bluuebunny/crossref_metadata_2025 huggingface dataset:
Dementia care in rural areas: A cross‐sectional study from the Wisconsin Alzheimer’s Institute (WAI) Dementia Diagnostic Clinic Network
Authors: Pinzon Maria C Mora , Krainer Jody , Houston Stephanie , Green‐Harris Gina , Norris Nia , Walaszek Art , Johnson Sterling C , Carlsson Cynthia M
Published: December 2020

Background

The Wisconsin Alzheimer’s Institute (WAI) Dementia Diagnostic Clinic Network includes 38 affiliated clinics across 24 healthcare systems in Wisconsin. Its purpose is to promote the use of evidence‐based strategies to provide high quality care for people with dementia across the state. The clinics follow a set of guidelines that are tailored to address the challenges of providing specialized care in rural areas (e.g. travel burden, transportation, limited resources, lack of trained healthcare providers, social isolation, among others). The purpose of this study is to describe the characteristics of patients seen in rural areas of Wisconsin, the care provided and how it compares to the models of care seen in urban areas.

Methods

Cross‐sectional study including the patients seen at the WAI’s Clinic Network between September 2018 and January 2020. Demographics, clinical diagnosis, and quality of care provided were compared according to rurality (metropolitan, micropolitan, rural) using the Urban‐Rural Classification Scheme for Counties (URCSC) which was assigned using the location of the submitting clinic.

Results

Over the study period, 1,769 patients were identified: 61% female, 69% between 65 and 84 years old, and 78% diagnosed with dementia or mild cognitive impairment. Overall, 15% of the patients were seen in rural areas, 8% in micropolitan areas, and 76% in metropolitan areas. Patients in rural areas were older, drove longer distances to the clinic, had lower educational attainment level, and were more likely to be self‐referred than those in metropolitan areas. Clinics in rural areas were more likely to provide educational materials, referrals to local resources in the first visit, and to refer patients for further neuropsychology or specialty evaluation before an etiology was identified. As a result, these clinics were less likely to provide a complete diagnosis in the first visit, but provide more caregiver support and management of behavioral symptoms.

Conclusions

WAI’s affiliated clinics in rural areas of Wisconsin use referral patterns that differ from their counterparts in metropolitan areas, including making more connections to local resources. More research is needed to identify additional resources and clinic models to improve dementia care in rural areas.
Characterizing chromogranin and secretogranin proteoforms in dementia pathophysiology
Authors: Quinn James P. , Kandigian Savannah E. , Trombetta Bianca A. , Arnold Steven E. , Carlyle Becky C.
Published: December 2020

Background

Chromogranins and secretogranins are neurotransmitter‐like molecules (neuropeptides) that are processed into functional peptides (proteoforms) by proteases. Full‐length chromogranins and secretogranins and their peptide proteoforms are involved in diverse neuronal and synaptic functions, but their specific processing pathways and contribution to dementia remain largely unknown. This project aims to investigate chromogranin and secretogranin proteolytic processing and validate if specific proteoforms may be useful cerebrospinal fluid (CSF) biomarkers of synaptic health in dementia.

Method

Mass spectrometry (MS) of intact processed peptides was used to produce a detailed map of identified proteoforms arising from chromogranins and secretogranins in the CSF of 5 control and 5 Alzheimer’s disease (AD) patients. This CSF profile was compared against known processed peptides and those used in CSF‐targeted MS assays. Proteasix was used to identify potential proteases involved in the production of identified proteoforms and the human cell atlas was used to identify whether they were expressed in the brain. The cleavage specificity was assayed in vitro using recombinant proteins, analysed by gel electrophoresis and western blotting with chromogranin and secretogranin antibodies.

Result

Using tryptic versus non‐tryptic MS techniques, we detected distinct chromogranin and secretogranin proteoform profiles, suggesting that tryptic digestion underestimates the complexity of proteoform profiles. We are now developing a targeted MS assay to characterize the profile of chromogranin and secretogranin proteoforms in CSF samples spanning controls, different stages of AD and other neurodegenerative diseases. Using Proteasix; members of the calpain, cathepsin, caspase and MMP families were identified to cleave chromogranins and secretogranins. These protease families are known to be expressed in the brain as shown by the human cell atlas and have been previously identified to be dysregulated in dementia. Recombinant assays identified that these proteases can cleave chromogranins and secretogranins to produce different proteoforms.

Conclusion

Our results show that (i) standard tryptic digestion methods underestimate the proteoform complexity of chromogranins and secretogranins, and (ii) that chromogranins and secretogranins are proteolytically processed by proteases relevant to dementia pathophysiology. This work improves our mechanistic understanding of chromogranin and secretogranin processing and further establishes them as a potential synaptic health biomarker in dementia pathophysiology.
Associations between an abbreviated CAIDE score and amyloid chronicity
Authors: Erickson Claire M , Koscik Rebecca L , Cody Karly Alex , Mueller Kimberly D , Chin Nathaniel A , Clark Lindsay R , Christian Bradley T , Betthauser Tobey J , Johnson Sterling C
Published: December 2020

Background

Efforts to quantify dementia risk have led to the development of indices that include health factors, like the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) index. Prior studies demonstrate that higher CAIDE is associated with cognitive decline and neurodegeneration. Few studies have analyzed the association between CAIDE and Alzheimer’s disease (AD)‐related pathophysiology, like beta‐amyloid. Recent studies suggest that duration of beta‐amyloid positivity (amyloid chronicity) is associated with cognitive decline. It is unclear whether health factors contribute to the onset of beta‐amyloid accumulation. This study examines the relationship between the three cardiovascular components of the CAIDE score and amyloid chronicity as assessed by [C‐11]PiB PET imaging.

