bluuebunny/crossref_metadata_2025 huggingface dataset:
Diverse patterns of Tau radiotracer binding progression in Alzheimer’s disease: A two‐year tau PET imaging study
Authors: Lagarde Julien , Olivieri Pauline , Tonietto Matteo , Gervais Philippe , Caillé Fabien , Moussion Martin , Bottlaender Michel , Sarazin Marie
Published: December 2023

Background

Positron emission tomography (PET) imaging enables the in vivo detection of amyloid and tau pathologies. The longitudinal progression of [18F]‐flortaucipir PET imaging could be of interest to better understand the spatial and temporal relationships between tauopathy, cortical atrophy, and the cognitive decline.

Method

We explored the longitudinal progression of the tau radiotracer binding and of cortical atrophy over 2 years in a cohort of 27 prodromal/mild AD patients (positive CSF biomarkers and amyloid‐PET) compared with twelve amyloid‐negative controls. All subjects underwent a complete neuropsychological assessment, 3T brain MRI, [11C]‐PiB and [18F]‐flortaucipir PET imaging (Tau1), and were monitored annually over 2 years, with a second brain MRI and tau PET imaging (Tau2) after 2 years. We studied the longitudinal progression of tau radiotracer binding (Tau2‐Tau1) in AD patients and used mixed effects models to explore the relations between the progression of tau binding or cortical atrophy and cognitive decline.

Result

We found an average longitudinal increase in tau radiotracer binding in most cortical regions, especially in the frontal cortex, but an average decrease in the lateral temporoparietal cortex. In this region, individual analyses revealed two distinct evolutions of tau radiotracer binding according to Tau1 uptake: low‐Tau1 AD patients (SUVr<1.6) demonstrated an increase in tau radiotracer uptake in all cortical regions and a slow clinical progression, whereas high‐Tau1 patients demonstrated a paradoxical plateauing or decrease of tau tracer uptake in the temporoparietal cortex and a faster clinical progression. Cognitive decline was weakly associated with Tau2‐Tau1, but strongly associated with the regional cortical atrophy progression.

Conclusion

Our results suggest that tau PET imaging could detect patients with a “more aggressive” biological form of AD characterized by high temporo‐parietal Tau1 binding. In these patients, the decrease of temporo‐parietal tau tracer binding over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. This information may be considered to improve the design of clinical trials and the definition of the neuroimaging outcomes (choice of the tau‐PET regions of interest, consideration of the evolution of cortical atrophy as a reliable reflection of the clinical progression).
Cognitive Health and Functional Abilities of Illiterate Older Peruvians
Authors: Caipa Maritza Pintado , Lanata Serggio , Custodio Nilton
Published: December 2023

Background

The demographic changes are clearly affecting developing countries like Peru. Is estimated that approximately 7% of the population in the capital city of Lima, Peru, lives with dementia but there is no knowledge of the cognitive health of illiterate older in urban and rural communities outside Lima, where 41.5% of older adults living in these communities are illiterate. On the other hand, Peru is home to tremendous social and geocultural diversity, which may mitigate the worrisome dementia risk. In this respect, it is interesting to note that many older Peruvians remain active preserved and prolonged functional independence in their respective communities for long periods of time. Additionally, in Peru, several brief cognitive tests have been validated in urban cohorts (mostly within Lima) with elementary level education, but, to our knowledge, no brief tests of cognition or functionality have been validated in illiterate Peruvians. These observations raise important research questions that the present pilot proposal seeks to begin investigating.

Methods

We are characterizing the cognitive health and functional abilities of rural and urban illiterate older adults living in two geoculturally‐distinct regions of Peru, the Andean and Amazonian regions. Within the Andes region, we are studying a cohort of illiterate older adults living in the urban area of Cuzco and another cohort from the rural area of Pomacanchis ‐ Cuzco; within the Amazon region, we will study a cohort of illiterate older adults living in the urban area of Iquitos and another cohort from the rural area of San Reyes. We are conducting a gold standard neurological, neuropsychological, and functional evaluations in all enrolled participants in each of the four cohorts and these will be used to arrive at a multidisciplinary consensus diagnosis of suspected normal aging, subjective cognitive impairment, mild neurocognitive disorder (or mild cognitive impairment), or major neurocognitive disorder (or dementia). We are correlating these diagnoses with results of brief cognitive tests and a brief functionality assessment, the MMSE, RUDAS, the BHA ‐ TabCAT, and the adapted version of PFAQ.

Results

In collection process

Conclusion

This pilot project represents the initial steps towards addressing these hypotheses and will generate unique data.
Molecular MRI Identifies Sexually Dimorphic AD Pathology in 3x Tg‐AD Mice
Authors: Parekh Parag A , Badachhape Andrew A , Menon Renuka , Bhavane Rohan , Srivastava Mayank , Sun Xianwei , Bhandari Prajwal , Devkota Laxman , Tanifum Eric , Ghaghada Ketan , Devaraj Sridevi , Annapragada Ananth
Published: December 2023

Background

Women exhibit higher prevalence of Alzheimer’s disease (AD) with faster cognitive decline compared to men, but the mechanisms of this dimorphism remain understudied. Astrocyte function and morphology is distinct in some regions of male and female adult brains which may reflect different courses taken by the neurodegenerative process. Additionally, the p‐tau levels are higher in females than in males. The 3xTg AD mouse model, which manifests amyloid and tau pathology, has been reported to exhibit similar sexual dimorphism. In this work, we investigated whether molecular MRI using a targeted agent that detects hyperphosphorylative cells expressing cell‐surface vimentin predominantly on neurons and the disease associated astrocytes in early states of tau pathology can be used for in vivo imaging of sexual dimorphism in AD pathology.

