bluuebunny/crossref_metadata_2025 huggingface dataset:
Special Circumstances: Agitation with Dementia in Emergency Departments
Authors: Rosenberg Paul B.
Published: December 2022

Background

Older persons presenting to the emergency department (ED) with agitation have a high prevalence of cognitive impairment which may not have been previously diagnosed.. Agitation in the ED may have many causes, one of the most prominent of which is delirium which occurs in 8–10% of older persons in the ED, and is often not diagnosed till hospital admission . The recently developed IPA algorithm for diagnosis and management of agitation in dementia is applicable to the ED environment particularly as it applies to delirium.

Method

This abstract describes the application of the IPA algorithm to the ED setting

Results

One of the major challenges of agitation management in the ED is taking a history, particularly for patients coming from a LTC environment. LTC staff can readily describe the index episode of agitation, but what is often missing is understanding the timeframe of agitation, including provoking and mitigating factors and any history of prior episodes and their causes. This makes it difficult to know if cognitive impairment is chronic or acute, the hallmark of delirium. A systematic approach to diagnosis and management is required. EDs are making increased use of well‐validated delirium screening assessments such as the Confusion Assessment Method (CAM). Other useful tools for management of delirium in the ED include ADEPT and the Delirium Triage Screen (DTS).

Nonpharmacologic strategies have an important role in treatment of agitated patients in the ED. Interventions to prevent or reduce delirium in acute care environments are becoming increasingly effective: a recent Cochrane review supported the effectiveness of interventions including re‐orientation (including use of familiar objects), cognitive stimulation, sleep hygiene, attention to nutrition and hydration, oxygenation, medication review, assessment of mood, and bowel and bladder care. EDs increasingly incorporate these interventions into routine care including the use of delirium‐focused order sets and deployment of geriatric management teams which have been shown to reduce 30‐day ED readmission rates.

Conclusion

Further studies should integrate diagnostic workflows and algorithms for behavioral interventions developed for both agitation and delirium management in the ED.
Plasma NfL predicts default mode network functional connectivity in older adults at higher risk for Alzheimer’s disease
Authors: Jung Youjin , Counts Scott E. , Hampstead Benjamin M. , Damoiseaux Jessica S.
Published: December 2022

Background

Neurofilament light (NfL) is a measure of neuronal damage and has the potential as a monitoring and prognostic biomarker of Alzheimer’s disease (AD) (Mattsson et al., 2019). Likewise, alterations in default mode network (DMN) functional connectivity (FC) may predict AD progression (Jones et al., 2016). Here, we investigated the relationship between plasma NfL levels and DMN FC along the continuum of AD, and explored whether APOE ε4 status influenced this relationship.

Method

Resting‐state functional MRI data and blood samples were available for 103 older adults (17 with AD dementia, age: 69.2±6.9; m/f: 8/9; CDR: 0.7±0.3; and 86 without dementia (includes amnestic MCI and control), age: 71.7±7.4; m/f: 21/65; CDR: 0.3±0.2). Plasma NfL was measured using a single‐molecule array (Simoa) assay. We calculated DMN FC using 32 high consensus DMN ROIs from Dworetsky et al. (2021). DMN FC was defined as the average correlation between the mean time‐series of three ROIs labeled as posterior cingulate cortex and those of all the other ROIs. Participants’ APOE status was defined as APOE ε4 carriers (ε3/ε4 or ε4/ε4) and noncarriers (ε3/ε3). Multiple regression was run with DMN FC as the outcome variable, plasma NfL as the predictor, and age and sex as covariates.

Result

Plasma NfL levels were higher in those with dementia compared to those without dementia (t = 4.4608, p = 0.0002) but did not differ between amnestic MCI and control (t = 1.6116, p = 0.1130). Across all participants, plasma NfL did not predict DMN FC (Β = 0.0045, p = 0.4830). However, higher plasma NfL was marginally associated with higher DMN FC in those with dementia (Β = 0.0045, p = 0.0657) but not in those without dementia (Β = 0.0021, p = 0.3160). Moreover, in those without dementia, higher plasma NfL predicted higher DMN FC in APOE ε4 carriers (Β = 0.0079, p = 0.0312) but not in APOE ε4 noncarriers (Β = 0.0023, p = 0.4871).

Conclusion

Our results indicate that the increase of DMN FC, seen at early stages of AD (Damoiseaux et al., 2012), is significantly associated with more neuronal damage in APOE ε4 carriers without dementia.
Using biological pathways in Machine Learning methods for Alzheimer’s disease risk prediction
Authors: Rowe Thomas , Leonenko Ganna , Williams Julie , Holmans Peter , Ivanov Dobril , Escott‐Price Valentina
Published: December 2022

Background

Recent genome‐wide studies have identified over 70 risk loci for late onset Alzheimer’s Disease (AD) (Kunkle et al. 2019, Bellenguez et el. 2021, Wightman et al. 2021). Analysis in this study focused on developing Machine Learning (ML) models to predict AD risk from genetic data. We compared the prediction accuracy of ML to polygenic risk scores (PRS) using SNPs in disease‐associated biological pathways.

Method

We used the Genetic and Environmental Risk for Alzheimer’s Disease consortium dataset (Harold et al. 2009). SNPs were selected from the AD associated pathways in Kunkle et al. 2019. Two decision tree‐based ML algorithms were used, Random Forests (RFs) and Gradient Boosting (GB). The prediction ability of these methods was compared to Polygenic Risk Score (PRS). RFs and GB models were developed using the Python library sklearn. These were trained and tested using 5‐fold cross‐validation. Clumping and thresholding (CT), as implemented in PLINK, was used to generate PRS, with logistic regression used for prediction. CT PRS was compared to the PRS generated by the PRS‐CS method (Ge, T., Chen, CY., Ni, Y. et al).

