bluuebunny/crossref_metadata_2025 huggingface dataset:
Reproducibility of applying multiple statistical analyses to data from the TRAILBLAZER‐ALZ clinical trial of donanemab in early symptomatic Alzheimer's disease
Authors: Sparks JonDavid , Lo Albert C. , Evans Cynthia Duggan , Chatterjee Saptarshi , Andersen Scott W. , Sims John R. , Brys Mirek , Mintun Mark A
Published: December 2021

Background

The Mixed Model for Repeated Measures (MMRM) is the most frequently used statistical analysis for clinical trial endpoints in Alzheimer’s disease (AD) but has the limitation of not efficiently leveraging data from intermediate time points due to the flexibility in the mean structure. In the TRAILBLAZER‐ALZ trial, donanemab, a humanized IgG1 antibody specifically targeting brain amyloid plaque, slowed disease progression in individuals with early symptomatic AD. The aim of this presentation is to apply different statistical models to clinical scale data gathered from this trial, as consistent conclusions following multiple methods would strengthen confidence in the results.

Method

TRAILBLAZER‐ALZ (NCT03367403) was a randomized, placebo‐controlled, double‐blind, multi‐center Phase 2 study assessing the safety, tolerability, and efficacy of donanemab in patients with early symptomatic AD. The change from baseline to 76 weeks was assessed using the Integrated AD Rating Scale (iADRS), a composite tool measuring cognition and daily function (primary endpoint), and the Clinical Dementia Rating Scale‐Sum of Boxes (CDR‐SB; secondary endpoint). In addition to MMRM, three statistical models were fit: Bayesian Disease Progression Model (DPM), Natural Cubic Spline (NCS) model, and Quadratic Mixed Model (QMM). Each model has unique assumptions and data handling, for example, in treating time categorically or continuously, which can lead to differences in power while still controlling the false‐positive rate to an allowable margin.

Result

The percent slowing estimates and treatment differences at 18 months from the models are consistent in supporting a positive treatment effect across the clinical scales. The DPM, NCS, and QMM provide a reduction in the standard error, which leads to tighter intervals due to the model assumptions generally being met.

Conclusion

The consistency of the results between the statistical models and across the clinical scales suggests the general robustness and strength of the data, regardless of the statistical model used. DPM, NCS, and QMM may provide a more detailed estimate of the longitudinal trajectory of each treatment group when there are small sample sizes and noisy data, and an MMRM model may not be an ideal choice in trial designs that may have sparse data at later time points.
Association of neighborhood‐level socioeconomic advantage with cognition and dementia risk factors in an Australian cohort
Authors: Cavuoto Marina G , Rowsthorn Ella , Lavale Alexandra , Yassi Nawaf , Maruff Paul T , Buckley Rachel F , Lim Yen Ying , Pase Matthew P
Published: December 2021

Background

Residing in areas of low socioeconomic advantage is associated with increased risk of dementia1 and associated brain pathology2,3. Given the long and insidious course of dementia pathologies, it is critical to establish the effect of ‘exposomic’ risk factors in midlife and to understand which groups of people are particularly vulnerable. Therefore, the objective of this study was to examine whether cognitive performance or dementia risk factors differed according to neighborhood‐level socioeconomic advantage in cognitively normal middle‐aged people.

Methods

Our sample comprised 4798 participants from the Healthy Brain Project, an online cohort of community‐dwelling Australians aged 40‐70 years. Socioeconomic advantage was computed by matching participants’ residential address to the Australian Bureau of Statistics’ Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD), assigning each participant a decile score (10 being the most advantaged). Scores were related to dementia risk estimated using the CAIDE dementia risk score and cognitive performance measured with the Cogstate Brief Battery (CBB) in linear regression models.

Results

Of the 4798 participants (mean age±SD 56±7 years, 26% male), 2762 (58%) were classified as living within an area of high neighbourhood socioeconomic advantage (IRSAD scores ≥ 8th decile), 1296 resided in rural or regional areas (27%), and 984 identified as “non‐European” (21%). Each decile unit increase in neighborhood socioeconomic advantage was associated with a lower CAIDE dementia risk score (β±SE= ‐0.088±0.024, p <0.001), following adjustments for race and rurality, and with better memory performance (β±SE= 0.084±0.024, p <0.001), following adjustments for age, sex, race, education, and rurality. An interaction was observed with differences in memory performance between levels of neighborhood advantage (comparing scores above and below the 8th decile) being larger at older ages and in people with higher dementia risk scores (Figure 1). There was no association between neighborhood‐level advantage and attention.

Conclusions

In a middle‐aged Australian cohort, higher neighborhood‐level socioeconomic advantage was associated with superior memory and lower dementia risk scores. Efforts to lower dementia risk factors, particularly in relation to reducing the negative impacts of disadvantage, are needed to curtail the growing burden of dementia.
Clinical performance of the beta‐amyloid 1‐42/1‐40 ratio determined from automated Lumipulse G1200 cerebrospinal fluid Abeta1‐42 and Abeta1‐40 assays, assessed by concordance with PET imaging status
Authors: Winslow John W. , Martone Robert L. , Badal Youssouf W. , Chenna Ahmed W. , Cai Suqin W , Sperinde Jeff W. , Ayonke Jeric W. , Vergara Jamie , Yee Brandon W. , Spiro Lisa W. , Ozegovich Terri , Nisenbaum Laura , Petropoulos Christos W.
Published: December 2021

Background

β‐amyloid measured in cerebrospinal fluid (CSF) has been widely used to assess Alzheimer’s disease (AD) patients. Reduced concentrations of Aβ1‐42 (Aβ42) in CSF are inversely correlated with increased retention of Aβ tracers in brain amyloid plaques observed with positron emission tomography (PET). Multiple studies, including those applying automated immunoassay platforms, have reported increased diagnostic accuracy of the CSF Aβ1‐42/Aβ1‐40 ratio (Aβ42/Aβ40 ratio) over Aβ42 levels alone. In the present study, the concordance between calculated CSF Aβ42/Aβ40 ratios derived from individual Lumipulse G1200 CSF Aβ42 and Aβ40 assays and PET imagining status was determined utilizing a well characterized patient cohort.