Method

Participants (n=272; Table 1) from the Wisconsin Registry for Alzheimer’s Prevention were included in this study based on the availability of PiB‐PET imaging data, APOE information, and cardiovascular CAIDE components (total cholesterol, BMI, and systolic blood pressure; CAIDE range 0‐3). Based on observed stability of CAIDE scores (Figure 1), a within‐person average was used in linear regression models assessing whether average CAIDE was associated with amyloid chronicity (calculated as last CAIDE assessment age – estimated age PiB(+)) or estimated age of PiB(+) onset (sensitivity analysis).

Result

The median average CAIDE was 0.4 (1st and 3rd quartiles = 0 and 1 CAIDE, respectively). The mean(SD) age of last PiB scan and last CAIDE ages were 66.55(6.74) and 66.53(6.45), respectively. After adjusting for covariates (education, sex, APOE status, last scan age), CAIDE score was not associated with amyloid chronicity (beta=‐0.47; p=0.74). Sensitivity analyses examining amyloid onset and amyloid positivity since last scan were consistent with our primary analysis. In secondary analyses, we found that CAIDE did not modify associations between APOE status and amyloid chronicity at time of last CAIDE (beta=‐0.28; p=0.87; see Table 2 for full model output).

Conclusion

Our results suggest that peripheral measures of vascular health do not relate to beta‐amyloid duration in a relatively healthy sample. These results add to recent findings suggesting the independent pathways leading to cognitive decline for vascular factors and amyloid. In the future, we will probe the relationship between health factors, AD‐related pathology, and cognition.
Agents of change: Establishment of quality improvement collaboratives to improve the quality of dementia care in Australia
Authors: Laver Kate , Cations Monica , de la Perrelle Lenore , Radisic Gorjana
Published: December 2020

Introduction

The quality of dementia care in Australia is dependent on the clinician involved and the extent to which they apply best available evidence. The Clinical Practice Guidelines for Dementia in Australia (the Guidelines) provided comprehensive guidance for clinicians about best practice for people with dementia and their care partners. Dissemination of guidelines is generally insufficient alone to achieve tangible improvements in practice.

Method

The Agents of Change project is an implementation research study that aims to improve clinician adherence to three key recommendations from the Guidelines. The clinicians participated in a training program and were supported to develop a quality improvement plan unique to their service context. Clinicians met regularly with their QIC to facilitate benchmarking and problem‐solving, and updated their plan iteratively using plan‐do‐study‐act cycles. The primary outcome was guideline adherence which was tracked over a period of 18 months.

Results

The majority of the participating clinicians were highly experienced and leaders within their service. Adherence to the specified guidelines increased steadily over time with an overall increase of 42% adherence. Increases in adherence over time were steady suggesting that each element of the quality collaborative intervention contributed to increased guideline adherence. There was great interest in joining the collaborative and few withdrawals over the duration suggesting an appetite from clinicians to be involved in this type of initiative.

Conclusions

Agents of Change is an innovative translational research project highlighting key elements of collaborative quality improvement efforts among clinicians working with people with dementia and their supporters.
Frailty trajectory related to Alzheimer’s dementia after controlling for neuropathological burden
Authors: Wallace Lindsay MK , Theou Olga , Godin Judith , Andrew Melissa K , Bennett David A , Rockwood Kenneth
Published: December 2020

Background

Frailty is an established risk factor for cognitive decline and Alzheimer’s disease. Changes in frailty have been associated with adverse health outcomes including mortality, health service use, institutionalization, and disability. Few studies have examined the longitudinal relationship between frailty and cognition. Here, we use data from a longitudinal clinical‐pathologic cohort study to extend this work and examine longitudinal change in frailty, how it is influenced by sex, neuropathology, and Alzheimer’s dementia.

Method

Participants of the Rush Memory and Aging project (n=443, 69.3% female, 83.1±5.9 years of age at baseline) underwent annual clinical evaluations (average 5.3±3.5 years of follow‐up) followed by post‐mortem neuropathologic assessment. A frailty index was constructed from 41 health variables at each annual study evaluation. Alzheimer’s dementia was determined (blinded to neuropathological data) at time of death. Age, sex, and education, and neuropathological burden (10‐item index including amyloid load, neurofibrillary tangle density, TDP‐43, hippocampal sclerosis, cerebral amyloid angiopathy, gross infarcts, gross chronic infarcts, atherosclerosis, arteriolosclerosis, and presence of Lewy bodies) were evaluated as covariates. Frailty trajectories were calculated using a mixed effects model.

Result

Frailty increased linearly at a rate of 3% per year on average. Higher baseline frailty was associated with being female (F(1)=22.45, p<0.0001), but not with neuropathological burden (p=0.25) or having Alzheimer’s dementia at death (p=0.142). Frailty trajectories differed as a function of sex, neuropathological index, and Alzheimer’s dementia status; specifically, female sex (p=0.04), higher neuropathological burden (p<0.0001), and Alzheimer’s dementia (p<0.0001) were associated with accumulating deficits at a significantly faster rate.