Result

Initial results demonstrate that PRS, PRS‐CS and ML perform similarly for pathway specific analysis (AUC∼69%) when pathways include APOE.

Conclusion

Subsequent analyses will compare the performance of the methods when APOE SNPs are removed from the pathways, and in multivariate analyses modelling multiple pathway effects simultaneously.
Processing of acoustically degraded emotional prosody in primary progressive aphasia and Alzheimer’s disease
Authors: Jiang Jessica , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Johnson Jeremy , Sivasathiaseelan Harri , Chokesuwattanaskul Anthipa , Russell Lucy L , Warren Jason D , Hardy Chris JD
Published: December 2022

Background

Accurately interpreting a speaker’s nonverbal emotional vocal signals (their prosody) is often essential for successful communication. In the noisy conditions of daily life, this presents the brain with a difficult computational challenge that may be vulnerable to neurodegenerative pathologies. However, processing of acoustically degraded prosody has not been studied in these diseases.

Method

Here we addressed this issue in patients representing all major syndromes of primary progressive aphasia (N = 33) and Alzheimer’s disease (N = 18) versus healthy age‐matched controls (N = 24). As a model paradigm for the degraded ‘noisy’ speech signals of everyday life, we used noise‐vocoding: digital division of the speech signal into a variable number of frequency channels constituted from amplitude‐modulated white noise, such that fewer channels convey less spectrotemporal detail and reduce intelligibility. We assessed the impact of noise‐vocoding on recognition of three canonical prosodic emotions (anger, surprise, sadness) at three noise‐vocoding levels.

Result

Compared with healthy controls, all patient groups were impaired recognising prosodic emotions (particularly anger) in clear speech, while patients with Alzheimer’s disease showed a disproportionate cost for recognition of the noise‐vocoded emotion of sadness.

Conclusion

Our findings open a window on a dimension of emotional communication that has been relatively overlooked in dementia, and suggest a novel candidate paradigm for investigating and quantifying this systematically.
Special Circumstances of Persons with Dementia and Agitation in Hospice Care.
Authors: Mintzer Jacobo E
Published: December 2022

Background

Approximately 45% of patients with dementia will experience agitation in the last stages of disease. Furthermore, approximately 35% of patients in the late stages of their lives will present agitation despite being treated with lorazepam, morphine, and atypical antipsychotics. Since agitation is particularly prevalent in hospice care, we estimate that at least 45% of the subjects with dementia in hospice care, or approximately 80,000 individuals a year, will die suffering from symptoms of agitation.

Methods

Differences between agitation in dementia at different stages of the disease were evaluated.

Results

Agitation in patients with dementia in the moderate stages of the disease requires the correction of the medical condition that could contribute to the presence of agitation. In hospice care eligible patients with agitation and dementia, these conditions are often untreatable and/or side effects associated with treatment could be more deleterious than the presence of agitation. In the treatment of hospice care eligible patients with agitation and dementia, the main concern is to control symptoms and improve patient’s comfort level while preserving alertness and controlling pain and other symptoms frequently present in terminal patients, including nausea and dyspnea, rather than to uncover and treat the potential underlying cause(s) of the syndrome. In addition, several distinct physiological processes develop both in the CNS and in the periphery during the last few weeks of an individual’s life, including changes in tissue concentrations of glucose, lactate, pyruvate, ATP, ADP, AMP, and phosphocreatine (reflecting brain energy metabolism changes observed during the process of dying and after cardiopulmonary resuscitation).

Conclusion

Symptoms of agitation in moderate demented patients appear to be biologically and symptomatically different than symptoms of agitation in hospice care eligible patients with dementia. Therefore, the hospice care eligible patients with agitation and dementia need to be better studied and treatments tailored to these specific conditions should be developed.
Physical Activity Level Moderates the Association Between Response Inhibition and Anterior Cingulate Cortex Volume in Older Adults
Authors: Stein Ryan G , Silva Narlon Cassio Boa Sorte , Brinke Lisanne F Ten , Handy Todd C , Hsiung Ging‐Yuek Robin , Liu‐Ambrose Teresa
Published: December 2022

Background

Aging is generally associated with a decline in executive function, a cognitive domain that is critical to functional independence. Response inhibition is an executive process that contributes to anticipation, planning, and goal setting. The anterior cingulate cortex (ACC) is a key brain structure that supports response inhibition and shows gray matter loss with age. Evidence suggests that both response inhibition performance and the Anterior Cingulate Cortex (ACC) are responsive to exercise training. Whether physical activity moderates the relationship between response inhibition and the ACC in older adults is unknown.

Method

A cross‐sectional analysis of a subset of community‐dwelling older adults enrolled in a 3‐arm, 8‐week proof of concept randomized control trial of computerized cognitive training, with or without exercise, who completed T1 magnetic resonance imaging (MRI) at baseline. Of the 68 MRI participants, 11 were removed from this analysis due to poor scan quality. Response inhibition was measured using the Flanker Task from the NIH Toolbox Cognitive Battery. Participants were split into either a high or low physical activity groups determined by their median Physical Activity Scale for the Elderly (PASE) score. Caudal and rostral ACC volumes were segmented and quantified using FreeSurfer. To assess for moderation, we performed linear regressions with age‐adjusted Flanker Task score as the dependent variable, and ACC volume, high/low PASE, and the interaction of ACC volume * high/low PASE as independent variables.

