bluuebunny/crossref_metadata_2025 huggingface dataset:
Late‐onset epilepsy with unknown etiology: A pilot study on neuropsychological profile, cerebrospinal fluid biomarkers, and quantitative EEG characteristics
Authors: Farotti Lucia , Cesarini Elena Nardi , Babiloni Claudio , Salvadori Nicola , Percio Claudio Del , Pascarelli Maria Teresa , Noce Giuseppe , Lizio Roberta , Da Re Fulvio , Isella Valeria , Tremolizzo Lucio , Romoli Michele , Francesco Jacopo C Di , Parnetti Lucilla , Costa Cinzia
Published: December 2020

Background

Despite epilepsy has been associated with cognitive decline, neuropsychological, neurobiological and neurophysiological features in patients with late‐onset epilepsy of unknown etiology (LOEU) are still unknown. This cross‐sectional study aims at investigating neuropsychological profile, cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD), and resting‐state quantitative electroencephalographic (qEEG) cortical rhythms in LOEU patients with mild cognitive impairment (LOEU‐MCI) and with normal cognition (LOEU‐CN), compared to non‐epileptic MCI (NE‐MCI) and cognitively normal (CN) controls.

Method

Consecutive patients in two clinical Units diagnosed with LOEU‐CN (19), LOEU‐MCI (27), and NE‐MCI (21) were enrolled, and compared to age and sex‐matched cognitively normal subjects (CN, 11). Patients underwent standardized comprehensive neuropsychological evaluation and CSF core AD biomarkers assessment (i.e., CSF Aβ42, phospho‐tau and total tau, classified through A/T/(N) system). Recordings of resting‐state eyes‐closed electroencephalographic (EEG) rhythms were collected and cortical source estimation of delta (<4 Hz) to gamma (>30 Hz) bands with exact Low Resolution Electromagnetic Tomography (eLORETA) was performed.

Result

Most of LOEU patients had MCI status at seizure onset (59%). Patients with LOEU‐MCI performed significantly worse on measures of global cognition, visuo‐spatial abilities and executive functions compared to NE‐MCI patients (p<0.05). Regarding MCI subtype, multiple‐domain MCI was 3‐fold more frequent in the LOEU‐MCI than in the NE‐MCI patients (OR 3.14, 95%CI 0.93‐10.58, p=0.06). CSF Aβ42 levels were lower in the LOEU‐MCI compared with the LOEU‐CN group. Finally, parietal and occipital sources of alpha (8‐12 Hz) rhythms were less active in the LOEU‐MCI than NE‐MCI and CN groups, and the opposite was true for frontal and temporal cortical delta sources.

Conclusion

MCI status was relatively frequent in LOEU patients, involved multiple cognitive domains, and might have been driven by amyloidosis according to CSF biomarkers. LOEU‐MCI status was associated with abnormalities in cortical sources of EEG rhythms related to quiet vigilance. Future longitudinal studies should cross‐validate our findings and test the predictive value of CSF and EEG variables.
Long‐term dietary intervention adherence among individuals with elevated risk of dementia: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)
Authors: Lehtisalo Jenni , Lindstrom Jaana , Ngandu Tiia , Solomon Alina , Laatikainen Tiina , Strandberg Timo , Antikainen Riitta , Tuomilehto Jaakko , Hänninen Tuomo , Soininen Hilkka , Kivipelto Miia ,   FINGER Study Group
Published: December 2020

Background

Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) is a multi‐center, randomized trial that showed beneficial effect on cognition with a multi‐domain lifestyle intervention including nutritional guidance. The aim here is to investigate how dietary changes are maintained after the active intervention period, and if baseline cognitive performance modifies the intervention effect.

Method

Individuals aged 60‐77 years and at risk of dementia were randomly allocated into intervention (n=631) or control (n=629) group for 2 years, with post‐intervention follow‐up visit at 5 and 7 years. Neuropsychological Test Battery was executed and a z‐score for global cognition calculated (14 tests). Three food records during the intervention and one at 7 years were used to calculate FINGER dietary adherence score based on national recommendations (9 goals, higher indicating better adherence). A linear mixed model was used to evaluate association between dietary change, group allocation and baseline cognition dichotomized at the median, adjusting for age, education, sex, study area, BMI, and total energy intake.

Result

Altogether 783 participated at the 7‐year visits. Better baseline cognition predicted 7‐year participation (p<0.01) and food record completion (p<0.01), which was lower than at earlier visits (73%; n=572). Dietary quality improved more in the intervention group compared with the control over the 7‐year period (p<0.01). Baseline cognitive function did not modify the intervention effect on diet during the first years of the study (p<0.05 for the intervention effect in both cognition groups at the 1st and the 2nd year, respectively). On longer term the interaction between baseline cognition and intervention group became significant (p=0.03 at the 7‐year follow‐up), and the intervention effect was especially seen with lower baseline cognition. Dietary quality declined only in the control group participants with lower baseline cognition.

Conclusion

The FINGER dietary intervention showed that beneficial dietary changes are achieved by older individuals and also maintained after the active intervention period. These results indicate that while dietary changes during the intervention are achieved regardless of baseline cognition, people with lower baseline cognition may benefit more in long term, because their dietary quality is more likely to worsen without an intervention.
Looking at competing events through a different lens in dementia research: Examples from the Rotterdam Study
Authors: Rojas‐Saunero Liliana Paloma , Ikram M Arfan , Swanson Sonja
Published: December 2020

Background

Our ability to both ask clear questions and obtain clear answers in dementia research is always challenged by the competing risk of death. For example, we might ask at least two questions: (1) what is the risk of dementia, regardless of risk of death, and (2) what is the risk of dementia if we were able to prevent death during the study period? We aim to demonstrate estimating these quantities in three comparisons: higher vs. lower education, women vs. men, and apoe4 carriers vs non‐carriers.

