Neurodegeneration in Asymptomatic Middle-aged and Older Adults.

Pragmatic biomarkers of preclinical dementia would allow for easy and large-scale screening of risk in populations. Physical function measures like grip strength and gait speed are potential predictive biomarkers but their relationship with plasma markers of Alzheimer's Disease and neurodegeneration have not been elucidated. To examine association between physical function measures and plasma markers of Alzheimer's Disease (AD) and neurodegeneration. Cross-sectional and longitudinal analyses. Community-based cohort in the city of Framingham, Massachusetts. 2336 participants of the Framingham Heart Study Offspring cohort with an average age of 61. Plasma Aβ40 and Aβ42 were measured in 1998-2001 (Exam-7) and plasma total tau measured 5 years later (Exam-8). Grip strength, fast walk speed and chair stand speed were measured at both exams. Quantification of Aβ isoforms in plasma was performed using INNO-BIA assays and plasma total-tau was measured using Quanterix Simoa HD-1 assay. Confounder-adjusted linear regression models examined associations between physical function and plasma markers, Results: Grip strength at Exam-7 was associated with plasma Aβ40 (β -0.006, p-value 0.032) at Exam-7 and plasma total-tau (β -0.010, p-value 0.001) at Exam-8. Grip strength and fast walk speed at Exam-8 were associated with plasma total-tau at Exam-8 (GS: β -0.009, p 0.0005; FWS: β -0.226, p-value <0.0001). Chair stand speed was not associated with plasma markers; Aβ42 was not associated with function. Grip strength and fast walk speed are associated with plasma markers of neurodegeneration in dementia-free middle aged and older individuals. Both these measures could be used as potential screening tools for identifying individuals at a higher risk for AD and related dementias alongside other validated markers.

Increased Plasma brain‐derived neurotrophic factor (BDNF) as a Biomarker for Differentiating Mild Cognitive Impairment from Cognitive Healthy: A case‐control study

AbstractBackgroundAcross the spectrum of Alzheimer’s disease (AD), we previously conducted a meta‐analysis and concluded significantly decreased brain‐derived neurotrophic factor (BDNF) in AD. However, there are inconsistent findings on peripheral BDNF levels in mild cognitive impairment (MCI), even across different meta‐analyses, which have been attributed to the high heterogeneity caused by multiple clinical and laboratory factors. Thus, BDNF’s discriminative accuracy for identifying all‐cause MCI and its subtypes remains unknown.MethodsThis study, while accounting for heterogeneity, compared a healthy control cohort (n=56, 45 female) and an MCI cohort (n=40, 28 female) to determine whether plasma BDNF (pBDNF), hs‐CRP, and DHEA‐S can differentiate between healthy and MCI individuals, including the two MCI subtypes (amnestic [aMCI] and non‐amnestic [non‐aMCI]). Furthermore, the associations between the biomarkers and detailed neurocognitive tests were examined. Adults with cerebral palsy were included as sensitivity analyses.ResultCompared to healthy controls, only pBDNF was significantly increased in all‐cause MCI, aMCI, and non‐aMCI. Furthermore, pBDNF had good (AUC=0.84, 95% CI=0.74 to 0.95, p&lt;0.001) and excellent discriminative accuracy (AUC=0.92, 95% CI=0.84 to 1.00, p&lt;0.001) for all‐cause MCI and non‐amnestic MCI, respectively. pBDNF was also significantly and positively associated with plasma hs‐CRP (β=0.26, 95% CI=0.02 to 0.50, p=0.038), despite attenuated association upon controlling for BMI (β=0.15, 95% CI=‐0.08 to 0.38, p=0.186). Multiple associations with detailed neurocognitive tests were observed.ConclusionThese findings support increased pBDNF as a compensatory mechanism in preclinical dementia, and the neurotrophic and inflammatory hypotheses of cognitive impairment.

Is item response theory superior to classical test theory in scoring A‐IADL?

