bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the associations of trajectories of depressive symptoms and self‐perceived health and incident dementia: An unsupervised machine learning approach
Authors: Klee Matthias , Leist Anja
Published: December 2021

Background

Risk factors for dementia show inter‐individually varying trajectories over the lifespan. However, risk factors have been mainly investigated with one time‐point assessments. New research suggests that certain risk factor trajectories are associated with increased risk of adverse cognitive outcomes (Demnitz et al., 2020 [https://doi.org/10.1101/2020.05.20.20106963]; Singh‐Manoux et al., 2018 [https://doi.org/10.1016/j.jalz.2017.06.2637]). However, it remains unclear how sequential and simultaneous changes of risk factors alter the individual risk for developing dementia. Testing the joint contribution of trajectories of depressive symptoms and self‐perceived health on incidence of dementia, we hypothesized that consistently poor as well as deteriorating trajectories increase the risk for incident dementia, and explored possible interactions of the trajectories.

Method

A total of 5,326 respondents to the SHARE survey, mean age 73.9 years, and 6 complete follow‐ups spanning ∼13 years, answered the EURO‐D depression scale, self‐perceived health (SPH) (t1‐t5), and self‐reported dementia diagnosis at last follow‐up (t6). To investigate the predictive ability of distinct longitudinal trajectories, we applied unsupervised statistical learning methods (K‐means cluster modelling). Clusters indicated distinct risk factor trajectories, which were used as exposures in stepwise logistic regressions to predict incident dementia, controlling for age, gender, education, and country.

Result

Cluster analysis revealed five distinct trajectories each for SPH and EURO‐D, with varying dementia incidence. In stepwise logistic regressions, respondents with trajectories “consistently poor health” and “consistently high depression” showed elevated risk of dementia (OR = 4.02 [1.39, 14.75] and OR = 2.26 [1.03, 4.95], respectively) compared to the combined baseline risk for “consistently low depression” and “consistently good health”. Interactions were not significant. However, respondents with the combination of “consistently high depression” and “consistently poor health” showed increased risk (N = 246; 6.1% dementia).

Conclusion

Applying unsupervised machine learning is helpful to incorporate longitudinal information on depressive symptoms and self‐perceived health and model these risk factors longitudinally to test their contribution to explain incidence of dementia. The predictive ability of the trajectories of depressive symptoms and self‐perceived health for dementia indicates the potential for improving the identification of people at risk for developing dementia in late life by exploiting trajectory information readily accessible through regular medical check‐ups in old age.
Identifying and characterizing patterns of functional decline in memory clinic patients
Authors: Dubbelman Mark A. , Caelers Michael , van der Flier Wiesje M , Scheltens Philip , Sikkes Sietske A.M.
Published: December 2021

Background

Alzheimer’s disease and related disorders (ADRD) are characterized by progressive cognitive and functional decline. To improve prognosis, it is important to predict the expected rate of functional decline. In the current study, we sought to uncover patterns of changes in everyday functioning among memory clinic patients, and to explore factors associated with said groups.

Method

Memory clinic patients (N=573, 64.7±7.9 years old, 39% female) underwent extensive dementia screening at baseline, and were followed over time (median 1.0 years, range 0.3–6.2 years, N observations=1632). Diagnoses included subjective cognitive decline, mild cognitive impairment, and dementia with varying etiologies. We measured everyday functioning with the Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q). Longitudinal latent class analysis (LLCA) was used to identify groups of patients based on their rate of change in IADL, including non‐linear trajectories. We subsequently used random forests to explore the associations between the LLCA groups and demographics, neuropsychological test performance, and magnetic resonance imaging rating scales for medial temporal and global atrophy.

Result

We identified six groups: two stable (high and average), three declining (slow, moderate, and fast), and one improving group (see Table 1, Figure 1). All groups differed in baseline A‐IADL‐Q scores, with the declining groups having lower scores. The fast declining group consisted mostly of dementia patients, whereas the high stable group consisted mostly of patients with subjective cognitive decline. The area under the curve of the random forest classification was .95, thus accurately assigning patients to the correct group based on baseline characteristics. The following variables contributed most to the classification of the groups: baseline A‐IADL‐Q score (mean decrease accuracy [MDA]=200.5), a visuospatial task (copy of Rey Complex Figure, MDA=36.6) and a processing speed task (Letter Digit Substitution Task, MDA=18.5). Atrophy rating scales contributed less.

Conclusion

Different trajectories of functional decline were distinguished, and associated with baseline levels of cognitive and daily functioning. Our findings suggest that neuropsychological assessment may provide additional information on future changes in daily functioning. These findings may contribute to a more accurate prognosis of future functional decline, and by extension, future care needs.
Dementia policy and its implication for supporting people with ADRD during the unprecedented time in China
Authors: Wang Huali
Published: December 2021

Background

Improving dementia care has been prioritized in a community‐based psychosocial support system in China. In 2020, the National Health Commission announced implementing the National Dementia Strategic Plan in more than 60 demonstration areas. The Plan intends to improve community‐based dementia care by utilizing the existing psychosocial support system, creating multidisciplinary teams, and establishing a collaborative network between specialists and primary care services. During the COVID‐19 pandemic, community service has played a pivotal role in supporting residents, especially older adults. Therefore, the study aimed to explore the implications of the National dementia strategic plan in supporting persons living with dementia during the unprecedented time.