Result

Physical activity level significantly moderated the association between left caudal anterior cingulate cortex (LCACC) volume and age‐adjusted Flanker Task score, (β = –6.428, t(53) = ‐2.075, p < .05). Among those with low physical activity levels (n = 30), greater LCACC volume was associated with better response inhibition (r = 0.44, p = .01) while there was no association among those with high physical activity levels (n = 27; r = ‐0.13; p = .52).

Conclusion

Higher physical activity may mitigate the negative effects of age‐related gray matter loss in the ACC on response inhibition performance in community‐dwelling older adults.
[18F]TRACK, a PET tracer for imaging of tropomyosin receptor kinases (Trk): efficient radiosynthesis and preliminary evaluation in the TgF344‐AD rat model of Alzheimer’s disease.
Authors: Kang Min Su , Thiel Alexander , Schirrmacher Ralf , Bernard‐Gauthier Vadim , Jaworski Carolin , Dorian Andreas , Hopewell Robert , Singleton Thomas A , Blinder Stephan , Soucy Jean‐Paul , Rosa‐Neto Pedro , Kostikov Alexey
Published: December 2022

Background

A family of tropomyosin receptor kinases (TrkA/B/C) plays important roles in the regulation of neuronal differentiation, growth, and survival via their interactions with neurotrophins. A growing body of literature suggests the downregulation of Trk in many neurodegenerative conditions of the central nervous system (CNS), including Alzheimer’s disease (AD). We recently reported the development of [18F]TRACK, the PET tracers for in vivo imaging of TrkB and its first in‐human study. Here, we wish to report a fully automated GMP‐compliant radiosynthesis of [18F]TRACK at high radiochemical purity (RCP) and molar activity and its preliminary evaluation in wild‐type and a transgenic rat model of AD.

Method

Radiosynthesis was performed using Scintomics GRP automated module via copper‐catalyzed 18F‐fluorination of the chiral boron pinacolate precursor. Brain imaging in wild‐type (n = 3) and TgF344‐AD rat models (n = 2) at 23 months was performed on microPET Concord R4 scanner.

Result

[18F]TRACK was synthesized with a 5.0±1.4 % radiochemical yield not corrected for decay (activity range 95–154 mCi) with >99% RCP and molar activities of 250 ± 75 GBq/µmol (n = 6). The synthesis was fully automated and all batches passed quality control procedures, including chemical purity, sterility and pyrogenicity. The tracer showed moderate brain uptake in wild‐type rats with the highest accumulation in the thalamus (SUVmax = 1.56 ± 0.28, 10 min post‐injection), consistent with the brain regional distribution in humans acquired in a parallel study. Preliminary data suggests lower tracer uptake in TgF344‐AD rat model of AD in thalamus, striatum and frontal cortex compared to wild‐type animals.

Conclusion

This study demonstrated the feasibility of the GMP‐compliant production of [18F]TRACK in sufficient doses and molar activities for scanning multiple subjects per day or long range deliveries. Preliminary biodistribution studies showed moderate brain uptake of the tracer with preferential accumulation in the thalamus across species. These findings warrants further studies of Trk brain expression and its implication in neurodegenerative and psychiatric pathologies using [18F]TRACK.
Longitudinal medial temporal lobe gray matter volume and cognitive changes in late middle‐aged and older adults with treated and non‐treated obstructive sleep apnea
Authors: Martineau‐Dussault Marie‐Ève , André Claire , Daneault Véronique , Baril Andree‐Ann , Gagnon Katia , Legault Julie , Montplaisir Jacques , Carrier Julie , Gosselin Nadia
Published: December 2022

Background

Neuroimaging studies in obstructive sleep apnea (OSA) have found both gray matter atrophy and hypertrophy in medial temporal lobe subregions, the latter probably reflecting edema. Whether and how these changes progress over time when OSA is treated or untreated remains unclear. Here, we investigated gray matter volume changes in medial temporal lobe subregions in treated OSA, untreated OSA and control participants aged > 55 years. We also explored whether the medial temporal lobe volume at baseline could predict cognitive decline.

Method

Twenty‐three non‐treated OSA participants (65.8 ±5.4 years) and twenty controls (64.0 ±6.4 years) were evaluated with overnight polysomnography, MRI session and neuropsychological assessment. Twelve OSA participants then started continuous positive airway pressure (CPAP) therapy and used it at least 4 hours per night, 4 nights per week. Eleven participants refused treatment. Participants were evaluated again with MRI and neuropsychology after 18 months. We extracted the entorhinal, hippocampal and parahippocampal volumes using FreeSurfer 7.1. We performed repeated‐measure ANOVAs with Group (treated OSA, untreated OSA and controls) and Time (baseline and follow‐up) on bilateral volumes. We also performed partial correlations between bilateral medial temporal volumes at baseline and changes in cognition (Montreal Cognitive Assessment, score at follow‐up – baseline) in each group separately. Analyses were corrected for age, sex, and total intracranial volume.

Result

We found a significant Group X Time interaction for bilateral parahippocampal volumes (F = 7.2; p = 0.002) where treated OSA participants showed a decreased volume over time (p tukey<0.001), while no changes occurred in the two other groups. Regarding the predictive value of medial temporal lobe volume, in untreated participants, higher bilateral hippocampal volume at baseline was associated with more severe cognitive decline over time (r = ‐0.77; p = 0.01). In treated participants, higher bilateral entorhinal cortex volume at baseline was associated with more cognitive decline (r = ‐0.74; p = 0.035). No associations were found in controls.

