bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo Braak‐staging using 18F‐Flortaucipir‐tau‐PET as a predictive marker for future cognitive decline in Alzheimer’s disease
Authors: Biel Davina , Brendel Matthias , Rubinski Anna , Buerger Katharina , Janowitz Daniel , Dichgans Martin , Franzmeier Nicolai
Published: December 2021

Background

The development of in vivo amyloid (Aβ) and tau biomarkers has greatly facilitated diagnosing AD (Jack et al., 2018), however, reliable prognosis of AD‐related cognitive decline remains a critical yet unmet challenge. Here, especially tau biomarkers may offer great potential for individualized risk prediction of clinical AD progression, since the progressive spread of tau tracks clinical status more closely than Aβ deposition (Ossenkoppele et al., 2016; Wang et al., 2016). Thus, positron emission tomography (PET) of tau may be a better predictor for future cognitive decline and clinical progression than amyloid‐PET. Here, we examined whether tau‐PET‐based Braak‐staging outperforms amyloid‐PET as a predictor of future cognitive decline and clinical progression in older adults with and without cognitive impairment.

Method

We included 396 cognitively normal to AD dementia subjects with Flutemetamol/Florbetapir‐amyloid‐PET, Flortaucipir‐tau‐PET and longitudinal cognitive assessments. Annual change rates in global cognition (i.e. MMSE, ADAS13) and episodic memory (i.e. ADNI‐MEM) were calculated via linear mixed models. We determined global amyloid‐PET (i.e. Centiloid) plus global and Braak‐stage‐specific tau‐PET SUVRs, which were stratified as positive(+)/negative(‐) at pre‐established cut‐offs. Using Braak‐stage‐specific binarized tau‐PET SUVRs, we classified subjects as BraakI+/BraakI‐IV+/BraakI‐VI+/Braakatypical+. In bootstrapped linear regression, we assessed whether global tau‐PET explained more variance in subsequent cognitive decline than Centiloid. Using ANCOVAs, we tested whether advanced Braak‐stage predicted faster future cognitive decline. All models were controlled for age, sex, education, clinical diagnosis, and baseline cognition. Lastly, we determined Braak‐stage‐specific conversion risk to mild cognitive impairment (MCI) or dementia.

Result

Higher global tau‐PET SUVR at baseline explained more variance in subsequent cognitive decline across ∼2 years of follow up compared to baseline amyloid‐PET, consistently for MMSE, ADAS13, and memory (all p<0.001; Fig. 1). The association between global tau‐PET and subsequent cognitive changes remained consistent when additionally controlling for baseline amyloid‐PET. Advancing Braak‐stage was associated with gradually worsening future cognitive decline, independent of Centiloid (p<0.001; Fig. 2), and elevated clinical conversion risk to MCI or AD dementia (e.g. 15.38% for BraakI+, 23.81% for BraakI‐IV+, 45.45% for BraakI‐VI+; Fig. 3).

Conclusion

Tau‐PET clearly outperforms amyloid‐PET in predicting future cognitive decline, where tau‐PET‐based Braak‐staging may be used for estimating patient‐specific risk for clinical AD progression.
Correlation of frontal atrophy and CSF tau levels with neuropsychiatric symptoms in patients with cognitive impairment: A memory clinic experience
Authors: Ramusino Matteo Cotta , Perini Giulia , Vaghi Gloria , Fabbro Beatrice Dal , Capelli Marco , Picascia Marta , Franciotta Diego , Farina Lisa , Ballante Elena , Costa Alfredo
Published: December 2021

Background

Behavioral and psychological symptoms of dementia (BPSD) are a distressful condition. We aimed to investigate the BPSD distribution in subjects with cognitive impairment, and the potential correlations between BPSD and neurodegeneration in terms of cerebrospinal fluid (CSF) tau and brain atrophy.

Method

One‐hundred patients with mild cognitive impairment (MCI) or dementia (Alzheimer’s disease; Lewy‐body disease, LBD; frontotemporal dementia; vascular dementia) underwent a complete diagnostic workup, including 3T‐MRI and/or CT and CSF. Cortical atrophy was assessed with medial temporal atrophy (MTA), posterior atrophy (PA) and global cortical atrophy‐frontal lobe (GCA‐F) scales. BPSD were rated using Neuropsychiatric Inventory (NPI), and BPSD clusters were defined according to the European Alzheimer Disease Consortium.

Result

Delusions, hallucinations and psychosis cluster were differently distributed among the diagnostic groups (p<0.05, p<0.001, and p<0.05), with LBD patients showing higher scores for hallucinations (vs MCI, p<0.001, and AD, p<0.05) and psychosis cluster (vs MCI, p<0.05). In primary dementias, we found a negative correlation between NPI total score and tau levels (p=0.08), confirmed by beta regression (p<0.01), while a positive non‐significant relationship was observed in MCI. Higher GCA‐F scores were associated with delusions and apathy (p<0.05, on both hemispheres) and to hallucinations (left: p<0.01, right: p<0.05). GCA‐F scores were positively correlated with psychosis cluster (right: p<0.05), and agitation/aggression (left: p<0.05). Conversely, nighttime disturbances were positively correlated with both GCA‐F and MTA scores (left: p<0.01; right: p<0.05).