Method

We conducted qualitative interviews with ten leaders of community health centers. All the interviews were audio‐recorded and transcribed. Thematic extraction was used for data analysis.

Result

This presentation will report the main findings of the qualitative studies, including the potential of integrating the Dementia strategic plan with community service during the unprecedented times, the barriers and enablers for the implementation, and the interaction between the Plan and the managerial regulations relevant to preventing the cross‐infection of COVID‐19.

Conclusion

Community service is mainstream both for COVID‐19 prevention and dementia care. There is a great potential to integrate the national dementia strategic plan with the community psychosocial support tackling the disaster response during the unprecedented time.
Electrophysiological differences between older women and men in the absence of disease: A step closer to personalized medicine
Authors: de Frutos Jaisalmer , Cuesta Pablo , Fernández Ricardo Bruña , Vilca Brenda Chino , Torres Lucia , Arrazola Juan , Higes Ramón López , Dolado Alberto Marcos , Maestú Fernando
Published: December 2021

Background

Multiple electrophysiological footprints have been identified to be associated with silent and clinical neuropathological processes predicting mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Nevertheless, it is important to bear in mind that women show greater risk of developing both MCI and AD. Therefore, it is crucial to understand in first place how sex differences might modulate these electrophysiological mechanisms in healthy older adults.

Method

240 healthy cognitively normal older adults (age = 60 ‐ 85) participated in this study. They were divided into two groups: women (n = 140) and men (n = 120), matched in age and educational level. Each individual underwent four minutes of closed eyes resting state MEG recording. The aim was to detect any clusters where power was significantly associated with sex and also any networks where functional connectivity was associated with sex (total intracranial volume and age where used as covariates p‐value < 0.01) in either frequency band (gamma, beta, alpha, theta and delta).

Result

Women showed greater power in the beta band in a posterior cluster composed of occipital and temporal brain regions. Additionally women also showed greater functional connectivity across all frequency bands, always in frontal brain networks.

Conclusion

Even in the absence of an undergoing neuropathological process, men and women present differential patterns of brain connectivity and power. The role that these differences play in the pathogenesis of Alzheimer’s disease remains to be fully understood. However, these differential baseline characteristics should be accounted for in studies aiming to establish electrophysiological markers of AD.
A multimodal study on the effect of sex on Alzheimer's disease clinical and biomarker changes in adults with Down syndrome
Authors: Iulita M. Florencia , Bejanin Alexandre , Vilaplana Eduard , Carmona‐Iragui Maria , Benejam Bessy , Videla Laura , Barroeta Isabel , Fernandez Susana , Altuna Miren , Pegueroles Jordi , Montal Victor , Valldeneu Sílvia , Giménez Sandra , González‐Ortiz Sofía , Muñoz Laia , Padilla Concepción , Aranha Mateus Rozalem , Estellés Teresa , Illán‐Gala Ignacio , Belbin Olivia , Tamayo Natalia Valle , Camacho Valle , Wilson Liam , Annus Tiina , Osorio Ricardo , Videla Sebastián , Lehmann Sylvain , Holland Anthony J , Zetterberg Henrik , Blennow Kaj , Alcolea Daniel , Clarimón Jordi , Zaman Shahid , Blesa Rafael , Lleó Alberto , Fortea Juan
Published: December 2021

Background

The study of sex differences in Alzheimer's disease (AD) is gaining increasing attention. Yet, few studies have examined the effect of sex in genetically determined forms of AD. Here, we explored the impact of sex on AD‐related clinical and biomarker changes in a population‐based cohort of adults with Down syndrome, who have a lifetime risk of over 90% to develop AD.

Method

This is a cross‐sectional study of 549 adults with Down syndrome. We compared AD prevalence, as well as cognitive and AD biomarker changes, in relation to age and sex in the whole cohort. Participants underwent neuropsychological examination with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG‐DS) and modified cued recall test (mCRT). Most also had at least one biomarker assessment of amyloid pathology (CSF Aβ42, Aβ42/40 ratio and amyloid‐PET), tau (CSF and plasma p‐Tau‐181) and neurodegeneration (CSF and plasma NfL, FDG‐PET and 3T structural MRI). We used within‐group locally estimated scatterplot smoothing (LOESS) models to compare the trajectory of biomarker changes with age in women versus men, as well as the interaction with the APOE ε4 allele.

Result

The prevalence of AD across five‐year age intervals and the mean age at AD diagnosis was similar between men and women. Men and women had similar trajectories in CAMCOG scores with age, but men showed lower mCRT scores from age 45 years. There were no differences between men and women in the CSF Aβ42/40 ratio or amyloid‐PET, or in the trajectories of tau and neurodegeneration biomarkers. When considering the APOE genotype, women carrying the ε4 allele showed an earlier age at AD diagnosis and higher prevalence of symptomatic AD between ages 40‐45 compared to non‐carriers. The female advantage on mCRT scores was lost in women carrying an ε4 allele.

