bluuebunny/crossref_metadata_2025 huggingface dataset:
State of science in nutrition clinical trials for dementia prevention
Authors: Scarmeas Nikolaos
Published: December 2021

Background

There is a number of clinical trials of nutrition interventions in relation to prevention of dementia and cognitive decline that have been done. Nevertheless, not only the overall number of such attempted interventional studies is relatively small, but there is also considerable variability in terms not only of results but also of related methodological approaches.

Method

We will review experience of various methodological aspects of performed high quality nutrition and multidomain clinical trials for prevention of dementia and cognitive decline.

Result

Performed trials have demonstrated considerable variability not only in terms of findings but also in terms many different aspects of methodological design including intensity of intervention, success of adherence to the intervention, degree of appropriateness of primary and secondary outcomes selected, duration of the study etc. Prudent participant selection both in terms of baseline cognitive and nutritional status but also in terms of representativeness and disparity dimensions has also been a major issue in most completed trials. All the above and additional methodological strengths and challenges have been also quite prominent in nutritional supplement trials.

Conclusion

Experience of shortcomings and lessons learned from up‐to‐date conduct of nutrition trials point to areas of specific methodological improvements that we need to consider in the future.
Designing future nutrition clinical trials for dementia prevention
Authors: Schneider Lon S
Published: December 2021

Background

Past clinical trials for dementia prevention through nutrition enhancement have been wanting; and taken together have been uninformative, and generally yielded uncertain outcomes.

Method

A study group of researchers reviewed past experiences and examples of prevention trials involving nutritional interventions, including design, execution, specific treatments, practical problems in execution, and suggested improvements.

Result

Past trials show substantial variations in design, types of interventions, timing of treatments, outcomes, duration, and differing views of life course or at‐risk models. We identified, first, an overall lack of effectiveness demonstrated in these prevention trials; and, second, numerous methodologic limitations, including high risks for bias, limited external validity or generalizability that considerably limit the inferences that can be made about outcomes. Further, we identified considerable practical challenges in designing and successfully implementing these long‐term trials. Specific issues involve identifying, defining, and recruiting appropriate research subjects, the nature and conceptualization of the interventions, e.g., single molecule or multidomain, compliance and length of these long‐term trials, and appropriate intermediate and final outcomes that track efficacy. The effectiveness of a given nutritional intervention may depend as well on when in the life course it is implemented.

Conclusion

Informed by previous trials, we conclude with recommendations for a range of approaches to designing nutritional trials for the prevention of dementia that address nutritional interventions, minimize risk of bias, and that are more likely to be seen as ecologically valid.
The combined influence of beta‐amyloid and vascular risk on prospective brain atrophy in clinically normal individuals
Authors: Rabin Jennifer S , Pruzin Jeremy J , Schultz Aaron P , Scott Matthew R , Hampton Olivia L , Hsieh Stephanie , Yang Hyun‐Sik , Yau Wai‐Ying , Hedden Trey , Rentz Dorene M , Johnson Keith A , Sperling Reisa A , Chhatwal Jasmeer P
Published: December 2021

Background

Amyloid‐beta (Aβ) and vascular risk factors are commonly observed together among cognitively unimpaired adults. Here, we examined the interactive associations of Aβ burden and systemic vascular risk with respect to longitudinal patterns of neurodegeneration. Secondarily, we assessed whether systemic vascular risk associations with brain atrophy were modified after adjusting for imaging based markers of white matter integrity (white matter hyperintensities (WMH) and diffusion‐derived fractional anisotropy).

Methods

Participants were 197 adults (age=73.5±6.1 years) from the Harvard Aging Brain Study with at least two MRI scans over a median of 4.5 years. Baseline Aβ burden was measured with Pittsburgh Compound‐B PET. Vascular risk was quantified with the Framingham Heart Study general cardiovascular disease risk score. Altered white matter microstructure was measured via diffusion‐derived fractional anisotropy and WMH burden was quantified using FLAIR images. Brain atrophy was assessed longitudinally with serial structural MRI. Aβ burden and vascular risk were examined as interactive and independent predictors of brain atrophy in separate linear mixed models, adjusting for age, sex, education, APOE ε4 status, and intracranial volume (where appropriate).

Result

We found a significant interaction between elevated Aβ burden and higher vascular risk in relation to faster atrophy within frontal (t=‐2.95, p=0.003) and anterior temporal lobes (t =‐2.32, p=0.021), thalamus (t=‐2.61, p=0.010) and striatum (t =‐2.17, p=0.031). Higher Aβ burden, but not vascular risk, was associated with faster atrophy in the parietal lobes (Aβ: t=‐4.14, p<0.001; vascular risk: t=‐1.54, p=0.124), occipital lobes (Aβ: t=‐2.95, p=0.003; vascular risk: t=‐0.63, p=0.526), and hippocampus (Aβ: t=‐2.72, p=0.007; vascular risk: t=0.207, p=0.836). These effects remained very similar after adjusting for WMH and fractional anisotropy measures.