Conclusion

Our results suggest that psychotic symptoms are significantly more represented in LBD patients, and that CSF tau and frontal atrophy are associated with the occurrence and severity of BPSD in clinical practice. Longitudinal studies are however required to ascertain their actual predictive value.
Telephone survey to identify factors predicting willingness to enroll in biomarker studies and disclosure‐related outcomes
Authors: Clark Lindsay R , Erickson Claire M , Chin Nathaniel A , Jonaitis Erin M , Edwards Dorothy Farrar , Zuelsdorff Megan , Gleason Carey E
Published: December 2021

Background

Alzheimer’s disease (AD) diagnostics is evolving rapidly, moving toward biomarker‐based diagnoses characterized by amyloid, tau, and neurodegeneration. To clarify benefits and risks of using this framework with cognitively unimpaired adults, particularly those from groups under‐represented in AD biomarker research, we developed a 30‐minute telephone survey to identify factors predicting willingness to enroll in biomarker studies and hypothetical disclosure‐related outcomes.

Method

Existing scales were modified for telephone administration to assess experience/concern about AD, perceived health, health locus of control, brain health social norms, trust in medical research, and experiences of discrimination. Five hypothetical scenarios assessed willingness to participate in biomarker studies with or without results disclosure. Three open‐ended items provided qualitative data on willingness to participate and share results with others. Forty‐one items assessed reasons for learning results and potential reactions following a hypothetical elevated result. Descriptive statistics were used to evaluate response patterns. Thematic analysis of open‐ended items was conducted using an inductive coding method.

Result

Cognitively unimpaired participants (N=334) included 148 Black/African Americans and 186 non‐Hispanic Whites; aged 45‐89; Table 1). Most participants had cared for someone with dementia (73%), desired to know if they will develop AD (82%) and trust medical research (mean RAQ‐7 = 30/35) (Table 2). Approximately 50% were very or extremely willing to participate in biomarker studies regardless of results disclosure; however, African Americans were less willing to participate if results were not disclosed. Common themes related to willingness to participate and learn results included wanting to know if at personal risk or to prevent/plan for AD and wanting to support science or help others. Misgivings/anxiety about knowing biomarker and concerns about invasiveness or lack of a cure for AD were common themes for those less willing (Table 3).

Conclusion

This survey assesses AD‐relevant, health, and experiential factors, willingness to participate in biomarker research, and disclosure‐related outcomes. Initial results suggest understanding risk, prevention/planning behaviors, and helping others are reasons for participating and learning biomarker results. Results may also inform recruitment of African Americans into biomarker studies. Future analyses will investigate factors predicting potential positive (e.g., planning, risk‐reducing behavior) and negative (psychological distress/stigma) disclosure outcomes.
Diffusion tensor imaging findings in empirically derived incident MCI subtypes
Authors: Machulda Mary M. , Lundt Emily S. , Mester Carly T. , Albertson Sabrina M. , Pillai Sheela Kumari Raghavan , Reid Robert I. , Schwarz Christopher G. , Graff‐Radford Jonathan , Jack Clifford R. , Knopman David S. , Mielke Michelle M. , Kremers Walter K. , Jones David T. , Petersen Ronald C. , Bondi Mark W. , Vemuri Prashanthi
Published: December 2021

Background

Early changes in white matter (WM) measured using diffusion tensor imaging (DTI) are sensitive markers of WM degeneration and predict future cognitive decline in mild cognitive impairment (MCI). We sought to examine whether changes in WM integrity differed among empirically derived subtypes of incident MCI.

Method

Participants included 66 individuals with incident MCI enrolled in the population‐based Mayo Clinic Study of Aging (MCSA) previously identified via cluster analysis as having one of four MCI subtypes: subtle cognitive impairment (SCI; n = 13, mean age 78; 15% women), amnestic (n = 24; mean age 79; 54% women), dysnomic (n = 8; mean age 79; 38% women), and dysexecutive (n = 21; mean age 82; 33% women). All participants completed 3T MRI at the time of the MCI diagnosis. We compared the MCI subtypes to 100 cognitively unimpaired (CU) participants (mean age 77; 49% women). We used tract‐based spatial statistics to examine voxel‐level differences in fractional anisotropy (FA). We also fit a linear regression model to regional FA data from the corpus callosum (CC), the major interhemispheric WM connection, to quantify the relative differences in WM damage.

Result

All MCI subtypes except the subtle cognitive impairment group had widespread decreased FA. Relative to CU, the amnestic cluster showed decreased FA in the CC (genu), cingulum, fornix and uncinate fasciculus (UF); the dysnomic cluster showed decreased FA in the CC (genu, splenium), fornix, UF, anterior thalamic radiation (ATR), and corticospinal tract (CST); and the dysexecutive group showed decreased FA in the CC (genu, body, splenium), cingulum, UF, ATR, CST, and superior longitudinal fasciculus. The dysexecutive cluster had the most severe bilateral involvement among all MCI subtypes. The regional analysis showed that the amnestic, dysnomic, and dysexecutive groups (but not the subtle cognitive impairment group) had significantly lower FA of the CC compared to CU (p<0.001; Figure 1).

Conclusion

We found widespread WM degeneration in the commissural and long association fibers in amnestic, dysnomic, and dysexecutive incident MCI subtypes. The extent of CC damage seen in Figure 1. confirmed the voxel‐level results and suggests that interhemispheric WM disconnection is relevant to the development of MCI.
Analyzing the future time perspective scale in the baseline period in the Anti‐Amyloid treatment in Asymptomatic Alzheimer's Disease (A4) Study
Authors: Stites Shana D. , Dedhia Mehek , Grill Joshua D. , Karlawish Jason
Published: December 2021

Background

Learning an Alzheimer’s disease (AD) biomarker result can impact a person’s expectations for their future. We assessed the behavior of the Future Time Perspective (FTP) scale in a sample of cognitively unimpaired older adults undergoing AD biomarker testing and disclosure.