Method

Liposomal Withaferin nanoparticles (WNP) that contain Gd/DOTA for an MRI readout were injected in 3xTg AD mice, at 2‐,5‐,7‐ 9‐ and 12‐ months of age. Animals (n = 14/timepoint, 7 males and 7 females) underwent contrast enhanced magnetic resonance imaging (MRI) using T1 weighted sequences to visualize hyperphosphorylative cells expressing cell surface vimentin. Animals were euthanized after the final time point and brains were harvested for histology and immunofluorescence analysis. CE‐MR images were analyzed for signal enhancement.

Result

In this study, we report the sexually dimorphic nature of the cell surface vimentin expressed by the hyperphosphorylative cells in the brain using the 3xTg AD mice. Both sexes were imaged at 2‐,5‐,7‐ and 9‐ months of age to reveal significant differences in the expression of VIM in males and . Signal enhancement in post‐contrast MRI scans over the baseline scans showed significantly higher enhancement in the females compared with the males (p<0.05) Simultaneously, we also investigate the plasma concentrations of total tau, ptau181, amyloid beta 40 and 42.

Conclusion

Female mice expressed higher vimentin in comparison with males, thus reflecting changes in the neurodegenerative processes in the brains of females and males of this strain. Sexually dimorphic molecular changes were successfully visualized by molecular MRI.
Phosphatases Pathways as a Potential Lithium Therapeutic Target in Alzheimer’s Disease: Preliminary Results
Authors: Paiva Iara Ribeiro , Forlenza Orestes Vicente , De‐Paula Vanessa V.J.
Published: December 2023

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, that apart from the classical pathological findings in neurons (neurofibrillary tangles and amyloid plaques), it is known that astrocytes and microglia play an important role leading to a pro‐inflammatory state (Heneka et al, 2015). Post‐translational modifications are major regulators of this response, notably phosphorylation. In this regard, lithium is a drug known for its neuroprotective effects due to inhibition of GSK3β (Forlenza et al, 2012; Rocha et al., 2021). Thus, we aimed to characterize by Gene Ontology (GO) the signaling pathways related to tau phosphatases to further evaluate them in response to lithium.

Method

A systematic literature search ascertained thirteen phosphatases (Ppp1cb, Ppp2r2d, Ppp1r1a, Ppm1b, Ppp5c, Ptpn5, Pten, Ptpn11, Ptpn13, Dusp1, Dusp6, Dusp22, Ppp2r4) (Braithwaite et al, 2012; Kerr et al, 2006; Kim et al 2019; Wang et al, 2017; Arango‐Lievano et al, 2016; Banzhaf‐Strathmann et al, 2014; Sanchez‐Mut et al, 2014; Luo et al, 2013). We obtained an enriched network of 50 interactions from these selected seed proteins in STRING, a database of documented and predicted protein‐protein interactions (PPI), using a confidence score of 0.7. Dusp22 and Ppm1b were removed due to lack of connection. From this network, we obtained a list of 63 proteins. Using a 0.001 false discovery rate and a 0.7 strength cut off, we reached 321 biological processes, 49 molecular functions and 39 cellular components. Ethical committee (1666/2021).

Result

GO study favored specific pathways on the biological process domain. Among these pathways, the most significant were “activation of mapk activity”, “interferon‐gamma‐mediated signaling pathway”, “response to tumor necrosis factor”, “cellular response to oxidative stress” and “cellular response to cytokine stimulus”. The analysis of the ontological pathways relating the hippocampal tissue with the biological pathways found is in progress.

Conclusion

The pathways identified by GO analysis are related to AD pathogenesis, particularly the mapk cascade as a regulator of pro‐inflammatory response. Therefore, understanding these pathways is essential as they are candidates for therapeutic targets for the disease.
Proteo‐genomics of soluble TREM2 in cerebrospinal fluid provides novel insights for TREM2 biology and identifies novel modulators for Alzheimer’s disease
Authors: Wang Lihua , Nykanen Niko‐Petteri , Western Daniel , Gorijala Priyanka , Timsina Jigyasha , Marquié Marta , Boada Mercè , Alvarez Ignacio , Aguilar Miquel , Pastor Pau , Ruiz Agustin , Hohman Timothy J. , Wyss‐Coray Tony , Sung Yun Ju , Cruchaga Carlos ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI),   Dominantly Inherited Alzheimer Network (DIAN)
Published: December 2023

Background

Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer’s disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). Here, we pursued the largest CSF study to identify additional novel genetic modifiers of sTREM2.

Method

We performed the genome‐wide association study (GWAS) of CSF sTREM2 in 3350 individuals of European ancestry from eight cohorts. To identify functional genes, we performed multi‐ethnic fine mapping with 250 non‐European individuals. Functional validation using peripheral blood mononuclear cell‐derived macrophages was performed. Colocalization and Mendelian randomization (MR) was performed for the causality of sTREM2 in AD.