Conclusion

Sex did not have a main effect on AD risk or biomarker changes. However, APOE ε4 modified the age at symptomatic AD diagnosis and age‐related mCRT scores in women, but not in men. These results emphasize the complexity of the relationship between biological sex and AD, and the need to further explore interactions with APOE ε4.
CSF tau phosphorylation occupancy at t217 increases in MAPT R406W mutation carriers without amyloid pathology
Authors: Sato Chihiro , Mallipeddi Nipun , Ghoshal Nupur , Wright Brenton A. , Day Gregory S. , Davis Albert A. , Kim Albert H. , Zipfel Gregory J. , Bateman Randall J. , Gabelle Audrey , Barthelemy Nicolas R.
Published: December 2021

Background

Tau hyperphosphorylation at Threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer disease (AD). However, it remains unclear whether pT217 could be modified in other tauopathies. Using immunoprecipitation and mass spectrometry, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid beta (Aβ) 42/40 ratio in cognitively normal controls, and individuals with AD, Progressive Supranuclear Palsy (PSP), Corticobasal Syndrome (CBS), and sporadic and familial Frontotemporal Dementia (FTD).

Method

CSF Aβ, tau and phosphorylated tau (p‐tau) were measured using immunoprecipitation and quantitative mass spectrometry methods. Amyloid and tau Positron Emission Topography (PET) imaging were measured in a subset of participants and analyzed for correlation. Quadrant analyses were performed to assess amyloid and p‐tau positivity.

Result

We confirmed the strong association between CSF Aβ 42/40 and pT217 measures in most samples. Individuals with AD had high CSF pT217/T217 and low Aβ 42/40. In contrast, controls and the majority of patients with other tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio relative to controls. Most of these individuals were identified as MAPT R406W mutation carriers, a tau mutation leading to 3R+4R tauopathy similar to AD but without amyloid pathology. Diagnostic accuracies of CSF Aβ 42/40 alone, CSF pT217/T217 alone, and combination of both biomarkers were examined. We show that combination of both biomarkers can separate MAPT R406W carriers from control (AUC=0.960) and other tauopathies that are primarily 4R tauopathies (AUC=0.934).

Conclusion

We demonstrate the importance of measuring both CSF Aβ 42/40 and pT217/T217 to improve AD diagnosis and differentiate MAPT R406W mutation carriers. This supports that changes in CSF pT217/T217 ratio is not a specific biomarker for AD but reflects common downstream tau pathology in these two 3R+4R tauopathies.
Moderate to vigorous physical activity and sedentary time as predictors of cognitive function in older adults with hypertension: NHANES 2011‐2014
Authors: Hoffmann Coles M , Petrov Megan E
Published: December 2021

Background

Hypertension is associated with increased risk for cognitive decline. Lifestyle behaviors such as moderate to vigorous physical activity (MVPA) and sedentary time (ST) may mitigate this decline, though limited research on the joint association exists. The aim of the study was to examine the joint association of MVPA and ST on cognitive function by hypertension status.

Methods

Adults (n=2916, ≥60yrs) from the 2011‐2014 National Health and Nutrition Examination Survey (NHANES) were assessed for their participation in MVPA (meets recommendations: ≥150min MPA and/or ≥75min MPA vs does not meet recommendations: <150min MPA and <75min VPA), self‐reported ST (≤7hrs ST vs >7hrs ST), hypertension, and cognitive function (Digit Symbol Substitution Test [DSST]; Animal Fluency [AF] test). Weighted linear regression analyses were conducted to assess joint association of MVPA and ST on cognitive function, and test the modifying effect of hypertension status (alpha level set at 0.1) after adjustment for demographics, cardiovascular disease, diabetes, body mass index (BMI), and depression.

Results

See Table. There were significant main effects for combined MVPA and ST on DSST (Wald F(3,30)=3.393, p=.031) and AF (Wald F(3,30)=17.33, p<.001). Participants who did not meet MVPA recommendations regardless of ST had significantly worse scores on DSST compared to participants who met MVPA recommendations and reported ≤7hr ST. Participants who did not meet MVPA recommendations and had ≤7hr ST had significantly worse scores on AF. There was a significant interaction between MVPA‐ST groups and hypertension status on AF (Wald F(3,30)=3.766, p=.021), but not on DSST. Stratified analyses indicated among individuals without hypertension significance was maintained. For participants with hypertension, not meeting MVPA recommendations regardless of ST was associated with significantly worse scores.

Conclusions

In a sample of adults, meeting recommendations for MVPA was associated with better cognitive outcomes regardless of ST. Among individuals with hypertension regular MVPA regardless of ST was significantly associated with higher scores on one measure of executive function. This research highlights the added importance for individuals with hypertension to participate in the recommended amount of MVPA.
Quantitative assessment of cortical excitability in Alzheimer’s dementia and its association with clinical symptoms: A systematic review and meta‐analyses
Authors: Joseph Shaylyn , Patterson Rachel A. , Wang Wei , Blumberger Daniel M. , Rajji Tarek K. , Kumar Sanjeev
Published: December 2021

Background

Alzheimer’s Disease (AD) is characterized by cognitive and neuropsychiatric symptoms (NPS). Studies using electroencephalography (EEG) have shown increased epileptiform and epileptic activity in AD. Transcranial magnetic stimulation (TMS) studies have also shown abnormal cortical excitability in AD, however findings have been inconsistent. Further, relationship between cortical excitability and clinical symptoms of AD is not clear. This review and meta‐analyses aims to synthesize the existing evidence for abnormal cortical excitability in AD and its relationship with clinical symptoms.