Conclusion

Elevated vascular risk was associated with accelerated Aβ‐related atrophy in frontal and anterior temporal regions. However, higher Aβ burden alone was correlated with greater atrophy in regions often associated with a canonical AD pattern of neurodegeneration, including the hippocampus and parietal regions. These findings highlight interactions between vascular and Aβ‐related pathways with respect to brain atrophy, and the potential benefit of managing vascular risk factors as a possible intervention to slow regional neurodegeneration in preclinical Alzheimer’s disease.
Examining misdiagnosis of mild cognitive impairment among Black/African American older adults
Authors: Kiselica Andrew M , Johnson Ellen , Lewis Kaleea , Trout Kate
Published: December 2021

Background

Black/African Americans are less likely to receive an accurate diagnosis of mild cognitive impairment (MCI) than their White counterparts. We examined rates of low cognitive test scores by race among older adults diagnosed with MCI to illuminate possible biases in the diagnostic process.

Method

We compared number of low scores (i.e., <9th percentile) on cognitive tests between Black (n = 545) and White (n = 3,542) participants diagnosed with MCI based on the Clinical Dementia Rating. Participants were drawn from the National Alzheimer’s Coordinating Center Uniform Data Set. Chi‐square tests were used to examine racial differences in rates of low scores for each cognitive test, and t‐tests were used to compare the number of low scores across groups.

Result

Compared to Black participants, White individuals demonstrated significantly higher rates of low scores on tests of memory, attention, and verbal fluency. White participants with MCI also evidenced a higher number of low scores overall (M = 3.67, SD = 2.46) than Black participants (M = 2.46, SD = 2.15), d = .48.

Conclusion

Results suggest there may be bias in MCI classification based on clinical interview, leading to overdiagnosis among Black individuals and/or underdiagnosis among White individuals.
Embedding dementia research in clinical practice: Progress of the Oxford Brain Health Centre
Authors: O'Donoghue M Clare , Blane Jasmine , Mitchell Robert , Aikin Nicola , Lindsay Karen , Campbell Jon , Semple Juliet , Raymont Vanessa , Martos Lola , Mackay Clare
Published: December 2021

Background

Launched in August 2020, the Oxford Brain Health Centre (BHC) is the UK's first psychiatry‐led joint clinical‐research service providing high‐quality assessments and increasing research opportunities for patients with memory problems. By embedding research in the NHS service, the BHC aims to address gaps between clinical practice and research advances into dementia. This abstract describes the first 60 referrals from the BHC pilot.

Methods

Patients from Oxford Health NHS Foundation Trust memory clinics were referred to the BHC for assessment prior to their diagnostic appointment. At the BHC, patients completed clinical assessments ‐ MRI scan, cognitive assessment and questionnaires – and could consent to use of clinical data for research, additional research assessments, and recontact about future research. Accompanying relatives completed a clinical informant interview and could consent to recontact about research. Patient/relative feedback was obtained via questionnaires.

Results

Between August and December 2020, the BHC received 60 referrals. 38% were returned to the memory clinic for reasons relating to the patient (n=9, e.g. patient unable to travel to the centre), the referral (n=3, e.g. patient already seen in clinic), or the MRI scan (n=11, e.g. claustrophobia, MR contraindication). BHC appointments occurred on average 26 days (range: 5‐63) after referral from the memory clinic. Only 3% did not attend. Of the 33 attendees in 2020, 58% were female, average age was 77.5 years (66‐90), and average ACE‐III score was 66.8 (9– 98; max: 100). 97% of patients consented to use of clinical data for research, 88% to additional research assessments, and 69% to recontact about research. 81% of relatives consented to recontact about research. Service‐user feedback was consistently high; 100% of responding patients were satisfied with the BHC service, particularly highlighting positive interactions with staff.

Conclusions

Since launching, we have demonstrated the feasibility of an integrated clinical‐research service for people with memory problems and demonstrated extremely high research uptake in this population. Evaluation of referrals, procedures, impact on diagnosis, and health economics at the end of the 6‐month pilot will inform sustainability and scalability of Oxford BHC to provide a model for a specialist service that can be adopted throughout the NHS.
Prediction of Alzheimer disease using plasma RNA sequences from dementia genes
Authors: Ibanez Laura , Bergmann Kristy , Eteleeb Abdallah , Wang Fengxian , Norton Joanne , Gentsch Jen , Harari Oscar , Cruchaga Carlos
Published: December 2021

Background

Alzheimer’s disease (AD) is inexorable, incurable, and in many cases very difficult to diagnose before symptom onset. Thus, there is a clear need to develop tools to detect the pathological changes that occur before clinical symptoms onset. Historically, proteins have been the preferred biomarker. However, biofluids also contains ribonucleic acid in its free form (cfRNA). The source of cfRNA in plasma is not fully understood, but it is thought to be the result of normal cell death throughout the body, thus providing a mirror of the status of a normal functioning body. Therefore, if some organs are functioning incorrectly, we can detect it by changes in cfRNA. To date, several species of cfRNA have been investigated as biomarkers for cancer, fetal development and AD. The aim of this study was to generate predictive models for AD using plasma cell‐free RNA species at different stages of the disease.

Method

We generated cfRNA‐Sequence data from AD cases at CDR=1 (N=44) and controls (N=45) and applied standard quality control. Gene expression was quantified with Salmon and corrected by library complexity and log transformed prior to analysis. Genes known to be involved in AD and other neurodegenerative diseases (N=25) were used to create a predictive model using step‐wise discriminant analysis in the CDR=1. APOE genotype was included in the model afterwards. The predictive power was tested in early (N=27) and pre‐symptomatic (N=21) stages of the disease.