Result

The known MS4A locus and three novel loci were identified at genome‐wide significance. In the MS4A locus, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drove the association through multi‐ethnic fine mapping. They showed an epistatic effect for sTREM2 and AD risk. The novel TREM2 locus on chromosome 6 contained two rare missense variants (rs142232675 p.D87N, P = 2.71×10‐10; rs75932628 p.R47H, P = 7.16×10‐19) associated with sTREM2 and AD risk. Another novel locus in the intergenic region between TGFBR2 and RBMS3 (rs73823326, P = 3.86×10‐9) included a regulatory variant with a microglia‐specific chromatin loop for promoters of TGFBR2. Using cell‐ based assays we demonstrate that TGFBR2, but not RBMS3, modify sTREM2 levels. The last novel locus NECTIN2 on chromosome 19 (rs11666329, P = 2.52×10‐8) was independent of APOE genotype and colocalized with cis‐eQTL of NECTIN2 in the brain cortex and cis‐pQTL of NECTIN2 in CSF (PP.H4 = 0.83). This variant was also associated with AD risk (P = 1.52×10‐66) and age at onset (P = 3.26×10‐5). Our MR results confirmed the significant protective effect of sTREM2 on reducing AD risk.

Conclusion

To our knowledge, this is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. We provided novel insights for MS4A and TREM2, the two well‐ known gens for AD risk. We also identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD.
Mechanisms linking proteins and structural brain integrity to biological markers of Alzheimer’s Disease
Authors: Turnbull Adam , Kim Yejin , Zhang Kai , Mao Tianrui , Jiang Xiaoqian , Henderson Victor , He Zihuai , Lin Feng Vankee Vankee , Lin Feng Vankee Vankee
Published: December 2023

Background

Medial temporal lobe (MTL) networks, including posterior‐medial (PM) and anterior‐temporal (AT) subnetworks, are early affected by Alzheimer’s disease (AD) pathologies (tau, neurodegeneration) and are critical for memory, which declines in AD. The biological pathways linking AD pathology, changes in MTL‐AT‐PM structural connectivity (SC), and cognitive decline, are unknown. Plasma protein levels reflect those in the cerebrospinal fluid, providing a low‐invasive potential means of understanding molecular brain changes that occur in AD. These measures may help explain how AD pathology, MTL‐AT‐PM SC, and cognitive decline are linked at the molecular level. We used predefined aging‐related plasma proteins from a meta‐analysis to explore links between MTL‐AT‐PM SC, AD pathologies, and cognitive decline.

Method

MTL‐AT‐PM SC scores and plasma protein levels from 100 participants (Stanford ADRC: mean age = 73.7y, 82 healthy control, 16 mild cognitive impairment, and 2 AD) were entered into an Coupled tensor and matrix factorization algorithm, generating clusters based on shared SC‐protein variance. Linear regression analyses were conducted to evaluate cluster relationships with domains of AD (memory, plasma tau, and neurodegeneration by plasma NfL and cortical thickness index).

Result

Two (out of 12 total) SC‐protein clusters significantly related to both tau and neurodegeneration. Both had similar highly contributing proteins (TNFRSF1B.3152.57.1, TNFRSF1B.8368.102.3, GRN.4992.49.1, TNC.4155.3.2, RPS3A.5484.63.3, CD163.5028.59.1, EFNA4.2614.28.2) and SC regions (bilateral: hippocampus, and left: parahippocampal cortex, precuneus, thalamus, and isthmus cingulate). Hippocampal laterality (bilateral vs. opposite directions for left vs. right) and the direction of their relationship to tau/neurodegeneration differentiated these clusters. A 3rd cluster was uniquely associated with composite memory (SC: bilateral: lateral occipital and parahippocampus, left: inferior temporal and hippocampus; proteins: EGFR.2677.1.1, SFRP1.3221.54.1, FAS.9459.7.3, ERBB3.2617.56.35, CFD.13678.169.3, LRP1.8601.167.3, and LPO.4801.13.3).

Conclusion

Protein‐SC clusters showed both overlapping and unique associations to AD‐associated memory, tau, and neurodegeneration. Two clusters centered on the hippocampus and proteins related to inflammation showed relationships to both tau and neurodegeneration, suggesting they may be important for linking these two aspects of AD pathology. A memory‐related cluster was dominated by neurogenesis related proteins, and occipital/parahippocampal cortex. These findings suggest molecular pathways may differentially affect the left vs. right hippocampus, and AD‐associated pathologies vs. cognition.
Anosognosia is associated with increased prevalence and faster development of neuropsychiatric symptoms in Mild Cognitive Impairment
Authors: Wang Sharon , Gagliardi Geoffroy Pierre , Mimmack Kayden J. , Cacciamani Federica , Elnemais Michael , Munro Catherine E , Gatchel Jennifer , Marshall Gad A , Vannini Patrizia
Published: December 2023

Background

Both the loss of awareness for cognitive decline (a.k.a anosognosia) and neuropsychiatric symptoms (NPS) are commonly seen in patients with Alzheimer’s disease (AD) dementia, even in the prodromal stages. Anosognosia and NPS may negatively affect caregiver burden and patient’s activities of daily living. Despite the high impact of these symptoms on patients and their caregivers, our knowledge of how they develop across the AD spectrum is limited. Here, we explored the cross‐sectional and longitudinal associations between anosognosia and NPS in individuals with mild cognitive impairment (MCI).