Method

5665 participants who were screened for a multisite randomized preclinical AD trial learned their result of an amyloid PET scan: 1182 elevated and 3310 not elevated. Each completed the FTP scale before and after learning the result. The FTP is a 10‐item scale that measures perceived remaining time. Items are rated on a 7‐point scale. Correlations, factor analysis, within‐subject comparisons, and polytomous analyses explored relationships between FTP and amyloid status. In multinomial logistic regression (MLR) analyses, the base outcome was no FTP change (50th%tile interquartile range of change score distribution). Decreased FTP was the lowest quartile of change score distribution while increased FTP was the upper quartile.

Results

Using items that showed high uniqueness scores (<0.40) and low ceiling effects (<20% endorsing maximum scale scores), we examined a 3‐item FTP subscale (FTP‐3, score range 1 to 7). Mean change in persons with elevated amyloid was 0.12 (95%CI 0.06 to 0.18) and 0.20 (95%CI 0.17 to 0.24) in those with a not elevated result.

In MLR analysis, the mean in the decreased FTP‐3 group was ‐0.89 points (95%CI ‐0.92 to ‐0.86), while the mean increased FTP‐3 was 1.26 (95%CI 1.22 to 1.29). Elevated amyloid results (0.22, 95%CI 0.06 to 0.39) and better self‐rated cognitive function (CFI, ‐0.03, 95%CI ‐0.05 to 0.01) made decreased FTP‐3 more likely than no FTP‐3 change. In the same analysis, lower MMSE scores (‐0.08, 95%CI ‐0.14 to ‐0.03) made increased FTP‐3 more likely than no FTP‐3 change.

Conclusion

The 3‐item FTP scale offers an option for a brief measure with limited ceiling effects. Additionally, while mean FTP change due to AD biomarker result disclosure is small (mean=0.18), our findings from polytomous analysis support the hypothesis that AD biomarker result knowledge may have notable effects on FTP (∼2SD). FTP warrants further study in preclinical AD with attention to associations with disease progression, well‐being, and life plans.
Clinical, cognitive and biomarker profiles in dominantly‐inherited versus sporadic early‐onset Alzheimer’s disease
Authors: Llibre‐Guerra Jorge J , Iaccarino Leonardo , Li Yan , Edwards Lauren , McDade Eric , Strom Amelia , Gordon Brian A. , Mundada Nidhi , Schindler Suzanne E. , Tsoy Elena , Fagan Anne M , La Joie Renaud , Benzinger Tammie L.S. , Soleimani‐Meigooni David N. , Aschenbrenner Andrew J. , Miller Zachary A. , Wang Guoqiao , Kramer Joel H , Hassenstab Jason , Rosen Howard J. , Morris John C. , Miller Bruce L. , Xiong Chengjie , Perrin Richard J. , Rabinovici Gil D. , Bateman Randall J.
Published: December 2021

Background

Approximately 5% of Alzheimer disease (AD) occurs before the age of 65, known as early onset AD (EOAD); 5‐10% of the patients with EOAD are caused by dominantly inherited mutations (DIAD) and the remainder appear to be sporadic EOAD (sEOAD). The extent to which clinical presentations, cognitive and biomarker profiles in DIAD and sEOAD overlap remains unknown.

Methods

We compared the clinical presentation, cognitive performance and cerebrospinal fluid (CSF) AD biomarker concentrations in DIAD and sEOAD. We included all DIAD symptomatic (CDR>0) participants (n=92) from the Dominantly Inherited Alzheimer Network (DIAN) cohort and 120 sEAOD symptomatic participants from the UCSF Alzheimer’s Disease Research Center. All EOAD cases were amyloid‐positive via PIB‐PET. All participants completed clinical measures, a battery of cognitive tests and CSF biomarker studies (Aβ‐42, p‐tau‐181, t‐tau). Baseline differences in clinical and biomarkers variables between sEOAD and DIAD were compared using t‐tests, and differences in the rates of decline on clinical and cognitive measures were compared using linear mixed effects models.

Results

DIAD participants had an earlier age at symptom onset compared to the sEOAD group (42.9y (±8.1) and 54.8y (±5.1) respectively, p<0.001). The sEOAD group showed a lower performance on executive measures, including verbal fluency (p=0.001), Trail making test (p=0.001) and digit span (p<0.001). CSF Aβ‐42 levels were significantly lower in DIAD compared to sEOAD participants (242.0 pg/ml [IQR=164.5, 318.8] vs 295.0 pg/ml [IQR=243.9, 364.1] respectively, p=0.014). Ptau‐181 levels were higher in the DIAD cohort (p=0.003), but no significant differences were found for t‐tau levels (p=0.11). Longitudinal analyses did not reveal significant differences in the rates of functional (CDRTM‐SB) and cognitive (MMSE) decline between two groups.

Conclusions

Although sporadic and inherited EOAD differed in AD core pathological CSF biomarkers concentrations and baseline cognitive profiles, the rates of functional and cognitive changes were similar across these groups. These findings provide unique insights into the similarities and differences between DIAD and sEOAD and may inform the design of future clinical trials.
A novel digital cognitive biomarker for mild cognitive impairment and Alzheimer’s disease
Authors: Fernández Gerardo , Schumacher Marcela , Orozco David , Sgrilli Gustavo , Echeverria Gustavo , Linares Ramiro , Parra Mario A.
Published: December 2021

Background

Recent evidence suggests that oculomotor behaviours linked to cognitive performance can be a biomarker of Alzheimer’s disease (AD). Short‐Term Memory Binding (STMB) declines in patients with AD dementia and in those at risk of dementia. STMB relies on brain regions relevant to visual processing which are known to support oculomotor behaviours. Viewmind is proposed as a novel “cognitive digital biomarker” with the potential of revealing phenotypic features of AD in the pre‐dementia stage of the pathology. Viewmind applies artificial intelligence to analyse eye movements and pupil responses during the performance of STMBT.