Method

We used data from individuals over 55 years with no prior history of dementia or cognitive impairment within the Rotterdam Study, a population‐based cohort followed since 1990. To estimate risk of dementia we used inverse probability weighting (IPW) for lost to follow‐up (LTFU) to answer question (1), and for the risk of death, and IPW for death and LTFU for question (2), with our models including time‐updating covariates (systolic blood pressure, body max index, smoking status, development of heart disease, diabetes and cancer). We calculated the risks at each time‐point using pooled logistic regression.

Result

Over 20 years of follow up, 4869 individuals where followed, 657 developed dementia, 1540 died and 1029 were lost to follow up. Regardless of whether we estimated risks for question (1) or (2), individuals with higher education had a lower risk of dementia compared to lower education. In contrast, women had an increased risk of dementia compared to men only when we approached question (2) rather than (1). Apoe4 carriers had an increased risk of dementia compared to the non‐carriers, though risks were lower for question (2) rather than (1).

Conclusion

Estimates for the risk of dementia will always be affected by how we include death in our research question, as demonstrated in our three examples. We will discuss the implications of these research questions, including whether they represent realistic scenarios of clinical or public health interest, and the considerations when conducting such analyses in the presence of competing events.
Harmony: Demographic and baseline characteristics from the 12‐week, open‐label treatment phase
Authors: Foff Erin P. , McEvoy Bradley , Erten‐Lyons Deniz , Sultzer David L. , Stankovic Srdjan
Published: December 2020

Background

Approximately 2.4 million patients in the U.S. experience delusions and hallucinations associated with dementia‐related psychosis (DRP) with no approved therapies. Pimavanserin is a 5HT2A inverse agonist/antagonist approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s disease psychosis. The objective is to examine baseline characteristics from patients with DRP enrolled in the HARMONY study, a pivotal Phase 3, placebo‐controlled, randomized withdrawal study.

Method

Eligible patients with dementia due to Alzheimer’s disease (AD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) or vascular dementia (VaD) with moderate to severe psychosis (SAPS H+D total score ≥10 AND a CGI‐S score ≥4 AND a SAPS H+D global item (H7 or D13) score ≥4) were enrolled into the 12‐week open‐label (OL) period where they received pimavanserin 34 mg once daily. Patients with sustained response to pimavanserin during the OL were randomized into the double‐blind portion of the trial where they received pimavanserin or placebo and were assessed for relapse of psychosis. Demographic and baseline characteristics of the population were summarized.

Result

Of 392 patients enrolled, 66.3% of patients had a most likely clinical diagnosis of AD,15.1% PDD, 9.7% VaD, 7.1% DLB, and 1.8% FTD. A non‐specific dementia diagnosis had been given in the past to 110/390 (28.2%) subjects, and 46.9% had previously used an off‐label antipsychotic for DRP. Most patients had moderate dementia (70.2%), and the mean (SE) duration of cognitive impairment was 4.3 (0.1) years. The population was expectedly frail: at baseline, mean age was 74.5 (0.4) years, 46.4% of patients were taking >5 concomitant medications, and 70.4% had at least 3 comorbid medical conditions. At baseline, mean (SE) scores for SAPS‐H+D, SAPS‐H, SAPS‐D, and CGI‐S were 24.4 (0.47), 14.2 (0.32), 10.2 (0.33), and 4.7 (0.03), respectively; mean (SE) MMSE score was 16.7 (0.24), and 84% had delusions and 79% visual hallucinations. Baseline and disease characteristics by clinical subtype will be summarized.

Conclusion

Baseline characteristics in the open‐label phase of HARMONY indicate target enrollment of patients with the most common neurodegenerative dementias and moderate to severe psychosis consisting mostly of elderly patients with multiple co‐morbidities.
The Israel Registry for Alzheimer's Prevention (IRAP) study of middle‐aged offspring of Alzheimer’s disease patients
Authors: Ravona‐Springer Ramit , Sharvit‐Ginon Inbal , Heymann Anthony , Beeri Michal Schnaider
Published: December 2020

Background

Parental family history of AD is a well‐established risk factor for late onset AD (LOAD). Since AD‐related neuropathology starts decades prior to dementia onset, studying middle‐aged asymptomatic offspring of LOAD patients provides an opportunity to assess the role of genetic, health related, lifestyle and environmental factors in the very earliest stages of the disease course.

Method

The Israel Registry for Alzheimer’s Prevention (IRAP) study follows a cohort of middle‐aged offspring of AD patients (FH+; n=409) and controls (FH‐, i.e. offspring of non‐demented parents; n=104). The study collects detailed cognitive, health‐related, genetic, lifestyle and brain imaging data. Follow‐up waves will be every 3 years. All participants are members of the Israeli HMO‐ Maccabi Health Services, so detailed medical information is available on them since 1998. Here we compare baseline socio‐demographic, lifestyle, health‐related and cognitive data of FH+ vs. FH‐ participants. Comparisons between groups were done using χ2 for categorical variables, ANCOVAs for continuous variables (laboratory and lifestyle) adjusting for age, sex and education, and MANCOVAs for cognitive scores done separately for tests of episodic memory, working memory, executive functions, and language.