Method

We included 310 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) with a baseline Clinical Dementia Rating global score of 0.5. Everyday Cognition (ECog) questionnaire scores were used to measure complaints from participants and study‐partners at baseline and annually over a mean of 4 years (SD = 3). Anosognosia was defined as the study‐partner having an ECog score ≥2.5/4 and the participant having an ECog score ≤2.5/4 on their baseline measure and their last observation and without having more than 2 consecutive deviating observations during the follow‐up period. The 12 study‐partner‐rated Neuropsychiatric Inventory items determined the presence or absence of specific NPS (see Table 1). The Mini‐Mental State Examination (MMSE), an assessment used to screen for cognitive impairment, was administered annually. Survival analyses were performed to analyze the rate of appearance of NPS over time in individuals with and without anosognosia.

Result

Sixty participants displayed anosognosia, while 250 did not. At baseline, groups had similar lengths of follow‐up. Participants with anosognosia had lower MMSE scores and a higher proportion of amyloid positivity (see Table 1). At baseline, the frequency of agitation and disinhibition was higher in the anosognosia group. Survival analyses showed earlier onset of all NPS in the anosognosia group (see Figure 1). Specifically, aberrant motor behavior, irritability, disinhibition, apathy, agitation, and hallucinations were highly significant.

Conclusion

Loss of awareness for cognitive decline is associated with greater frequency and faster onset of NPS over time in participants with MCI. These results support the hypothesis of a potential common underlying neurophysiological process, a finding that needs to be addressed further in future studies.
Mitochondrial DNA variants and Cognitive Function
Authors: Odden Michelle , Li Yongmei , Jotwani Vasantha , McGeever Lea , Jones Robyn , Desprez Pierre‐Yves , Tranah Gregory J.
Published: December 2023

Background

Mitochondrial dysfunction is a hallmark of aging and manifests in age‐associated disorders, including neurodegenerative diseases. Previous work on mitochondrial DNA variants and neurocognitive outcomes has been limited to known variants of interest.

Method

We sequenced the mitochondrial genome in buffy coat samples from two studies, LIFE (Lifestyle Interventions and Independence for Elders) and HABC (Health Aging and Body Composition), and examined the association of shared common variants and cognitive function, after adjustment for 10 principal components to account for population stratification. Participants included self‐reported Black (n = 229 in LIFE and 393 in HABC) and White (n = 1134 in LIFE and 395 in HABC) adults aged ≥ 70 years. Cognitive function was measured by the digit‐symbol substitution test (DSST), a measure of processing speed, and the Modified Mini‐Mental State Exam (3MSE), a measure of global cognition.

Result

There were 96 variants which had a minor‐allele frequency ≥5% in both studies. There were 8 variants associated with DSST in White participants LIFE at the p<0.05 level and 1 at the Bonferroni‐adjusted level (m16223ct). Four reached statistical significance at the p<0.05 level in meta‐analyses of LIFE and HABC (m16223ct, m16093tc, m10873tc, m3106cnc). There were 7 variants associated with 3MSE in White participants in LIFE at the p<0.05 level and none at the Bonferroni‐adjusted level. One reached statistical significance at the p<0.05 level in meta‐analyses of LIFE and HABC (m10873tc). In Black participants, the variants had differential associations with the cognitive outcomes by study, and no associations reached statistical significance after Bonferroni correction or in meta‐analysis. The 4 variants of interest in White participants are located in the 1) hypervariable region 1 of the D‐loop (m16093tc, m16223ct), 2) gene MT‐ND4 coding for subunit ND4 of complex 1 (m10873tc), and 3) gene MT‐RNR2 coding for the 16S ribosomal RNA (m3106cnc).

Conclusion

Previous work has identified associations between m16223ct and hippocampal sclerosis and endurance capacity; and ND4 variants and Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Leigh’s disease. In addition, the m10873tc ND4 coding variant is a defining mutation for European Haplogroup N. Mitochondrial genetics may contribute to cognitive health. More research is needed on mitochondrial genetics among Black individuals.
Feature extraction by orthonormal projective non‐negative matrix factorization and longitudinal association between brain atrophy patterns and Alzheimer’s disease
Authors: Shui Lan , Shibata Dean , Chan Kwun Chuen Gary , Haynor David R.
Published: December 2023

Background

Orthonormal projective non‐negative matrix factorization (OPNMF) was a recently developed approach for feature extraction techniques of neuroimaging data. However, there has been few studies applying this to brain MRI to better characterize the anatomic changes seen in Alzheimer’s Disease (AD) and correlate these patterns with cognitive changes.

