bluuebunny/crossref_metadata_2025 huggingface dataset:
Peripheral and total circulating extracellular vesicle levels of advanced glycation end‐products and RAGEs as possible biomarkers for mild cognitive impairment and Alzheimer's patients
Authors: Haddad Mohamed , Khedher Morgane , Khedher Mohamed Raâfet Ben , Fulop Tamas , Ramassamy Charles
Published: December 2020

Background

Advanced glycation end‐products (AGEs), their precursors methylglyoxal (MG), glyoxal (GO) and their receptors RAGEs are known to be involved in the pathophysiology of Alzheimer’s disease (AD). The aim of our study was to evidence the presence of RAGEs and glyoxalase‐1 (GLO‐1), the main enzyme involved in the degradation of MG, in the circulating extracellular vesicles (pEVs) from control subjects, mild cognitive impairment (MCI) and AD patients.

Method

EVs were isolated from plasma of control, MCI and AD subjects at different stages of the disease (early , moderate and severe). Their size, shape and density were characterized. The presence of EVs specific proteins TSG101, CD63, GAPDH were confirmed by Western Blot. MG and GO levels in serum were determined by HPLC. In addition, serum Pentosidine and CML levels were determined by competitive ELISA.

Result

Our data showed lower levels of RAGE in pEVs from MCI, early and moderate stage of AD patients as compared to the severe stage of AD patients. GLO‐1 levels in pEVs were significantly decreased in early AD as compared to controls and MCI. Interestingly, RAGEs and GLO‐1 levels in pEVs were correlated with the clinical cognitive scores. MG and GO levels in serum were higher in MCI and receiver‐operating characteristic curves analysis showed that serum MG levels have higher sensitivity to differentiate MCI from controls but not from AD. Meanwhile, serum GO levels differentiate MCI from control and AD groups. The levels of CML in albumin‐free serum proteins were higher in the early stage of AD while, the levels of pentosidine remained unchanged and were negatively correlated with the clinical cognitive scores MMSE and MoCA. In contrast, the levels of N‐(1‐carboxymethyl)‐L‐lysine in pEVs were lower in the moderate stage of AD.

Conclusion

Levels of some AGEs and RAGEs in serum and in total circulating EVs could be used as possible biomarkers for MCI and AD. This work was supported by the Chaire Louise & André on Alzheimer’s disease, Foundation Armand‐Frappier (CR) and CIHR grant (TF).
Mapping behavior symptoms in dementia using passive radio sensing
Authors: Vahia Ipsit V. , May Rose , Kabelac Zach , Owoyemi Praise , Hoti Kreshnik , Munir Usman , Katabi Dina
Published: December 2020

Background

Behavioral and Psychotic Symptoms in dementia (BPSD) are associated with negative outcomes including increased mortality and morbidity, increased cost of care and caregiver burnout. Newer technologies are leading to a greatly enhanced ability to monitor and predict these symptoms using passive sensing and sophisticated analytics that rely on signal processing and potentially machine learning. In this study we utilized a novel passive sensing approach supported by AI to demonstrate how highly specific behavioral phenomena can be detected in real time with a need for limited in‐person supervision and monitoring.

Methods

Emerald is a device developed at MIT for in‐home, non‐intrusive patient monitoring. The device transmits low‐power radio signals (100x lower power than WiFi) and monitors the reflection of these signals from people/their environment to map behavioral information. Signal data are uploaded to the cloud where customized machine learning algorithms process the data to extract gait speed, sleep patterns, spatial location, respiration Subject: We installed the device in the rooms of 13 adults with Dementia in an assisted living facility outside Boston. We measured the subjects’ behavior continuously for 3 months. Sensor data findings were compared to staff observations around specific behavior phenomena. Our goal was to demonstrate Emerald’s ability to accurately capture a range of BPSD

Results

Over the course of the study, we identified a range of behavioral phenomena using the sensor, that were verified by staff and validated by standardized behavioral measures. These represent positive and negative states of activation. The sensor also captured the impact of pharmacotherapy.