Method

A subset of n=171 patient CSF samples from the Australian Imaging, Biomarkers and Lifestyle study (AIBL), and n=24 samples from an independent study cohort were included for a total of n=195 patients having amyloid PET status. Amyloid PET‐positivity was 51%. Clinical diagnosis groups included AD (n=43; 95% PET+), mild cognitive impairment (MCI; n=46; 67% PET+); subjective memory complainers (SMC; n=59; 39% PET+), non‐memory complainers (NMC; n=45; 9% PET+), and non‐AD dementia (frontotemporal dementia; n=2; 0% PET+). CSF Aβ42 and Aβ40 were measured with analytically validated Lumipulse G1200 immunoassays (Fujirebio Diagnostics), performed by state‐certified laboratory scientists under CLIA conditions, and the ratio calculated. An optimal cutoff for the Aβ42/Aβ40 ratio was determined from the maximal Youden J index.

Result

The median Aβ42/Aβ40 ratios for PET+ (0.088) and PET‐ (0.042) patient groups were significantly different (Wilcoxon p<0.001). An optimal Aβ42/Aβ40 ratio cutoff of 0.058 was determined, resulting in a sensitivity, specificity, PPV and NPV of 96.0% (CI 90.0%‐98.4%); 96.9% (CI 91.2%‐98.9%), 96.9% (CI 91.3%‐98.9%), and 95.9% (CI 89.9%‐98.4%), respectively. Receiver operating characteristics area under the curve (ROC‐AUC) was 0.968.

Conclusion

Excellent concordance was observed between amyloid PET status and Aβ42/Aβ40 ratio determined from Lumipulse G1200 assays, including results from patients diagnosed with earlier stage disease. The sensitivity and specificity of the CSF Aβ42/Aβ40 ratio determined with the Lumipulse system, together with high analytical performance, support its clinical utility as a biomarker of amyloid status and clinical assessment.
Inflammatory biomarkers in patients undergoing therapeutic plasma exchange with albumin replacement as a treatment for Alzheimer’s disease
Authors: Ortiz Ana Maria , Minguet Carla , Gonzalo Ricardo , Núñez Laura , Ruiz Agustin , Lopez Oscar L. , Boada Mercè , Páez Antonio , Costa Montserrat
Published: December 2021

Background

Increasing evidence suggests that Alzheimer’s disease (AD) pathogenesis is not restricted to the neuronal compartment but would involve peripheral inflammatory mechanisms that contribute to cognitive impairment. The AMBAR phase 2b/3 trial is a therapeutic approach for mild‐moderate AD patients (MMSE:18‐26) based on a 14‐month program comprising 18 plasma exchange with albumin replacement (PE‐Alb) to remove neurotoxic Aβ and other pathological substances from plasma, thus slowing AD progression. The aim of this study was to assess PE‐Alb effects on inflammatory biomarkers across the AMBAR study.

Method

Twenty‐three inflammatory biomarker levels (IFN‐γ, IL‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, TNF‐α, Eotaxin, MIP‐1β, Eotaxin‐3, TARC, IP‐10, MIP‐1α, MCP‐1, MDC, MCP‐4, SAA, CRP, VCAM‐1, ICAM‐1) were measured through three electrochemiluminescence V‐plex panels (Meso Scale Discovery). Up to 105 PE‐treated and 37 placebo [sham‐PE] patients’ samples serum (8 time points) and cerebrospinal fluid (CSF) (3 time points), collected from 2016 onwards, were assessed. Evaluable biomarkers (those that were detectable in more than 30% of the samples at baseline and final visit), were analyzed over time as the change from baseline with a mixed model for repeated measures (MMRM) approach. Fixed effects factors for month, treatment group, and month*treatment interaction, with adjustment for age, baseline MMSE, and baseline biomarker levels were used. Patient was included as a repeated factor and differences from placebo were estimated using least squares means (LSM) (± standard error of the mean [SEM]).

Result

Nineteen inflammatory biomarkers in serum and 11 out of 23 in CSF resulted evaluable. In serum, the LSM difference from baseline showed statistical significance (p<0.05) of PE‐treated patients compared to placebo in six biomarkers. Two presented a significant reduction before the last procedure of the first 6‐week intensive PE‐Alb period (1.5‐month), intermediate (2‐month) and at final visit (14‐month). Other four biomarkers showed a significant decrease at 1.5‐month, 2‐month, and/or 14‐month. CSF analysis indicated a significant decrease at 2‐month for two entries out of the biomarker panel.

Conclusion

PE‐Alb procedures used in AMBAR induced changes in tested patients’ CSF and serum inflammatory profiles. This supports the multimechanism basis of AMBAR therapeutic approach that may contribute to slowing AD progression.
Alcohol consumption and risk of dementia: 11‐year follow‐up of UK Biobank cohort study
Authors: Wei Chang , Zhao Ziyi , Li Bingyu , Sha Feng
Published: December 2021

Background

The negative effect of alcohol consumption on cognitive function is found to be J‐shaped. We analyzed the association between alcohol consumption and the risk of dementia and examined the effect modification by APOE genotypes.