Method

STMBT assesses the ability to temporarily hold bicoloured objects whose colours had to be remembered either as individual features (baseline) or integrated within unified representations (binding). Viewmind’s technology powered by Artificial Intelligence improved STMBT for identifying MCI patients and their potential conversion to AD.

Result

The 3 years Longitudinal Study involved 42 healthy older adults and 61 patients with Mild Cognitive Impairment (MCI). Viewmind retrospectively classified 91% of the MCI patients who later converted to AD as AD patients. From those MCI patients that Viewmind predicted as no AD, none later converted to AD but they progressed to Fronto‐temporal or Parkinson’s Disease.

Conclusion

Taken together, the results above suggest that Viewmind can (1) unveil novel features of AD dementia unknown to date, and (2) provide a more sensitive tool which can detect and trace aspects of such phenotype in people at risk, thus helping to ascertain the presence of the prodromal stages of the disease.
Evaluating a system to promote timely detection of cognitive impairment in primary care practice
Authors: Fitzpatrick Annette L , Belza Basia , Raetz Jacqueline G. , Suchsland Monica Zigman , Illes Judit , Gaster Barak
Published: December 2021

Background

Dementia and mild cognitive impairment (MCI) are underdiagnosed with evidence indicating that clinical diagnoses frequently occur late in the process of cognitive decline. Increasing evidence that dementia may be preventable or delayed has led to an international focus on earlier evaluation, diagnosis and intervention.

Method

Using the impetus of “Memory Brain Wellness” as a priority growth program at University of Washington (UW) Medicine, we are developing synergistic strategies to improve timely detection of cognitive impairment across primary care in 15 neighborhood clinics in the Pacific Northwest. This presentation will describe current quality‐improvement efforts to promote engagement across multiple stakeholders including health‐care system leadership, practice care management, primary care providers (PCPs) and clinic staff. This lifespan approach is based on the KAER (Kickstart‐Assess‐Evaluate and Refer) Model and Toolkit (2020 Edition) developed by the Gerontological Society of America (GSA).

Results

Program activities to be described include 1) results of interviews with the primary care team to determine acceptability and support needed to implement timely cognitive evaluation; 2) implementation of a training intervention to initiate discussions, conduct cognitive assessment, and manage care; and 3) identification of support services and resources to be used in provider consultation. Input from a Technical Advisory Committee and local Community Advisory Board were incorporated into the training and resource inventory for patient/caregiver support. Topics in the training include normalizing the conversation, team approach, moving toward evaluation, assessment tools, alternate diagnoses/modifiable risk factors, multi‐disciplinary and community referrals, patient counseling, long‐term management, and advance care planning. Changes in practice patterns of PCPs will be reviewed using extracted data from the electronic health record (EHR). Details of each strategy will be provided to explain system‐wide decisions, pragmatic applications, results of trainings held to‐date and feed‐back from the primary care team.

Conclusion

This is the first study to refine and utilize the GSA KAER toolkit addressing change in practice patterns in a large multi‐clinic primary care system. Results of this program will be used to extend efforts beyond the Seattle region to address timely cognitive evaluation across the 5‐state WWAMI region (Washington, Wyoming, Alaska. Montana and Idaho) served by UW Medicine.
Residual approaches to capture resilience and resistance in aging and Alzheimer’s disease: A meta‐analysis
Authors: Bocancea Diana I. , van Loenhoud Anna C. , Groot Colin , Barkhof Frederik , van der Flier Wiesje M. , Ossenkoppele Rik
Published: December 2021

Background

There is currently no consensus on how to optimally define and measure resistance and resilience in aging and Alzheimer´s disease (AD). Residuals from regression analyses can be used to quantify whether an individual´s capacity to avoid (resistance) or cope with (resilience) cerebral damage is higher or lower than expected. We aggregated the rapidly‐growing literature on neuroimaging‐based residual methods in the context of aging and AD into a meta‐analysis in order to investigate associations of residual measures of resilience and resistance with longitudinal cognitive and clinical outcomes.

Method

A systematic literature search of PubMed and Web‐of‐Science databases (consulted until March 2020) and subsequent screening led to 10 studies eligible for the meta‐analysis. The included studies employed a residual measure to investigate associations between either resistance or resilience and rate of cognitive decline or clinical progression (i.e., conversion to MCI or dementia). We extracted standardized regression coefficients for the former and hazard ratios (HRs) for the latter, and assessed overall effects using random‐effects models in the R(v3.6.1) metafor package(v2.4‐0).

Result

Resistance was most commonly measured with age‐based residuals (also known as “brain age” methods) that capture the extent to which an individual preserves brain integrity despite chronological aging. Cognitive resilience residuals quantified deviations in cognition from expected levels based on the amount of neurodegeneration [Figure 1]. There is considerable methodological variability in how the residual measures were derived and validated. Despite these methodological differences across studies (reflected in the moderate to high heterogeneity estimates), our meta‐analysis showed significant associations between resistance and risk of dementia/AD (HR[95%CI]=1.12[1.07‐ 1.17], p<0.0001, I2
=70.2%), with a lower level of resistance indicating a higher risk of progression. Cognitive resilience was significantly associated with risk of progression (HR[95%CI]=0.46[0.32‐0.68], p<0.001, I2
=94.2%) and also with rate of cognitive decline (β[95%CI]=0.05[0.01‐0.08], p<0.01, I2
=80.3%), suggesting an overall protective role of resilience across studies (i.e. a lower level of resilience is associated with an increased risk of dementia and a faster decline) [Figure 2].