Method

We systematically searched and reviewed publications that quantitatively assessed cortical excitability, using TMS resting motor threshold (rMT), active motor threshold (aMT), motor evoked potential (MEP) or directly from the cortex using TMS‐EEG via TMS‐evoked potential (TEP). Effect sizes and 95% confidence intervals (CI) of rMT and aMT were calculated using Hedges’ g and meta‐analyzed using a random effects model. Heterogeneity among studies was assessed by Cochran’s Q and I2 statistic.

Result

We identified 895 publications out of which 68 were reviewed in full‐text and 37 were included in the final review. Thirty studies using rMT and seven using aMT were included in the meta‐analyses. The AD group had reduced rMT (Hedges’ g = ‐0.99, 95% CI [‐1.29, ‐0.68], p < 0.00001) and aMT (Hedges’ g = ‐0.87, 95% CI [‐1.50, ‐0.24], p < 0.00001) as compared with control groups, indicative of higher cortical excitability. Evidence of considerable heterogeneity was found across the studies (Q (29) = 85.68, p < 0.00001, I2 =81%). Qualitative review of the literature showed some evidence of increased MEP amplitude (n = 2 studies), however findings related to TEP were inconsistent. Further, there was some evidence (n = 4 studies) supporting an inverse association between cortical excitability and global cognition. No publications reported on the relationship between cortical excitability and neuropsychiatric symptoms (NPS).

Conclusion

There is strong evidence of increased motor cortex excitability in AD and some evidence of an inverse association between excitability and cognition. Future studies should assess cortical excitability from non‐motor areas and examine its relationship with cognition and NPS.
Assessments of instrumental activities of daily living in low‐middle income countries: A systematic review
Authors: Ardle Ríona Mc , Yemm Heather , Goodon Michaela , Poole Marie , Narytnyk Alla , Dotchin Catherine , Paddick Stella‐Maria , Robinson Louise
Published: December 2021

Background

Dementia prevalence in low‐middle income countries (LMIC) is projected to rise exponentially by 2050. However, less than 10% of people with dementia have a formal diagnosis, partially due to difficulties in clinically recognizing and diagnosing dementia. Culturally‐appropriate screening tools for dementia are needed. As functional impairments are fundamental elements of dementia diagnosis, assessments of instrumental activities of daily living (IADLs) may be appropriate screening tools. IADLS are complex daily tasks required to maintain functional independence (e.g. managing finances). They are susceptible to cultural variation, such as differences in gender roles cultural responsibilities of older adults in LMICs (e.g. social‐orientated activities). IADL assessments validated in high‐income countries may not be appropriate for LMICs. The aim of this systematic review is to identify IADL assessments which have been developed, validated or adapted for use in LMICs, and report how accurate, valid and reliable these tools are for identifying dementia.

Method

2,507 articles were systematically reviewed during title and abstract screen. 46 full‐text articles were reviewed for inclusion, with 16 English‐language articles confirmed and 13 currently undergoing final adjudication.

Results

From the confirmed 16 articles, 10 LMIC countries are represented (Figure 1). 16 different IADL assessments were investigated; two studies compared two different IADL tools. Eight (50%) were existing tools translated from their original language into a target language (in Brazil (n=4), Turkey (n=2), Iran (n=1), Argentina (n=1)), three (19%) were existing scales culturally adapted and translated to a target language (Brazil (n=3)), and six (38%) were novel tools developed for specific cultures (in Tanzania (n=1), India (n=2), Thailand (n=1), Nigeria (n=1), Republic of Congo and Central African Republic (n=1)). Eight studies (50%) reported accuracy of tools to correctly identify dementia. Sensitivity ranged between 63‐97% and specificity between 69‐100%.

Conclusion

From preliminary trends, bespoke culturally‐specific tools are more likely to be investigated in African and South Asian countries, while translated Western tools are more likely to be investigated in South American and West Asian countries. It is currently unclear which approach is best, but further synthesis will lead to recommendations regarding future validation and adoption of valid, reliable IADL tools in LMICs.
Everyday functioning in a community‐based volunteer population: Factors associated with concordance between participant and study partner—Report
Authors: Verrijp Merike , Dubbelman Mark A. , Visser Leonie N.C. , Jutten Roos J. , Nijhuis Elke W , Van Hout Hein PJ , Scheltens Philip , van der Flier Wiesje M , Sikkes Sietske A.M.
Published: December 2021

Background

With the shift towards preclinical phases of Alzheimer’s disease (AD) and other neurodegenerative diseases in research studies and clinical trials, the question arises if participants can reliably self‐report their level of everyday functioning. Here, we aim to investigate the factors related to concordance between participant‐ and study partner‐report versions of the Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q) in a community‐based volunteer population.