Result

Out of the 25 genes, eight were included in the predictive model after step‐wise discriminant analysis. After inclusion of APOE genotype, the area under the ROC curve was 0.96, 0.99 and 0.82 for CDR=1, CDR=0.5 and pre‐symptomatic stages respectively (Figure 1).

Conclusion

Cell‐free RNA is a promising minimally invasive biomarker for AD with an accuracy comparable to the one obtained using CSF biomarkers. This approach can provide a new screening tool for AD that can be used at population level and to evaluate disease‐modifying therapies that target amyloid beta and tau.
Neuroprotective effect of silymarin against 3‐nitropropionic acid‐induced Huntington’s like symptoms in rats
Authors: Chandolia Priyanka
Published: December 2021

Background

Neuroprotective effect of silymarin against 3‐nitropropionic acid‐induced Huntington’s like symptoms in rats.

Method

Huntington's disease (HD) is a chronic neurodegenerative and hyperkinetic movement disorder characterized by degeneration of GABAergic medium spiny neurons, mainly affecting striatum and cortex. 3‐nitropropionic acid (3‐NP) acts as a suitable animal model to induce HD like symptoms in rats. Therefore, the present study aimed to investigate the neuroprotective effect of silymarin against 3‐NP induced HD like symptoms in rats. Rats were administered 3‐NP (10 mg/kg; i.p) for 21 days, whereas silymarin (50, 100 and 200 mg/kg; p.o) was given once a day, 1 hour before the 3‐NP treatment for 21 days. Body weight and behavioral parameters (rotarod, open field test, and narrow beam walk activities) were assessed on 1st, 7th, 14th, and 21st days. On the 22nd day, the animals were sacrificed, and the rat striatum and cortex were isolated to perform biochemical parameters (lipid peroxidation; glutathione; superoxide dismutase; nitrite and catalase).

Result

Systemic 3‐NP treatment significantly reduced body weight, motor‐coordination, and oxidative defense. Pretreatment with silymarin significantly attenuated the 3‐NP induced alterations in body weight, locomotor activities, and oxidative defense.

Conclusion

Our results revealed that in a 3‐NP model of HD, silymarin could underlie the possible neuroprotective effect, which may provide insight into the therapeutic potential of silymarin for HD.
Objective subtle cognitive decline is associated with a more rapid increase in plasma phosphorylated‐tau181 levels over time
Authors: Thomas Kelsey R. , Bangen Katherine J. , Edmonds Emily C. , Weigand Alexandra J. , Walker Kayla S. , Bondi Mark W. , Galasko Doug R.
Published: December 2021

Background

Early identification of Alzheimer’s disease (AD) is imperative for early intervention and planning. Objectively‐defined subtle cognitive decline (Obj‐SCD) criteria, based on sensitive neuropsychological scores, is associated with AD biofluid and neuroimaging markers as well as progression to mild cognitive impairment (MCI) and dementia. However, the relationship between Obj‐SCD and newer plasma markers, such as plasma phosphorylated‐tau181 (p‐tau181), is unknown. Therefore, we examined baseline and longitudinal plasma p‐tau181 across CN, Obj‐SCD, and MCI groups.

Method

953 Alzheimer’s Disease Neuroimaging Initiative participants without dementia had plasma p‐tau181 data, which were log‐transformed prior to analyses. Participants were classified as CN (n=403), Obj‐SCD (n=200), or MCI (n=350) based on actuarial neuropsychological criteria. Baseline analyses compared p‐tau181 across groups. Linear mixed effects models, adjusting for age, sex, APOE e4 allele frequency, and pulse pressure, examined 4‐year p‐tau181 rate of change in Obj‐SCD and MCI participants relative to CN. Follow‐up analyses examined whether the group p‐tau181 x time trajectories differed by Aβ‐PET positivity status.

Result

CN and Obj‐SCD groups had lower baseline plasma p‐tau181 than the MCI group and did not differ from one another (Figure 1). However, longitudinally, the Obj‐SCD group had the steepest increase in plasma p‐tau181 over four years and was the only group to differ from CN participants (Figure 2; b=.016, 95% CI: .003‐.018, p=.016). When groups were split by Aβ status, only the Aβ‐negative Obj‐SCD group showed a slightly faster increase in p‐tau181 relative to the Aβ‐negative CN group (b=.019, 95% CI: .001‐.037, p=.044).

Conclusion

Baseline plasma p‐tau181 did not differ between CN and Obj‐SCD; however, consistent with prior findings, Obj‐SCD was associated with future pathologic changes, including those measured by plasma p‐tau181, prior to frank impairment associated with MCI. Importantly, these results do not appear to be driven by Aβ+ Obj‐SCD participants. Despite the long‐held assumption that cognitive changes invariably follow biomarker changes, these findings suggest that early neuropsychological difficulties may emerge before or in tandem with measurable changes in plasma markers. Future work will examine the prognostic impact of combining Obj‐SCD and plasma markers, which both have the potential to be accessible early markers of future AD‐related declines.
Early detection of neuropsychiatric, language and motor symptoms in genetic frontotemporal dementia (FTD): Defining prodromal FTD
Authors: Samra Kiran , Russell Lucy L , Greaves Caroline V , Convery Rhian S , Rohrer Jonathan D ,   Genetic Frontotemporal Dementia Initiative (GENFI)
Published: December 2021

Background

The prodromal stage of genetic frontotemporal dementia (FTD) is currently poorly defined. Whilst the majority of people with genetic FTD develop behavioural symptoms, a number of people present with primary progressive aphasia (PPA), neuropsychiatric symptoms, parkinsonism, including corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP), or amyotrophic lateral sclerosis (ALS). Such variable phenotypes pose a barrier to clearer definitions of prodromal FTD.