Conclusion

This meta‐analysis supports the validity of residual measures to quantify resilience and resistance, as they capture clinically meaningful information in aging and AD.
Association of sleep duration at age 50, 60 and 70 with incidence of dementia
Authors: Sabia Séverine
Published: December 2021

Background

Sleep dysregulation is a feature of dementia but whether sleep duration prior to old age is also associated with incidence of dementia remains unclear. We examined the association of sleep duration in midlife with risk of late‐life dementia.

Method

Data were drawn from 7959 participants (women=33.0%) of the Whitehall II cohort study, established in 1985‐1988, from which self‐reported sleep duration at age 50, 60, and 70 was extracted and categorized as “short: ≤6 hours per night”, “normal: 7 hours per night”, “long: ≥8 hours per night”. Incident dementia (N=521) cases were identified through electronic health registers until March 2019.

Result

Compared to normal sleep duration, higher risk of incident dementia was observed among those with short sleep duration at ages 50 and 60 (mean follow‐up 25 and 15 years, respectively), although not significantly at age 70 (hazard ratio 1.22 (95% confidence interval 1.01‐1.48), 1.37 (1.10‐1.72), and 1.24 (0.98‐1.57), respectively). Persistent short sleep duration at age 50, 60, and 70 compared to persistent normal sleep duration was also associated with a 32% (hazard ratio 1.32 (1.02‐1.72)) increased risk of dementia independently of sociodemographic, behavioural, cardiometabolic, and mental health factors. These associations were also evidence when analyses were restricted to participants without a history of mental illness before age 65 years. In a subsample with objective measure of sleep (accelerometer data, N=3888), the association of short sleep duration with increased risk of dementia was confirmed.

Conclusion

This study paying attention to both age at sleep duration and length of follow‐up along with inclusion of a wide array of covariates shows that short sleep duration in midlife is associated with an increased risk of dementia. Public health messages to encourage good sleep hygiene, may be particularly important for people at higher risk of dementia.
Study design of FINGER‐NL: A multidomain lifestyle intervention in Dutch older adults to prevent cognitive decline
Authors: Zwan Marissa D. , Deckers Kay , Claassen Jurgen A.H.R. , Oosterman Joukje M. , de Heus Rianne A.A. , van de Rest Ondine , de Groot Lisette C.P.G.M. , Smidt Nynke , Broersen Laus M. , Counotte Danielle , Sikkes Sietske A.M. , van Boxtel Martin P.J. , Aarts Esther , van der Flier Wiesje M , Koehler Sebastian
Published: December 2021

Background

Previous multidomain lifestyle intervention trials to prevent cognitive decline in non‐demented elderly have found conflicting effects, with positive findings including the multidomain FINnish GERiatric intervention (FINGER) study (Ngandu T, Lehtisalo J, Solomon A, et al. Lancet 2015), and in specific at‐risk subgroups in other trials (Moll van Charante EP, Richard E, Eurelings LS, et al. Lancet 2016; Andrieu S, Guyonnet S, Coley N, et al. Lancet Neurol. 2017). As part of a world‐wide effort to replicate and build on these results, FINGER‐NL aims to investigate the effectivity of a 2‐year multidomain lifestyle intervention in Dutch older adults to prevent cognitive decline.

Method

FINGER‐NL is a Dutch multi‐center, randomized, controlled, multidomain lifestyle intervention trial among 1,206 adults at risk for cognitive decline with a duration of 24 months. Inclusion criteria are 60‐80 years of age and presence of both modifiable (based on LIfestyle for BRAin health (LIBRA) score) and non‐modifiable (family history, worries about subjective cognitive decline) dementia risk factors. Participants will be randomized in a 1:1 ratio to the structured intervention group or the self‐guided control group. The multidomain lifestyle intervention comprises 8 modules, namely physical exercise, cognitive training, management of metabolic and vascular risk factors, nutritional counseling, Souvenaid®, sleep counseling, stress management, and social activities. The structured intervention group receives a personalized, supervised and hybrid (both online and at study site) intervention consisting of group meetings and individual sessions. The self‐guided control group receives online lifestyle‐related health education. Primary outcome is 2‐year change from baseline on a cognitive composite score covering processing speed, executive function and memory. Secondary outcomes including changes in specific cognitive domains, Amsterdam Instrumental Activity of Daily Living Questionnaire (A‐IADL‐Q), LIBRA score, EQ‐5D‐5L, lifestyle component specific outcomes. Participant recruitment will start in June 2021 and FINGER‐NL is expected to be completed in 2024.

Result

Results of FINGER‐NL will provide further insight in the effectivity and feasibility of a multidomain lifestyle intervention to prevent cognitive decline in older adults.

Conclusion

Given the current lack of curative treatment options and the growing prevalence of cognitive impairment and dementia, lifestyle interventions may play an important role in preventing or delaying disease onset.
Lower cognitive resilience against brain atrophy in cognitively unimpaired elderly is partly explained by Alzheimer's disease pathology
Authors: Svenningsson Anna L , Ossenkoppele Rik , Stomrud Erik , Palmqvist Sebastian , Hansson Oskar
Published: December 2021

Background

Cognitive resilience refers to processes involved in coping with effects of brain pathology on cognition. Factors contributing to cognitive resilience against brain atrophy are unclear, as there have been few longitudinal studies investigating this. Therefore we aimed to identify factors explaining the discrepancy between brain atrophy and longitudinal cognitive decline. One proposed method of investigating cognitive resilience is a residual approach, which suggests using the variance in cognition not explained by a specified predictor as a measure of resilience.