Conclusion

This study demonstrating the feasibility of an AI‐backed passive sensor‐based device to accurately phenotype a range of behavioral phenomena. Our initial findings demonstrate that this technology can identify movement‐based behavior symptoms in a manner comparable to the current standard for measuring behaviors.
Cognitive and imaging impacts of left ventricular hypertrophy in people with type 2 diabetes
Authors: Restrepo Carolina , Patel Sheila , Werden Emilio , Khlif Mohamed Salah , Singleton Rebecca , Bird Laura J. , Ekinci Elif , MacIsaac Richard , Srivastava Piyush , Burrell Louise , Brodtmann Amy
Published: December 2020

Background

Older adults with type 2 diabetes mellitus (T2DM) are at an increased risk of cognitive decline and dementia. Left ventricular hypertrophy (LVH) is prevalent in T2DM and is independently associated with cognitive decline. We conducted a study to establish whether T2DM patients with LVH have increased rates of brain atrophy and cognitive impairment.

Methods

Thirty‐seven cognitively healthy adults (50 years and older) with T2DM were divided into those with (n=13) and without (n=24) LVH. All participants completed neuropsychological assessments, health‐and‐lifestyle questionnaires, 24‐hour ambulatory blood pressure monitoring, an echocardiogram and a 3T‐MRI scan. FreeSurfer (version 6.0) was used to estimate total brain volume (TBV), mean cortical thickness and subcortical volumes, including the thalami and caudate nuclei. TBV was expressed as a percentage of intracranial volume. Averages between left and right volumes were calculated for subcortical structures. Left ventricular mass was indexed to height2.7 using the American Society of Echocardiography criteria. LVH was defined as >49g/m2.7 for males and >45g/m2.7 for females. Three cognitive domains (visuospatial skills, verbal memory and executive functions) were derived through factor analysis. These variables were used to compare cognitive performance between individuals with and without LVH.

Results

There was a higher percentage of women (x2=11.01, df=1, p<0.01) in the LVH group. No differences in cortical thickness and TBV were found between groups. The LVH group showed significantly lower volume in the cerebellar cortex (F(1, 32)=5.25 p=0.029) and in the amygdala (F(1, 32)=6.24 p=0.018) after correcting for sex, age, blood pressure and BMI when compared to the no LVH group. Significant differences were found in the visuospatial skills factor (F(1, 43)=4.09; p = 0.049), with the LVH group performing worse than the no LVH group.

Conclusions

The presence of LVH in individuals with T2DM was associated with atrophy in the cerebellar cortex and in the amygdala, as well as with poorer visuospatial function.
Modulation of amyloid deposition and neuroinflammation by the microbiome
Authors: Sisodia Sangram S.
Published: December 2020

Background

Animal models of Alzheimer’s disease (AD) recapitulate the severe amyloidosis and neuroinflammation that is evident in the human disease. It is now well established that inflammation associated with amyloid deposition reflects the activation of astrocytes and microglia in response to injury, but the role of peripheral tissues and more importantly, the microbiota in regulating innate immunity that in turn leads to CNS dysfunction has not, to date been defined. We have tested the hypothesis that the composition of the intestinal microbiome plays a key role in modulating neuro‐inflammation that will ultimately influence amyloid deposition in two established mouse models of Aβ‐amyloidosis.

Methods

We orally administered a combination of antibiotics to induce rapid and sustained alterations in gut microbial populations in two mouse models of amyloidosis. The antibiotic cocktail was administered either postnatally or throughout the lifetime of the animal prior to cull and we employed IHC, biochemical and molecular assays to evaluate amyloid deposition and neuroinflammation in the mouse models. Newly‐generated germ‐free mouse models are being evaluated.

Results

Our studies indicate that alterations in the microbiome parallel changes in plasma cytokines and chemokines, reductions in amyloid deposition and modulation of morphological and transcriptional landscapes of microglia. These effects are unique to male, but not female animals.