Methods

1139 people have been recruited to the Genetic FTD Initiative (GENFI), a deep phenotyping international multicentre cohort study of FTD. Clinical data on symptoms within the language, neuropsychiatric and motor domains have been collected on presymptomatic and symptomatic mutation carriers, as well as mutation‐negative controls using the GENFI Symptom Scales.

Results

Language: In the symptomatic phase, 19 participants met Gorno‐Tempini diagnostic criteria for primary progressive aphasia (PPA), the majority (17) of whom had a progranulin (GRN) mutation. The phenotype in these cases was either nonfluent variant (8) or did not meet criteria for a specific variant (9). Additionally, 42 presymptomatic participants had subtle early language problems. Neuropsychiatric: Symptoms were reported most frequently in symptomatic C9orf72 mutation carriers (91.7% of all symptomatic C9orf72 carriers) and to a lesser extent in GRN and MAPT mutation carriers. Depression and anxiety were common in mutation‐negative controls (14%) as well as mutation carriers. Motor: ALS and FTD‐ALS were most frequent in C9orf72‐associated FTD (12.5% of all symptomatic C9orf72 carriers). Parkinsonism (including PSP and CBS) was present to a lesser extent in C9orf72, GRN, and MAPT mutation carriers.

Conclusions

Language, neuropsychiatric and motor features are common in genetic FTD and will need to be included in any prodromal staging system. Improved, operationalised measurement of such symptoms will allow improved stratification of individuals, and aid clinical trials. Future work should unravel the temporal trajectory of such symptoms within each form of genetic FTD.
Assessing cognition in the era of COVID19: Do we need methods to assess cognitive function virtually?
Authors: Saxena Saket , Factora Ronan , Hashmi Ardeshir , Jones Robert , Baranek Laura , Sefcik Mary , Alexio Gabriel
Published: December 2021

Background

With an aging population, cognitive impairment has become increasingly prevalent. Early symptoms are often missed in primary care and may progress to clinical dementia before being noticed. Screening for dementia has been a challenge. No clear guideline describes how to assess for cognition in primary care despite the robust data suggesting that early identification of dementia allows for mobilization of resources to support patients and caregivers, and there is no harm in proactive assessing cognition in older patients. In addition, most of the cognitive assessment methods requires in‐person cognitive testing in primary care practices, this may be affected by situations where the in‐person visitations to the physician offices are limited such as in the COVID 19 pandemic. Our study aims to access performance of in‐person cognitive assessment in primary care during COVID 19 pandemic.

Methods

Cleveland Clinic implanted MiniCog as a cognitive screening tool in primary care at Cleveland Clinic Community Care (4C). Inclusion criteria are‐ Age 65+, Annual Wellness visit, no preexisting diagnosis of dementia, normal MiniCog in previous year. Data were registered from from January 2019 until November 2020.

Results

Figure 1 displays the number of MiniCog performed at 4C averaging 360 MiniCog every month. Total number of MiniCogs performed during the study period was 7126 out of which 6739 were normal (95%) and 387 were abnormal (5%). Figure 2 displays the impact of COVID 19 pandemic on in‐person visits in 4C, resulting an impressive decline in cognitive assessment process leading to no cognitive testing in April and only two tests in May.

Conclusion

Most of the cognitive assessment tools used in clinical practice requires in‐person office based and are often needed to diagnose dementia. Telephonic cognitive interviews such as TICS and MoCA 5 minute protocol are available, but are difficult to administer in primary care. The substantial drop in the performance of in‐person cognitive assessment during the COVID 19 pandemic raises the need of validated tools to virtually assess cognitive function and also highlights the negative impact of COVID 19 pandemic on already frail processes of assessing cognitive health of older adults in primary care.
Evaluating predictability in outdoor mobility: A potential pathway to personalized assistance for people with dementia
Authors: Bayat Sayeh , Naglie Gary , Rapoport Mark , Stasiulis Elaine , Ye Bing , Mihailidis Alex
Published: December 2021

Background

People with dementia (PwD) often become lost, which is commonly attributed to spatial disorientation, one of the earliest symptoms of dementia, particularly of the Alzheimer’s disease type. Spatial disorientation can limit a person's ability to navigate in an outdoor environment. As a result, PwD experience outdoor mobility decline, which, in turn, can have a negative impact on their cognitive functions. Thus, enabling safe outdoor mobility is important for dementia research. Artificial Intelligence (AI) methods in conjunction with Global Positioning System (GPS) data show great potential for supporting the outdoor mobility needs of PwD. The objective of this work is to evaluate the extent to which we can predict future destinations of PwD by learning from their past mobility habits.