Conclusion

These preliminary results showed that presenting hypertrophy of the medial temporal lobe subregions at baseline is associated with worse cognitive outcome at 18‐month follow‐up in OSA participants. In the CPAP group, the decrease in parahippocampal volume might represent a reduction in hypertrophy, possibly by limiting edema.
Distinct dimensions of depression are associated with different brain‐related biomarkers
Authors: Soleimani Laili , Beeri Michal Schnaider , Heymann Anthony , Livny Abigail , Lesman‐Segev Orit H. , Lin HungMo , Ouyang Yuxia , Ravona‐Springer Ramit
Published: December 2022

Background

Management of depression, a potentially modifiable risk factor for dementia, is of great importance in older adults with Type 2 Diabetes (T2D), specifically because of their higher risk for both conditions. We previously showed in older adults (aged ≥65) with T2D in the Israel Diabetes and Cognitive Decline (IDCD) study, that different depression‐dimensions were associated with distinct patterns of cognitive outcomes. Specifically, apathy, but not other depression‐dimensions, was associated with faster decline in executive functions. Here, we investigated the cross‐sectional relationship between depression‐ dimensions with different neuropathologies, i.e., total gray matter (GM) volume, white matter hyper‐intensities (WMH) and amyloid burden.

Method

Among IDCD participants [mean age = 70.55 (SD = 4.25), 38.5% female], 209 had a brain MRI, 42 of whom also had an amyloid PET. Depression dimensions were defined based on the Geriatric Depression Scale‐ 15 item (GDS‐ 15): dysphoric mood, apathy, anxiety, hopelessness and subjective memory complaint. Gray Matter and WMH volumes were examined using a high‐resolution 3‐Tesla brain MRI. Amyloid‐β burden was defined as mean standardized uptake value ratios (SUVRs) of [18F] flutemetamol in the frontal, parietal, and temporal cortices compared to the cerebellum as reference region. We used two‐step linear regression models to study the association of GDS–domains and brain imaging markers.

Result

Higher total GDS score was associated with lower GM volume (r = ‐0.14; p = 0.037) and higher volume of WMH (r = 0.20; p = 0.003), but not with brain amyloid‐β burden (r = ‐0.13; p = 0.37). Among specific depression‐ dimensions, apathy (r = 0.22; p = 0.001), and hopelessness (r = 0.15; p = 0.033) were associated with higher WMH burden, whereas the subjective memory complaints dimension was associated with lower total GM volume (r = ‐0.15; p = 0.026). Depression dimensions were not associated with amyloid burden.

Conclusion

In cognitively normal older adults with T2D, higher depression scores, even below the cutoff defined as clinically significant, were associated with lower GM and higher WMH volumes. Apathy was the main driver of the association with higher WMH burden and subjective memory complaints drove the association with brain atrophy. No association was found between depression‐dimensions and amyloid‐β burden, consistent with previous findings in non‐T2D samples, on the role of vascular, rather than AD pathology, in depression.
Longitudinal change in plasma biomarkers by amyloid PET status
Authors: Bilgel Murat , An Yang , Walker Keenan A , Moghekar Abhay , Resnick Susan M.
Published: December 2022

Background

It is important to better understand the longitudinal trajectories of plasma measures of proteins implicated in Alzheimer’s disease among cognitively normal older adults.

Method

We investigated whether baseline levels and longitudinal rates of change of three Quanterix SIMOA plasma measures (amyloid‐beta 42 to 40 ratio [Aβ42/Aβ40], glial fibrillary acidic protein [GFAP], and neurofilament light chain [NfL]) differ by amyloid group as determined using Pittsburgh compound B (PiB) PET in the Baltimore Longitudinal Study of Aging (N=147 PiB– and 57 PiB+; 640 longitudinal measures). All participants were cognitively normal at baseline. We used linear mixed effects models with longitudinal plasma measures as the outcome. We conducted an unadjusted analysis that included binary PiB group, time from baseline, and their interaction. We also conducted an adjusted analysis that additionally included the following explanatory variables: baseline age and its interaction with time, sex, APOE ε4 carrier vs noncarrier, race, and estimated glomerular filtration rate (eGFR) from serum creatinine concurrent with plasma measurements. All variables except time were mean‐centered.

Result

Participant characteristics are presented in Table 1. Figures 1 and 2 illustrate plasma biomarkers versus age and longitudinal visit schedule per participant, respectively. PiB+ individuals had lower Aβ42/Aβ40, higher GFAP, and higher NfL at baseline (Table 2). Both PiB groups exhibited longitudinal increases in GFAP and NfL (Table 3). Aβ42/Aβ40 declined longitudinally in the PiB– group, but annual change in the PiB+ group was not statistically significant. PiB group difference in rates of change in plasma measures was statistically significant for Aβ42/Aβ40 but not for NfL. Difference in rate of change in GFAP was statistically significant in the unadjusted model only. Adjusted model fixed effect estimates are depicted in Figure 3.

Conclusion

Steeper decline in plasma Aβ42/Aβ40 in the PiB– group suggests that individuals may exhibit decline in this measure prior to the onset of amyloid PET positivity. Despite exhibiting baseline PiB group differences, plasma GFAP and NfL have similar rates of increase in both PiB groups. Reliable detection of such changes at the individual level, prior to the onset of cognitive impairment, may enable better personalized prediction of future outcomes.
Sex‐specific decoupling of cerebral blood flow and glucose metabolism in Alzheimer’s disease mouse model
Authors: Zhao Yifan , Jin Tao , Fitz Nicholas F , Koldamova Radosveta , Iordanova Bistra
Published: December 2022

Background

Cerebral blood flow (CBF) dysregulation and neurovascular impairment are central to Alzheimer’s disease (AD) etiology1. Even though two‐thirds of the AD patients are women, the sex differences in vascular and metabolic risk factors are still unclear2. Previously, we described sex‐specific CBF trajectories in mouse model of AD3. In the present study, we connect these CBF changes with cerebral glucose metabolism in the same males and females. We quantify the correlation between metabolic rate and vascular flow and identify unique points of divergence across lifespan.