Conclusions

Our studies reveal an unexpected, but significant alteration in amyloid deposition and microglial phenotypes in the brains of male transgenic mice upon treatment with orally administered antibiotics. Acknowledgments: This work was supported by Cure Alzheimer’s Fund (CAF) Open Philanthropy Fund, Alzheimer’s Association and Good Ventures Foundation. SSS is a paid Consultant of AZTherapies Inc.
Capturing longitudinal impacts on cognition following stroke in rodent models using touchscreen testing
Authors: O'Brien Katrina R , Brait Vanessa H , Jackman Katherine A , Ermine Charlotte M , Thompson Lachlan H , Brodtmann Amy , Nithianantharajah Jess
Published: December 2020

Background

Up to two thirds of ischaemic stroke survivors develop cognitive impairment, predominantly impacting executive and attentional processing. Animal models are essential for effective translation and development of therapies. However, accurately modelling cognitive dysfunction in animal models of stroke has been limited. To address this, we aimed to longitudinally examine changes in attentional processing, spatial working memory and processing speed using two rodent ischemic injury models: the middle cerebral artery occlusion (MCAO) in C57BL/6J mice and the endothelin‐1 injury in Long Evans rats.

Method

Using the rodent touchscreen cognitive platform, we assessed attention in mice and rats employing the Continuous Performance Task (CPT) paradigm, and spatial working memory in mice using the trial unique non‐matching to location (TUNL) paradigm. Cognitive performance in adult mice and rats was assessed before inducing stroke, and at 4, 12, 24, 36 and 48 weeks post‐injury.

Result

Mice exposed to MCAO showed robust, long‐lasting deficits in attentional processing and spatial working memory post‐stroke. In comparison, we observed no changes in attentional processing following endothelin‐1 injury to the motor cortex in rats.

Conclusion

Our findings provide the first evidence for longitudinal cognitive changes in a rodent model of stroke, recapitulating that observed in the clinic. Our results identify a valuable model and behavioural approach to advance mechanistic understandings of the trajectory of cognitive dysfunction following stroke, and provide a platform with which to identify novel therapies. Moreover, our work further strengthen the need for preclinical animal studies to assess different species and injury models that are critically needed for better modelling clinical stroke and truly enabling the translation of research targeting cognitive symptoms.
Subjective cognitive decline is associated with neurocognition in the SOL‐INCA study
Authors: Zlatar Zvinka , Tarraf Wassim , Chai Albert , Vasquez Priscilla M , Marquine Maria J , Lipton Richard B , Gallo Linda , Khambaty Tasneem , Zeng Donglin , Youngblood Marston , Estrella Mayra L , Isasi Carmen R , Daviglus Martha , Gonzalez Hector M
Published: December 2020

Background

Subjective cognitive decline (SCD) is the experience of cognitive decline not yet apparent through formal neuropsychological testing. SCD is required to meet clinical criteria for mild cognitive impairment (MCI) and is a potential early risk marker of neurocognitive changes. Despite increased risk of cognitive decline in US Hispanics/Latinos, SCD research in this group is lacking. We investigated if SCD is cross‐sectionally associated with objective neurocognitive performance in SOL‐INCA, a large community‐based sample of diverse Hispanics/Latinos.

Method

Participants (N=5,282) were age 50+ and without reported dementia. The Everyday Cognition Short Form (ECog‐12) scale measured SCD. A global score, as well as memory and executive ECog‐12 sub‐scale scores, were calculated by averaging across z‐scores of individual items assessing memory and executive functional abilities (all items were averaged for the global score). Objective neurocognitive function was measured with tests of memory (Spanish English Verbal Learning Test‐Sum and Recall scores) and executive functions (word fluency, Trail Making Test A & B, and Digit Symbol Substitution scores). Memory, executive, and global neurocognitive composite scores were created by averaging across z‐scores for each cognitive domain listed above, and across all tests for the global composite. Regression models interrogated associations of ECog‐12 (global and sub‐scale scores) with their respective objective neurocognitive function counterparts (global cognition, memory, and executive function neurocognitive composite scores), adjusting for age, sex, education, Hispanic/Latino background, depression, anxiety, and cardiovascular risk factors.