Method

Eight cognitively‐intact older adults (CTL) and seven older adults with dementia completed four weeks of GPS recording. Each participant’s stops and trips were extracted from their trajectories. We determined the predictability of each participant’s mobility patterns using three approaches. First, we assumed each stop is visited with equal probability, thus, disregarding temporal aspects of travel. Next, we built on the previous approach by including stop visitation probability, thus, capturing the heterogeneity of visitations. Finally, to capture the full spatiotemporal characteristics of mobility, we added in‐depth temporal characteristics including the visitation frequency, the order in which the stops were visited, and the time spent at each stop.

Result

Relying solely on the spatial dimension of mobility yielded no predictive power across the two groups. Adding the heterogeneity of visitation patterns, we observed an increase in the predictability power; PwD displayed a trend toward higher predictability compared to the CTLs, but the student’s t‐test did not reach statistical significance (0.833±0.085vs.0.768±0.029, t(13)=‐2.06, p=0.06; d=‐1.07). Finally, relying on full spatiotemporal characteristics, a 4‐week record of mobility patterns displayed 95% (SD=2%) and 92% (SD=1%) predictability among PwD and CTLs, respectively. This value was significantly higher among PwD, t(13) = ‐3.39, p<.01; d=‐1.75.

Conclusion

Our findings offer new perspectives on the predictive mobility models based on GPS data and AI that can be used to provide personalized assistance for outdoor navigation of people with dementia.
Lessons from SPRINT‐MIND on interventions to prevent dementia
Authors: Williamson Jeff D.
Published: December 2021

Background

The Systolic Blood Pressure Intervention Trial (SPRINT) and the Systolic Blood Pressure Intervention Trial: Memory and cognition IN Decreased hypertension (SPRINT‐MIND) have contributed substantially to recent advances in the fields of hypertension, cardiovascular disease prevention, and prevention of cognitive decline.

Method

Randomized clinical trial of 9,361 adults (mean age, 67.9 years) with hypertension and increased risk for cardiovascular disease with a mean follow‐up of 5.5 years. Participants were from diverse communities in the United States and were 27.8% black and 10.5% Hispanic.

Result

SPRINT‐MIND has already demonstrated in this randomized trial that intensive blood pressure control significantly reduces the risk of incident overall mild cognitive impairment (HR, 0.81; 95% CI, 0.69‐0.95). However results related to subtype of MCI have not been released. This presentation will expand on findings related to intensive blood pressure control and the incidence of mild cognitive impairment (MCI) and Probable Dementia. The beneficial effect on MCI largely reflected in amnestic subtypes (HR, 0.78 [95% CI, 0.66‐0.92]) and multi‐domain MCI subtypes (HR, 0.78 [95% CI, 0.65‐0.93]), with no significant differences for non‐amnestic and single domain MCI subtypes. Data on the the mean scores each component of the cognitive battery according to adjudicated participant classification of 1) No impairment, 2) MCI or 3)Probable dementia will also be presented.

Conclusion

Findings from the SPRINT‐MIND trial continue to enhance understanding of the importance of cardiovascular disease prevention approaches as a pathway for also reducing the burden of cognitive impairment and dementia.
Can we re‐purpose drugs from the cardiology medicine cabinet? Should we look in the rheumatology, metabolic and hematology cabinets as well?
Authors: Quinn Terence J ,   Dementias Platform UK Vascular Experimental Medicine Group
Published: December 2021

Background

Despite substantial investment, the dementia drug development pipeline has failed to produce a convincing new pharmacological treatment. This situation is in stark contrast to drug development in oncology, metabolic and cardiovascular medicine, where many novel agents are entering phase III trials or clinical practice. Some of the commonly prescribed medications for brain disorders were originally developed for another therapeutic indication (memantine and tPA are examples). In this session we will consider whether re‐purposing existing or novel drugs from other disease areas could offer a treatment for dementia?

Method

The ultimate test of a new medication is the randomised controlled trial. Contemporary trials are costly. For drug repurposing we can exploit available data from trials and registries to inform the choice of candidate drugs and ‘de‐risk’ the development process. There are various approaches, and we will consider: expert consensus; systematic review and meta‐analysis; individual participant level evidence synthesis; genome wide association studies; drug wide association studies. Secondary analysis of existing trial and healthcare data can also inform the design, sample size and conduct of a repurposing study. As part of the Dementias Platform UK (DPUK) portfolio, we are utilising all these methods with the anticipation of selecting the most promising candidates to take forward to clinical trials.

Result

There are already good examples where existing data have informed or are informing drug repurposing studies. These include non‐steroidal and other anti‐inflammatory drugs (e.g. cilostazol); antithrombotic agents (e.g. dabigatran); antihypertensive or vasodilator medications (e.g. losartan, tadalafil); novel drugs developed for heart failure and diabetes mellitus (e.g. GLP1 agonists, such as liraglutide). Emerging data are already suggesting plausible candidates, while also giving new insights into the pathogenesis that underlies cognitive decline. We will share progress made within the DPUK Vascular group and offer a roadmap for future repurposing research.