Method

157,172 Participants with nearly equal alcohol consumption compared with ten years previously were included from UK Biobank cohort study. Levels of alcohol consumption were evaluated on both categorical scales such as abstainers, occasional drinkers, monthly drinkers, light‐to‐moderate drinkers (0‐ 14 units per week), and heavily drinkers (over 14 units per week) and continuous scales (total average weekly units of alcohol consumption), with Cox regression models and restricted cubic splines (RCS). Models over all participants and stratified on APOE genotypes were conducted to assess the risk of dementia, adjusted for sociodemographic, health behaviors, and health‐related variables.

Result

709 (0.45%) out of the 157,172 participants developed dementia over a mean follow‐up of 11.4 years. Among all participants, abstainers (HR = 1.75, 95% CI 1.25 to 2.45) and occasional drinkers (1.45, 1.03 to 2.02) have an increased risk compared with light‐to‐moderate drinkers, whereas monthly drinkers (0.77, p = 0.25) and heavy drinkers (1.02, p = 0.86) do not show a significant difference. In the stratified analysis, among APOE ɛ4 allele carriers, there’s no significant difference between any category of drinkers and mildly weekly drinkers. In RCS with Cox models, 589 (0.44%) out of the 132,417 participants developed dementia over a mean follow‐up of 11.4 years. A J‐shape association between total average weekly alcohol consumption and dementia incidence was found only among APOE ɛ4 allele non‐carriers.

Conclusion

The effect of alcohol consumption on the risk of dementia differs between APOE ɛ4 carriers and non‐carriers. The association between light‐to‐moderate alcohol consumption and dementia will be further examined.
Creatinine and body mass index influence on plasma amyloid ratio, p‐tau217 and neurofilament light
Authors: Binette Alexa Pichet , Janelidze Shorena , Cullen Nicholas , Mattsson‐Carlgren Niklas , Hansson Oskar
Published: December 2021

Background

With the advent of blood‐based biomarkers, it is important to consider whether measurements of such markers are affected by factors related to blood filtration or volume. Previous studies suggested that amyloid‐beta (Aβ) and neurofilament light (NfL) measured in blood are related to creatinine levels. Here we first investigated whether creatinine and body mass index (BMI) were related to various blood‐based biomarkers, and then evaluated whether these markers affected the associations between plasma and cerebrospinal fluid (CSF), or conversion to dementia.

Method

Participants with plasma, CSF, creatinine, and BMI data from BioFinder1 (n=748) and BioFinder2 (n=560) cohort were included in the study and analyzed separately (Table 1). In both cohorts, the plasma and CSF biomarkers of interest were Aβ42/Aβ40, p‐tau217, and NfL. Linear regression models were first used to assess plasma associations with BMI and creatinine. Subsequent models compared whether plasma estimates predicting corresponding CSF levels or conversion to dementia within a 4‐year period (BioFinder1 only) were improved if creatine and BMI were added as covariates.

Result

In both cohorts, creatinine levels were positively correlated with plasma p‐tau217 and NfL, while BMI was negatively correlated with the same markers. No associations were found with the Aβ42/Aβ40 ratio (Table 2). In both cohorts, looking at plasma‐CSF associations, plasma NfL coefficients were significantly higher in models including creatinine and BMI as covariates, but plasma p‐tau217 coefficients were unchanged (Figure 1). For Aβ42/Aβ40, only in BioFinder2 was the plasma estimate higher with creatinine and BMI as covariates. In BioFinder1, where longitudinal data was available, plasma p‐tau217 and NfL estimates were somewhat higher in discriminating participants who developed AD or any cause dementia respectively when including creatinine and BMI as covariates (Figure 2; AUC change of only 0.01).

Conclusion

In two cohorts covering the full spectrum of AD, creatinine and BMI were related to plasma levels of almost all markers. BMI and creatinine improved some plasma estimates of associations with the CSF counterparts and conversion to dementia, but to a low magnitude. Although creatinine and BMI relate to plasma levels, the clinical relevance of including such factors seems to be minor.
Corneal nerve fiber measures independently predict progression from MCI to dementia: Follow‐up of the Qatar Longitudinal Study Cohort
Authors: Ponirakis Georgios , Malik Rayaz A
Published: December 2021

Background

There is an urgent need for biomarkers of neurodegeneration to identify individuals with MCI at higher risk for developing dementia. Corneal confocal microscopy (CCM) is a non‐invasive imaging biomarker which has identified corneal nerve loss in individuals with mild cognitive impairment (MCI) and dementia. This study assessed the predictive capability of CCM and MRI brain volumetry for progression from participants with MCI to dementia.

Method

In this prospective study, participants aged 50‐85 with MCI underwent assessment of clinical dementia rating (CDR), Montreal cognitive assessment (MoCA), MRI brain volumetry and CCM at baseline and CDR and MoCA at 1‐4 year follow‐up.