Method

Cognitively unimpaired subjects (n=406) from The Swedish BioFINDER Study with magnetic resonance imaging (MRI) and cognitive test results from at least two time points were included. Using FreeSurfer, global cortical thickness was calculated. A cognitive composite score was calculated from Mini Mental State Examination, Alzheimer´s Disease Assessment Scale – Cognitive Subscale delayed word recall, Trail Making Test B, and Animal fluency. For each subject, the beta coefficients for change in cortical thickness and change in cognition over time were calculated. Linear regression was performed between the two beta coefficients, and the residuals were used as a measure of cognitive resilience. Associations were calculated between this resilience measure and baseline demographics, biomarkers of amyloid (cerebrospinal fluid (CSF) β‐amyloid (Aβ) 42/40 ratio), tau (CSF phosphorylated tau (p‐tau)), and vascular (MRI white matter lesion (WML) volume) pathology as well as neurodegeneration (CSF neurofilament light (NfL)). For dichotomous variables (sex and pathologic Aβ42/40 ratio) independent samples t‐tests, and for continuous variables (all other variables) Pearson correlations, were performed.

Result

In univariate models, lower age at baseline, female sex, higher cortical thickness and better cognitive results at baseline were associated with higher cognitive resilience against cortical atrophy, while education was not. Further, pathological Aβ42/40 ratio and higher levels of p‐tau, NfL, and WMLs at baseline were negatively associated with cognitive resilience in univariate analyses. In a multivariable linear regression model, lower baseline cortical thickness, a pathological Aβ42/40 ratio, and higher NfL were significantly associated with worse cognitive resilience (Figure 1, Table 1).

Conclusion

Markers of Alzheimer´s disease pathology and neurodegeneration are associated with worse than expected cognitive decline at a given rate of brain atrophy.
Amyloid discordance analysis in cognitively normal monozygotic twins demonstrates that the memory domain is affected first in preclinical AD
Authors: Tomassen Jori , den Braber Anouk , Van Berckel Bart N.M. , Yaqub Maqsood , Boomsma Dorret I , Scheltens Philip , Tijms Betty M. , Visser Pieter Jelle
Published: December 2021

Background

The earliest cognitive changes in Alzheimer’s disease (AD), even before amyloid‐beta (Aβ) is abnormal, remain largely unclear. We recently observed in a cohort of cognitively normal older monozygotic twins that 15% of twin‐pairs were discordant for Aβ status (Fig. 1). In this cohort, we investigated early cognitive changes by comparing cognitive decline over 4 years among twin‐pairs discordant for Aβ status (one twin normal Aβ and co‐twin abnormal Aβ), twin‐pairs with both normal Aβ (concordant Aβ‐), and twin‐pairs with both abnormal Aβ (concordant Aβ+). We expected the rate of cognitive decline to depend on baseline Aβ status with the least decline in concordant Aβ‐ twins and increasing decline from discordant Aβ‐, discordant Aβ+ to concordant Aβ+ twins.

Method

From the EMIF‐AD PreclinAD study we selected monozygotic twins with normal cognition at baseline who had a [18F]flutemetamol PET scan and at least one cognitive follow‐up available (n=188; 90 twin‐pairs) (Table 1). We defined Aβ group status using visual read of dynamic [18F]flutemetamol PET images. We tested whether twin Aβ concordance status at baseline was associated with cognitive performance at baseline and over 4 years time with two repeated measures in memory, attention, executive function (EF) and language domains using linear mixed models adjusted for age, sex, education and genetic relatedness.

Result

At baseline concordant Aβ+ twins showed impaired performance in all domains (Fig. 2). Discordant Aβ+ and concordant Aβ+ twins showed lower memory scores compared to concordant Aβ‐ twins (discordant Aβ+, p=0.02; concordant Aβ+, p=0.04). Over time, we found that for concordant Aβ‐ twins memory improved over time (p=0.002), discordant Aβ‐ twins did not change over time (p=0.15), while discordant Aβ+ and concordant Aβ+ twins declined on memory (concordant Aβ+, p=0.03; discordant Aβ+, p=0.07). No significant changes over time were observed in the other domains.

Conclusion

Our findings provide further support that the earliest cognitive changes in AD are found in the memory domain and that subtle memory changes may already by present before amyloid pathology can be detected on a PET scan.
Long‐term cognitive and motor decline across the spectrum of Lewy body disease
Authors: Gonzalez Maria Camila , Maple‐Grødem Jodi , Tovar Diego , Williams‐Gray Caroline H. , Camacho Marta , Forsgren Lars , Bäckström David , Lawson Rachael A , Macleod Angus D. , Counsell Carl E. , Paquet Claire , Falup‐Pecurariu Cristian , Blanc Frédéric , Padovani Alessandro , de Lena Carlo , D'Antonio Fabrizia , Alves Guido , Aarsland Dag
Published: December 2021

Background

This study aims to compare the progression of motor and cognitive decline in dementia with Lewy bodies (DLB) compared with Parkinson’s disease (PD) using a large multicentre international consortium with up to 15 years of follow‐up.