Result

Participants characteristics by family history status are presented in Table 1. Mean subjects' age is 54.83 (SD=6.7), 16.47 (SD=3.06) years of education; 35.7% are men; 69% of FH+ have maternal AD. Compared to FH‐, FH+ were younger (p=0.007), more often men (p=0.003) and with higher rates of the Apo E4 allele (p=0.036). Groups did not differ in other laboratory, medical and lifestyle (exercise, alcohol consumption, smoking) variables, depression scores (CES‐D) or rates of subjective memory complaints. FH+ performed worse in episodic memory (F=2.224; p=0.025) and in executive functions (F=2.850; p=0.015) but not in working memory (F=1.172; p=0.322) and language (F=1.210; p=0.303) (Table 2). Additional adjustment for APOE‐4 resulted in loss of significance for episodic memory (F=1.830; p=0.070), while executive functions remained significant (F=2.462; p=0.032).

Conclusion

Asymptomatic middle‐aged offspring of AD patients perform worse on tests of episodic memory and executive functions consistent with a decades‐long prodromal course of disease. APOE4 mediates the association of FH with episodic memory but not with executive functions.
Cerebrospinal fluid proteomic profiles predict progression to dementia in prodromal AD
Authors: Tijms Betty M. , Del Campo Marta , Tomassen Jori , den Braber Anouk , Scheltens Philip , Teunissen Charlotte E. , Visser Pieter Jelle
Published: December 2020

Background

Individuals with mild cognitive impairment (MCI) and abnormal amyloid are at increased risk to develop dementia and are considered to have prodromal Alzheimer’s disease (AD). Still, the precise pathophysiological processes that lead to dementia remain unclear. We studied in prodromal AD whether alterations can be detected in cerebrospinal fluid (CSF) proteomics that are related to progression to dementia.

Method

We selected from the Amsterdam Dementia Cohort 44 individuals with prodromal AD (67±7 years old, 22(44%) female), who had CSF proteomic data measured with Olink multiplex panels. Of 1010 proteins available, 501 (49%) were detected in at least 10 individuals per group and considered for further analyses. To aid interpretation, protein concentrations were Z transformed according to a normal control group (from the EMIF preclinAD study: 56 individuals with normal cognition and normal CSF amyloid and tau (68±6 years old, 28(50%) female) measured within the same experiment. Within prodromal AD, associations of protein levels with progression to dementia were tested with Cox proportional Hazard models, adjusting for p‐tau levels, age and sex. ClueGO was used for biological pathway enrichment analyses.

Result

Fourteen (33%) individuals with prodromal AD developed dementia over 2.6±1.4 years. In total 49 of the 501 proteins were associated with progression to dementia: for 90% of proteins a standard deviation lower concentration was associated with a 2 to 9‐fold increased risk to develop dementia (Figure 1a). Figure 1b shows a progression curve for individuals labelled according to tertiles of a protein summary score combining these proteins, with individuals having low concentrations showing an 4‐fold increased risk to progress to dementia compared to individuals with high concentrations (p<.01). Proteins associated with progression showed enrichment for several biological pathways that clustered together into 6 groups and were associated with regulation of MAPK cascade, angiogenesis, leukocyte activation in immune response, extracellular matrix organisation and regulation of neuronal death (Figure 1c; all pfdr <.05).

Conclusion

Neurodevelopmental pathways, angiogenesis and the leukocyte activation in immune response are involved in early AD pathophysiology and related to subsequent progression to dementia. Furthermore, CSF proteomics may have potential as a stratification tool to select fast decliners within prodromal AD.
Validation and replication of a prognostic machine learning model for enrichment of cognitive decliners in clinical trials
Authors: Dansereau Christian , Laurent César , Tam Angela
Published: December 2020

Background

Identifying individuals who will experience cognitive decline is paramount to evaluating novel treatments in Alzheimer’s clinical trials. We propose to use highly specific neuroimaging and genetic signatures that are indicative of the risk of cognitive decline in individuals with mild Alzheimer’s disease and mild cognitive impairment.

Method

Baseline measurements of gray matter volumes, from structural magnetic resonance imaging, APOE4 status, age and sex were provided to a machine learning prognostic enrichment solution Cog‐Foresight from Perceiv Research Inc. Canada to identify signatures of individuals at risk of cognitive decline up to two years of follow‐up. The resulting three cohorts of individuals were: (a) low‐risk, (b) moderate‐risk, (c) high‐risk of decline according to the enrichment tool. ADAS‐cog11, CDR‐SB and MMSE were used as clinical endpoints to evaluate the trajectory of each cohort. The prognostic tool was evaluated on three independent datasets: ADNI1 (n=345), ADNI2 (n=238) [1], and the placebo arm of an 18‐month Phase 3 study in mild AD (n=110).

Result

From the 693 individuals selected from the three datasets, 40% were deemed low‐risk and 23% were deemed high‐risk. In ADNI1, the mean rate of change at 18 months from baseline for the CDR‐SB for the low‐, moderate‐, and high‐risk groups were 0.51 points, 1.08 points, and 1.83 points, respectively. In ADNI2, the mean rate of change at 18 months from baseline for the CDR‐SB for the low‐, moderate‐, and high‐risk groups were 0.09 points, 0.57 points, and 1.79 points, respectively. In the Phase 3 study, the mean rate of change at 18 months for the CDR‐SB for the low‐, moderate‐, and high‐risk groups were 0.5 points, 0.88 points, and 2.04 points, respectively. Similar trajectories and conclusions were found for all other endpoints.