AbstractBackgroundThe Amsterdam IADL Questionnaire (A‐IADL‐Q) is increasingly being used in Alzheimer disease (AD) trials to assess activities of daily living. The authors of this scale (Sikkes et al., 2012) originally proposed an Item Response Theory (IRT) based scoring. While such an approach has some potential advantages, it requires a complex model, assumptions about population score distributions, and can be difficult to interpret clinically. An alternative to IRT scoring is the Classical Test Theory (CTT) method, which is relatively simple and easier to interpret. The present study compared IRT and CTT for scoring A‐IADL as a function of global cognition in healthy older adults and patients with mild‐to‐moderate AD.MethodAggregated data from three multinational clinical trials including subjects at the preclinical, early symptomatic, and moderate dementia phase of AD were analyzed. A‐IADL and CDR assessments at initial visits were evaluated and participants were classified into three groups based on CDR Global Scores: 0, 0.5, and 1. For IRT scoring, Graded Response Model (GRM) was used to estimate individual’s latent score. For CTT method, scaled average of scored responses were calculated. ROC analysis was conducted to evaluate the utility of each method in distinguishing between CDR groups.ResultThere were a total of 2,694 A‐IADL assessments across the three CDR groups. There was a very high correlation between CTT and IRT estimates of A‐IADL total score (r = 0.996, p &lt; 0.05). As CDR Global Score increased, A‐IADL scores declined for both methods. In IRT scoring, the Item Characteristics Curve showed an overlap for most item responses, and the test information curve was narrow with a peak to the right of theta 0. Importantly, the ROC curve showed slightly better performance for CTT [AUC: 0.829 (0.812‐0.847)] compared to IRT [AUC: 0.809 (0.788‐0.830)].ConclusionThe current study found that CTT scoring of A‐IADL performed slightly better in distinguishing AD populations as a function of global cognition/function. Given the procedural complexities and required assumptions for IRT scoring, the CTT method, which has the advantages of being more straightforward and familiar to clinicians, represents a better choice for most applications of this instrument.

Impact of clinical symptoms and diagnosis: The electronic Person‐Specific Outcome Measure (ePSOM) development programme

AbstractBackgroundRegulatory bodies recommend that outcome measures used in Alzheimer’s disease (AD) clinical trials capture clinically meaningful changes for the trial participant. However, commonly used cognitive outcomes are limited in this regard. The aim of the electronic Person‐Specific Outcome Measure (ePSOM) programme is to better understand what outcomes matter to patients in early Alzheimer’s disease.MethodAs part of the ePSOM programme, we designed and ran an online study to understand what matters to individuals when developing new treatments for AD. The ePSOM survey ran Aug 2019 – Dec 2019 (UK) and collected primarily free text responses which were analysed using Natural Language Processing (NLP) techniques. Here, we focus on the responses from individuals diagnosed with Mild Cognitive Impairment (MCI); Alzheimer’s dementia or Other dementias. We compared each of these groups to the ‘no‐diagnosis’ group by undertaking chi‐squared tests for key demographic variables. Differences between the target and no‐diagnosis groups were looked for.ResultThe survey was completed by 5808 respondents, of whom 167 (2.9%) (women n=91, men n=69, other n=7) had received one of our three target diagnoses: [1] MCI n=61, 1.1% (mean age 69.42, SD=10.8); [2] Alzheimer’s Dementia n=57, 1.0% (mean age 71.24, SD=9.79; and [3] Other dementia n=49, 0.8% (mean age 69.67, SD=9.00). Respondents in the Alzheimer’s and Other dementia group were more likely to have lower educational level, whereas this effect was not found in the MCI group. Several thematic clusters were significantly more important for the target diagnostic groups in comparison with respondents who did not have a target diagnosis, e.g.,: “Expressing opinions” for the MCI group; “Playing Golf” for the Alzheimer’s dementia group; and “Maintaining Personal traits and social skills” for the Other dementia group.ConclusionThe results of the ePSOM survey focusing on the individual’s views with a MCI or Dementia diagnosis provide evidence for what these groups consider important when developing treatments for AD. The numerous clusters which were significantly more likely to be important for those with a particular diagnosis indicate that priorities shift along the preclinical, prodromal and overt dementia continuum. This has important implications for the development of outcome measures.

Written Discourse Task Helps to Identify Progression from Mild Cognitive Impairment to Dementia

Purpose: We aimed to investigate: (1) the clinical, diagnostic value of a written discourse task, and (2) the relationship between executive functions and written discourse within the spectrum of individuals with mild cognitive impairment (MCI). Method: To determine whether written discourse performance predicts clinical course among individuals with MCI, we retrospectively classified individuals with MCI as converters (N = 26) who were later diagnosed with dementia or as a stable MCI group (N = 45). We quantified core word measures from written discourse samples obtained from the Cookie Theft picture description task. Result: Written discourse measures differentiated converters from the stable MCI group. Converters produced a fewer number of core words than the stable MCI group. A measure of executive function significantly predicted performance on the production of core words in written discourse for the converters. In a multivariable regression, production of core words remained the only explanatory variable closely associated with the progression to dementia in MCI. Conclusion: Written discourse tasks can predict the likelihood of MCI progressing to dementia, independently of recall and an executive function measure. Correlational results suggest that written discourse performance was associated with executive function as measured by the Trail Making Test. Our findings emphasize the usefulness of including written discourse tasks in language assessment batteries targeting preclinical dementia populations.