Result

The study cohort comprised 107 participants with MCI aged 68.4±7.7 years. Over a median follow‐up of 2.4 years, 33 of 107 participants (30.8%) with MCI progressed to dementia. Corneal nerve fibre density (P<0.0001), branch density (P<0.0001) and length (P<0.0001) were significantly lower in MCI participants who progressed to dementia. Reduced baseline corneal nerve fiber density (≤25 fiber/mm2), length (≤15 mm/mm2) and branch density (≤44 branches/mm2) accurately predicted future dementia (area under the curve (AUC) = 71‐74%, P≤0.0001). Reduced baseline intra‐cranial volume percentage (ICV %), hippocampus (≤0.44%), whole brain (≤69.4%), frontal lobe (≤10.8%), amygdala (≤0.17%), cortical gray matter (≤29%), thalamus (≤0.90%) and increased ventricle (≥3.0%) volume predicted future dementia (AUC = 65‐78%, P<0.05), whilst temporal, parietal, occipital lobe, entorhinal cortex, cingulate gyrus and brainstem did not. The adjusted odds ratios (AOR) for progression to dementia were 5.1‐11.1 times higher with abnormal corneal nerve fiber measures (P<0.05), 5.9 higher with abnormal hippocampal volume (P<0.05) and 10.8 times higher with whole‐brain volume (P<0.05).

Conclusion

The predictive capability of CCM is comparable to hippocampal and whole brain volume for progression to dementia in individuals with MCI.
Adiponectin as a biomarker in dementia: A systematic review and meta‐analysis
Authors: Salcido‐Montenegro Alejandro , Quintanilla‐Sanchez Carolina , Nañez‐Terreros Homero
Published: December 2021

Background

Alzheimer disease (AD) and Vascular dementia (VaD) are the most common causes of dementia. At mild stages, clinical differentiation is frequently not possible, creating the requirement of complex laboratory test and imaging technique that may not be available worldwide. Therefore, more practical, and effective biomarkers are need. Serum adiponectin is a modulating hormone of vasculature structure and function. Altered serum adiponectin levels had been reported in patients with AD and VaD compared to controls. To determine if serum adiponectin levels could be used to differentiate between AD and VaD, we conducted a systematic review and meta‐analysis.

Method

A systematic review following PRISMA guidelines was conducted. The search strategy included terms related to dementia and adiponectin and was conducted in 4 databases (MEDLINE, Ovid, Scopus, and EMBASE) up until April 2021. The studies were screened by 2 authors in a two‐step approach. Original studies comparing serum adiponectin between AD and VaD patients were included. Risk of bias was assessed using QUADAS. In the meta‐analysis, we compared the mean difference values of adiponectin between AD and VaD patients.

Result

A total of 917 studies were screened. After applying eligibility criteria, 72 studies were fully screened, and 3 articles were reviewed and included in the meta‐analysis. A total of 454 patients with AD and 148 with VaD were analyzed. Although patients with AD have slightly higher mean adiponectin values than VaD patients, there were no statistically significant differences (mean difference, 1.61, 95% CI ‐0.61 to 3.84; P=0.16, I2
=96%) (Fig. 1). The main risk of bias concerns was the retrospective study design in most of the studies, the heterogeneity in dementia diagnosis, and the lack of report and consideration of factors that could alter adiponectin.

Conclusion

There was no difference in the serum adiponectin levels between patients with AD and VaD. Nevertheless, factors that could alter serum adiponectin such as metabolic comorbidities (e.g., hypertension, type 2 diabetes, cardiovascular disease), weight and medicaments were not considered when comparing adiponectin levels between AD and VaD patients. Hence, further studies should account and adjust for these factors when comparing serum adiponectin in different types of dementia.
Falls risk among high‐ and low‐ frequency sleep medication users with and without dementia
Authors: Anderson Loretta R , Wennberg Alexandra MV
Published: December 2021

Background

Sleep disturbances and falls are common in older adults, particularly in people living with dementia (PLWD). Increasing sleep disturbances occur with increasing age (M. Ohayon, 2002), and one third of those 65 and older experience falls at least once per year (World Health Organization, 2007). Sleep medication use is associated with falls in older adults, but little is known about its impact in PLWD. This study seeks to determine if there is a differential association between high‐ and low‐ frequency sleep medication use among those with and without dementia.

Method

Using data from the 2011 National Health and Aging Trends Study (n=8,245), we used logistic regression models to examine the association of high‐ versus low‐ frequency sleep medication use with falls in community‐dwelling older adults with and without self‐reported dementia.

Result

In our fully adjusted model, PLWD (n=176), high‐frequency sleep medication users were more likely to fall than low‐frequency sleep medication users (OR=3.86, 95% CI: 1.31, 11.37). Among those without self‐reported dementia (n=6,658), high‐frequency sleep medication users were more likely to fall than low‐frequency sleep medication users (OR=1.40, 95% CI: 1.11, 1.77).

Conclusion

After controlling for potential confounders, PLWD who have high ‐ frequency sleep medication use are almost 4 times more likely to experience falls than PLWD who have low‐frequency sleep medication use. Reducing sleep medication use in older adults with and without dementia may help reduce the risk of falls and fall‐related outcomes in older adults. Future studies to examine sleep medication alternatives are warranted.
Preliminary assessment of the clinical effects of lecanemab following 18 months of treatment in the open label extension of the phase 2 proof of concept study, BAN2401‐G000‐201, in subjects with early Alzheimer’s disease
Authors: Swanson Chad J , Dhadda Shobha , Irizarry Michael C , Kanekiyo Michio , Li David JianJun , Kaplow June , Gordon Robert , Heanue‐Travers Helena , Hodgkinson Mark , Kramer Lynn D
Published: December 2021

Background

Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (oligomers, protofibrils) and insoluble fibrils. Lecanemab reduced amyloid and slowed clinical decline in an 18‐month Phase 2 proof of concept study in early Alzheimer’s disease (Alz Res Therapy 13; 2021). An Open label extension (OLE) with 10 mg/kg IV biweekly lecanemab dosing was implemented after analysis of the Core study, with an intervening gap period off‐treatment ranging from 9‐54 months (mean 24 months). The present study assesses longitudinal clinical status (CDR‐SB, ADAS‐cog, ADCOMS) for subjects completing the Core and 18 months of treatment in OLE.