Conclusion

The use of multimodal biomarkers with a machine learning‐based targeted selection was successful in identifying a sub‐cohort that will, on average, have a higher rate of decline than the rest. The proposed identification of decliners has the potential of reducing trial costs by minimizing the enrolment of cognitively stable individuals into trials. Reference: (1) The ADNI1 and ADNI2 datasets were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu).
Between‐country harmonization and differences of the Lifetime of Experiences Questionnaire (LEQ) for lifespan complex mental activity assessment
Authors: Ourry Valentin , Marchant Natalie L , Schild Ann‐Katrin , Wirth Miranka , Coll‐Padros Nina , Reyrolle Leslie , Bachelet Romain , Whitfield Tim , Demnitz‐King Harriet , Boton Maëlle , Lebahar Julie , Gonneaud Julie , Molinuevo Jose Luis , Rauchs Géraldine , Vivien Denis , Sayette Vincent De , Valenzuela Michael , Chetelat Gael , Arenaza‐Urquijo Eider M. ,   Medit‐Ageing Research Group
Published: December 2020

Background

The Lifetime of Experiences questionnaire (LEQ, Valenzuela and Sachdev, 2007) is an instrument that comprehensively assesses mental activity (education/occupation and leisure activities) across the lifespan (13‐30, 30‐65, 65‐present). The LEQ has been associated with brain health outcomes and cognitive decline. Challenges for the use of this questionnaire across countries include the different education systems and occupation classifications. The objectives of this study were to (1) harmonize the LEQ across Spain, United Kingdom (UK), France and Germany, (2) assess its correlation with a similar tool and (3) assess between‐country differences.

Method

The LEQ was administered to 359 cognitively unimpaired older adults (age: 71.2 ± 6 years, education: 13.2 ± 3.5 years) from IMAP+ and Medit‐Ageing European projects. The original scale was translated from English to Spanish, French and German by a professional translation service and iteratively edited by native speakers. Education systems and classification of occupations were harmonized considering between‐country differences and in line with international guidelines. Scoring guidelines were adapted to allow between‐country comparison. We performed Pearson correlations with a similar instrument, the Cognitive Activities Questionnaire (CAQ, Wilson et al., 2003). Between‐country differences were assessed using ANOVA models.

Result

There were no between‐country differences in participant’s age and education (p>0.1). Between and within countries, the total LEQ score showed moderate to strong associations with the total CAQ score (full sample: r=0.48, Spain: r=0.74, UK: r=0.56, France: r=0.46, all p<0.001; Germany: r=0.41, p<0.05) (Figure 1). Correlation coefficients between the CAQ and LEQ were stronger within (all r>0.35) than between (all r≤0.35) periods. We observed between‐countries differences in lifespan mental activities (p=0.019, Spain > France and Germany > France), notably, during young adulthood (p=0.01, Germany > France) and late life (p=0.01, Spain > UK, Spain > France) (Figure 2). These differences were explained by leisure activities engagement rather than by differences in education and occupation (p<0.001, Young adulthood and Midlife: Spain > UK & France, Germany > France; Late life: Spain > UK & France & Germany) (Figure 3).

Conclusion

The harmonized LEQ allowed comparison of complex mental activities ‐ including education and occupation ‐ across countries and was related to another questionnaire measuring mental activity across the lifespan.
Sex and sex hormones largely explain associations between glucose levels and brain atrophy in AD‐sensitive regions
Authors: Pappas Colleen , Wang Qian , Klinedinst Brandon S. , Le Scott T. , Pollpeter Amy , Larsen Brittany , Willette Auriel A.
Published: December 2020

Background

High glucose levels are related to worse cognitive performance and brain health in AD‐sensitive regions. Sex hormones are thought to be a protective factor against hyperglycemia and many of its sequelae, where menopause and andropause in mid‐life lead to pronounced decreases in sex hormone secretion. It is unknown if sex and sex hormones modulate relationships between high glucose and regional brain atrophy or cognitive performance.

Method

The study consisted of 15,506 participants from the UK Biobank with complete brain volume, blood glucose measures, and demographic data. Multiple linear regression models tested relationships between fasting serum glucose and key brain regions of interest. Covariates included age, sex, intracranial volume, white matter hyperintensity load, and education in lieu of intracranial volume for cognition outcomes. To examine sex differences, moderation analyses were conducted. The sample was also separated by sex to test sex hormone by blood glucose interactions for the brain volume and fluid intelligence measures.

Result

For the overall sample, higher glucose or glycated hemoglobin (Hba1c) levels were associated with less total grey matter and regional grey matter in amygdala and parahippocampus. Higher Hba1c levels also predicted poorer fluid intelligence performance. Sex interactions indicated that higher HbA1c levels were related to relatively more brain atrophy among men in the hippocampus and amygdala. Due to these observations, testosterone and oestradiol levels were tested as moderators in a subset of participants with available data (n=13,858). Hormone levels only among women impacted blood glucose and brain volume relationships. Higher oestradiol and testosterone levels led to more atrophy in hippocampus and amygdala per unit increase in glucose levels.