Method

We used 9.4T MRI of APPswe.PSEN1dE9 mice (23 males, 24 females; young 3‐7 months, middle age 7‐15 months, and old 15‐24 months) and B6C3F1/J controls (n=20). We quantified CBF (qCBF) using T1‐weighted mapping and continuous arterial spin labeling (CASL) as previously described3.The glucose uptake rate (ΔR1ρ) was measured using chemical exchange‐sensitive spin lock (CESL) and computed as the difference between the steady state before and after intravenous injection of 2‐Deoxy‐d‐glucose (2DG)4. Region of interests were drawn manually on the cortex and subcortical areas.

Result

We found that AD females, but not AD males had lower cortical glucose metabolism than age‐matched controls, while both AD groups had lower CBF than controls. These differences were not significant in the subcortical regions. The metabolic trajectory during aging was similar between AD males and females (Fig 1A), however, the CBF trajectory of AD males showed a transient increase from young to middle age, while the female group showed an opposite trend (Fig 1B). The sex‐specific divergence between glucose consumption and CBF appeared during middle age. Male AD mice had higher positive correlation between glucose metabolism and CBF in the cortex compared to females (Fig 2A). Additionally, in both AD groups, this correlation was positive in the cortex but not in the subcortical region (Fig 2).

Conclusion

When interpreting metabolic rate of glucose and CBF as AD biomarkers, age, sex and brain region should be taken into consideration.
Cortical Microstructure Mediates CSF Amyloid and Tau Associations with Episodic Memory Performance
Authors: Nir Talia M , Salminen Lauren , Reina Julio E Villalon , Haddad Elizabeth , Zheng Hong , Thomopoulos Sophia I , Thompson Paul M , Jahanshad Neda
Published: December 2022

Background

Episodic memory impairment is common in early stages of Alzheimer’s disease (AD) and has been linked to atrophy in cortical regions that are vulnerable to AD neuropathological processes (e.g., amyloid and tau accumulation). Volumetric measures are relatively insensitive to microstructural brain changes that can occur in earlier disease stages. Microstructural properties of brain tissue can be non‐invasively assessed using advanced diffusion MRI (dMRI) models such as neurite orientation dispersion and density imaging (NODDI). While a number of studies have related white matter microstructure to AD pathology and memory, few have evaluated advanced dMRI indices in cortical gray matter where the earliest histopathological changes are thought to occur.

Method

We evaluated 66 ADNI participants (age 71.8±6.2 years; 25 Males; 46 CN/18 MCI/2 AD) with available MRI (T1‐weighted and multi‐shell diffusion) and CSF Aβ1–42, pTau181, and pTau181/Aβ1–42 data (Fig1A). Episodic memory was assessed using WMS‐R delayed logical memory scores (Del‐Mem). We estimated average NODDI ICVF, ECVF, ISOVF, and ODI (Fig1B) in an AD‐metaROI of cortical gray matter regions that are sensitive to early AD (Fig1C,D). We tested whether the effect of CSF biomarkers on Del‐Mem were mediated by metaROI measures (Fig2A), adjusting for age, sex, education, and MRI site as a grouping variable. For comparison, we re‐ran analyses with AD‐metaROI cortical thickness as the mediator.

Result

Lower CSF Aβ1–42 and higher pTau181/Aβ1–42 were significantly associated with lower Del‐Mem performance (FDR; q=0.05); pTau181 was not associated (Fig2B).

Lower cortical ICVF, ODI, and thickness and higher ISOVF were associated both with lower Aβ1–42 and higher pTau181/Aβ1–42 (Fig2C).

The effect of Aβ1–42 on Del‐Mem was fully mediated by ICVF. The effect of pTau181/Aβ1–42 on Del‐Mem was partially mediated by ISOVF. Del‐Mem was not mediated by ODI or thickness (Table1). Sensitivity analyses in the 64 non‐demented individuals revealed comparable results.

Conclusion

Lower cortical ICVF and higher ISOVF with greater Aβ and pTau/Aβ burden, respectively, may indicate neuronal loss or edema. While both ICVF and ISOVF findings can be driven by reduced diffusion restriction, larger pTau/Aβ effects on episodic memory mediated through ISOVF may indicate that tau hyperphosphorylation and aggregation induces a greater degree of inflammation, neuronal dysfunction and death.
Presenilin1 FAD mutants and γ‐secretase inhibitors decrease VEGFR2 signaling and block angiogenic functions of brain endothelial cells
Authors: Pandey Rukmani , Robakis Nikolaos K , Georgakopoulos Anastasios
Published: December 2022

Background

Alzheimer’s disease (AD) is a multifactorial and progressive neurodegenerative disease where cerebrovascular abnormalities are commonly observed. Various factors, including decreased sprouting angiogenesis, can cause a reduction in capillary density observed in AD. In addition, brain vascular alterations occur before the appearance of neuropathology in animal AD models. Brain angiogenesis is a reparative function in response to toxic insults and is regulated by endothelial cells (ECs) and angiogenic factors such as the VEGF; impairment in this function would render the brain vulnerable to insults. In present study, we examine the effects of Presenilin 1 (PS1)‐Familial AD (FAD) mutants and γ‐secretase in the VEGF‐induced angiogenic signaling and functions of brain ECs.