Conclusion

Findings suggest a strong link between health status as measured by a frailty index and Alzheimer’s dementia, after controlling for neuropathology. Frailty trajectories over 18 years in older adults predicted dementia risk, underscoring the importance of frailty intervention and management in later life.
Hippocampal subfield volumes on 7T MRI in normal cognition, subjective memory impairment, and early Alzheimer’s disease
Authors: Blom Kim , Koek Huiberdina L , Zwartbol Maarten H.T. , Biessels Geert Jan , Geerlings Mirjam I.
Published: December 2020

Background

The hippocampal formation is considered to be one of the first brain structures affected in Alzheimer’s disease. High resolution brain MRI has made it possible to visualize the subfields of the hippocampal formation in greater detail. We estimated volumes of hippocampal subfields on 7T MRI in normal aging and early Alzheimer’s disease. We hypothesized that the subfields were differentially affected in normal cognition, subjective memory impairment, Mild Cognitive Impairment (MCI) and Alzheimer’s disease.

Method

We included 336 participants (68±9 years; 35% women) from memory clinics and from existing cohorts (SMART‐MR study and PREDICT‐MR study), and participants without dementia and MCI recruited from medical files from general practices, all of whom had 7T brain MRI using the same scan protocol. Using ASHS, hippocampal subfields (entorhinal cortex, subiculum, CA1, CA2, CA3, CA4/dentate gyrus, and tail) were segmented. Participants were categorized as having normal cognition (n=175), subjective memory impairment (n=66), cognitive impairment or MCI (n=75), and Alzheimer’s disease (n=20). General linear models with multivariate outcomes (Z‐scores of hippocampal subfield volumes) were estimated across cognitive groups, and adjusted for age, sex and intracranial volume.

Result

In the total study sample, subfield volumes (left and right hemisphere summed) (mm3) were 817±167 for entorhinal cortex, 1143±181 for subiculum, 2923±382 for CA1, 117±23 for CA2, 195±47 for CA3, 1547±245 for CA4/DG, and 284±69 for the tail. Compared to all other groups, Alzheimer’s disease patients had significantly smaller subfield volumes (p<0.05 for all subfields). Participants with cognitive impairment or MCI had smaller CA1 and CA4/dentate gyrus (p<0.05), compared to normal cognition, but not other subfields. Participants with subjective memory impairment did not differ significantly from the group with normal cognition (Figure 1).

Conclusion

This study suggests that in MCI the CA1 and CA4/dentate gyrus are primarily affected, and that all hippocampal subfields are progressively affected in Alzheimer’s disease. No volume loss was observed in participants with subjective memory impairment, potentially due to inclusion of participants with etiologies other than Alzheimer’s disease.
Results from a pilot study: The effects of nicotinamide riboside on mild cognitive impairment
Authors: Orr Miranda E. , Kotkowski Eithan , Bair‐Kelps Darcy , Romo Terry , Espinoza Sara , Musi Nicolas , Powers Becky ,   San Antonio Claude D. Pepper Center
Published: December 2020

Background

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme in cellular metabolism. NAD(+) levels decrease with aging. Experimentally boosting NAD(+) improves cognitive function and synaptic plasticity in Alzheimer's disease mouse models. NAD(+) can be synthesized from dietary intake of its precursors, including nicotinamide riboside (NR), a readily available non‐prescription nutritional supplement. Recent studies have demonstrated that dietary NR increases blood NAD(+) levels in healthy older adults. We hypothesize that NR supplementation will positively affect brain function in older adults with mild cognitive impairment (MCI).

Method

Phase 2 randomized, double‐blind, placebo‐controlled trial with a 10‐week treatment period. Adults aged ≥65‐years‐old with a prior diagnosis of normal cognition [Montreal Cognitive Assessment (MoCA) score 26‐30] or MCI (MoCA score of 21‐25) participated at UT Health San Antonio. Dose escalation with NR over a 4‐week period was used to reach 1g/day, or maximum tolerated dose, for the final 6 weeks of the study. The primary outcomes were change from baseline on the MoCA and hippocampal blood flow as assessed by functional MRI (fMRI). Secondary outcomes included psychometric and frailty measures. Levels of blood NAD(+) and metabolites were determined at baseline and at the end of the study.

Result

Baseline levels of NAD(+) did not significantly differ between MCI and control groups (21.4 ± 0.75 versus 19.3 ± 2.04μM, mean ± SEM, MCI and control, respectively; p = 0.24). NR was well tolerated and significantly increased blood NAD(+), NAAD, and Me4PY (log2fold change: 1.2, 2.6, 3.3, respectively; p < 0.0001). NR treatment was associated with positive functional changes in the brain and frailty measures, but changes in cognitive measures were not observed.

Conclusion

A 10‐week supplementation of NR was well tolerated and significantly increased NAD(+) and associated metabolites in the blood of older adults with MCI. NR improved fMRI and physical function, our primary and secondary outcome measures, respectively. However, differences in cognition were not achieved in this small pilot study. Our results provide supporting evidence for further testing of NR as a method to maintain brain structure and function in older adults with MCI.
An RCT to identify best practices for disclosure of amyloid imaging results in mild cognitive impairment: The ABIDE simulation study
Authors: Fruijtier Agnetha D , van Maurik Ingrid S , Scheltens Philip , Bouwman Femke , Pijnenburg Yolande AL , Ebenau Jarith , Van Berckel Bart NM , Smets Ellen M , van Der Flier Wiesje , Visser Leonie NC
Published: December 2020

Introduction

Concerns about Mild Cognitive Impairment (MCI) patients’ understanding of disclosure of amyloid‐positive status and the emotional impact of this complex message have resulted in disclosure‐frameworks based on expert opinion. To date, evidence lacks which communication strategy works best. Our study aimed to empirically study the effectivity of six different communication strategies on patients’ understanding, and emotional state when receiving a positive amyloid status.