Conclusion

In general, higher glucose levels were associated with poorer neural and cognitive outcomes. Men showed this relationship more strongly, but not due to sex hormone levels. Comparatively, sex hormones in women largely accounted for detrimental glucose associations with AD‐sensitive brain regions. Future research should examine other mechanisms that may explain sex differences observed with glucoregulatory function and brain health.
Plasma levels of an N‐terminal tau fragment are highly associated with future cognitive decline and neurodegeneration in clinically normal elderly
Authors: Chhatwal Jasmeer P. , Schultz Aaron P. , Dang Yifan , Ostaszewski Beth , Liu Lei , Yang Hyun‐Sik , Johnson Keith A. , Sperling Reisa A. , Selkoe Dennis J
Published: December 2020

Background

Advances in high‐sensitivity biofluid assays have accelerated the development of novel tools to study Alzheimer's disease (AD) pathobiology. Recent work demonstrates levels of an N‐terminal fragment of tau (NT1), measured in cerebrospinal fluid or plasma, can differentiate clinically‐normal people from those with clinically‐evident AD with high sensitivity and specificity. However, the potential of plasma NT1 to capture the earliest, preclinical signs of AD remains unclear. Accordingly, we examined the potential for plasma NT1 to predict prospective cognitive decline and neurodegeneration in a large, longitudinal cohort of clinically‐unimpaired elderly at‐risk of future cognitive decline.

Method

Baseline plasma samples from participants in the Harvard Aging Brain Study (n=236) were assayed for NT1 and neurofilament light (NfL) using single‐molecule array (Quanterix Simoa). Baseline NT1 and NfL were assessed alone or interactively with β‐amyloid (11C‐Pittsburgh C‐mpound‐B PET; PiB‐PET) as predictors of longitudinal cognitive decline (Preclinical Alzheimer's Cognitive Composite; PACC) and neurodegeneration (vMRI) using linear mixed effects models. In participants with available longitudinal 18F‐Flortaucipir PET (FTP‐PET), we assessed plasma NT1 as a potential predictor of tau neurofibrillary tangle accumulation.

Result

Greater plasma NT1 at baseline was highly predictive of greater cognitive decline during longitudinal follow‐up (median 5.04+/‐0.99 yr; p<0.0001; Figure 1). This effect was synergistic with baseline β‐amyloid burden (p<0.005). Greater NT1 was also associated with greater decreases in cortical gray matter and hippocampal volumes. In the subset of participants with longitudinal tau PET, plasma NT1 levels at the time of initial tau PET were predictive of increases in temporal tau PET signal over time in people with high b‐amyloid burden. Baseline plasma NT1 levels were strongly associated with neurofilament light chain (NfL) levels, but NfL was a much weaker predictor of future cognitive decline in this preclinical cohort.

Conclusion

These results suggest plasma NT1 may be a novel, non‐invasive, and inexpensive biomarker that captures risk of imminent cognitive decline and neurodegeneration even in unimpaired, at‐risk elderly. The pattern of results further suggests NT1 may be a powerful compliment to existing biomarkers of β‐amyloid burden, as we observed synergistic associations between NT1 and β‐amyloid PET in predicting neurodegeneration, cognitive decline, and tau accumulation.
Human brain and serum advanced glycation end products are highly correlated: Preliminary results of their role in Alzheimer’s disease and type 2 diabetes
Authors: Uribarri Jaime , Buchman Aron S , Cai Weijing , Haroutunian Vahram , Beeri Michal Schnaider
Published: December 2020

Background

Serum levels of advanced glycation end products (AGEs), a large group of pro‐oxidant and pro‐inflammatory compounds, particularly carboxymethyl lysine (CML) and methylglyoxal (MG), are generated endogenously and by dietary consumption2. Accumulating evidence suggests that modifying dietary AGEs consumption might affect the accumulation of AD pathology and dementia especially those with type 2 diabetes (T2D). However, there is a paucity of human data about the relationship of serum and brain levels of AGEs in older adults.

Method

AGE levels were measured in serum and tissue from superior temporal gyrus of four groups of decedents: T2D+AD (N=6); T2D/no AD (N=10); no T2D+AD (N=10), and no T2D/no AD (N=10). T2D was defined by medical records (diagnosis of T2D or use of T2D medications). CERAD criteria classified pathologic diagnosis of AD. Participants with stroke were excluded. Diagnoses of hypertension and myocardial infarction were defined by ICD9. Frozen brain samples were thawed and AGE protein content was determined by competitive ELISA for MG‐H1 (3D11 mab) and CML (4G9 mab).

Result

Analyses of variance demonstrated that adults with AD were older but postmortem interval and sex were similar in all four groups (see Table). The groups significantly differed in levels of serum MG, brain MG, and serum CML such that consistently the T2D+AD group had the highest levels of AGEs while the no T2D/no AD group had the lowest. There were strong correlations between serum and brain CML levels (r=0.64; p<0.0001) and MG levels (r=0.59; p<0.0001)‐See Figure; higher levels in serum were associated with higher levels in the brain. Adjusting for each of the demographic or cardiovascular variables did not alter the results.

Conclusion

This study demonstrates strong and significant relationships between serum and brain AGE levels; the highest brain levels of AGEs were found in participants who had both T2D and AD. We have previously shown similar findings in mice, but we believe this is the first demonstration of such associations in humans. This was a small cross‐sectional study and the findings need to be replicated in a larger clinico‐pathological longitudinal study, which is currently ongoing, and will provide new data at AAIC2020.
Incidence of subjective cognitive decline is associated with amyloid‐β pathology, whereas stability relates to neurodegeneration
Authors: Sánchez‐Benavides Gonzalo , Grau‐Rivera Oriol , Suárez‐Calvet Marc , Milà‐Alomà Marta , Niñerola‐Baizán Aida , Perissinotti Andrés , Salvadó Gemma , Arenaza‐Urquijo Eider M. , Gispert Juan Domingo , Vilor‐Tejedor Natalia , Sala‐Vila Aleix , Crous‐Bou Marta , González‐de‐Echávarri José Maria , Minguillón Carolina , Fauria Karine , Cacciaglia Raffaele , Operto Greg , Falcon Carles , Kollmorgen Gwendlyn , Zetterberg Henrik , Blennow Kaj , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