Result

Women comprised 53% of the sample and 25% of the sample were age 70+. Global score, memory, and executive sub‐scale ECog‐12 scores were significantly associated with global (B= ‐0.14), memory (B= ‐0.11), and executive function (B= ‐0.11) neurocognitive composite scores respectively (all p‐values <.001), such that higher ECog‐12 scores (more complaints) were related to lower neurocognition for all three neurocognitive composites.

Conclusion

Contrary to previous research in non‐Hispanic Whites, SCD is associated with concurrent objective neurocognitive function among Hispanic/Latino community‐dwelling adults. SCD may have utility as an early risk marker in this population. More research is needed to determine the predictive value of SCD reporting within Hispanics/Latinos as well as the utility of informant’s report in predicting neurocognitive change.
Functional network disconnection precedes structural atrophy in longitudinally confirmed multi‐domain amnestic MCI
Authors: Broadhouse Kathryn M , Winks Natalie J , Summers Mathew J
Published: December 2020

Background

It is widely accepted that numerous neurological changes occur prior to dementia onset, with recent work suggesting that aberrant functional neurocircuitries arising prior to significant cognitive deficits. However, the use of unrefined mild cognitive impairment (MCI) diagnostic criteria in many studies has hampered the investigation of biomarker relationships.

Method

Pilot structural and resting‐state functional MRI data were acquired in healthy controls (HC), longitudinally confirmed multi‐domain amnestic‐MCI (mdaMCI) and mild AD (mAD). Group differences in cortical thickness, hippocampal volume and functional connectivity were investigated.

Result

Hippocampal subvolumes differentiated mAD from HC and mdaMCI. Functional decoupling of fronto‐temporal networks implicated in memory and executive function differentiated HC and mdaMCI. Decreased functional connectivity in these networks was associated with poorer cognitive performance scores.

Conclusion

Preliminary findings suggest the large‐scale decoupling of fronto‐temporal networks associated with cognitive decline precedes measurable structural neurodegeneration and may represent a potential biomarker for disease progression.
GABA and glutamate associate with evidence of preclinical Alzheimer disease in humans: A 7 Tesla MRSI and 11C‐PIB PET study
Authors: Schreiner Simon J. , Kirchner Thomas , Van Bergen Jiri M.G. , Wyss Michael , Steininger Stephanie C. , Gietl Anton F. , Buck Alfred , Treyer Valerie , Nitsch Roger M. , Pruessmann Klaas P. , Hock Christoph , Henning Anke , Unschuld Paul G.
Published: December 2020

Background

Early stage Alzheimer disease (AD) is characterized by brain change that includes altered neuronal inhibition and excitation. However, only few data is available for clinical populations. Here, we tested the hypothesis that GABA and glutamate (Glu), the major inhibitory and excitatory neurotransmitters, associate with changes in episodic memory performance, beta‐amyloid (Aß) burden, and genetic risk of AD in old‐aged adults with normal cognition.

Method

Thirty old‐aged adults underwent genotyping of the apolipoprotein E epsilon 4 allele (APOE4), MRI and MRSI at 7 Tesla (7T) for estimating GABA and Glu levels (referenced to creatine) in grey and white matter of the posterior cingulate and precuneus region, positron emission tomography with 11C‐Pittsburgh compound‐B for measuring Aß burden, and cognitive testing at two time points for assessing longitudinal change in verbal episodic memory performance.

Result

Higher levels of GABA and Glu were associated with higher Aß burden (GABA: ß=0.59; p=0.005; R2=0.41; Glu: ß=0.57; p=0.006; R2=0.30), which was particularly evident in APOE4 carriers (significant interaction of Aß burden and APOE4; GABA: ß=0.93; p<0.001; R2=0.80; Glu: ß=0.81; p<0.001; R2=0.59). GABA classified subjects with high vs. low PiB‐SUVR with good accuracy (AUC=0.77; Figure 1). APOE4 and high Aß burden were associated with declining performance at the Verbal Learning and Memory Test (VLMT), immediate recall. However, these associations were attenuated by GABA and Glu, which both associated with VLMT decline (GABA: ß= ‐0.48; p=0.015; R2=0.18; Glu: ß= ‐0.41; p=0.024; R2=0.15; Figure 2). These associations, however, did not survive adjustment for age, sex and education. All findings were exclusively observable for grey and not white matter levels of GABA and Glu.