Method

We applied OPNMF with refinement to identify distinct spatial components of voxel‐wise volume loss in the structural MRI (3D T1 MPRAGE images) of subjects with AD (N = 109, mean age = 74.6 (7.9), ADNI2) relative to healthy young controls (N = 104, mean age = 24.0 (2.9), ABIDE1). Non‐negative least squares (NNLS) was then used to extract non‐negative coefficients representing subject‐specific quantitative measures of regional atrophy. This calculation of coefficients was extended to images not used for component discovery which also included Mild Cognitive Impairment (MCI) and controls. To investigate the cross‐sectional and longitudinal associations between cognitive assessments scores and regional atrophy severity in different diagnostic groups, we used multiple linear regression models and liner mixed‐effects models with random intercepts and slopes controlled for age, sex, educational level, APOE ε4 genotypes were utilized. A validation analysis was performed using ADNI3 images.

Result

We derived 6 atrophy components upon the same training set and there was a sharp decrease in the magnitude of the reconstruction error gradient when moving from 5 components to 6 components, and the components have meaningful interpretation. In the whole cohort, atrophy in 5 of the 6 regions was significantly associated with all three cognitive scores. There is evidence of overall positive trends between diagnosis group and atrophy severity changing rate in all 6 regions. The increased atrophy in all 6 regions was associated with decreases in MMSE and MOCA scores and increases in CDRSB scores in the whole cohort as well as in LMCI cohort. From the validation analysis, we showed that our result from OPNMF is stable in atrophy pattern discovery.

Conclusion

We developed a robust pipeline for detecting spatially distinct atrophy components in AD and associated these atrophy patterns with cognitive changes which may help us better characterize the underlying pathology of types of AD and other dementias on MRI.
Fully remote Parkinson’s disease study served by mobile research nurses
Authors: Gerken‐Booco Alicia
Published: December 2023

Background

Because Parkinson’s disease is a progressive brain disorder that leads to shaking and stiffness, eventually causing difficulty with walking, balance and coordination, patients are at very high risk of fractures from multiple and sometimes severe falls. Researchers are studying whether zoledronic acid, approved by the FDA to treat osteoporosis by increasing bone strength, will reduce fractures in people with Parkinson’s disease.

Method

The TOPAZ trial seeks to enroll 3,500 participants over the age of 60, making it the largest double‐blind, placebo‐controlled, randomized, fully decentralized clinical trial ever attempted in people with parkinsonism. Due to the mobility constraints of the study population, it is necessary to design a study that can recruit a large number of participants from across a wide geography and develop a multi‐step protocol that can be done entirely from participants’ homes. The study recruitment began October 1, 2020 and is expected to be completed within three years. To date, 1807 participants have been enrolled.

Result

The patient‐centric nature of the study enabled participant recruitment from a broad geographic area to enhance diversity and be more representative of “real world” patients. The study is achieving an estimated cost savings of 80% per participant compared with a similar trial conducted in a clinical site due to lower overhead and the fact that a home‐based study forces researchers to engage only in those activities necessary for the study.

Conclusion

Mobile research nurses are necessary for certain studies, including those involving a large number of patients with a disabling disease. Due to the limited mobility of many of the participants in this study and the need to enroll so many patients, the only way this trial is possible is by using decentralized clinical trial methods including mobile research nurses. This study illustrates the many advantages of home‐based clinical trials, including: increased convenience for patients; larger number of study participants; potential for increased diversity in clinical trial participation; and reduced study costs.

References:

1. Tanner, Caroline M., et al. “The TOPAZ study: a home‐based trial of zoledronic acid to prevent fractures in neurodegenerative parkinsonism.” NPJ Parkinson’s disease 7.1 (2021): 1‐6.
Six Year Effects of Hearing Treatment on Cognitive Decline and Dementia: Design and Statistical Considerations of the Aging and Cognitive Health Evaluation in Elders – Brain Health Follow‐Up Study
Authors: Huang Alison R , Pike James R. , Arnold Michelle L , Burgard Sheila , Chisolm Theresa , Couper David , Deal Jennifer A , Goman Adele M , Gravens‐Mueller Lisa , Hayden Kathleen M. , Jack Clifford R. , Mitchelle Christine , Mosley Thomas H. , Pankow James , Reed Nicholas S , Sanchez Victoria A , Schrack Jennifer A , Coresh Josef , Lin Frank R ,   for the ACHIEVE Collaborative Research Group
Published: December 2023

Background

Hearing loss is associated with cognitive decline and dementia. The ongoing ACHIEVE Study was the first randomized trial to test the effects of hearing treatment on three‐year cognitive change. The ACHIEVE – Brain Health Follow‐Up Study will extend follow‐up to six years post‐randomization to determine the long‐term and potentially nonlinear effects of hearing treatment vs. health education control with delayed treatment on dementia and cognitive decline.

Methods

Participants will be recruited from the 977 participants enrolled in the ACHIEVE Study. After Year 3, hearing intervention participants will continue to receive hearing care and the control group will be offered the hearing intervention. Co‐primary study outcomes will be cognitive decline and a composite of incident mild cognitive impairment (MCI)/probable dementia. Secondary outcomes include domain‐specific cognitive decline, brain structural changes on magnetic resonance imaging (MRI), and other functional outcomes (e.g., physical activity, social isolation). Power analyses for the co‐primary outcomes assumed an annual attrition rate of 10% and an immediate, lagged, or cumulative treatment effect.