Methods

We performed a Randomized Controlled Trial with an online video‐vignette design [3,4]. Communication strategies were varied across otherwise standardized, enacted videotaped consultations. Healthy individuals aged > 50, instructed to imagine themselves in the situation of the video‐patient [5], were randomly assigned to one of seven conditions: 1) Control, 2) Non‐specified risk, 3) Explicit PET‐scan and Alzheimer’s disease information, 4) Showing the PET‐scan, 5) Risk best‐practice, 6) Emotional response, and 7) The teach‐back. Questionnaires measuring emotional state (PANAS) and anxiety (STAI) were administered prior to‐ (T0) and directly after viewing the vignette (T1). The T1 questionnaire contained questions assessing information recall (coding of open‐ended questions is currently ongoing), information recognition (multiple‐choice), behavioral intentions, uncertainty, trust in the clinician, and satisfaction.

Results

We included 1017 participants (table 1). We found differences between conditions on information recognition (P=.001, figure 1A), uncertainty (P=.000, figure 1B), trust in the physician (P=.008, figure 1C), and satisfaction (P=.000, figure 1D). Information recognition (P=.046), and satisfaction (P=.013) were highest in the emotional response condition. Risk‐best practice led to higher uncertainty (P=.000), yet trust in the clinician was higher when risk‐estimate was mentioned (control‐condition), compared to no mention of a specified risk‐estimate (P=.017). Satisfaction was best in the emotional response condition (P=.013).

Conclusion

This is the first study to provide empirical evidence of best strategies for disclosure of amyloid PET to MCI patients. Disclosing a positive amyloid PET result with risk information does not increase negative emotions and anxiety, although it enhances feelings of uncertainty. Actively attending to emotions after providing risk information results in enhanced recognition of information, trust in the clinician, and satisfaction. We can use these results to inform an evidence‐based practice recommendation for amyloid disclosure in a clinical setting.
The association between white matter hyperintensity shape and cognitive functioning: The SMART‐MR study
Authors: Zwartbol Maarten H.T. , Ghaznawi Rashid , Jaarsma‐Coes Myriam , Kuijf Hugo J. , Hendrikse Jeroen , de Bresser Jeroen , Geerlings Mirjam I.
Published: December 2020

Background

White matter hyperintensities (WMHs) are associated with cognitive decline and increased risk of dementia, including Alzheimer’s disease. However, the association between WMH and cognitive functioning is weak, presumably due to heterogeneity of the underling WMH pathology. Recently, WMH shape has been related to the severity of the underlying pathology and, compared to volume, may provide a novel metric for WMH burden. We examined the relationship between WMH volume, shape and cognitive functioning in patients with arterial disease. We hypothesized that WMH shape was related to cognitive functioning, independent of WMH volume.

Methods

In the SMART‐MR study, we performed cross‐sectional analyses in 563 patients (58±10 years) with available brain MRI and data on cognitive functioning. WMH volume and shape were automatically determined on MRI data. Linear regression analyses were used to estimate the association between Z‐scores of WMH volume, WMH shape features (concavity index, solidity, convexity, fractal dimension and eccentricity) and Z‐scores of cognitive functioning, adjusted for age, sex, education, and reading ability.

Results

A larger WMH volume was associated with poorer executive functioning (b=0.09; 95% CI ‐0.17 to ‐0.01; p=0.02), but not memory functioning. A more complex shape of periventricular/confluent WMH was associated with poorer executive functioning (concavity index: [b=‐0.13; 95% CI ‐0.20 to ‐0.06; p <0.0001]; solidity: [b=0.09; 95% CI 0.02 to 0.17; p=0.014) and poorer memory scores (fractal dimension: b=‐0.10; 95% CI ‐0.18 to ‐0.02; p=0.02). Moreover, the association between WMH shape measured by the concavity index and executive functioning was independent of WMH volume (b=‐0.12; 95% CI ‐0.19 to ‐0.04; p=0.003). Figure 1 presents an example of two patients with similar WMH volume but a 2.7 standard deviation difference in concavity index.

Conclusions

A more complex shape of WMH shape was associated with poorer cognitive functioning. Our results suggest that WMH shape contains additional information about WMH burden, not otherwise captured by WMH volume.
Diabetes can increase risk for developing abnormal cognition
Authors: Li Wei , Wang Ge
Published: December 2020

Background

Diabetes has been shown as a risk factor for cognitive impairments. However, it is still not clear about the time course of developing abnormal cognition in these with diabetes especially if the morbidity accelerates the cognitive deterioration process.

Method

A retrospective analysis was performed using data collected by the National Alzheimer’s Coordinating Center. Incidence, prevalence and age at onset (AAO) of either mild cognitive impairment (MCI) or dementia were compared between participants with and without diabetes.

Result

During a follow‐up period of more than 10 years, the diabetic group had a higher incidence and prevalence of MCI or dementia than the non‐diabetic group. However, the AAO of either MCI or dementia was independent of the diagnosis of diabetes.