Conclusion

The search for an effective dementia intervention continues. It is possible that we already have useful medications that we can ‘borrow’ from other clinical fields. The increasing number of medications coupled with access to large volume, robust data‐sets creates an ideal landscape for selecting candidate drugs for repurposing.
The association between diabetes and Alzheimer’s disease pathophysiology
Authors: van Gils Veerle , Vos Stephanie JB , Jansen Willemijn J , Martinez‐Lage Pablo , Hort Jakub , Ramakers Inez HGB , Soininen Hilkka , Laakso Markku , Zetterberg Henrik , Dalsgaard Søren , Verhey Frans RJ , Visser Pieter Jelle ,   EMIF‐AD MBD Consortium
Published: December 2021

Background

Diabetes is common in persons with dementia and associated with cognitive decline. However, the relation between diabetes and AD pathophysiology is still unclear. Our aim is to assess the association of diabetes diagnosis and blood glucose regulation with CSF AD biomarkers across the AD clinical spectrum, and the potential moderating effects of vascular factors in this relationship.

Method

As part of the PRIME project, we included individuals from five European memory clinic cohorts with normal cognition (NC, n=419) mild cognitive impairment (MCI, n=363) and dementia (n=151). Inclusion criteria were availability of diabetes diagnosis, fasting blood glucose or HbA1c levels and cerebrospinal fluid (CSF) biomarkers amyloid‐beta42, p‐tau and t‐tau. Center‐specific cut‐offs were used to define biomarker positivity. We performed logistic and linear regression models adjusted for age, education years, gender, cohort, to assess the relation between diabetes and AD biomarkers, as well as the potential influence of hypertension, hypercholesterolemia and BMI on this relationship.

Result

We included 933 participants in our analysis with an average age of 66.1 years (Table 1). Diabetes was associated with lower odds of being amyloid positive in the total group and in individuals with NC and dementia (Table 2). Diabetes was associated with a lower risk for p‐tau and t‐tau positivity in the total group and in the MCI subgroup. Similar trends were found with HbA1c and blood glucose as predictors. A higher BMI was associated with less t‐tau pathology in persons with diabetes only. Presence of hypertension and hypercholesterolemia did not influence the association between diabetes and AD biomarkers. Additionally, post‐hoc analyses with diagnostic group stratified for amyloid positivity were performed. These analyses indicated that amyloid‐negative demented individuals more often had diabetes than amyloid‐negative NC and MCI individuals (Figure 1). Relative to amyloid‐negative NC, amyloid‐negative demented individuals had higher HbA1c and glucose levels (Figure 2). Amyloid‐positive demented individuals had higher HbA1c levels than amyloid‐positive NC and MCI patients.

Conclusion

Diabetes and impaired glucose regulation are associated with non‐AD dementia but not with AD‐related cognitive impairments. Surprisingly, amyloid positive individuals with normal cognition less often had diabetes.
CSF apolipoprotein B levels predict future visuospatial cognitive decline and synaptic pathology in cognitively unimpaired healthy elderly with a parental history of Alzheimer’s disease
Authors: Poirier Judes , Nilsson Nathalie I.V. , Labonté Anne , Rosa‐Neto Pedro , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Breitner John , Villeneuve Sylvia , Picard Cynthia , Group Prevent‐AD Research
Published: December 2021

Background

We examine the role of brain apolipoprotein B (apoB) as a putative CSF indicator of early tau pathology in pre‐symptomatic Alzheimer’s disease (AD).

Method

Among 129 cognitively unimpaired elderly at increased risk of AD (PREVENT‐AD cohort), we assessed blood and cerebrospinal fluid apoB, apoC3 and apoE protein levels with those of amyloid β42, total tau and phosphorylated tau. We compared results with amyloid‐b (NAV4694) and tau (flortaucipir) positron emission tomography uptake and cognitive assessment alterations over 6‐8 years. Tangle and plaque pathologies were contrasted with cortical APOB, APOC3 and APOE mRNA levels in 240 autopsied subjects enrolled in the Religious Orders Study and Memory and Aging Project (ROSMAP) studies with diagnoses of cognitively unimpaired, mild cognitive impairment, or AD.

Result

Among cognitively unimpaired participants, we observed significant correlations between baseline CSF, but not blood, apoB levels and both CSF t‐tau (R2 = 0.23, P < 0.0001) and P‐tau (R2 = 0.28, P < 0.0001). Similar associations were observed when using PET flortaucipir‐binding in entorhinal, parahippocampal and fusiform regions. No association was detected between CSF apoB and CSF Aβ42 levels or cerebral Ab deposition. Baseline CSF apoB levels were associated with visuospatial cognitive decline over the course of 6‐8 years (R2 = 0.13, P < 0.02) and alterations in several synaptic proteins in the CSF. Contribution from peripheral apoB was found to be negligible. In ROSMAP, APOB gene expression failed to correlate with either tangle pathology or amyloid plaque deposition.

Conclusion

CSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at‐risk individuals predisposed to develop visuospatial cognitive decline over time.
Tools for harmonization of data in World‐Wide FINGERS
Authors: Talton Jennifer W , Fernandez Shane , Garcia Katelyn R , Crivelli Lucia , Snyder Heather M , Lovato Laura , Martins Ralph N , Kivipelto Miia , Mangialasche Francesca , Pérez Kristal Morales , Espeland Mark A
Published: December 2021

Background

World‐Wide FINGERS (WW‐FINGERS) is a global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention (Kivipelto et al., 2020). With over 30 countries conducting studies within the network, harmonizing interventions and data collection wherever possible is a priority. However, study‐specific adaptations are inevitable to accommodate differences in language, culture, and environment. Thus, a single data collection system is not feasible across WW‐FINGERS and opportunities for synergies between study‐specific systems should be explored.