Method

At entry into the core study, subjects were required to have early AD (amyloid positive) with global CDR of 0.5 or 1. MMRM analyses modeled clinical scales across the Core, variable gap period off lecanemab, and the OLE period. Analyses were stratified based on subjects who were: (1) global CDR ≤1 at OLE baseline; or (2) who had progressed beyond the early AD stage to CDR global >1 by OLE baseline.

Result

In subjects with global CDR ≤1 at OLE baseline, lecanemab treatment differences relative to placebo observed after 18 months of treatment in the Core were maintained at a 3 month (off drug) follow‐up visit and at the end of the gap period (OLE baseline). In the gap period, the rates of progression were similar between those treated with lecanemab and placebo in the core period. Clinical progression in the OLE appeared to plateau with lecanemab treatment among those who were global CDR ≤1 at the OLE baseline, while those who were global CDR >1 continued to progress.

Conclusion

Clinical data from the gap period suggest that subjects may need continued treatment with lecanemab, even though amyloid PET and plasma biomarker findings indicate amyloid has been removed. Apparent differences in clinical progression between those with global CDR ≤1 and those with global CDR >1 suggest the hypothesis that early AD subjects may be more likely to benefit from treatment. These concepts will be further explored in ongoing Phase 3 lecanemab clinical trials.
Lipophilic statins in cognitively normal subjects: Associations with conversion to mild cognitive impairment in a long‐term longitudinal multi‐center study
Authors: Padmanabham Prasanna S , Liu Stephen , Silverman Daniel H
Published: December 2021

Background

Studies of the relationship between the use of statins (HMG‐CoA reductase inhibitors) and subsequent cognitive performance have been variously reported to demonstrate beneficial, harmful, or no significant effects. We aimed to help clarify the relationship between statin use and long‐term trajectory in subjects cognitively normal at baseline, comparing users of statins with known moderate (atorvastatin) or high (simvastatin) lipophilicity and blood‐brain barrier penetrance (LS), to non‐users (nonS), or users of other statins (OS).

Method

From a consecutive series of 2305 subjects enrolled in the Alzheimer’s Disease Neuroimaging Initiative, 69 were excluded for taking combination statin drugs. Excluding statin users with less than 66 months of usage resulted in 340 CN subjects ( 189 nonS, 121 LS, and 30 OS) who were further studied. Subjects were stratified into groups with low (<175mg/dl), medium (175‐207mg/dl), or high ( ≥207mg/dl) baseline cholesterol levels. The significance of differential conversion rates was assessed by Chi‐Squared tests for homogeneity. Survival trajectories were created using the Kaplan‐Meier method, where an event was defined as conversion to mild cognitive impairment (MCI), and the significance of difference was assessed by the log‐rank test.

Result

While serum cholesterol levels at baseline ranged widely (112‐174 mg/dl), among 112 subjects with low baseline cholesterol, levels did not significantly differ between those who did convert to MCI within 72 months (157 mg/dl) vs. those who did not (155 mg/dl), but their rates of conversion to MCI significantly differed according to LS use: 39.5% among LS vs. 14.8% among nonS+OS converted (p=0.025). The 6‐year event‐free survival of the nonS+OS group (88.7%; 95% CI 0.785‐1) and the LS group (64.0%; 95% CI 0.519‐0.789) also differed significantly (p=0.019). LS usage was associated with an increased absolute (+24.7%) and relative (+167%) risk.

Conclusion

Lipophilic statin use was associated with more than double the risk of declining to MCI over 72 months of follow‐up in cognitively normal patients with low baseline cholesterol. In separate analyses, no such risk was observed among other statin users, nor among subjects with medium or high baseline cholesterol levels.
Non‐alcoholic fatty liver disease, liver fibrosis and patterns of regional amyloid and tau pathology in middle‐aged adults: The Framingham Study
Authors: Weinstein Galit , O’Donnell Adrienne , Zelber‐Sagi Shira , Beiser Alexa S , Seshadri Sudha
Published: December 2021

Background

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. Accumulating evidence points to an association of NAFLD with cognitive impairment, brain aging and decreased brain activity, yet the association with Alzheimer’s disease is unclear. Evidence suggests that liver fibrosis, rather than the existence of hepatic steatosis per se, is a strong prognostic factor for long‐term extra‐hepatic complications. We examined whether NAFLD and risk for advanced fibrosis assessed using a non‐invasive index, are associated with in vivo quantification of brain amyloid and tau pathology.

Method

The study sample included participants from the Offspring and Third generation of the Framingham Study. We included participants who underwent positron emission tomography (PET) imaging for assessment of amyloid and tau deposition who do not consume excessive amount of alcohol. Additionally, we included those with information on NAFLD from CT imaging (n=169) or those with all components of the FIB‐4 index (i.e. age, platelets count, aspartate aminotransferase and alanine aminotransferase; n=177). Linear regression models were performed to assess the relationship of NAFLD and risk of advanced fibrosis with amyloid FLR and amyloid and tau regional measures, adjusting for age, sex, time between exposure and PET, and camera, and additionally for body mass index, alcohol consumption, systolic blood pressure, smoking, cardiovascular disease, physical activity, C‐reactive protein, cholesterol, insulin resistance, diabetes, hypertension and visceral adipose tissue.