Method

Community based volunteers (participants) and their study partners were recruited from a Dutch brain research registry. IADL concordance between participant and study partner was investigated using intraclass correlation coefficient (ICC). Dyads were subsequently categorized as (1) concordant (<2 points differences in A‐IADL‐Q score); (2) discordant, with study partner reporting more difficulties (study partner>participant) and (3) discordant, participant>study partner. Multinomial logistic regression models were used to investigate the association between subjective cognitive decline, depressive symptoms (Geriatric Depression Scale‐5), type of relationship, objective cognitive functioning (Cognitive Online Self‐Test Amsterdam), and concordance as dependent variable.

Result

A total of 1213 participants (18‐93 years of age, 68.3% female) and 1213 study partners (18‐88 years, 45.8% female) completed the A‐IADL‐Q. The majority of participants (52.8%) and study partners (59.5%) reported no IADL difficulties. Figure 1 shows the percentage of IADL difficulty reported for individual activities by both participants and study partners. Of the dyads, 653 (53.8%) were in concordance, with an ICC of .55 (95%CI=[.51, .59], Figure 2). Depressive symptoms and memory complaints increased the odds of participants reporting more IADL difficulties compared to their study partner (odds ratio (OR)=1.31, p<.01 and OR=2.56, p<.01, Table 1). An inverse association was found between A‐IADL‐Q and concordance, to the extent that higher A‐IADL‐Q scores were associated with a lower odds of study partner>participant discordance (OR=0.68, p<.01).

Conclusion

A slight majority of dyads showed concordance between participant‐ and study partner‐reported IADL scores. Our findings suggest that concordance is less likely in the presence of memory complaints, depressive symptoms and with lower levels of everyday functioning. These findings implicate that participant‐ and study partner report capture different aspects of functional decline, which might influence the study design of longitudinal aging studies.
Plasma biomarkers predict longitudinal amyloid accumulation, tau burden, brain atrophy and cognitive decline in early Alzheimer’s disease
Authors: Pereira Joana B. , Janelidze Shorena , Stomrud Erik , Palmqvist Sebastian , Dage Jeffrey L. , Mattsson‐Carlgren Niklas , Hansson Oskar
Published: December 2021

Background

It is currently unclear whether plasma biomarkers can be used as independent prognostic tools for early Alzheimer’s disease (AD). In this study we sought to address this question by assessing whether plasma biomarkers can predict changes in amyloid load, tau accumulation, brain atrophy and cognition in non‐demented individuals.

Method

To achieve this, plasma amyloid‐β 42/40 (Aβ42/40), phosphorylated‐tau181 (P‐tau181), phosphorylated‐tau217 (P‐tau217) and neurofilament light (NfL) were determined in 120 non‐demented individuals, 123 patients with AD dementia and 15 patients with a non‐AD dementia from the Swedish BioFINDER‐2 study, who underwent longitudinal amyloid (18F‐flutemetamol) and tau (18F‐RO948) positron emission tomography (PET), structural magnetic resonance imaging (T1‐weighted) and cognitive testing.

Result

Our univariate linear mixed effect models showed there were several significant associations between the plasma biomarkers with imaging and cognitive measures. However, when all biomarkers were included in the same multivariate linear mixed effect models, we found that increased longitudinal amyloid‐PET signals were independently predicted by low baseline plasma Aβ42/40 (p = 0.011), whereas increased tau‐PET signals, brain atrophy and worse cognition were independently predicted by high plasma P‐tau217 (p < 0.004). These biomarkers performed equally well or better than the corresponding biomarkers measured in the cerebrospinal fluid and showed a similar performance to binary plasma biomarker values, which can be more easily implemented in the clinic and were defined using the Youden index as the optimal cut‐offs that could discriminate a sample of Aβ‐negative cognitively normal individuals from AD dementia patients. In addition, plasma Aβ42/40 and P‐tau217 did not predict longitudinal changes in patients with a non‐AD dementia.

Conclusion

In conclusion, our findings indicate that plasma Aβ42/40 and P‐tau217 could be useful in clinical practice, research and drug development as prognostic markers of future AD pathology.
Breast cancer therapies reduce risk of Alzheimer’s disease and dementia: A claims‐based retrospective study with clinic to bench implications
Authors: Branigan Gregory L , Torrandell‐Haro Georgina , Brinton Roberta Diaz
Published: December 2021

Background

Worldwide, breast cancer is the most common non‐skin cancer in women. Currently, Alzheimer’s disease affects 1 in 9 persons in the US over the age of 65, two thirds of whom are women. The high global prevalence and economic impact of Alzheimer’s disease presents a significant public health challenge while the identification of therapies to prevent Alzheimer’s disease (AD) remains a challenge. The object of this study was to determine whether estrogen modulating therapy (EMT) exposure is associated with risk of Alzheimer’s (AD) in women with breast cancer in the Symphony claims data set and identify potential mechanisms by which these drugs may impact risk.

Methods

Patients receiving EMT for breast cancer treatment were identified and survival analysis, stratified by age and by individual therapeutics, was used to determine the association between EMT exposure and diagnosis of AD. A propensity score approach was used to minimize measured and unmeasured selection bias. The impact of the impact of EMT on mitochondrial bioenergetics and dynamics were determined using Metabolic flux analysis and live cell imaging using Rat E18 hippocampal neurons.