Results

When comparing multi‐year cognitive decline (Table 1), in the scenario of a constant treatment effect that assumes a strong and immediate treatment effect, the benefit of extended follow‐up is not greater power, but additional information on the long‐term effects of hearing intervention. In a scenario of a lagged treatment effect, a two‐year lag in the treatment effect causes the Year 3 assessment to be severely underpowered (28%) but provides sufficient power (80%) at Year 6 despite attrition. In a scenario of a cumulative treatment effect that increases with time, analyses are similarly underpowered at Year 3 (65%) but not at Year 6 (82%). The same pattern is evident when estimating the power at Year 3 (57%) and Year 6 (80%) to detect incident MCI/probable dementia in a Cox regression model that assumes a protective hazard ratio of 0.70 (Figure 1).

Conclusion

Across all non‐constant scenarios of potential treatment effect, six years of follow‐up increases precision and provides valuable information to better delineate long‐term cognitive trajectories. The ACHIEVE ‐ Brain Health Follow‐Up Study will be completed in 2025.
Development and validation of a caregiver‐reported outcome measure for Alzheimer’s disease: the Alzheimer’s Disease Caregiver Reported‐Health Index (ADCR‐HI), a fully validated tool to bolster clinical trial and research infrastructure
Authors: Rosero Spencer , Varma Anika , Seabury Jamison , Weinstein Jennifer , Engebrecht Charlotte , Dilek Nuran , Arky Abigail , Santos Elizabeth , Heatwole Chad
Published: December 2023

Background

As therapeutic advancements are made in the field of Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI), it is important to have a fully validated, sensitive, and reliable, disease‐specific outcome measures that can accurately measure changes in AD and MCI symptomatic disease burden. The U.S. Food and Drug Administration has encouraged the use of caregiver reported outcome measures (CRO) to measure therapeutic benefit of new treatments on patient populations when a patient is unable to report on themselves. This research describes the creation, testing, and validation of a novel, multifactorial CRO: The Alzheimer’s Disease Caregiver Reported‐Health Index (ADCR‐HI).

Methods

We conducted interviews and a large cross‐sectional study involving individuals with AD and MCI and their caregivers to determine what symptoms and issues are most important to patients (Figure 1). Questions were selected for the ADCR‐HI based on their importance to patients with MCI and AD, potential to respond to therapeutic intervention, and generalizability. We beta tested the ADCR‐HI with caregivers of individuals with MCI and AD to determine its clarity, ease of use, and relevance to those with MCI and AD. We performed test‐retest reliability, known groups validity, internal consistency, and area under the curve analyses of the ADCR‐HI to assess the statistical characteristics, performance, and clinical meaningfulness of the outcome measure.

Results

The content of the ADCR‐HI was validated using a cross‐sectional study of 329 caregivers. The ADCR‐HI contains 8 subscales that measure disease burden in the following areas: 1. Memory, 2. Cognitive health, 3. Social Health, 4. Physical Health, 5. Communication, 6. Fatigue, 7. Sleep, and 8. Emotional Health. The ADCR‐HI was identified as easy to use, relevant to the patient population, responsive, and clear during beta testing. The ADCR‐HI was shown to be reliable during test‐retest reliability testing with 34 caregivers and able to distinguish between patient cohorts with different disease severities.

Conclusion

The ADCR‐HI is a valid, sensitive, and reliable marker of disease burden in AD. This disease‐specific outcome measure is available for use by researchers, clinicians, patient organizations, and companies to measure changes in disease burden during therapeutic trials.
In vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in frontotemporal degeneration and corticobasal syndrome.
Authors: Lagarde Julien , Olivieri Pauline , Tonietto Matteo , Lehéricy Stéphane , Moussion Martin , Caillé Fabien , Gervais Philippe , Bottlaender Michel , Sarazin Marie
Published: December 2023

Background

Neuropathological studies have shown alterations in both locus coeruleus (LC) and basal forebrain in frontotemporal degeneration (FTD) and corticobasal syndrome (CBS) particularly in progressive supranuclear palsy (PSP). We aimed to investigate in vivo the LC and nucleus basalis of Meynert (NBM) integrity in patients with FTD and CBS.

Method

We compared the LC signal intensity (LC‐I), which reflects the LC integrity, and the NBM volume on 3T MRI in i) FTD patients (n = 17) ii) CBS patients (n = 8;) iii) prodromal/mild AD (n = 34) and iv) amyloid‐negative controls (n = 15). PiB‐PET and/or AD CSF biomarkers were negative in all FTD and CBS patients, and positive in all AD patients. All subjects underwent a complete neuropsychological assessment and 3T brain MRI performed on the same scan. The four groups were age‐matched. The MMSE score did not differ significantly between the 3 groups of patients.

Result

Compared to controls, LC‐I and NBM volume were significantly decreased in FTD (p = 0.05 and 0.00015, respectively) and AD patients (p = 0.0005 and 0.002, respectively). LC‐I and NBM volume were also decreased in CBS in comparison with controls but the difference was not statistically significant. In addition, we found no statistically significant difference in LC‐I and NBM volume between the three groups of patients. We observed no correlation between LC‐I or NBM volume and amyloid load, either when considering the whole group of patients or AD and FTD/CBS patients separately.