Method

Longitudinal data from 12 cohorts of patients with PD and DLB were included. The PD cohort (n=1108) included newly diagnosed patients from large, on‐going studies. The DLB cohort (n=290) included patients with probable DLB from the European DLB consortium (Table 1). The Mini Mental State Examination (MMSE) was used to explore cognitive functioning and UPDRS‐III for motor impairment. The differences in the rate of progression of MMSE and UPDRS‐III were analyzed with Linear Mixed Effects Model (LMEM) adjusted for baseline variables, with interactions for time. We used square root transformation of the number of errors to obtain an MMSE variable with normal distribution.

Result

Both DLB and PD groups presented motor and cognitive decline. The MMSE (figure 1A) showed a mean annual worsening of 2.35 points (95% CI 1.67‐3.03) for DLB patients and 1.05 points (95% CI 0.62‐1.47) for PD patients (P <0.001). In PD the rate of decline increased with time and from the tenth year, the annual rate of decline of the transformed MMSE scores matched the rate in the DLB group. While DLB patients had lower UPDRS‐III scores at baseline, the rate of decline in UPDRS‐III (figure 1B) scores was faster in DLB compared to PD (P <0.001). The annual increase in UPDRS III in DLB was 5.8 points (95% CI 5.71‐5.90), while in PD it was 1.9 points (95% CI 1.76‐1.97).

Conclusion

Our findings suggest that patients with DLB experience not only more rapid cognitive decline, but also accelerated motor deterioration compared to patients with PD. After ten years of follow‐up (and 12.9 years from the onset of symptoms), PD patients reach DLB's degree of yearly cognitive decline. This is the first large study to compare the natural history of PD and DLB and provides important information about the prognosis of these diseases.
The neuroinflammation signatures in different stages of the Alzheimer’s disease continuum
Authors: Wang Yi‐Ting , Benedet Andréa Lessa , Tissot Cécile , Lussier Firoza Z. , Bezgin Gleb , Therriault Joseph , Servaes Stijn , Arias Jaime Fernandez , Gauthier Serge , Rosa‐Neto Pedro
Published: December 2021

Background

The natural history of Alzheimer’s disease (AD) comprises a long preclinical stage characterized by pathological changes that start decades before symptoms arise. Despite that AD is defined based on the presence of amyloid‐β (Aβ) and tau pathology, increasing evidence supports neuroinflammation as one of the earliest pathomechanistic alterations throughout the AD continuum. Microglia and astrocytes are key cellular drivers and regulators of neuroinflammation. However, it remains unclear if there are patterns of spatial and temporal susceptibility to neuroinflammatory processes in the brain that may synergize with Aβ and tau accumulation, which drives neurodegeneration in a self‐reinforcing manner.

Method

This was a cross‐sectional study examining a total number of 283 subjects from the TRIAD cohort at McGill University Research Centre for Studies in Aging, Canada. Cerebral amyloid and tau neurofibrillary tangles were assessed using positron emission tomography (PET) radiopharmaceuticals [18F]AZD4694 ([18F]NAV4694) and [18F]MK6240 respectively. Cerebrospinal fluid (CSF) biomarkers including Aβ42, Aβ40, phosphorylated tau (p‐tau), total tau (t‐tau), neurofilament light (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL40 and glial fibrillary acidic protein (GFAP) were also measured. Voxelwise analyses were performed to evaluate the relationships between cerebral amyloid load, tau burden and neuroinflammation biomarkers.

Result

We modelled biomarker changes as a function of amyloid PET standardized uptake value ratio (SUVR) and tau PET SUVR as proxies of disease progression. The earliest changes observed in the AD continuum were the decrease in the Aβ42/40 ratio and the increases in astrocytic biomarkers CSF YKL40 and CSF GFAP. This is followed by a steep increase in CSF pTau231 and, to a lesser extent, CSF pTau217 and CSF pTau181. Voxelwise analyses revealed that YKL40 and GFAP are associated with amyloid and tau load in the brain, after accounting for age, sex, education and pathological status.

Conclusion

Neuroinflammation involving astrocytic activation is altered very early in the Alzheimer’s continuum and could be targeted as a promising biomarker.
Novel CSF inflammatory markers MIF and TREM‐1 are increased in Alzheimer’s disease
Authors: Hok‐A‐Hin Yanaika S. , van der Flier Wiesje M. , Lemstra Afina W. , Del Campo Marta , Teunissen Charlotte E.
Published: December 2021

Background

There is a lack of biomarkers reflecting Alzheimer‐relevant pathological processes such as inflammation, to improve Alzheimer’s differential diagnosis. Our recent discovery cerebrospinal fluid (CSF) proteomics study, revealed potential AD‐specific biomarkers related to inflammatory pathology, such as migration inhibitory factor (MIF) and triggering receptor expressed on myeloid cells 1 (TREM‐1). Here, we aimed to validate these findings including also samples from patients with dementia with Lewy Body (DLB) using a novel sensitive technology purposed for clinical implementation.

Method

MIF and TREM‐1 levels were measured in CSF from patients with AD (n=38, 66 ± 6 years, 97% males), DLB (MIF: n=50, TREM‐1: n=40, 67 ± 7 years, 95% males) and controls (cognitively unimpaired, n=37, 66 ± 6 years, 95% males) using assays on the antibody‐based SimplePlex technology, in‐house validated for CSF analysis. Differences in protein levels between diagnostic groups and correlations to AD CSF biomarkers and mini‐mental state examination (MMSE) scores were tested by analysis of covariance (corrected for age and sex) and Spearman correlations. An optimal prediction panel was identified using backward elimination logistic regression analysis with likelihood ratio and ROC analyses.