Result

Of the subsample with NAFLD information (mean age 52±9y; 57% males), 57 (34%) had NAFLD. Prevalent NAFLD was not associated with PET amyloid and tau. Of the subsample with information on liver fibrosis (mean age 50±10y; 51% males), 34 (19%) had increased risk of advanced fibrosis (FIB4>1.3). One unit increment of FIB‐4 index (but not advanced fibrosis) was significantly associated with increased tau in the inferior temporal, parahippocampal, entorhinal and rhinal brain regions (table 1). Among individuals with prevalent NAFLD (n=57), liver fibrosis (both continuous and using the 1.3 cutoff) was related to all amyloid and tau measures except for entorhinal amyloid (table 2).

Conclusion

This pioneering study suggests a possible association between liver fibrosis and early Alzheimer’s disease markers, independently of vascular risk factors.
The significance of reticulon‐4A in Parkinson’s disease
Authors: Mroczko Barbara , Kulczynska‐Przybik Agnieszka , Mroczko Piotr , Dulewicz Maciej , Borawska Renata , Slowik Agnieszka
Published: December 2021

Background

Parkinson's disease (PD) is one of the most common causes of dementia worldwide. Cognitive impairment resulting from the development of PD is important not only from a medical but also from a legal point of view. It can affect a person's ability to fully control their behavior and make rational decisions also concerning medical procedures. Consent for the performance of clinical procedures, such as the collection of cerebrospinal fluid by lumbar puncture are regulated by the norms of medical law. This has a significant impact on the patient's criminal responsibility. It is suggested that Reticulon‐4A (RTN4‐A) plays a pivotal role in PD. The myelin‐associated protein Nogo‐A is classified as the potent neurite growth inhibitor, which also takes part in regeneration following injury of the central nervous system. It has been demonstrated that RTN4‐A regulates the neurotoxicity in PC12 cells, commonly used in vitro PD model, via the mTOR/STAT3 signaling pathway. However, little is known about the changes of RTN4‐A levels in CSF patients with PD. Therefore, the purpose of the present study was to measure RTN4‐A levels in the cerebrospinal fluid (CSF) patients with PD and subjects from control group. We also evaluated a relationship between CSF concentrations of RTN4‐A and other markers indicating development of the dementia disorder.

Method

The concentrations of RTN4‐A and amyloid beta 1‐42 (Aß‐42), amyloid beta 1‐40, Tau, as well as pTau181 were measured in 34 subjects, including 18 PD patients and 16 individuals from control group by means of quantitative enzyme‐linked immunosorbent assay (ELISA).

Result

The CSF concentration of RTN4‐A was significantly higher in PD group in comparison with cognitively normal individuals. Furthermore, in group of patients with PD it was observed statistically significant lower CSF levels of Aß‐42 than in control group. Additionally, the CSF levels of RTN4‐A significantly correlated with tau proteins and age in whole study group.

Conclusion

Our preliminary study indicates a potential role of RTN4‐A protein in the pathology of PD and its potential usefulness as a candidate biomarker of PD, but these investigations need to be further clarified using a larger study group.
The association between sleep apnea and neurodegenerative disorders: A systematic review and meta‐analysis with an emphasis on precision‐medicine
Authors: Guay‐Gagnon Martin , Desmarais Philippe
Published: December 2021

Background

Previous meta‐analyses that assessed the possible link between sleep apnea (SA) and dementia included cohorts with patients having self‐reported diagnoses of SA as exposures and nonspecific cognitive diagnoses as outcomes, undermining clinical implications. We aimed to assess the association between SA and specific neurodegenerative causes of dementia and to review the use of precision‐medicine tools supporting clinical diagnoses in studies.

Method

We performed a systematic review and meta‐analysis in conformity with the PRISMA guidelines. Two investigators searched the Web of Science Core Collection databases from inception to March 1st, 2021. Cohort studies were included if they: 1) used either polysomnography (PSG) or International Classification of Diseases (ICD) codes for SA diagnosis, and 2) measured the risk of all‐cause dementia, mild cognitive impairment, Alzheimer’s disease (AD), vascular dementia (VaD), Parkinson’s disease (PD), Lewy body dementia (LBD), frontotemporal dementia (FTD), and/or mixed dementia. The use of biomarkers to support clinical diagnoses in eligible studies was collected. Studies of cross‐sectional design, that used self‐administered questionnaires for the diagnosis of SA, or that measured solely cognitive scores as outcomes were excluded. Pooled analyses of hazard ratios (HR) were obtained for every type of dementia using a random effects model.

Result

Among the 1,191 records identified, 8 studies were included, representing a total of 1,249,975 patients. Patients with SA had a 43% increased risk of developing any of the aforementioned types of dementia (HR: 1.43 [1.26‐1.62], 95% CI). They were 34% more likely to develop all‐cause dementia (HR: 1.34 [1.15‐1.57], 95% CI), 28% more likely to develop AD (HR: 1.28 [1.16‐1.41], 95% CI) and 54% more likely to develop PD (HR: 1.54 [1.30‐1.84], 95% CI). No statistically significant association was found with VaD. One study reported a two‐fold increased risk of LBD with SA. No study used biomarkers such as regional cortical atrophy on brain imaging or genetic testing. Results remained consistent after sensitivity analyses.