Conclusion

Our results are in line with neuropathological data and suggest that both cholinergic and noradrenergic systems are altered in AD and FTD. Post mortem data have suggested that, in FTD, both structures were more impaired in tau than in TDP‐43 proteinopathy, which cannot be explored in our study. In CBS, our results are less clear‐cut, probably due to the small sample size. Taken together, our data support the pathophysiological model in which both LC and NBM play a critical role not only in AD but also in other diseases and proteinopathies like FTD.
Review of Clinical Trials Showing the Efficacy of Memantine in Patients with Alzheimer’s Disease
Authors: Schuh Olivia , Khanna Deepesh
Published: December 2023

Background

Over 6 million Americans suffer from Alzheimer’s disease (AD), a neurodegenerative disease characterized by changes in behavior, personality and progressive decline in cognitive function and memory. Therapies may slow the progression and aid in symptomatic relief of AD. One of these is Memantine, an N‐methyl‐D‐aspartate receptor antagonist. The objective of this review is to analyze clinical trials testing the efficacy of Memantine in the treatment of AD.

Method

A search for clinical trials was conducted through clinicaltrials.gov with keywords search of “Alzheimer’s disease” and “United States” resulting in a total of 1592 clinical trials. Further inclusion criteria selected included; interventional clinical trial, with results, 65+, phase 4 which led to 23 clinical trials. Four of the 23 clinical trials were selected based upon their commonality of studying the efficacy of the drug Memantine in patients with AD.

Result

A clinical trial studied whether Memantine (10mg BID) delayed the progression of driving impairment in participants with mild AD. In the group that received memantine, 100% of participants were able to pass the DriveABLE On‐Road Test at month 12 in contrast to an 83% passing rate in the placebo group. Another clinical trial reported improvements in the ratios of N‐acetylaspartate (NAA) to Creatine (Cr), NAA to choline (Cho), and NAA to myo‐inositol in comparison to baseline. Researchers analyzed the effects of implementing an individualized management program (IMP) and Memantine (10 mg BID) versus Memantine (10 mg BID) alone. Patients in the IMP and Memantine group markedly improved their Clinician Interview‐Based Assessment of Change Plus Caregiver Input Global Score while the Memantine group alone markedly got worse. Patients who took Memantine (10 mg BID) to assess the slowing of behavioral decline were reported to have improved caregiver assessment of behavioral disturbances while the placebo group did not show improvement.

Conclusion

Memantine may be effective in delaying the progression of driving impairment and behavioral decline. Implementing an IMP plus Memantine showed to have better outcomes than Memantine alone. None of these institutions provided data analysis to determine if data was significant.

Reference: Medicine, U. S. N. L. o. (2023). “Clinicaltrials.gov.” Retrieved 01/23/2023, 2023, from https://clinicaltrials.gov/.
Disparities in Research Participation within a Multi‐Racial SARS‐CoV‐2 Cohort for Evaluation of Ultrahigh Field (7T) MRI and Clinical Precursors of Alzheimer’s Disease and Related Dementias
Authors: Vahidy Farhaan S , Hosseini Akram A. , Girard Timothy D. , Ibrahim Tamer , Jacobs Heidi I.L. , Roman Gustavo C , Masdeu Joseph C. , Li Karl , Garbarino Valentina R. , Goss Monica , Nair Rejani R , Patel Vibhuti N , Snyder Heather M , Tannous Jonika D , Snitz Beth E. , Ganguli Mary , Seshadri Sudha
Published: December 2023

Background

The COVID‐19 pandemic has disproportionately affected ethno‐racial minority populations and people with greater social deprivation. It is unknown whether such disparities influence research participation for investigations of long‐term neuro‐cognitive effects of SARS‐CoV‐2 infection.

Method

Across 3 US and 1 UK sites, we are enrolling a multi‐racial cohort of SARS‐CoV‐2 infected individuals and age, sex, race‐matched non‐infected controls. Utilizing harmonized protocols for cognitive assessments and 7‐Tesla MRI, we aim to provide ultra‐high‐field data on natural history of COVID‐19 driven microstructural and microvascular cerebral changes and associated cognitive trajectories. We will also compare the imaging markers to those observed in an existing cohort of early onset Alzheimer’s Disease and Related Dementias (ADRD). We analyzed screening and enrollment data to determine potential age, sex, race, ethnicity, and social deprivation disparities in research participation. We derived address‐based Area Deprivation Index (ADI) (scale 1 ‐10), with higher ADI indicating greater deprivation. Logistic regression models were fit to evaluate associates of non‐response and refusal. Odds Ratios (OR) and 95% confidence intervals (CI) are reported.

Result

Over a 11‐month period, at a single US site, a total of 1,046 SARS‐CoV‐2 infected people and their controls were contacted, and 379 (36.2%) responded. In univariable analyses, non‐response was associated with younger age, male sex, non‐White race, and higher ADI (Table 1). In the fully adjusted model, non‐White race was independently associated with higher likelihood of non‐response [OR (CI) for Black vs. White: 1.49 (1.04, 2.12) and for Asian vs. White: 1.88 (1.28, 2.76)]., Independent of race, higher ADI was also associated with likelihood of non‐response (Table 2 and Figure 1). Among the responders, 228 (60.2%) refused. Although, no socio‐demographic factors were significantly associated with likelihood of refusal, the point estimates in the fully adjusted model suggest potential racial disparities in providing consent (Tables 1 and 2). Aggregated data from all sites will be presented.