Conclusion

Although diabetic patients have a higher incidence and prevalence of abnormal cognition than those without diabetes, diabetes does not accelerate the cognitive deterioration process.
BSI whole‐brain volume change estimation initialised with fully automatic LEAP segmentation
Authors: Joules Richard , Wolz Robin
Published: December 2020

Background

Whole brain atrophy as measured from T1‐wieghted MR images is a key biomarker for progression in Alzheimer's disease (AD) and employed as marker for treatment efficacy in clinical trials. The Boundary Shift Integral (BSI) methodology (Freborough;IEEE;1997) is the widely established standard and well validated method for volume change. BSI requires initialisation with a whole‐brain segmentation at both timepoints, manual segmentations remain the gold standard, however the BSI approach is robust to minor segmentation, potentially facilitating the use of automatic segmentation approaches. Furthermore, to improve sensitivity to volume change and exploit the probabilistic nature of many automatic segmentations a generalised form of the BSI (gBSI) pipeline has been proposed (Prados;NeurobiolAging;2015). The use of a fully automatic pipeline to estimate volume change provides a scalable solution for clinical trial deployment without the burden of manual segmentation or edits and associated variability introduced. Here we assess the use of LEAP (Ledig;ProcISBI;2012), a fully automatic whole brain segmentation tool providing both binary and probabilistic parcellations, to initialise the BSI, as implemented in MIDAS, and gBSI pipelines.

Method

Whole brain volume change over 1 year was estimated for 48 participants, acquired as part of a clinical trial, with the BSI and gBSI methods initialised with 1) manually generated whole brain segmentations and 2) automatically estimated whole brain segmentations generate with LEAP. No manual corrections were performed; all LEAP segmentations passed a visual quality control inspection.

Result

Figure 1 shows the relationship between the manually initialised BSI and the fully‐automated LEAP‐BSI approach. Table 1 shows average measures of volume change across all tested methods. All measures were significantly correlated with non‐significant differences in reported mean volume change.

Conclusion

LEAP offers segmentations suitable for initialisation of the BSI method providing a pipeline for fully automatic volume estimation consistent with the semi‐automated BSI approach, providing a scalable solution for clinical trial deployment without the associated variability and resource burden required for fully manual segmentations. Furthermore the probabilistic output of LEAP allows for the use of the gBSI methodology with the associated potential of increased sensitivity to volume change.
Pre‐screening models for patient engagement: The MOPEAD project
Authors: Boada Mercè , Winblad Bengt , Jessen Frank , Visser Pieter Jelle , Kramberger Milica G. , Rodrigo Adrián , Simó Rafael , Rodriguez Octavio , Sannemann Lena , Bon Jaka , Zwan Marissa D. , Alegret Montserrat , Sanabria Angela , Rosende‐Roca Maitee , Krivec David , Jamilis Laura , Trigueros Paloma , Kivipelto Miia , Johansson Gunilla , Wimo Anders , Valero Sergi , Shering Craig , Glaysher Bridget , Tarraga Lluis , Dumas Annette , Georges Jean , Campo Laura
Published: December 2020

Background

Alzheimer’s disease (AD) is a devastating condition that not only impacts greatly on the patient’s health but also poses an important burden on the patient’s immediate family circle. Early detection of AD allows patients to have an active role in managing their condition, and to plan how to minimize the strain on their dear ones. Despite known benefits, a large proportion of dementia cases remains undiagnosed or receives a late stage diagnosis. The MOPEAD project aims to address this issue by exploring innovative strategies to emerge “hidden” cases of cognitive impairment.

Method

Memory clinics located in five different European countries participated in the project. Four innovative pre‐screening strategies were implemented to detect cognitive decline among individuals aged 65‐85 years who had never received a dementia related diagnosis: a) a web‐based pre‐screening tool along with an online marketing campaign, b) open house initiatives where people with memory complaints were invited to receive a quick evaluation at participating memory clinics, c) a primary care‐based protocol for early detection of cognitive decline using easily administered tools, and d) a tertiary care‐based pre‐screening at diabetologist clinics specifically designed to assess risk of dementia among patients with diabetes. A positive pre‐screening result implied that individuals were at high risk of having mild cognitive impairment or AD.

Result

The number of individuals enrolled, and the proportion of those with positive pre‐screening results varied across strategies. The web‐based tool evaluated the largest number of individuals (n=1487) and yielded 547 positive results (36.8%). The Open house initiative pre‐screened 661 subjects of whom 235 (35.6%) obtained a positive result. A total of 435 patients were pre‐screened in the primary care‐based strategy and 193 of them (44.4%) were found to have a positive result. Finally, 264 patients from diabetes clinics underwent pre‐screening and 154 (58.3%) showed a positive result.