Result

CSF MIF levels were increased in AD (1.2‐fold, p=0.002) and DLB (1.14‐fold, p=0.036) compared to controls (figure 1A). MIF levels correlated with total‐ and phosphorylated‐Tau (t‐Tau, ρ=0.670, p<0.001; p‐Tau, ρ=0.686 p<0.001) and Amyloid‐beta 42 (Aβ42, ρ=‐0.189, p<0.05) but not with MMSE (p>0.05). CSF TREM‐1 levels were increased in AD compared to DLB (1.4‐fold, p=0.016) and controls (1.5‐fold, p=0.003, figure 1B) and correlated with all three AD CSF biomarkers (t‐Tau: ρ =0.472, p=0.001; p‐Tau: ρ=0.414, p=0.001; Aβ42: ρ=‐0.267, p=0.018) but not with MMSE (p>0.05). A panel combining MIF, t‐Tau and p‐Tau differentiated AD from DLB with high accuracy (AUC=0.941 (95%CI: 0.892‐0.989, 88% sensitivity, 89% specificity, figure 2).

Conclusion

Inflammatory‐related proteins MIF and TREM‐1 are increased in AD. We here validated previous proteomics findings in an independent cohort using a technology that is used as a first preparatory step towards clinical implementation. This data highlights the importance of biomarkers reflecting different pathological processes as these proteins could be used to provide insight into an ongoing neuroinflammatory response.
Men and women show partly distinct effects of physical activity on markers of brain integrity
Authors: Gonneaud Julie , Moreau Ilana , Felisatti Francesca , Arenaza‐Urquijo Eider M , Ourry Valentin , Touron Edelweiss , De la Sayette Vincent , Vivien Denis , Chetelat Gaël ,   the Medit‐Ageing Research Group
Published: December 2021

Background

Physical inactivity in older adults has been linked to an increased risk of dementia. On the other hand, increasing evidence indicates that sex is likely to influence Alzheimer’s disease (AD) pathophysiology, leading to a differential susceptibility to the disease in women versus men. We propose to investigate the interplay between sex and physical activity on brain integrity.

Method

We included baseline data of 134 cognitively unimpaired older adults (>65 years old, 82 women; Table) from the Age‐Well randomized control trial. They underwent multimodal neuroimaging, including structural MRI, FDG‐ and AV45‐PET, providing measures of grey matter volume (GMv), glucose metabolism, perfusion and Aβ burden. The Modifiable Activity Questionnaire was used to measure leisure time physical activity over the last 12 months. We assessed 1) the effect of sex on the amount of physical activity reported, 2) the main effects of sex and physical activity on each neuroimaging measure and 3) the interaction between sex and physical activity on the same variables. All analyses were controlled for age, education and APOE4 status.

Result

There was no sex differences in physical activity levels. GMv and brain perfusion in frontal medial regions were associated with both sex and physical activity, such that volume and perfusion were higher in women than in men and increased as a function of physical activity, without significant interaction between both terms. In contrast, there was an interaction between sex and physical activity on precuneus and posterior cingulate cortex perfusion and, at a trend level, on Aβ deposition (Figure). More specifically, the effect of physical activity on perfusion was stronger in women (higher activity being associated with higher perfusion), while its effect on amyloid burden was stronger in men (higher activity being associated with lower amyloid burden).

Conclusion

Our results suggest that physical activity has both sex‐dependent and sex‐independent effects on markers of brain integrity. Interestingly, the interaction between physical activity and biological sex suggests the existence of different reserve mechanisms in men and women, which might in turn influence their risk of AD.
A HABLE study of the relationship of blood‐based biomarkers of AD and cognition functioning in the cognitively normal: The impact of ethnicity
Authors: Hall James R. , Petersen Melissa , Johnson Leigh Ann , O'Bryant Sid
Published: December 2021

Background

Blood‐based biomarkers of amyloid accumulation (Abeta40, Abeta 42), markers of neurodegeneration (NfL) and markers of neuronal injury (Tau) have all been proposed as biomarkers of early brain changes linked to the development of cognitive impairment and Alzheimer’s disease. The impact of ethnic differences on this relationship has received little attention. The current study examined the relationship of these blood‐based biomarkers to performance on cognitive tests in cognitively normal older Mexican Americans (MA) and Non‐Hispanic Whites (NHW) to assess the impact of ethnicity.

Method

Cognitively normal participants were drawn from a community‐based, longitudinal study of cognitive aging in MAs. 647 MAs (447 females, 200 males) and 644 NHWs (372 females, 272 males) were administered a neuropsychological battery to assess current level of cognitive functioning. Levels of plasma total tau, Abeta 40, Abeta 42and NfL were assayed via Single Molecule Array (Simoa) technology. Data were analyzed using t tests and linear regression.

Result

MAs were significantly younger and had significantly fewer years of education than NHWs. MAs had higher levels of Abeta 40, Abeta 42 and NfL and lower levels of total tau. Regression analyses by ethnicity controlling for age and education revealed no significant relationship between any of the markers and any of the cognitive tests for MAs. Regression analyses for NHWs showed significant relationships between measures of memory, language, processing speed and Abeta 40; executive functions and NfL and attention and tau and Abeta 42.

Conclusion

The results of the current research support the importance of assessing ethnic differences in the relationship of these biomarkers to cognitive functioning. It is likely that other biomarkers may be better predictors of cognitive functioning and cognitive decline for MAs. Further investigation of the nature of the relationship of specific biomarkers to specific cognitive functions in cognitively normal NHWs including neuroimaging is warranted.