Background

Subjective Cognitive Decline (SCD) is a risk factor for cognitive decline and increases the likelihood of abnormal Alzheimer’s disease (AD) biomarkers. A set of SCD features (SCDplus) has been proposed to be more strongly related with AD pathology, like onset within 5 years. Limited evidence suggest that there is an association between recent SCD onset and amyloid‐β (Aβ) levels but longitudinal studies exploring this association are lacking. Our objective was to explore the association between incidence and stability of SCD and biomarkers of AD pathology, synaptic dysfunction and neurodegeneration.

Method

We analyzed clinical, neuroimaging and cerebrospinal fluid (CSF)‐biomarkers data from 261 cognitively unimpaired individuals from the ALFA+ study [mean age 57(5) at baseline]. SCD status was recorded at baseline and follow‐up [mean interval 48.5(8.6) months, 80% before 60 months] using the SCD‐Q question: Do you perceive memory or cognitive difficulties? Individuals were classified as Stable‐SCD [SCD at both visits (n=28)], Incident‐SCD [SCD only at follow‐up (n=44)], Unstable‐SCD [SCD only at baseline (n=21)], and non‐SCD [no SCD at any visit (n=168)]. All remained cognitively unimpaired at follow‐up. We defined amyloid status by visual reads (Aβ+/Aβ‐) from [18F]flutemetamol PET scans. Aβ40, Aβ42, p‐tau, t‐tau, neurogranin and Neurofilament Light (NfL) were measured with Roche NeuroToolKit and Elecsys® immunoassays (Roche Diagnostics). Logistic regression models were used to predict Aβ status and ANCOVA models to explore differences in biomarkers, adjusting for age, sex and interval between visits.

Result

The proportion of Aβ+ individuals was higher in Incident‐SCD as compared to non‐SCD (OR=2.5, p=0.04, Table 1). Further, Incident‐SCD group displayed lower Aβ42/Aβ40 than non‐SCD (p=0.02, partial Eta2=0.02). While Stable‐SCD did not show differences in amyloid measures as compared to controls, NfL was significantly increased (p<0.0001, p‐Eta2=0.08) and t‐tau approached significance (p=0.08).

Conclusion

Recent SCD onset was associated with amyloid‐β pathology, while stable SCD, even without clinical progression, was associated to biomarkers of neurodegeneration but not to amyloid pathology. These results support the usefulness of the onset in the last 5 years as SCDplus feature to detect amyloid pathology, while also highlights the role of neurodegeneration in SCD maintenance.
Development of the Snellen Memory Test (SMT): An episodic memory test to screen for AD risk in a clinical optometry/ophthalmology setting
Authors: Aker Ryan , Arthur Edmund , Thompson Louisa I , Maruff Paul T , Snyder Peter J , Alber Jessica
Published: December 2020

Background

Although we have been working to discover and validate retinal imaging biomarkers for preclinical AD risk, the cognitive assessment of episodic memory function remains the most commonly relied on screening approach. Here, we sought to develop a brief screening test for episodic memory, to augment retinal biomarkers in the early detection of AD. By relying on the standard Snellen Eye Chart as the stimulus field, we aim to create an instrument that can be seamlessly incorporated into standard clinical optometry/ophthalmology practices. This pilot study sought to identify episodic memory questions of equivalent difficulty, based on the Snellen Eye Chart, that can eventually be scored using a mobile application.

Method

12 cognitively normal (CN) older adults (24‐56 years) completed the SMT, consisting of 2 x 11 question forms, with both free‐ and cued‐recall components: one form immediately after encoding and one form after a 20‐minute delay. Item analysis was performed for each test question at immediate and delayed recall, and the mean difficulty index (DI) of all questions was computed along with a 95% confidence interval (CI).

Result

The mean DI for all questions at immediate recall was 0.66 (95% CI: 0.53‐0.79) with two questions falling below the 95% CI lower bound (0.53). The mean DI at delayed recall was 0.70, (95% CI: 0.57, 0.82) with one question falling below and one falling above the 95% CI upper bound. We eliminated 4 questions, leaving a pool of 18 questions of equivalent difficulty at immediate and delayed recall.

Conclusion

Many of the items for the SMT were moderately difficult for CN individuals. These questions may be further developed to screen for AD risk in CN older adults in a clinical setting. We are currently collecting data in a cohort (N=100) of CN older adults (55‐80) at both low‐ and high‐risk for preclinical AD, which will be used to further refine this novel memory test. Our next step is to validate the SMT against gold standard neuropsychological assessments of episodic memory, and to examine the added prognostic value of this test in conjunction with our panel of retinal imaging AD risk biomarkers.
Cross‐sectional and longitudinal associations of white matter hyperintensities and cortical thickness in the biomarkers of Alzheimer’s Disease in Down Syndrome (ADDS) study
Authors: Lao Patrick J , Luo Linggang , Igwe Kay C , Rizvi Batool , Sathishkumar Mithra , Rosas H. Diana , Lai Florence , Mapstone Mark , Head Elizabeth , Silverman Wayne , Lott Ira T , Schupf Nicole , Yassa Michael A , Brickman Adam M
Published: December 2020

Background

There is a general consensus that cerebrovascular change plays a role in the clinical presentation of Alzheimer’s disease (AD) but considerable debate about its role in disease pathogenesis. Adults with Down syndrome (DS), like those with autosomal dominant mutations for AD, develop AD pathology and symptoms by their 40s and 60s, respectively. Unlike the general population, individuals with DS have low prevalence of classical vascular risk factors, like hypertension, but high prevalence of cerebrovascular disease in AD. We examined the association of cerebrovascular disease and cortical thinning in adults with DS.