Conclusion

While SA appears to be associated with an increased risk of all‐cause dementia, notably for AD, PD and LBD, future studies will have to be conducted using more rigorous precision‐medicine tools in order to better characterize the specific associations between these conditions.
Omega 3/6 ratios: Usage and epigenetic changes in health and Alzheimer's disease
Authors: Andrade Victor
Published: December 2021

Background

From our previous research, we identified circulating metabolites that are associated with cognitive performance and dementia including polyunsaturated fatty acids (PUFA), in particular plasma levels of Omega‐3. To follow up on this finding, we sought to explore potential mechanism mediating the effect of Omega‐3 and Omega‐6 on these neurodegenerative phenotypes. Herein, we hypothesized that modulation of immune response and inflammation may mediate the effect of PUFA on neurodegenerative diseases.

Methods

1.Validate our PUFA ratios hypothesis on the MAPT intervention study. 2.Evaluate the epigenetic mechanisms modulation derived from genetics using genome‐wide association studies. 3.Corroborate previous results on real methylation data from the DELCODE study using the EPIC array. 4.Evaluate the biological age derived by epigenetics and its implications in healthy and cognitively affected subjects.

Results

The effect of the PUFA ratios follows the same trend on the MAPT study as previously described during our first period. We observed that the methylation of the genes coding for key enzymes of PUFA metabolism is modulated by levels of Omega‐3. Likewise, these methylation changes have been described in susceptibility genes for Alzheimer’s disease (AD) that modulate immune response. Finally, methylated signals also enabled the prediction of biological age. We observed that biological age in DELCODE participants differs from chronological age depending on the status of the participants.

Conclusions

The present analysis suggests that PUFA ratios are associated with cognitive decline as we previously described. Moreover, we suggest that genetic signals located in the immune‐related gene cluster MS4A are modulated by changes in DNA methylation. The same epigenetic modulation seems to mediate the genetic effect discovered in the sTREM2 GWAS. Interestingly, methylation modulation in MS4A gene has been previously reported using an independent approach. Likewise, TREM2 locus seems to be affected by methylation changes. Finally, our methylation data allowed us to analyze the biological age of cognitively affected individuals and find some clear differences with their chronological ages. Using our results, we will explore whether PUFA levels, and the ratio built on Omega‐6 and Omega‐3, modulate levels of CSF sTREM2 offering thereby a potential connection between PUFA levels and neuroinflammation in the context of AD.
How knowledge of elevated amyloid impacts neuropsychological performance in cognitively normal older adults: Findings from the REVEAL SCAN Study
Authors: Karlawish Jason , Harkins Kristin , Chen Clara A , Cupples L. Adrienne , Roberts J. Scott , Welsh‐Bohmer Kathleen A. , Green Robert C.
Published: December 2021

Background

Alzheimer’s disease (AD) prevention trials enroll cognitively unimpaired persons with AD biomarkers. The REVEAL‐SCAN trial tested whether knowledge of elevated amyloid affects these persons' cognitive test performance.

Method

Cognitively unimpaired adults age 65‐80 with a first degree relative with AD, intact cognitive and functional status, and no unstable psychiatric or medical conditions received an AD dementia risk estimate and random assigned to either learn their amyloid (18F‐amyvid) PET scan result (D+) or to learn it 6 months later (D‐). At 6 weeks and 6‐months post‐disclosure, participants completed the ADCS‐PACC battery, a composite of 4 measures: Free and Cued Selective Reminding Test (free portion only), Logical Memory IIa test, Digit‐Symbol Substitution test, and Mini Mental State Exam. Scores from each test are standardized to a common Z‐score metric and a composite score is calculated by summing these standardized Z‐scores. We hypothesized that follow‐up ADCS‐PACC scores would be lower among elevated (A+) disclosed participants (D+) than elevated (A+) nondisclosed (D‐) participants.

Result

315 participants were randomized (84 elevated (41 A+D+/43 A+D‐), 231 not elevated (118 A‐D+, 113 A‐D‐)). We report analyses comparing PACC scores between A+D+ and A+D‐. Table 1 shows no statistically significant between group differences in participant characteristics. Both before and after multiple imputation and dropping outliers that were >2 SD from the mean, PACC scores did not differ between groups at baseline. Linear regression mixed‐effects with repeated measures model (MMRM) adjusted for baseline PACC scores and time point showed that estimated mean scores at 6‐week and 6‐month did not differ between A+/D+ and A+D‐ participants (Model 1: D+ estimated mean 0.35, 95% CI: ‐0.13 to 0.84, compared to D‐ estimated mean 0.84, 95% CI: 0.38 to 1.31). The effect of disclosure on follow‐up PACC scores remained non‐significant after additionally adjusting for gender, race, education, and completion of follow‐up testing during COVID (Model 2: D+ estimated mean ‐0.38, 95% CI: ‐1.10 to 0.33, compared to D‐ estimated mean 0.06, 95% CI ‐0.65 to 0.78).

Conclusion

Knowledge of elevated amyloid among cognitively unimpaired individuals does not change performance on measures of cognition. Inspection of the variance suggests a dampening of practice effect.
Effects of intermittent theta burst stimulation (iTBS) on executive function and neuropsychiatric symptoms in older adults with mild to moderate dementia due to Alzheimer's disease: Preliminary findings of a randomized double‐blind clinical trial
Authors: Costa Mônica Vieira , de Paula Jonas Jardim , Viana Bernardo de Mattos , Burgos Ivonne Carolina Bolaños , Ávila Rafaela , Hansen Erika de Oliveira , Braga Nayara Rodrigues , Faria Karen Costa , Bicalho Maria Aparecida Camargos
Published: December 2021

Background

Studies on brain networks indicate that the functional integration between brain networks decreases progressively with Alzheimer`s disease (AD). The intermittent Theta Burst Stimulation (ITBS) has been shown to modulate the connectivity of DMN administered to parietal (PPC) and dorsolateral prefrontal (DLPFC) cortex.