Method

Primary cortical ECs (pCECs) from brains of wild‐type (WT) and knock‐in (KI) mice expressing either PS1 M146V or PS1 I213T FAD mutant in heterozygous state were isolated and cultured. These mice constitute a “humanized” FAD model having the same genotype as human FAD patients. We performed the in vitro angiogenesis assays using pCEC cultures. Processing of VEGFR2 was detected in HEK293 cells overexpressing VEGFR2 in the presence or absence of VEGF‐A and γ‐secretase inhibitor (RO4929097). The same processing was also analyzed by western blotting in PS1 M146V and I213T mutant pCECs treated with VEGF‐A. VEGF‐induced phosphorylation of signaling molecules downstream of VEGFR2 such as p38 kinase and PLCγ1 was also examined in WT and PS1 M146V mutant pCECs by western blotting.

Result

We found that VEGFR2 is processed by γ‐secretase and that this processing together with VEGF‐induced sprouting, tube formation, migration and angiogenic complexes between VE‐cadherin and Rok‐α kinase are decreased in the presence of γ‐secretase inhibitor or by PS1 FAD mutants. Furthermore, the VEGF‐induced phosphorylation of p38 and PLCγ1 is decreased in PS1 FAD mutant pCECs.

Conclusion

Our findings suggest that VEGFR2 is processed by γ‐secretase and that γ‐secretase promotes VEGF‐induced angiogenic functions of brain ECs through activation of VEGF‐VEGFR2 downstream signaling. Our data also show that a PS1 FAD mutant decreases both the VEGFR2 processing by γ‐secretase and the VEGF‐induced signaling and angiogenic functions of pCECs, providing a mechanism via which FAD mutants affect brain angiogenesis.
Triglyceride and VLDL cholesterol are lower in cognitively healthy individuals with Amyloid pathologies than those without
Authors: Arakaki Xianghong , Buennagel David P , Nolty Anne , Spezzaferri Mitchell , Rising Shant , Sin Caleb , Chui Helena C , Fonteh Alfred N. , Kloner Robert A
Published: December 2022

Background

Framingham, or cardiovascular (CVD) risk score, as a composite score can accurately predict long‐term CVD risk in the general population. General lipid profiles contribute to CVD risk and Alzheimer’s disease (AD) with inconsistent reports: both high and low triglyceride or body mass index (BMI) have been linked with AD risk. However, the knowledge of their contribution to early AD is limited. To study the changes of CVD risk score and lipid in early AD, we explored the CVD risk score and lipid profile risk factors in our aging cohort.

Method

We compared estimated CVD risk score (Erisk) between cognitively healthy (CH, n=137) individuals, in participants with mild cognitive impairment (MCI, n=54), AD (n=42), and other dementia (OD) (n=23). We also compared lipid profile risk factors (BMI, triglyceride, cholesterol, high‐density lipoprotein (HDL) cholesterol, low‐density lipoprotein (LDL) cholesterol, and very low‐density lipoprotein (VLDL) cholesterol). Furthermore, we compared those risk factors in CH participants subgroups with different status of CSF amyloid (A), phospho‐tau (T), and total‐tau (N): between those with AD risk (A+T±N±: ChA+) and those without (ChA‐T‐N‐). Bonferroni correction was used for multiple comparisons.

Result

Erisk and lipid profiles were not different between CH, MCI, AD, or OD. We observed lower triglyceride and VLDL cholesterol, and marginally lower BMI, in ChA+ group than in ChA‐T‐N‐ group (p<0.008, Fig 1).

Conclusion

These pilot results suggest that CH participants with amyloid pathology presented with lower triglyceride and VLDL cholesterol values, and marginally lower BMI. Although these data need to be confirmed in a larger population, our study supports the concept that lower levels of triglycerides, VLDL cholesterol, or BMI may be linked to amyloid pathology in the CH stage. Further studies examining related factors and pathways that contribute to amyloid pathology such as APOE genotype and VLDL‐receptor expression are needed to fully understand the implications of our findings.
Increasing awareness and interest in AD/ADRD clinical trials using culturally tailored messages: A synthesis of three national surveys, 2019–2021
Authors: Massett Holly A , McGowan Melissa , Simoneau Elizabeth , Bui Elise , Jarvis‐Gibson Jeanne , Mitchell Alexandra , Rehberg Kathryn , Miscally Memi
Published: December 2022

Background

Limited participation of Black/African American (B/AA), Hispanic/Latino (H/L), and Asian American & Pacific Islander (AAPI) communities in AD/ADRD clinical trials (CT) is partly due to few researchers offering trial opportunities and inadequate CT information that is culturally relevant. We present the results of three National Institute on Aging (NIA) national surveys conducted with B/AA, H/L, and AAPI samples to assess the impact of culturally tailored outreach materials for each group, respectively, on individuals’ likelihood to consider participating in CTs.

Method

Online panel surveys were conducted with B/AA (N = 616; 2019), H/L (N = 545; 2020), and AAPI (N = 756; 2021) individuals who: 1) had a family history AD/ADRD, 2) were caring for an individual with AD/ADRD, or 3) reported no family history of AD/ADRD. The surveys assessed if viewing creative concepts (four print/photo ads developed specifically with and for each population using focus groups) positively impacted participants’ likelihood to consider participating in an AD/ADRD CTs.