Method

REDCap (Research Electronic Data Capture) is a secure, web‐based software platform which supports validated data capture for research studies (Harris et al., 2009). The underlying blueprint for each REDCap project is a ‘data dictionary’ – a .csv file containing all metadata required to recreate case report forms (CRF) for each point of data collection, including variable names and response options. Data dictionaries can be easily exported, shared, and imported into other REDCap instances. This enables utilization of the same overall structure where possible and preserves response options and variable names while making needed adaptations. Within the WW‐FINGERS network, the study to Protect Brain Health through a Lifestyle Intervention to Reduce Risk (U.S. POINTER) developed a REDCap system based on its protocol and shared its data dictionary with two other WW‐FINGERS studies – AUstralian‐Multidomain Approach to Reduce Dementia Risk by PrOtecting Brain Health with Lifestyle Intervention (AU‐ARROW) and LatAm FINGERS (Latin American initiative for lifestyle Intervention to Prevent Cognitive Decline and reduce risk study).

Result

AU‐ARROW and LatAm FINGERS are in the process of incorporating relevant pieces of the U.S. POINTER REDCap project into REDCap systems developed for their studies. While the systems are not identical given the different intervention structures, we aim to standardize 50‐75% of the common variables used across the studies.

Conclusion

Using REDCap allows each WW‐FINGERS study to develop its own customized system for data capture, while easily standardizing common variable names, response options, and CRFs; along with exporting de‐identified data. As a result, data sharing and analysis across the WW‐FINGERS network can be streamlined. Furthermore, this process may serve as a roadmap for other global consortia’s similar efforts.
Public health interventions to reduce Alzheimer’s risk: Need for tailored approaches
Authors: Nianogo Roch A , Rosenwohl‐Mack Amy , Yaffe Kristine , Carrasco Anna , Barnes Deborah
Published: December 2021

Background

We have previously estimated that 30% of Alzheimer’s disease in the U.S. may be attributable to modifiable risk factors, and that the most important risk factors to target are physical inactivity, depression, and smoking. However, estimates in the U.S. population as a whole may not be ideal for guiding public health messaging about Alzheimer's risk reduction because they do not take into consideration the unique risk factor profiles of different regions. In this study, we estimate the proportion of Alzheimer’s disease cases that are potentially attributable to modifiable risk factors in California, which has the largest and most diverse population in the U.S.

Method

We calculated individual and combined population attributable risks (PARs) for Alzheimer’s disease in California for eight modifiable risk factors: physical inactivity, smoking, depression, low education, diabetes, midlife obesity, midlife hypertension, and hearing loss. Relative risks for each risk factor were extracted from recent meta‐analyses. Risk factor prevalence and communality were determined using data from the 2017 and 2018 California Behavioral Risk Factor Surveillance Survey, a population‐based survey weighted to provide representative estimates. To account for non‐independence of the risk factors, we estimated the communality and uniqueness of each risk factor via principal component analysis and applied them to Levin’s formula.

Results

In California, the estimated PARs (95% confidence intervals) for modifiable risk factors were as follows: low education: 14.0% (13.3%, 14.8%), midlife obesity: 13.4% (12.9%, 13.9%), physical inactivity: 10.3% (9.8%, 10.8%), midlife hypertension: 7.4% (7.2%, 7.7%), depression: 7.4% (7.0%, 7.7%), diabetes: 6.7% (6.2%, 7.2%), smoking: 4.5% (4.2%, 4.8%), and hearing loss: 1.9% (1.7%, 2.1%). The combined PAR estimate was 29.4% (28.1%, 30.7%) incorporating the correlations between risk factors.

Conclusion

Consistent with our previous U.S. estimates, we found that about a third of Alzheimer’s disease cases in California might be attributable to modifiable risk factors. However, the most important risk factors differed, with low education, midlife obesity and physical inactivity contributing to the largest proportion of cases. Public health interventions to reduce dementia risk may be more effective if tailored to address the most important risk factors in the region.
Generational differences in cognitive function in middle‐aged to older adults
Authors: Merten Natascha , Pinto A Alex , Paulsen Adam J , Carlsson Cynthia M , Chen Yanjun , Schubert Carla R , Cruickshanks Karen J
Published: December 2021

Background

Cognitive impairment and dementia are major health concerns. While the number of cases is expected to increase with the aging populations, recent research shows that age‐specific dementia prevalence rates are declining. This may be due to reduced risks of cardiovascular and metabolic diseases and harmful environmental exposures and healthier lifestyles. Given the decades‐long preclinical phase of dementia, detection of early cognitive changes might improve future treatment and prevention methods. However, research on generational differences in cognitive function in middle‐aged to older adults is limited. The aim of this study was to determine whether individuals from more recent generations show better cognitive function.