Method

We selected 9 patients with AD, and a randomized double‐blind clinical trial was performed comparing the active iTBS (n=5) with sham group (n=4)of older adults with mild to moderate AD. Active iTBS condition were submitted to 21 iTBS sessions on the right and left DLPFC and the right and left PPC. All participants were assessed at baseline, week 3,week 6, 3 and 6 months. Executive functions were assessed by validated and standardized tests for this population. Behavioral symptoms were evaluated by Neuropsychiatric Inventory (NPI). The changes in performance between assessments were compared using the reliable change index (RCI).

Result

On phonemic verbal fluency two participants from intervention group show decline of this ability. One of them in the 3rd week (RCI = ‐2.16) and in the 6th week (RCI = ‐3.24). And another only in the 6th week (RCI = ‐3.24). After this period, the performance was similar to that of the baseline for both. Despite this, there were three patients who showed change in phonemic verbal fluency in the third week. One participant from sham group also showed improvement in the sixth week (RCI = 2.16).

Regarding working memory, a sham participant showed decline in this ability after the sixth week assessment (RCI = ‐7.38) and this performance remained below that presented in the baseline until the sixth month. And another from intervention group showed improvement in the third week (RCI = 2.46), but from the sixth week on, the performance returned to the same level as the baseline.

Conclusion

The improvement and impairment of cognitive variables in comparison to baseline was associated with temporal proximity of neurostimulation procedures for both groups. It is still necessary to expand the sample size to clarify which factors impact on this outcomes.
Frailty may not be a predictor of progression from MCI to dementia
Authors: Rogers Emily , Pascual‐Leone Alvaro
Published: December 2021

Background

Some studies have reported that an individual’s degree of frailty influences the risk of progression from MCI to dementia and correlates with the extent to which those with AD manifest the clinical symptoms of dementia. However, the construct of frailty generally includes factors that can directly compromise cerebro‐vascular function (e.g., cardiac disease or hypertension) or be manifestations of mental and cognitive impairment due to brain pathology. This broad definition of frailty may be problematic in that it measures what it seeks to predict.

Method

To explore the utility of frailty to predict progression from MCI to dementia, we tracked clinical, health, demographic, executive function and behavioral features from the National Alzheimer’s Coordinating Center (NACC) dataset. In 5923 samples over 65 years, with a diagnosis of MCI and at least one visit after MCI diagnosis, 3359 remained MCI at the end of the study while 2564 progressed to dementia. We analyzed common frailty contributors, as well as all other possible variables with sufficient data coverage.

Result

Among these, only 7 of the 40 most commonly considered contributors to frailty were statistically significant differences between MCI patients progressing to dementia and those remaining MCI. The 7 significant features were difficulty in remembering dates, in paying bills, in shopping, in traveling around the neighborhood, in preparing meals, feelings of apathy and change in appetite. Using statistical tests to determine significant categorical features differentiating MCI patients progressing to dementia from those remaining MCI, we found a total of 34 features, of which 21 might be considered executive functioning measures and 5 behavioral symptoms.

Conclusion

Our findings show that the metrics of frailty that are predictive of progression from MCI to dementia are essentially cognitive measures and thus the construct of frailty may simply be identifying patients with more advanced brain disease, who predictably would be at a greater risk of becoming diagnosed with dementia. The frailty construct may thus mainly offer a metric of dementia severity, and not really a predictor of developing it.
Identification of key genes and pathways involved in Alzheimer’s disease through bioinformatic analysis
Authors: Tunali Nagehan Ersoy , Düzenli Ömer Faruk
Published: December 2021

Background

Although there has been an intensive research on the molecular mechanisms of AD, there’re still unexplored pathways due to the heterogeneity of the disease mechanisms and variations in experimental approaches. Therefore, bioinformatics to would be helpful in deciphering the key gene expression patterns in existing datasets, which will eventually serve as biomarkers for AD.

Method

In this study, we aimed to identify the key genes and miRNAs involved in AD via bioinformatic analyses. We selected the GEO dataset GSE48350, which contains the microarray data collected from entorhinal cortex (EC), hippocampus (H), postcentral gyrus (PCG) and superior frontal gyrus (SFG) of the 80 AD and 173 healthy brains. We first identified the differentially expressed genes (DEGs) using the GEO2R web tool. Then, functional enrichment analysis (FEA) was performed by using DAVID. Protein‐protein interaction (PPI) networks were drawn by using STRINGdb and the hub proteins were detected by using the Cytohubba module in the Cytoscape program. miRNA detection was performed by using the miRDB web tool.

Result

We identified 12, 49, 69, 7, and 26 downregulated and 16, 51, 245, 10, and 44 upregulated genes as in all parts of the brain, EC, H, PCG and SFG regions, respectively. PPI analysis revealed the top three hub proteins as: GFAP, CXCR4, FOS in the EC; SNAP25, GRIN1, SLC32A1 in H; GFAP, SST, CXCR4 in FG regions and GFAP, SLC32A1, SST in the whole brain. According to FEA, the identified genes are involved in chemical synaptic transmission, neurotransmitter release, extracellular matrix organization, and inflammatory response. Upon analysis of the miRNA target database, we identified seven miRNAs targeting these genes. The most exciting miRNA turns out to be hsa‐miR548 family, since it targets CXCR4, FOS and GFAP.

Conclusion

The identified DEGs may serve as biomarkers and drug targets for AD. Therefore, additional experiments on expressions of these genes in the plasma or cerebrospinal fluid samples of the patients should be performed. Also, miR‐548 family should be explored as a candidate drug target.