Method

To date, 66 adults (50±7yrs, 38% women, 33% MCI‐DS/dementia) enrolled in the ADDS study have undergone longitudinal processing of MRI (1.3±2yrs follow‐up) and clinical evaluation at three US sites. The ADDS study is a natural history study investigating biomarkers relevant to the transition into dementia in older adults with DS. Participants were classified as cognitively‐stable, MCI‐DS, possible AD dementia, definite AD dementia, or indeterminate based on consensus conference diagnosis. Cerebrovascular disease was operationally‐defined as white matter hyperintensity (WMH) volume measured at baseline. Neurodegeneration was defined as cortical thickness, measured with FreeSurfer at baseline and follow‐up. We examined the association of baseline WMH with baseline and longitudinal [%/yr] cortical thickness.

Result

Cross‐sectionally, there was higher cortical thickness in cognitively‐stable individuals in the parietal lobe compared with MCI‐DS/dementia (p=0.02). Higher global WMH was associated with lower global cortical thickness (p=0.004), mostly driven by parietal and frontal lobe WMH distributions. The association of WMH with global cortical thickness was stronger among MCI‐DS/dementia than in cognitively‐stable (interaction; p=0.04). Longitudinally, higher baseline global WMH was associated with faster cortical thinning in cognitively‐stable compared with MCI‐DS/dementia (interaction; p=0.02), such that there was observable cortical thinning with WMH in cognitively‐stable compared to little‐to‐no cortical thinning with WMH in MCI‐DS/dementia.

Conclusion

Higher WMH burden is associated with lower cortical thickness in adults with DS, particularly in parietal lobe and among those with MCI‐DS/dementia. However, higher WMH burden is more strongly associated with cortical thinning in those who are cognitively‐stable, suggesting that effect of vascular disease on neurodegeneration occurs prior to the onset of cognitive symptoms.
The effects of Mediterranean diet on memory and Alzheimer's disease biomarkers
Authors: Ballarini Tommaso , Schröder Alina , van Lent Debora Melo , Wolfsgruber Steffen , Priller Josef , Teipel Stefan J , Buerger Katharina , Laske Christoph , Peters Oliver , Wiltfang Jens , Düzel Emrah , Spottke Annika , Perneczky Robert , Fließbach Klaus , Schneider Anja , Heneka Michael T , Jessen Frank , Wagner Michael
Published: December 2020

Background

In the absence of effective therapies against Alzheimer's disease (AD), the identification of modifiable risk/protective factors is crucial. Many studies have shown the influence of diet on aging and diseases of late life, including neurodegenerative disorders. However, the mechanisms underlying these effects are largely unknown. Here we investigated the effects of Mediterranean diet (MD) on memory performance and on biomarkers for AD in a large cohort of non‐demented individuals from the German multicenter Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Specifically, we aimed to test if the know association between adherence to MD and improved memory is mediated by effects on hippocampal volume and biomarkers of AD pathology in cerebrospinal fluid.

Method

The sample included memory clinic patients with subjective cognitive decline (n=235) or mild cognitive impairment (n=100), cognitively normal siblings of AD patients (n=56), and healthy volunteers (n=179). A MD score was computed for each subject by means of an established Food Frequency Questionnaire. Linear regression models adjusted for age, gender and education were run to investigate the association between MD and 1) memory performance, 2) total‐tau, phosphorylated‐tau and amyloid‐beta 42 levels from cerebrospinal fluid and 3) bilateral hippocampal volumes obtained via segmentation of 3T MRI data in Freesurfer.

Result

Overall, higher MD scores were associated with better memory function, lower levels of total and phosphorylated tau proteins and increased volume in bilateral hippocampi. In contrast, no significant effects of MD on amyloid were identified. Subsequent mediation analyses revealed that the effect of MD on memory performance was mediated by both hippocampal volumes and tau protein levels.

Conclusion

Our results support the view of Mediterranean diet as a protective factor against memory decline and AD‐related neurodegeneration. Moreover, we propose that MD acts on hippocampal volume and tau protein accumulation, which in turn leads to preserved memory performance. Further studies are needed to validate and expand our findings, especially investigating the effects of specific combinations of nutrients and their interplay with AD‐biomarkers and cognitive decline during follow‐up.
Six‐month decline in language, but not other cognitive domains, identifies increased risk of conversion from MCI to AD in ADNI
Authors: Tommet Douglas , Choi Seo‐Eun , Rabin Laura , Sikkes Sietske A.M. , Jutten Roos J. , Grandoit Evan , Foldi Nancy , Jones Richard N. , Lamar Melissa , Gibbons Laura E. , Mukherjee Shubhabrata , Lee Michael L. , Sanders R. Elizabeth , Saykin Andrew J. , Trittschuh Emily H. , Mez Jesse , Risacher Shannon L. , Crane Paul K. ,   the Alzheimer's Disease Neuroimaging Initiative
Published: December 2020

Background

Identifying people with MCI at greatest risk of AD conversion is an important research goal. Our objective was to determine whether changes in domain‐specific cognitive functioning over 6 months could identify people at greatest risk of AD conversion.