Method

This cross‐sectional study is based on data from 4439 participants from the Epidemiology of Hearing Loss Study (EHLS) and Beaver Dam Offspring Study (BOSS), two studies of adults in Beaver Dam, Wisconsin. Each participant’s birth year was used to assign a birth cohort (1901‐1924: Greatest Generation; 1925‐1945: Silent Generation; 1946‐1964: Baby Boom Generation; 1965‐1984: Generation X). Cognitive function was assessed by Trail‐making Test A and B (TMTA, TMTB). We used multivariable linear regression models adjusted for age and sex to determine birth cohort (generational) differences in TMT performance. We repeated models adjusting for education.

Result

In preliminary analyses, TMTA performance was better in more recent generations as compared to the Greatest Generation (Silent: ‐26.88 seconds (s); 95 % confidence interval (CI) ‐30.60,‐23.15; Baby Boom: ‐25.70s; 95% CI ‐30.64,‐20.77; Generation X: ‐17.82s; 95% CI ‐24.37,‐11.27). Performance on TMTB showed larger generational differences as compared to the Greatest Generation: Silent: ‐50.04s; 95% CI ‐58.11,‐41.97; Baby Boom: ‐63.38s; 95% CI ‐73.83,‐52.93; Generation X: ‐43.53s; 95% CI ‐57.23,‐29.83. Although education levels differed by generation, including education did not change these patterns.

Conclusion

This study suggests better processing speed and executive function performance among more recent generations even when adjusting for educational levels. This implies that future burdens of cognitive decline and dementia may be lower than currently estimated. The difference also suggests that there are modifiable risk factors that may help to explain the etiology of cognitive decline and provide potential pathways for healthy brain aging and prevention of Alzheimer’s disease and other dementias.
Soluble P‐tau217 reflects both amyloid and tau pathology in the human brain and mediates the association of amyloid with neocortical tau
Authors: Mattsson‐Carlgren Niklas , Janelidze Shorena , Bateman Randall J. , Smith Ruben , Stomrud Erik , Serrano Geidy E. , Reiman Eric M. , Palmqvist Sebastian , Dage Jeffrey L. , Beach Thomas G. , Hansson Oskar
Published: December 2021

Background

Alzheimer’s disease is characterized by β‐amyloid plaques and tau tangles. Plasma levels of phospho‐tau217 (P‐tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β‐amyloid plaque accumulation, tau tangle accumulation, or both.

Method

We studied plasma P‐tau217 in a cohort with post‐mortem neuropathological data (N=88), for correlations with plaque and tangle density, and in a cohort with β‐amyloid and tau PET imaging (“BioFINDER‐2”, N=426).

Result

In the cohort with post‐mortem neuropathological data, both plaque and tangle density contributed independently to higher P‐tau217 (Fig 1). Several findings were replicated in the cohort with PET imaging, where β‐amyloid and tau PET were independently associated to P‐tau217. P‐tau217 correlated with β‐amyloid PET (but not tau PET) in early disease stages, and with both β‐amyloid and (more strongly) tau PET in late disease stages (Fig 2). Finally, P‐tau217 mediated the association between β‐amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe (Fig 3).

Conclusion

These findings support the hypothesis that plasma P‐tau217 is associated with both β‐amyloid plaques and tau tangles and is congruent with the hypothesis that P‐tau is involved in β‐amyloid‐dependent formation of neocortical tau tangles (Fig 4).
Digital Trail Making Test‐Black & White: Normal vs MCI
Authors: Simfukwe Chanda , Youn Young Chul , Kim Sangyun , An Seong Soo
Published: December 2021

Background

Trail Making Test‐Black and White (TMT‐B&W) was developed to assess the cognition of patients with mild cognitive impairment (MCI), dementia, and Alzheimer’s disease. Collection and analysis of test results have been limited due to scoring time and efforts required from both administrators and patients during and after taking the test. To increase efficiency and reducing scoring time, a computer version touchscreen‐based digital trail making test‐black and white (dTMT‐B&W) was developed on Android and it was administered on MCI versus cognitively normal controls (NC) participants. The current study examines the sensitivity of newly developed computer version dTMT‐B&W on NC and MCI subjects.

Method

dTMT‐B&W was developed using MIT app inventor software, a web‐based integrated development environment (IDE) with the Android development tools that are used to build fully functional applications for smartphones and tablets. A total of 44 participants were included, comprised of 22 NC and 22 MCI. The dTMT‐TMT‐B&W was administered to all NC and MCI subjects.

Result

dTMT‐B&W was designed to be as consistent with the pen‐paper TMT‐B&W (ppTMT‐B&W) where the application is a standalone installation. dTMT‐B&W is divided into two parts (Part‐A and Part‐B), in which the subject attempts to connect black and white numbered circles sequentially as quickly as possible, while still maintaining accuracy. Similarly, the paper‐based TMT‐B&W requires the subject to connect black and white numbered circles in ascending order, except on a sheet of paper rather than a tablet. dTMT‐B&W successfully distinguished NC from MCI subjects.

Conclusion

dTMT‐B&W is an Android application that was successfully developed to be as consistent as possible with the original pen‐paper TMT‐B&W to establish equal concurrent validity, with some improved features embedded into the design and dTMT‐B&W revealed a significant correlation with frontal executive function and this can help in early diagnosing subjects with MCI among NC subjects.