Conclusion

Our findings may provide clinical evidence of higher inhibitory and excitatory capacity associated with episodic memory decline, genetic risk and pathology of AD.
The twelve months’ follow‐up, second version, after an intervention using a rehabilitation program of physical and cognitive rec‐xercise (REPCREC) for the elderly with mild cognitive impairment (MCI)
Authors: Kanemaru Akiko , Kato Takayuki , Honda Takuya , Hiraoka Tomo , Kawaji Yoshie , Makita Ayaka , Kuwata Naoya , Shimizu Aya , Higuchi Wakana , Sugawara Yasuhiro , Uemura Honoka , Yamazaki Ritsuko , Kanemaru Kazutomi
Published: December 2020

Background

Whether our rehabilitation program of physical and cognitive Rec‐Xercise (REPCREC) for the elderly with MCI can bring any difference in cognition and QOL.

Method

Subjects are sixty‐nine cases, out of 73 enrolled individuals for more than three years, have undergone our evaluation and intervention program (REPCREC). The subjects have been divided into four groups; group A has taken the cognitive REPCREC, group B physical REPCREC, group C both cognitive and physical REPCREC and group D control. The design of this study is a non‐randomized controlled trial. Three intervention groups have received the each session once per week up to 12 times. Before and after the intervention, and, three, six and twelve months after the intervention, we have evaluated the following items: physical function, Geriatric Depression Scale, POMS2, Visual analog scale (VAS‐1: healthy life, VAS‐2: satisfaction), neuropsychological tests [MMSE, RBMT, TMT, Ravenʼs Colored Progressive Matrices (RCPM), Rey‐Osterrieth Complex Figure Test (ROCF), story retention, coding and Miyake's paired verbal associate learning test (MPVALT)]. A one‐day booster program has been provided at the time of evaluation. For statistical analysis, Fisher's exact test and Kruscal‐Wallis test for the baseline data, and linear mixed model (LMM) analysis and Friedman’s test for the prolonged effect of REPCREC have been performed.

Results

The median age 79.0 years old, median MMSE score 28.0 points, the number of each group is A 22, B 22, C 25, and D 7cases. At the baseline, no difference between groups. LMM analysis revealed the significant difference in RCPM, ROCF (recall), MPVALT (non‐related), MPVALT (related), coding and VAS‐2 (respectively p=0.000, 0.000, 0.000, 0.001, 0.011 and 0.006). Friedman's test showed significant difference in RCPM of group A (p=0.046) and C (p=0.042), ROCF (recall) group C (p=0.022), VAS‐2 of group A (p=0.013) and C (p=0.011), MPVALT (non‐related) of group A (p=0.007), MPVALT (related) of group A (p=0.016) and C (p=0.048).

Conclusions

The program REPCREC showed the prolonged effects on non‐verbal intelligence, visuospatial abilities, memory, attention, planning, working memory etc. [(RCPM), ROCF (recall), MPVALT] in group A and C comparing with control in the elderly with MCI.
Efficient intracellular degradation of tau in neurons through engineered nuclear transport
Authors: Cho Yongku P.
Published: December 2020

Background

Targeted protein degradation is an attractive modality of therapeutic intervention for a wide range of neurodegenerative diseases. Intervention at the protein level is highly desired since pathogenic changes such as conformational change or post‐translational modifications can be directly targeted.

Method

We designed protein constructs that contain an intracellular binding domain for targeting tau fused to a domain for recruiting the ubiquitination machinery. We expressed these constructs in a cultured human cell line and dissociated cultures of mouse hippocampal neurons expressing human tau. We assessed the degradation of human tau using fluorescence microscopy and by tau quantification using immunoblotting.