Result

After reviewing their respective ads, B/AA and H/L at‐risk, caregiver, and healthy audiences, and AAPI at‐risk individuals, all significantly increased their reported pre‐posttest “likelihood to consider a CT”. AAPI caregivers started with and maintained a high level of interest but did not change their likelihood to consider a CT. Across all groups, there was a median 12.5% increase of individuals reporting “very” or “extremely interested” in AD/ADRD CTs. Persons with family history had greater increases among B/AA and AAPI, while caregivers did among H/L. Motivating CT messages for all groups were: help/hope for their future generations (family/community) the potential to prevent/treat the disease. B/AA respondents also were motivated to find treatments that could work for all races.

Conclusion

The findings highlight that culturally appropriate outreach materials, developed with and for specific groups, can generate significant interest in participation of AD/ADRD clinical trials after viewing only four ads. Though common themes emerged, focus groups and surveys indicated specific yet critical nuances differentiating message preferences across B/AA, H/L, and AAPI groups. This is the only known research to systematically explore AD/ADRD CT communication needs within and across traditionally underserved populations.
The mean diffusion propagator model revealed cortical microstructural changes associated with both amyloid‐β and tau pathology and astroglial activation
Authors: Spotorno Nicola , Strandberg Olof , Vis Geraline , Stomrud Erik , Nilsson Markus , Hansson Oskar
Published: December 2022

Background

Markers of downstream events are a key component of clinical trials of disease‐modifying therapies for Alzheimer’s disease (AD). Morphometric metrics like cortical thickness are established measures of atrophy but are not sensitive enough to detect Aβ‐related changes that occur before overt atrophy become visible. We aimed to investigate to what extent diffusion MRI can provide sensitive markers of cortical microstructural changes that could complement morphometric macrostructural measures.

Method

We applied the mean apparent diffusion propagator model (MAP‐MRI) to diffusion MRI data from 492 cognitively unimpaired elderly and patients with mild cognitive impairment from the Swedish BioFINDER‐2 cohort. MAP‐MRI extends diffusion tensor imaging and provides metrics sensitive to subtle changes in the cortex. Participants were stratified in Aβ‐negative/tau‐negative, Aβ‐positive/tau‐negative, and Aβ‐positive/tau‐positive based on Aβ‐ and tau‐PET uptake. Cortical regional values of both MAP‐MRI metrics and CT were compared across groups. Associations between regional values of MAP‐MRI metrics and both Aβ‐ and tau‐PET uptake were also investigated as well as the association between MAP‐MRI metrics and plasma level of GFAP, a marker of astroglial activation (available in 292 participants).

Result

Mean square displacement (MSD) from MAP‐MRI revealed widespread microstructural differences already between Aβ‐negative/tau‐negative and Aβ‐positive/tau‐negative participants with a spatial distribution that closely resembled the pattern of Aβ accumulation. In contrast, differences in cortical thickness appeared to be more limited (figure 1). MSD was also highly correlated with both Aβ‐ and tau‐PET uptake even independently from one another (figure 2). Regional MSD values were associated with GFAP with a pattern that resemble Aβ accumulation, and GFAP partially mediated the association between Aβ and MSD. A sensitivity analysis controlling for cortical thickness revealed that the associations between MSD and Aβ‐PET, tau‐PET and GFAP were largely independent from macrostructural changes (figures 2‐3).

Conclusion

Metrics of cortical microstructural alteration derived from MAP‐MRI are highly sensitive to multiple aspects of the AD pathological cascade. Of particular interest is the link between MSD, Aβ‐PET and GFAP which suggests MSD might reflects microstructural changes related to the astrocytic response to Aβ aggregation. Therefore, MSD could help monitoring the response to anti‐Aβ treatments in clinical trials.
Blood immune response genes are correlated with brain glucose metabolism
Authors: Ramos Vanessa G. , Povala Guilherme , De Bastiani Marco Antônio , Bellaver Bruna , Pascoal Tharick A , Ferreira Pamela C.L. , Zimmer Eduardo R.
Published: December 2022

Background

Imaging techniques such as positron emission tomography (PET) have been fundamental to develop our understanding about Alzheimer's disease (AD) underlying features. Evidence suggests that neuroinflammation plays a complex role in the pathophysiology of AD. Nevertheless, whether peripheral inflammation affects brain function remains to be defined. In this context, the integration of blood‐based measures and imaging modalities can facilitate the understanding of the periphery‐brain interface in AD. Here, we developed a method to integrate immune response‐related genes, derived from blood transcriptomics, with [18F] Fluorodeoxyglucose ([18F]FDG)‐PET imaging data. We hypothesized that the differential expression of immune‐related genes would be associated with brain metabolism as indexed by [18F]FDG‐PET signal.

Method

Blood transcriptome profiles and imaging data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Differential gene expression analysis was performed in 99 Cognitively Unimpaired (CU) and 218 Cognitively Impaired (CI) individuals, whose differentially expressed genes (DEGs) underwent functional enrichment analysis Gene Ontology (GO). Immune‐related GO terms were clustered by semantic similarity using the GOSemSim method for biological processes ontology. All computations analysis were performed in the R statistical environment. Integration with [18F]FDG‐PET images was performed using voxel generalized linear regression (GLR) models considering the covariates age, gender, education, and APOE ε4 status (RMINC package).

Results

Peripheral blood cells transcriptome analysis identified 10 enriched GO terms associated with the immune response. For each term, the GLR models were used to calculate voxel‐wise associations between [18F]FDG and gene expression, resulting in a t‐statistical map. Figure 1 demonstrated the uncorrected statistically significant correlated voxels (t‐value > 2.0). At the voxel level, biological processes related to regulatory mechanisms of innate immunity presented a 32% Correspondence with [18F]FDG‐PET signal in the gray matter of the medial frontal‐orbital gyrus.