Results

In this cohort study of propensity score matched perimenopausal to postmenopausal aged women with breast cancer, EMT exposure was associated with decrease in diagnosis of neurodegenerative disease, most specifically AD (RR, 0.85; 95% CI, 0.78‐0.92; P < 0.001) and Dementia (RR, 0.88; 95% CI, 0.84‐0.93; P < 0.001). The preventative effect of EMT was shown to increase with age and was associated with a 5‐year shift in disease conversion rate. Mitochondrial bioenergetic data suggest that tamoxifen and the aromatase inhibitors show estrogen‐like response.

Conclusion

Among female patients with breast cancer, exposure to estrogen modulating therapies was associated with a decrease in diagnosis of AD and Dementia. If tamoxifen and aromatase inhibitors are acting to increase estrogen‐related actions in brain tissue, the argument for the protective association of estrogen with AD‐related outcomes is strengthened. Funding: This study was supported by grants from the Women’s Alzheimer’s Movement, National Institute on Aging grants P01AG026572 Perimenopause in Brain Aging and Alzheimer's Disease and T32AG061897 Translational Research in AD and related Dementias (TRADD) to RDB.
Individual classes of prostate cancer therapies impact risk of Alzheimer’s disease: A claims‐based retrospective study
Authors: Branigan Gregory L , Torrandell‐Haro Georgina , Brinton Roberta Diaz
Published: December 2021

Background

Prostate cancer is the most prevalent non‐skin cancer in men and the second leading cause of cancer related deaths among men worldwide. There are growing concerns regarding a potential association between androgen targeting therapeutic exposure and Alzheimer’s disease (AD) where the existent literature is limited and highly controversial. The object of this study was to determine whether androgen targeting therapy (ATT) exposure is associated with risk of Alzheimer’s (AD) in men with prostate cancer in the Symphony claims data set.

Methods

Patients receiving ATT for prostate cancer treatment were identified and survival analysis, stratified by age and by individual therapeutics, was used to determine the association between EMT exposure and diagnosis of AD. A propensity score approach was used to minimize measured and unmeasured selection bias. Individual classes of ATT were examined to determine risk impact profiles for each therapeutic target of hormone ablation in prostate cancer treatment.

Results

In this cohort study of propensity score matched men, all ATT class exposure taken together was associated with no impact in diagnosis of neurodegenerative disease (RR, 1.01; 95% CI, 0.96‐1.07; P = 0.56). The class of androgen synthesis inhibitors were associated with a decreased risk of AD (RR, 0.61; 95% CI, 0.46‐0.80; P < 0.001) whereas the class of androgen receptor blockers were associated with an increased risk of AD (RR, 1.29; 95% CI, 1.13‐1.34; P < 0.001). All other classes of ATT were associated with increased AD risk.

Conclusion

Among male patients with prostate cancer, exposure to the androgen synthesis inhibitor class of androgen targeting therapy was associated with a decrease in diagnosis of AD and Dementia. All other types of ATT were associated with an increased risk of AD diagnosis. These data help to explain the current controversies in the literature where groups reporting impact of ATT as a composite of each individual drug suggest contradicting results on AD risk. Funding: This study was supported by grants from the Women’s Alzheimer’s Movement, National Institute on Aging grants P01AG026572 Perimenopause in Brain Aging and Alzheimer's Disease and T32AG061897 Translational Research in AD and related Dementias (TRADD) to RDB.
Mitigation of cognitive decline and brain pathology after transaortic constriction by Mas agonists
Authors: Reyes‐Reyes Elsa M , Jadhav Sachin , Soto Maira , Gaffney Kevin , Rodgers Kathleen E
Published: December 2021

Background

Mas and A(1‐7), the endogenous ligand of Mas, were first characterized for their ability to counter regulate the pathological actions of A‐II and AT1R. A(1‐7) has been shown to decrease inflammation and OS and increase cerebral blood flow reactivity. Plasma A(1‐7) levels were decreased in AD patients as compared to age and gender matched controls. Intra‐cerebroventricular (ICV) infusion of A(1‐7) improved cognitive and cerebrovascular function in mice receiving ICV infusion of A‐II. In SAMP8 and in P301S mice, low brain levels of A(1‐7) were correlated with increased tau hyperphosphorylation. However, the short half‐life and lack of oral bioavailability of A(1‐7) make it challenging to develop as a therapeutic modality. In order to overcome this shortcoming, our lab has developed equipotent small molecule analogs of A(1‐7), RASRx1902 and RASRx1911.

Method

C57/Bl6 mice underwent transaortic constriction (TAC). One week later, echocardiography was performed and the animals randomized based on their TAC gradient and treatment (vehicle or 2 mg/kg RASx1902 or RASRx 1911 subcutaneously, once daily for 12 weeks. After 10 weeks of treatment, the mice underwent novel object recognition. At necropsy, brain tissue was analyzed by flow cytometry and levels of inflammatory cytokines by MSD.

Result

TAC surgery alone resulted in reduced cognitive function measured by NOR. This cognitive decline was reversed by RASRx1902 and RASRx1911 treatment. Treatment with RASRx1902 and RASRx1911 also reduced the levels of microglial and neuronal mitochondrial dysfunction, oxidative stress (OS) and inflammation seen in saline treated mice to levels comparable to sham controls.