Result

We found that the ubiquitin ligase substrate adaptor speckle‐type POZ protein (SPOP), when fused to camelid‐derived single‐domain antibody fragments (nanobodies), allows efficient degradation of nanobody binding proteins imported to the nucleus. We found that the endogenous SPOP domain contains a strong nuclear localization signal, resulting in nuclear accumulation and aggregation of tau. Based on this we hypothesized that the strong nuclear localization signal overloaded the intracellular protein degradation capacity, disrupting the cellular homeostasis. To test this, we engineered SPOP variants with altered nuclear transport efficiency. The engineered variants altered the degree of tau degradation and nuclear accumulation. Interestingly, this regulated degradation approach resulted in preferential degradation of tau dissociated from the microtubule, leading to nearly exclusive colocalization of tau to the microtubule in mammalian cells and primary mouse hippocampal neurons.

Conclusion

The new constructs developed here allow fine tuning of nuclear translocation rate and degradation efficiency of tau. This controlled degradation strategy may be beneficial in developing therapeutic approaches for regulated tau degradation without overloading the proteasomal capacity.
‘δ’ is for dementia: Genomic architecture of the latent variable δ homolog (dEQ) in Mexican Americans and non‐Hispanic Whites
Authors: Colmenarez Micaela , Silzer Talisa , Royall Donald R. , Palmer Raymond F. , Barber Robert , Phillips Nicole
Published: December 2020

Background

The latent variable δ homolog (dEQ) has been established as a reliable indicator of cognitive performance and a predictor of future dementia. Here, we sought to identify genetic variants underlying dEQ in both non‐Hispanic White (NWH) and Mexican American (MA) populations, hypothesizing that novel genomic risk loci for dementia will be implicated in the MA cohort.

Method

Genotyping was performed on the TARCC cohort using the Illumina® MEGA Array, which includes ∼1.7 million SNPs. dEQ was generated by Donald Royall and Ray Palmer (UT Health Science Center @ San Antonio) for the entire genotyped cohort (nNHW = 1572; nMA = 1030). Association testing was conducted using PLINK (Purcell et al., 2007) according to standard procedures (Anderson et al., 2010).

Result

The primary genetic association with dEQ in NHW is the TOMM40/APOE locus (rs4420638, p = 9.477 × 10−32); the association for this locus in the MA cohort was much less significant (p = 3.886 × 10−5). Among MAs, three interesting and unique loci emerged as suggestive: XIRP2 (chr2, rs7595556 p = 8.165 × 10−6), KIF13a (chr6, rs7766167, p = 3.404 × 10−6), and LINC00907 (chr18, rs237972, p = 7.88 × 10−7).

Conclusion

The loci discovered in the MA cohort have not previously been implicated in dementia/Alzheimer’s disease; interestingly, however, variants in these genes have been associated with metabolic phenotypes that are particularly relevant to the pathophysiology of cognitive decline in MAs: BMI, diabetic neuropathy, epigenetic aging, and childhood obesity. Further investigation of these genomic regions may shed light on the mechanisms by which metabolic syndromes may confer risk for earlier onset of age‐related cognitive decline in MAs.
Association between cerebrospinal fluid biomarkers of neurodegeneration and PET measurements of synaptic density in Alzheimer’s disease
Authors: Mecca Adam P. , Ashton Nicholas J , Chen Ming‐Kai , O'Dell Ryan S. , Naganawa Mika , Toyonaga Takuya , Harris Joanna E. , Bartlett Hugh H. , Banks Emmie R. , Kominek Victoria L. , Nabulsi Nabeel B. , Najafzadeh Soheila , Wyk Brent C. Vander , Brinkmalm Ann , Kvartsberg Hlin , Schöll Michael , Arnsten Amy F.T. , Huang Yiyun , Blennow Kaj , Zetterberg Henrik , Carson Richard E. , van Dyck Christopher H.
Published: December 2020

Background

Studies using [11C]UCB‐J–PET have shown significant reductions in synaptic glycoprotein 2A (SV2A) specific binding as a marker of synaptic density in early Alzheimer’s disease (AD). The extent of these reductions indicates widespread neocortical synaptic loss that corroborates previous postmortem studies. The relationship of PET measures of synaptic density and cerebrospinal fluid (CSF) biomarkers may provide important information related to neuronal damage and synaptic health.