Conclusion

Using innovative pre‐screening strategies, we were able to identify 1129 individuals at high risk of having dementia who had otherwise remained unnoticed. Initiatives like this, show us the way to go in order to shift the paradigm of AD towards an earlier diagnosis.
Higher CSF STREM2/P‐tau ratio levels attenuate effects of polygenic Alzheimer’s disease risk on cognitive decline and neurodegeneration
Authors: Franzmeier Nicolai , Suárez‐Calvet Marc , Frontzkowski Lukas , Morenas‐Rodríguez Estrella , Kleinberger Gernot , Shaw Leslie M. , Trojanowski John Q. , Haass Christian , Ewers Michael ,   Alzheimer's Disease Neuroimaging Initiative (ADNI)
Published: December 2020

Background

Loss of function of TREM2, a key receptor expressed on microglia, is associated with increased Alzheimer’s disease (AD) risk. In biomarker‐defined AD patients, we found previously that higher cerebrospinal‐fluid (CSF) levels of soluble TREM2 relative to the level of p‐tau (sTREM2/p‐tau ratio) are associated with attenuated clinical AD progression. This suggests that higher sTREM2/p‐tau, indicative of more activated microglia at a given level of pathology, may be beneficial in AD. Here, we asked the more general question whether higher sTREM2/p‐tau ratio levels attenuate the general risk to develop AD‐related cognitive decline and neurodegeneration in a large sample of cognitively normal to AD dementia subjects. To assess AD risk, we used a pre‐established polygenic hazard score (PHS) including 31 SNPs that are associated with age of AD onset (e.g. Tan et al., Brain, 2019). We determined whether higher sTREM2/p‐tau levels attenuate the effect of polygenic AD risk (i.e. PHS) on future cognitive decline and neurodegeneration.

Methods

We included 648 elderly cognitively normal to dementia subjects from ADNI with available CSF‐biomarker data (i.e. sTREM2, Aβ1‐42 and p‐tau), longitudinal cognitive assessments and structural MRI (∼4yrs follow‐up). The PHS was determined on GWAS data. Using linear regression, we tested the association between PHS, CSF‐assessed AD biomarkers or sTREM2, controlling for age, gender, education and diagnosis. Second, we determined whether higher sTREM2/p‐tau levels moderated the effect of PHS on annual change rates in global cognition (i.e. ADAS13), memory (i.e. ADNI‐MEM) and MRI‐assessed hippocampal volume, controlling for age, gender, education and diagnosis and baseline cognition.

Results

Higher polygenic AD risk, i.e. PHS, was associated with lower CSF Aβ1‐42 (β=‐0.354,p<0.001) and higher p‐tau levels (β=0.328,p<0.001), but not with sTREM2 (β=0.007,p=0.864; Figure 1). We found significant sTREM2/p‐tau x PHS interactions, such that individuals with higher sTREM2/p‐tau ratios had a lower effect of PHS on global cognitive (β=‐0.210,p=0.002) and memory decline (β =0.258,p=0.002) as well as hippocampal atrophy rates (β=0.262,p=0.002; Figure 2).

Conclusion

A higher sTREM2/p‐tau ratio is protective against the AD‐related polygenic risk for faster cognitive decline and hippocampus atrophy.
Measuring neurodevelopmental effects of polygenic risk for Alzheimer's disease via longitudinal study of brain and cognitive variables in periadolescent children
Authors: Warren David E. , Phipps Connor J. , Eckel Medea , Rangel Anthony , Heller Abi M. , Maerlender Arthur C. , Phatak Vaishali S. , Cramer Justin A. , Blair James , Murman Daniel L. , Smith Shelley D.
Published: December 2020

Background

Individual variability in Alzheimer’s disease (AD) risk is greatly affected by genetic factors, and those factors may exert early influence on brain development. Specifically, genetic/genomic AD risk factors may bias brain development toward vulnerability to late onset AD. We are conducting a five‐year study (funded by the National Institute on Aging) to test the hypothesis that polygenic AD risk alters neurodevelopment of brain systems most affected by AD in ways that increase vulnerability to late‐onset AD. If true, then properties of AD‐vulnerable brain structures (e.g., hippocampus) and AD‐vulnerable brain networks (e.g., default mode network) will vary with polygenic AD risk even during youth. Here, we describe our study aims, approach, and predictions.

Methods

We have implemented our project as the Polygenic Risk of Alzheimer’s disease in Nebraska Kids (PRANK) study. The PRANK study will measure neurodevelopmental effects of AD polygenic risk scores (ADPRS) with three aims: 1) measure effects of ADPRS on development of AD‐vulnerable brain regions; 2) quantify how ADPRS affects development of functional brain networks vulnerable to AD; and 3) evaluate effects of ADPRS on development of AD‐vulnerable cognitive abilities. To address these aims, we are developing a new dataset which combines neuroimaging (brain structure/function), neuropsychology (cognition), and genomics (ADPRS) in a longitudinal design. Our study is currently enrolling healthy youth age 8‐13 years; our multi‐year recruitment goal is N = 270. Participants will return for follow‐up two years after initial participation.

Results

Our study is ongoing, but we will discuss our design and preliminary findings. We predict that higher ADPRS in otherwise typically developing youth will be associated with: 1) smaller hippocampal volume and decreased cortical thickness in AD‐related ROIs; 2) lower connectivity in functional brain networks and less brain activity in memory tasks; 3) lower scores on measures of AD‐related cognitive abilities (e.g., memory and executive functions) after accounting for IQ.