Conclusion

In conclusion, RASRx1902 and RASRx1911 resulted in improved cognition and reduced OS and inflammation in the brain of mice that had undergone TAC surgery.
Measuring the developmental relationship between memory ability and organization of a functional brain network vulnerable to Alzheimer’s disease: Preliminary findings from the PRANK study
Authors: Behm Lillian , Phipps Connor J. , Sexton Jennifer N. , DeCesare Thomas A. , Heller Abi M. , Maerlender Arthur C. , Phatak Vaishali S. , Cramer Justin A. , Blair James , Murman Daniel L. , Warren David E.
Published: December 2021

Background

The hallmark memory impairments of typically presenting Alzheimer’s disease (AD) are associated with pathological changes of the hippocampus. While it is known that the hippocampus is necessary for normal relational memory performance, the development of functional brain networks associated with the hippocampus is not well characterized, particularly in the periadolescent epoch. The development of the hippocampus and its associated functional brain network may be influenced by genetic, environmental, or other risk factors for AD, potentially creating vulnerabilities to AD in later life. This project explores the neurodevelopment of this hippocampal network to determine how individual differences in functional connectivity impact relational memory abilities during the periadolescent epoch. Here, we utilized preliminary data from the NIA‐funded Polygenic Risk of Alzheimer’s Disease in Nebraska Kids (PRANK) study, which aims to improve insight regarding how brain and cognitive development is affected by polygenic risk for Alzheimer’s disease. Our continuing study is recruiting healthy periadolescent individuals (8‐13 years of age). Here we report preliminary cross‐sectional findings from the PRANK study exploring how individual differences in hippocampal resting‐state functional connectivity (RSFC) covary with declarative/relational memory ability.

Method

Analyses were conducted on preliminary data from healthy periadolescent participants (n=40). Declarative/relational memory performance was measured with Cambridge Cognition’s Paired Associates Learning (PAL) task. Resting‐state functional MRI data was analyzed using a seed‐based approach with the bilateral hippocampus as the seed region of interest. RSFC data were analyzed to determine their covariance with relational memory ability (operationalized as PAL performance).

Result

Our analysis revealed patterns of hippocampal RSFC that were broadly consistent with prior work, sharing the territory of the default mode network (DMN). We also observed regional covariance between hippocampal RSFC and performance on the PAL task.

Conclusion

The present work describes preliminary findings of the ongoing PRANK study. Our preliminary observations are consistent with the perspective that hippocampal RSFC covaries with hippocampal‐dependent declarative/relation memory ability among periadolescent children. To understand whether this hippocampal network development is susceptible to genetic risk factors for AD, future work from the PRANK study will utilize participants’ AD polygenic risk scores to determine whether those scores are related to individual differences of hippocampal RSFC.
Dual‐task gait and mild behavioral impairment: Findings on the interface between non‐cognitive dementia markers in the COMPASS‐ND study
Authors: Guan Dylan X. , Chen Hung‐Yu , Camicioli Richard , Montero‐Odasso Manuel , Smith Eric E. , Ismail Zahinoor
Published: December 2021

Background

Mild behavioral impairment (MBI) and poor dual‐task gait performance are non‐cognitive markers for dementia. Both MBI and dual‐task gait performance have been associated with an increased risk of cognitive decline, but to our knowledge the relationship between them has yet to be investigated.

Method

Cross‐sectional data from 193 non‐demented participants (10 cognitively normal, 48 subjective cognitive decline, 135 mild cognitive impairment; MCI) in the COMPASS‐ND study (February 2020 release) were analyzed. MBI was approximated using the Neuropsychiatric Inventory Questionnaire (NPI‐Q) using a published algorithm. Dual‐task gait cost (DTGC), operationalized as the percentage difference between dual‐task and preferred walking speeds, was assessed under three cognitive tasks: animal naming, counting backwards by one, and serial seven subtractions. Multivariable linear regression was used to determine the association between global MBI burden and DTGC, adjusting for age, sex, years of education, and Montreal Cognitive Assessment (MoCA) score, or diagnosis. Models were additionally fitted for the subgroup of participants with MCI alone. Mediation analyses were conducted using bootstrapping to determine if the association between MBI and DTGC was mediated by global cognition (MoCA), executive function (Trail Making B), verbal (Rey Auditory Verbal Learning Test) or working (Digit Span) memory.

Result

Participants on average were 72.4 years old (52.8% female) and had completed 15.8 years of education. MBI symptoms were observed in 46.6% of participants. Greater overall MBI burden was associated with reduced gait speed and higher DTGC for all three gait conditions in MCI, and in all participants without dementia when controlling for diagnosis or MoCA (Table 1), except for DTGC under animal naming conditions when controlling for MoCA. The associations between MBI and DTGC were mediated by executive function but not global cognition, verbal or working memory (Table 2).