Conclusion

It is imperative to recognize and mitigate persistent disparities in the COVID‐19 pandemic, particularly pertaining to participation in long‐COVID research. Mechanisms of such persistent disparities need to be studied in context of cultures, beliefs, access, and clinical factors.
Bad questions: addressing non‐response and respondent feedback in a social and structural determinants of health (SSDoH) questionnaire
Authors: Stites Shana D. , Halberstadter Kimberly , Houston Jada Jeanette , Schumann Rosalie , Mechanic‐Hamilton Dawn
Published: December 2023

Background

Scientists must be able to characterize and measure social and structural determinants of health (SSDoH) in order to study their influences on Alzheimer’s disease and related dementias outcomes. Constructing measures that capture this heterogeneity is challenging. We summarize SSDoH questions that participants skipped and critiqued and our response.

Method

An online survey of 225 items capturing SSDoH was administered to cognitively unimpaired participants (n = 135) in the UPenn Alzheimer’s Disease Research Center clinical cohort. Self‐report questionnaire categories were: (1) Education, (2) Occupation, (3) Economic Status and Strain, (4) Stressors and Subjective Stress, (6) Subjective Social Support and Status, and (7) Sociodemographic data, which included age, race, language, disability, neighborhood, sex, sexual orientation, and gender identity questions. We summarize pilot data on item and instrument completion rates, participant feedback, and survey revisions to address participant critiques.

Result

The response and completion rates were 66% and 95% respectively. Most often skipped items were: mother’s highest education level (17% skipped), number of years attending a segregated school for those who did attend (15% skipped), childhood zip‐code (14% skipped), transportation mode around one’s neighborhood (13% skipped), and current worldview compared to during childhood (12% skipped). Few participants (n = 5/135) reported dislike or discomfort with any questions, with 3 of the 5 citing that questions about childhood caused discomfort. Participants also critiqued questions about education for not capturing their individual schooling experiences. In response to feedback, we conducted follow‐up discussions with participants about their reactions to specific childhood questions and expanded questions to capture more educational pathways, including trade school experiences and apprenticeships. We also added answer choices to often‐skipped items with insufficient answer options.

Conclusion

Overall, most SSDoH items had high completion rates, and few questions were consistently skipped by participants. While investigators often worry about offending or upsetting research participants, those in our study wanted to help improve questions. Participants acknowledged that some questions elicited strong emotions, but in most cases were both willing to complete these questions and appreciative of the chance to share their experiences. Designing questions that capture a fuller range of educational pathways was a valuable contribution to data collection.
Decay in Entorhinal White Matter/Gray Matter contrast in Alzheimer’s Disease Patients is reduced by 40Hz sensory stimulation
Authors: Da Xiao , Hempel Evan , Malchano Zach , Vaughan Brent , Megerian Jonathan Thomas , Hajos Mihaly , Cimenser Aylin
Published: December 2023

Background

Previous research has shown that white matter (WM) and gray matter (GM) tissues exhibit regionally selective pathological changes in Alzheimer’s disease (AD). The contrast between WM and GM signal intensities (WM/GM contrast) measured by magnetic resonance imaging (MRI) has previously been proposed as a method for quantifying these changes. It has been shown that WM/GM contrast can provide sensitive, independent, and distinct information about pathologies compared with traditional MRI measures. Studies have also shown, including entorhinal WM/GM contrast to traditional MRI measures resulted in better discrimination between AD and controls. We previously demonstrated that 40Hz auditory‐visual stimulation therapy reduced WM atrophy and myelin loss in AD patients. The present study quantified the effects of the therapy on the WM/GM contrast in the entorhinal region.

Method

This study used neuroimaging data from Overture, a phase I/II randomized, placebo‐controlled feasibility study (NCT03556280) in patients on the AD spectrum. Treatment group received 40Hz gamma sensory stimulation daily at home for six months, whereas placebo group received sham stimulation. Structural MRI was obtained at baseline, month 3 and month 6 visits using 1.5 Tesla scanner. FreeSurfer was used to process T1 MRI including entorhinal parcellation and cortical reconstructions for 38 participants (66% Treatment, 34% Placebo). For each vertex, WM signal intensity (WMI) is sampled at 1mm below, and GM signal intensity (GMI) is sampled at 30% of cortical thickness above the WM/GM border. WM/GM contrast was calculated as 100*(WMI–GMI)/(0.5*(WMI+GMI)) %. Bayesian linear mixed effects modeling was used to model changes in WM/GM contrast in the entorhinal region.

Result

Following 6 months of treatment, we observed that the treatment group demonstrated 0.06±0.99% decrease and the placebo group demonstrated 1.26±1.04% decrease in WM/GM contrast (p<0.022).

Conclusion

We found that six months of 40Hz gamma sensory therapy reduced the decline in WM/GM contrast in the entorhinal region. Since WM/GM contrast is associated with AD severity, and the entorhinal region is of particular interest in the early stages of AD, early intervention of the therapy may result in enhanced tissue preservation and reduced neurological damage.