Conclusions

Findings from the PRANK study will improve the field’s understanding of how developmental effects of ADPRS relate to clinical and epidemiological challenges of AD. Measuring how genetic/genomic factors associated with late‐onset AD affect brain development will elucidate lifelong trends for AD risk while highlighting new opportunities for early intervention.
Multiple pathophysiological biomarkers are associated with gray matter volume and cerebral glucose metabolism in the early preclinical Alzheimer's continuum
Authors: Gispert Juan Domingo , Salvadó Gemma , Milà‐Alomà Marta , Cacciaglia Raffaele , Falcon Carles , Operto Greg , Grau‐Rivera Oriol , Arenaza‐Urquijo Eider M , Shekari Mahnaz , Minguillón Carolina , Fauria Karine , Kollmorgen Gwendlyn , Eichenlaub Udo , Zetterberg Henrik , Blennow Kaj , Suárez‐Calvet Marc , Molinuevo Jose Luis ,   ALFA Study
Published: December 2020

Background

The pathophysiological events that occur early in the preclinical Alzheimer’s disease (AD) continuum are not fully understood. Here, we sought for associations, in cognitively unimpaired individuals, between cerebrospinal (CSF) biomarkers of the main pathophysiological events described in AD vs. patterns of gray matter volume (GMv) and cerebral glucose metabolism (rCMRGlu).

Method

The first consecutive 381 participants of the ALFA+ study with valid T1w MRI, [18F]FDG‐PET scans and CSF samples were included. CSF biomarkers were measured with the NeuroToolKit robust prototype assays and Elecsys® immunoassays (Roche Diagnostics) and related to amyloid (Aβ42, Aβ40) and tau (pTau) metabolism, neuronal and axonal damage (NfL), synaptic dysfunction (neurogranin), neuroinflammation (sTREM2, YKL40, GFAP, S100, IL6), and α‐synuclein. Individuals were staged using the A/T system and pre‐established cut‐offs for the Aβ42/40 ratio and pTau concentrations. Modulated GMv maps were obtained from T1w scans. [18F]FDG uptake was normalized to the pons. Exploratory voxelwise associations between maps of GMv and rCMRGlu vs. CSF biomarkers (and differences between A/T groups in the AD continuum) were assessed with SPM12 (p<0.005, k>50 voxels) after accounting for the effect of age, sex, education, and APOE‐ε4 carriership, as well as for the Total Intracranial Volume (TIV) in the GMv analysis.

Result

Demographics are shown in Table 1. Figure 1 shows regional differences in GMv and rCMRGlu between A/T groups and Figure 2 associations with biomarkers. Compared to the A‐T‐ group, A+T‐ individuals presented a widespread pattern of higher GMv. Higher pTau levels were associated with an extensive pattern of higher GMv and rCMRGlu. Higher sTREM2 values were associated with higher GMv in the temporoparietal junction and posterior cingulate cortex overlapping pTau GMv effects (Figure 3). Lower Aβ42/40 values were also associated to lower rCMRGlu in bilateral hippocampus and anterior cingulate. Higher NfL levels were coupled with lower GMv in bilateral parietotemporal cortices.

Conclusion

Results suggest that pathogenic events in very early stages of the Alzheimer’s continuum are unexpectedly associated with higher GMv and rCMRGlu. The overlap of pTau and sTREM2 effects in GMv may point towards a TREM2‐mediated microglial reaction to initial tau pathology. Interactions between biomarkers and A/T groups will be presented.
Development of monoclonal antibodies specific for the calpain‐generated ∆48 kDa calcineurin fragment, a marker of distressed astrocytes
Authors: Gollihue Jenna L. , Kraner Susan D. , Weiss Blaine E. , Artiushin Irina A. , Sompol Pradoldej , Norris Christopher M.
Published: December 2020

Background

Calcineurin (CN) is a Ca2+/calmodulin‐dependent protein phosphatase expressed at high levels in brain. In healthy tissue, CN exists mainly as a full‐length (∼60 kDa) highly‐regulated protein involved in essential cellular functions. However, in diseased or injured tissue, CN is proteolytically converted to a constitutively active fragment that has been causatively‐linked to numerous pathophysiologic processes. The 48 kDa CN fragment (DCN) appears at high levels in human brain at early stages of cognitive decline associated with Alzheimer’s disease. DCN tends to show‐up in regions of frank amyloid and cerebrovascular pathology, especially in select subsets of astrocytes, both in humans and in animal models. Our goal was to develop monoclonal antibodies to DCN for use in neuropathology research.

Method

A peptide encompassing the calpain sensitive region of the CN carboxyl terminus was used for antibody generation. Antibodies were screened in ELISAs against the immunizing peptide, but decision‐making screens were carried out as a Western analysis of 5XFAD mouse brain extracts, which express high levels of the DCN fragment.

Result

We identified 2 monoclonals, one of which (17E1) was highly reactive to DCN in Western blots, but not in ELISAs, of 5xFAD brain extracts. In contrast, the second antibody (26A6) reacted well against the peptide in ELISAs, but worked only modestly in Westerns. Importantly, neither antibody reacted with full‐length (60 kDa) CN, nor did antibodies detect DCN in extracts from healthy WT mice. In immunostaining assays, both antibodies strongly labeled subsets of GFAP‐positive astrocytes in 5xFAD mice with a high signal‐to‐background. Some GFAP‐negative cells also labeled positively for DCN. Consistent with Westerns, there was no antibody reactivity to WT mouse brain sections.