Conclusion

In this group of older adults at risk but without dementia (SCD and MCI spectrum), MBI is associated with DTGC, which in itself is a dementia risk marker. Our findings support the role of these non‐cognitive dementia markers in the detection of at‐risk individuals. Identification of older adults at risk of incident dementia may be enhanced by considering MBI and DTGC in conjunction.
Ketones and improved cognition in MCI: Links to ApoE and white matter energetics
Authors: Cunnane Stephen , Roy Maggie , Rheault François , Fortier Melanie , Descoteaux Maxime , Castellano Christian‐Alexandre , St. Pierre Valerie , Bocti Christian , Fulop Tamas
Published: December 2021

Background

The capacity of ketones to improve cognition in mild cognitive impairment (MCI) may depend on ApoE4 status. In the BENEFIC RCT (NCT02551419), improvement in three cognitive domains was directly related to ketones from medium chain triglyceride (kMCT) improving global brain energy status. Post‐kMCT, ketone uptake increased 2.9‐fold in total white matter (WM) and was significantly positively correlated to improved processing speed composite score in 8/9 WM fascicles, especially the fornix (r = 0.47‐0.61; p = 0.014‐0.072; n=16‐17/group). Here we report from the same trial the relationship to both ApoE4(‐) and to WM structural properties post‐intervention.

Methods

In MCI, cognitive outcomes were assessed before and after a 6‐month intervention involving an active arm (15 g kMCT twice/day; n=39) and placebo arm (non‐ketogenic vegetable oil; n=43), both emulsified into a lactose‐free skim milk drink. Brain imaging (18F‐fluorodeoxyglucose [FDG] and 11C‐acetoacetate PET, diffusion MRI at 3 Tesla) was done on a subset of the main cohort.

Results

Participant demographics and imaging methods were previously reported (Fortier et al. Alz Dementia 2019). In ApoE4(‐) participants, two measures of executive function (verbal fluency [p≤0.016] and Stroop total errors [0.008]) improved more post‐kMCT (n=28) compared to placebo (n=32). Faster completion of the Trail‐making test (motor speed and visual scanning conditions that measure attention and processing speed), was also directly correlated to higher ketone uptake in most of these nine fascicles. Six months on kMCT did not significantly affect WM fascicle structural properties measured by diffusion imaging (apparent fiber density, free water). Diffusion‐tensor imaging metrics and FDG uptake were also unaffected in total WM and in most individual fascicles.

Conclusions

In MCI, the beneficial effect of kMCT on executive function was greater in ApoE4(‐). Better processing speed and attention was directly linked to improved WM energetics, specifically higher ketone uptake in fascicles affected in AD, but did not alter WM structural properties measurable by diffusion imaging. Ketones improved outcomes in all five main cognitive domains in MCI so a ketone‐based prevention‐type trial to delay the onset of AD is warranted. Acknowledgements: Supported by the Alzheimer Association, Nestlé Health Science, MITACS, FRQS and USherbrooke.
Entorhinal thickness: A marker of DHA supplementation efficacy?
Authors: Yassine Hussein N , Solomon Victoria A , He Xulei , Cordova Isabella , Kono Naoko , Mack Wendy J , Chui Helena C , Schneider Lon S , Harrington Michael G , Braskie Meredith N , Fonteh Alfred N
Published: December 2021

Background

The entorhinal cortex (ERC) area in the brain is affected early in AD, particularly among APOE4 carriers. We previously reported a positive association between plasma phospholipid docosahexaenoic acid (DHA) levels and the ERC thickness in the Aging Brain Program. We hypothesize that increases in plasma DHA after high‐dose DHA supplementation protects against thinning of the ERC when started before cognitive impairment including in APOE4 carriers, and that ERC thickness can be a useful marker for DHA supplementation efficacy.

Method

We examined the effect of DHA treatment and association of plasma DHA species on the changes in the ERC area in the DHA Brain Delivery Pilot Trial (NCT02541929). T1‐weighted MRI scans were collected at 3T and FreeSurfer software was used to segment the ERC thickness. Total DHA, DHA in phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and phosphatidylethanolamine (PE) were measured in plasma together with Red blood cell (RBC) DHA levels before and after randomization to 2 grams of triglyceride DHA per day vs placebo over 6 months (n=28). Participants were all cognitively normal, consumed less than 200 mg of DHA per day, and were stratified by APOE4 genotype before randomization.

Result

DHA treatment, adjusted for APOE4, was associated with a significant increase in ERC area thickness compared with placebo (mean group difference in ERC change (95% CI) 0.161 (0.003, 0.319), p=0.046). Among DHA subspecies measured, greater increase in plasma PC DHA levels after supplementation was significantly correlated with greater ERC area (mean ERC change per SD of PC DHA=0.103, p=0.011). The association persisted after adjusting for APOE4 status (mean ERC change per SD of PC DHA=0.109, p=0.007), indicating that the effect was independent of APOE4 status.

Conclusion

These preliminary findings support a protective effect of high dose DHA in preserving the ERC thickness, including among APOE4 carriers. This finding supports early intervention, before the onset of cognitive impairment, with high dose DHA supplementation in individuals at risk of cognitive decline. PREVENTE4 trial (NCT03613844) is ongoing to help understand whether high dose DHA can prevent cognitive decline in individuals at increased risk of AD.

HNY is supported by AA NIRG‐15‐361854, R01AG054434, R21AG056518, ADDF GC‐201711‐2014197.