Conclusion

Here, we demonstrated a significant association between brain glucose metabolism and immune‐related blood DEGs. Our findings suggest that peripheral inflammation that occurs in AD patients might have an impact on [18F]FDG‐PET metabolism.
Genetic analyses of diffusion MRI phenotypes: a lifespan exploration of cSVD determinants
Authors: Grand Quentin Le , Tsuchida Ami , Koch Alexandra , Breteler Monique M.B. , Seshadri Sudha , Tzourio Christophe , Crivello Fabrice , Debette Stéphanie
Published: December 2022

Background

Cerebral small vessel disease (cSVD) is a leading cause of vascular cognitive impairment and dementia. Mounting evidence suggests that early life factors contribute to cSVD. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI‐marker of cSVD in older age, were recently found to show strong associations with white matter microstructure on diffusion tensor imaging (DTI) already in young adults in their twenties. Here we aimed to use multi‐shell diffusion imaging to further explore genetic determinants of white matter microstructure across the adult lifespan and its relation with cSVD.

Method

In 1,758 participants (mean age: 22.1 [18 to 35] years) from the i‐Share student cohort who underwent multi‐shell diffusion imaging, we used neurite orientation dispersion and density imaging (NODDI) to generate tissue‐based markers of white matter microstructure including neurite density index (NDI), orientation dispersion index (ODI), and isotropic volume fraction (ISOVF) in 28 brain regions. We ran genome‐wide association studies (GWAS) of all 84 NODDI markers in i‐Share and looked up genome‐wide significant variants in UK Biobank (N = 33,224, mean age: 64.3 [45 to 82] years) to identify loci with a lifecourse effect on these phenotypes. Next, we studied the association of genetically determined WMH volume and blood pressure with NODDI phenotypes in i‐Share using Mendelian randomization (MR).

Result

This first GWAS of 84 NODDI phenotypes in young adults identified 21 genome‐wide significant loci. Three of them, associated mostly with NDI, also showed significant association with NODDI phenotypes in middle‐aged to older UK Biobank participants, including a known WMH locus near VCAN, a cerebrovascular matrisome gene. Using MR we found that genetically determined WMH, previously shown to predict Alzheimer‐type dementia, was associated with lower NDI in young adults. In contrast, genetically determined blood pressure, although an important risk factor for WMH volume, did not show any significant association with NODDI phenotypes in young adults.

Conclusion

Our results suggest that NODDI markers, especially NDI, have a substantial genetic component already in early adulthood and may inform early mechanisms underlying the vascular contribution to dementia. Replication of these findings in additional CHARGE cohorts (Rhineland study, Framingham Heart study) is underway.
The Neurofilament Surveillance Project (NSP): A biomarker study to sample blood quarterly in familial frontotemporal lobar degeneration
Authors: Acuna‐Narvaez Rachel , Heuer Hilary W. , Forsberg Leah K. , Alward Anne , Graham Danielle , Fishman Ann , Nelson Kevin M , Kolander Tyler , Fillit Howard M , Galpern Wendy R , Hung Serena , Mason Chris , Mignon Laurence , Ni Yan G , Simen Arthur , Tesseur Ina , Tsai Richard , Yeh Felix L , Mester Carly T. , Ljubenkov Peter A. , Rosen Howard J. , Boeve Bradley F. , Boxer Adam L. , Pearlman Rodney , Mitic Laura L ,   NSP Site Investigators
Published: December 2022

Background

In familial frontotemporal lobar degeneration (f‐FTLD), plasma levels of neurofilament light (NfL) are elevated at least two years prior to symptom onset and predict future clinical status. The Neurofilament Surveillance Project (NSP), an actively recruiting observational study, seeks to obtain higher resolution data of temporal changes in plasma NfL to better understand its clinical utility in f‐FTLD interventional trials. The NSP is a pre‐competitive collaboration sponsored by the Bluefield Project to Cure FTD and funded by biotechnology and pharmaceutical companies and nonprofit organizations.

Method

Participants must be members of families with disease‐causing mutations in C9orf72, MAPT or GRN and enrolled in the ALLFTD natural history study. Up to 335 participants, with roughly equal representation across mutation type, provide plasma quarterly for 3 years (4355 samples total) to enable the observation of peripheral NfL levels longitudinally during disease onset and progression. Plasma is collected by certified mobile research nurses during remote visits, and NfL is measured in batch at least every 6 months. NfL measurements from one plasma aliquot per draw will be correlated with annual assessments obtained in the ALLFTD study, including measures of disease severity (CDRÒ+NACC‐FTLD, CGI, etc.), cognitive function from the UDS Neuropsychology Battery, and volumetric MRI data. Additional plasma aliquots are reserved for future analyses of other biomarkers during the course of the study; another subset of aliquots is reserved to share with interested investigators after the study ends.

Result

As of 1/19/22, the NSP had enrolled 161 participants, including 62 from C9orf72 kindreds, 60 from MAPT kindreds, and 28 from GRN kindreds. One‐hundred forty‐five participants had completed their initial visit, and 109 had completed more than 3, and up to 5, quarterly blood draws. Enrollment and study visits are ongoing despite COVID‐related limitations.

Conclusion

The quarterly blood sampling from this study, combined with annual comprehensive clinical assessments through the ALLFTD natural history study, will enable a more detailed understanding of when and how NfL levels change during phenoconversion and/or disease progression in f‐FTLD mutation carriers. These data will be especially informative in the context of the targeted investigational therapeutics for f‐FTLD now entering clinical trials.