Conclusion

New monoclonals are highly selective for the 48 kDa CN proteolytic fragment and label subsets of astrocytes, and possibly other cell types, under pathological conditions. These antibodies could be a useful tool for marking insidious brain pathology and identifying novel astrocyte phenotypes.
The North American Prodromal Synucleinopathy (NAPS) Consortium: Baseline neuropsychological findings in 136 participants
Authors: Fields Julie A. , Boeve Bradley F. , Forsberg Leah K. , Louis Erik K. St. , Kraft Ruth A. , Nelson Kevin M. , Timm Paul C. , Teigen Luke N , Avidan Alon Y. , Rivera Adreanne , Postuma Ronald B. , Gagnon Jean‐François , Pelletier Amelie , Howell Michael J. , Schenck Carlos H. , De Kam Josh , Ryberg Kelly J. , Summers Rebekah L. , Bliwise Donald , Huddleston Daniel , Wood‐Siverio Cathy , Videnovic Aleksandar , Stauder Matthew , Hersh Samantha , Criswell Susan R. , McLeland Jennifer S. , Ju Yo‐El ,   NAPS Consortium
Published: December 2020

Background

It is important to determine the natural history of individuals with RBD and generate clinical and neuropsychological data for planning disease‐modifying trials to delay or prevent phenoconversion of RBD to an overt synucleinopathy such as dementia with Lewy bodies, Parkinson’s disease, or multiple system atrophy. Our objective is to present initial neuropsychological data on 136 participants with REM sleep behavior disorder (RBD) without an overt synucleinopathy who are in the North American Prodromal Synucleinopathy (NAPS; R34AG056639) Consortium.

Method

As part of the NAPS protocol (www.naps‐rbd.org), investigators at 10 centers in North America are enrolling a target of 360 participants with RBD. A comprehensive clinical battery and a set of neuropsychological measures (using the National Alzheimer Coordinating Center Uniform Data Set version 3 or UDS3) are performed at each visit.

Result

Participants were 82% male, ranging in age from 35‐85 (Mean=65.9, SD=15.9) and education from 8‐20 years (Mean=15.9, SD=3.1). Only 17 participants (13%) were impairment‐free across all tests administered. The proportions of participants with impaired scores were tabulated as follows (< ‐1.5 SD after adjustment for age, sex, and education): global cognition – 17%; attention/executive functioning – 10‐20% across measures; language – 14‐24% across measures; visuospatial – 16%; and episodic learning/memory – 18‐25% across measures. Of all participants, 79 (58%) showed impairments < ‐2 SD. Moreover, 53% of those with cognitive impairment involved impact in 2 domains, an additional 20% in 3 domains, and another 4% was impaired in all domains. The combination of attention/executive and language was most often observed.

Conclusion

Collection of a comprehensive set of clinical and neuropsychological measures is feasible and tolerated in RBD patients. Using the UDS3 neuropsychological test battery, impairment in one or more measures was present in 87% of participants, and 58% showed impairments greater than 2 SD below the mean in the absence of a clinical diagnosis of dementia. Impairments in > 2 domains was common, most frequently involving attention/executive and language. Future longitudinal assessments will be required to determine the predictive utility of neuropsychological performance for phenoconversion of RBD to an overt synucleinopathy.
MRI‐assessed locus coeruleus integrity is heritable and associated with cognition, Alzheimer’s risk, and sleep‐wake disturbance
Authors: Elman Jeremy A. , Puckett Olivia K. , Beck Asad , Panizzon Matthew S. , Sanderson‐Cimino Mark E. , Gustavson Daniel E. , Lyons Michael J. , Franz Carol E. , Kremen William S.
Published: December 2020

Background

The locus coeruleus (LC) is one of the earliest sites of Alzheimer’s disease (AD) pathology, and it experiences extensive neurodegeneration through the disease course. The LC has long been associated with arousal and the sleep‐wake cycle, which are commonly disrupted in AD. Recent research implicates the LC in modulating cognitive function, suggesting an additional path by which LC dysfunction can contribute to cognitive decline in AD. Recent advances in MRI allow for in vivo measures of LC integrity, which may detect early effects of AD or other diseases. We examined whether an MRI measure of LC structural integrity was heritable and whether it was associated with cognitive performance, mild cognitive impairment (MCI), and sleep‐wake disruption.

Method

Participants were 481 late‐middle‐aged men (mean age=67.5; range=62‐71.7) from the Vietnam Era Twin Study of Aging. Rostral LC structural integrity was indexed by contrast‐to‐noise ratio (LCCNR) in manually marked regions of an FSE T1‐weighted MRI scan. We determined heritability with the classical twin method comparing monozygotic and dizygotic twins. Cognitive performance was assessed using factor scores across multiple domains, and amnestic MCI (aMCI) was diagnosed according to Jak‐Bondi criteria. The Pittsburgh Sleep Quality Index was used to measure sleep‐wake disruption.

Result

Genetic influences (heritability) accounted for 62% of variance in LCCNR. The remaining variance was accounted for by unique environmental variance. Participants with aMCI showed significantly greater daytime dysfunction on the Pittsburgh scale compared to cognitively normal participants. Lower LCCNR was associated with increased odds of aMCI and greater daytime dysfunction. Lower LCCNR was also associated with lower episodic memory, general fluency, semantic‐specific fluency, and processing speed factor scores.

Conclusion

These results demonstrate that MRI‐assessed LC integrity is a meaningful biological index. They suggest that LC damage may contribute to sleep‐wake disturbances and cognitive impairment among those with aMCI. Further research is needed to determine whether and how these factors are causally linked. Associations with factor scores across multiple domains highlight the potentially widespread impact of reduced LC integrity on cognition. Furthermore, these findings in late‐middle‐aged adults highlight the potential utility of MRI‐based measures of LC integrity in early identification of AD risk.