Method

We used modern psychometric methods applied to the ADNI cognitive battery to develop composite scores for memory, executive functioning, language, and visuospatial functioning. We considered scores at baseline and 6‐month visits for the 809 participants who had prevalent MCI in ADNI1, ADNIGO, and ADNI2, and characterized people based on quartiles of 6‐month changes in each domain. We used Cox models to determine whether 6‐month changes for each domain associated with risk for conversion to AD. We compared 6‐month changes to APOE genotype and the AD CSF biomarker signature, controlling for age, sex, and years of education.

Result

305 participants (38%) had zero bottom quartile change scores (most decline); 296 (37%) had one; 138 (17%) had two; 60 (7%) had three; and 10 (1.2%) had all four. Cox model results for 6‐month changes in all four domains without and with APOE genotype are shown in Table 1. There were 173 people with CSF results to characterize the AD biomarker signature. Cox results are shown in Table 2. Compared to people in the top quartile for 6‐month language change (most learning), people in the bottom quartile (most decline) were at increased risk of AD conversion, independent of APOE genotype and the AD biomarker signature. For 6‐month memory change, the hazard ratio for the bottom quartile (most decline) was attenuated when APOE genotype was included in the model, and it was null when the CSF biomarker signature was included. 6‐month changes in executive functioning and visuospatial functioning were not associated with risk of AD conversion.

Conclusion

6‐month changes in language identify people with MCI at highest risk of AD conversion. This effect is not explained by APOE genotype or CSF biomarkers. 6‐month language scores may identify people to target in AD prevention trials.
Functional status among community‐dwelling older adults is determined by cognitive status
Authors: Gray Michelle , Gills Joshua L. , Glenn Jordan M. , Madero Erica N. , Hall Aidan , Fuseya Nami , Vincenzo Jennifer , Bott Nicholas T.
Published: December 2020

Background

Since 2008, the number of older adults has increased by 34% and is expected to nearly double by 2060. Among US older adults over 70 years of age, 22‐30% report difficulty performing at least one activity of daily living (ADL). ADL performance is associated with functional fitness parameters. Negative longitudinal changes in functional performance among older adults are associated with cognitive decline and may be able to predict future cognitive impairment. Thus, it is imperative to understand the influence of cognition on functional fitness among older adults.

Method

84 older adults (80.9+5.4 years) consented to have their functional fitness and cognition assessed. Functional fitness parameters included the following assessments: Short Physical Performance Battery (SPPB), 10‐meter walk (habitual and fast), dual‐task (habitual and fast), power chair stand assessment (average and peak power and velocity). Cognition was assessed using the Montreal Cognitive Assessment (MoCA) and a digital Visual Paired Comparison (VPC) task. Categories of low and high cognitive function were determined using the VPC results. A one‐way ANOVA was conducted to determine differences between cognitive groups.

Result

Participants with high cognitive performance scored significantly better on the SPPB, 10‐meter fast walk, dual‐task fast condition, and average velocity during the power chair stand assessment. SPPB scores were 10.2% lower among older adults with low cognitive performance (p = .04). The high cognition group walked 16.5% (0.16 m/s) faster when compared to the low cognitive group (p = .04). Dual‐task (fast) performance was 13.2% slower among the low cognition group (p = .03). Additionally, low cognitive older adults moved 16.7% slower when rising from a seated position during the power chair stand task (p = .01). MoCA was 2.76 points lower among the low cognition group (p < .001).

Conclusion

Based on the current results, a relationship exists between functional fitness and cognitive performance in older adults. However, it remains unknown whether functional fitness can influence cognition or vice versa and how these impact ADL performance. Future research is warranted to determine if and how the relationship between cognitive function and functional fitness changes over time in older adults.
The impact of creative engagement in museum activities on the well‐being of people living with dementia, their carers, and family members: The arts programming “Susitikime muziejuje” case in Lithuania
Authors: Petkutė Ieva , Karpavičiūtė Simona
Published: December 2020

Background

Caring for people living with dementia presents profound challenges to families and society, and the growing global burden is vastly underestimated. WHO (2019) recommends to integrate the arts in the social care and health sectors to support health and well‐being throughout the life course and across the continuum of care. In museum programming “Susitikime muziejuje we are tackling this challenge by developing cross‐sectorial partnerships that create access to the art for people living with dementia, their carers and family members.

Method

The programme “Susitikime muziejuje” includes training for museum staff, museum tours, workshops in residential care settings and the evaluation of the programme’s impact on the well‐being of people living with dementia, their carers and family members. Evaluation carried out in 2019 included observation of the museum activity sessions and focus group interviews with the participants after the sessions. The qualitative data was analysed using the thematic analysis.

Result

The project “Susitikime muziejuje“ in Lithuanian Art museums provides opportunity for people living with dementia, their carers and family members to engage in art activities. The programme created a platform to experience the art in a safe, failure free and friendly environment; stimulated learning and self – expression in equal participation; increased self‐esteem; helped to relax; enhanced participants’ mood while experiencing a meaningful and joyful here and now moment; increased a sense of community and improved communication. Participants experienced a range of positive emotions, learned new things about each other with no negative experiences of the participation in the programme were stated.

Conclusion

Museum arts programme “Susitikime muziejuje” had a positive impact on the well‐being of people living with dementia and their carers. The study contributes to the research in dementia care and supports the evidence the cultural sector can play an active role in cross‐sectorial partnerships development and supporting person‐centered approach in dementia care.