Methods

SV2A binding was measured with [11C]UCB‐J–PET in 21 participants with early AD (CDR=0.5‐1.0, PiB+) and 7 cognitively normal (CN) participants (CDR=0, PiB–). PET scans were performed on a HRRT from 60 or 90 min after a bolus injection of [11C]UCB‐J. Binding potential non‐displaceable (BP
ND) was calculated using SRTM2 and a centrum semiovale reference and converted to a distribution volume ratio (DVR) with a cerebellum reference. CSF biomarkers of AD, as well as synaptic and neuronal health were assayed, including Aβ42, Aβ40, total tau (t‐tau), phosphorylated tau (p‐tau), neurofilament light chain (NFL), growth‐associated protein 43 (GAP‐43), neurogranin (Ng), synaptosomal‐associated protein 25 (SNAP‐25), and synaptotagmin‐1 (SYT‐1).

Results

Synaptic density was significantly lower in AD participants in the hippocampus, entorhinal cortex, lateral parietal cortex, lateral temporal cortex, and lateral occipital cortex. There were significant group differences in Aβ42, Aβ42/Aβ40, t‐tau, p‐tau, GAP‐43, Ng, SNAP‐25 short, and SNAP‐25 total. In the overall sample, only Aβ42 (r=0.40, P=0.03) and Aβ42/Aβ40 (r=0.48, P=0.01) had significant correlations with synaptic density in the hippocampus. Aβ42/Aβ40 (r=0.46), t‐tau (r=‐0.38), p‐tau (r=‐0.40), NFL (r=‐0.42), GAP‐43 (r=‐0.46), and SNAP‐25 total (r=‐0.49) were significantly correlated with synaptic density in a composite of commonly affected AD regions (P<0.05, Figure 1). Most CSF biomarkers were significantly correlated with synaptic density in the neocortex only (Figure 2). In addition, CSF Aβ42/Aβ40 and synaptic density were significantly correlated in regions of the medial temporal lobe (Figure 2).

Conclusion

This study explores the relationship between synaptic density and CSF biomarkers of neuronal and synaptic health in AD. The spatial relationship between synaptic density reductions and CSF synaptic biomarkers may provide valuable information that will contribute to the understanding of AD and lead to novel treatments and therapeutic biomarkers.
Lifestyle and genetic risk: Revisiting the association with incident dementia
Authors: Faul Jessica D , Ware Erin B , Kabeto Mohammed U , Langa Kenneth M , Llewellyn David J , Galama Titus
Published: December 2020

Background

Previous work using data from the UK Biobank has shown that both unfavorable lifestyle and genetic risk are associated with higher dementia risk; however, it is not known whether these results transfer to more representative samples and across country.

Methods

Data come from the Health and Retirement Study (HRS), a cohort study of Americans 65 years of age and older without dementia at baseline. Adults of European descent are included in the analyses. Dementia was determined using Medicare claims from 2000‐2016. 6,870 individuals were followed for an average of 11 years (Median 12; IQR 8.6 – 15.6 years) with mean age of 68.8 (5.4). Polygenic scores (PGS) for dementia from 2 large, replicated genome‐wide association studies (Lambert et al. and Kunkle et al.) were used along with a weighted lifestyle score (including measures of smoking, drinking, and physical activity) to predict incident dementia. The association between the PGS and lifestyle was assessed using ordered logistic regression. Cox proportional hazard regression models were used to examine the association of genetic risk, lifestyle, and the interaction with time to incident dementia.

Result

Overall, 22.9% (n=1,580) were diagnosed with dementia during the observation period. 23.8% of participants had a favorable lifestyle, 50.7% had a moderately favorable lifestyle, and 25.5% had an unfavorable lifestyle. There was no significant association between the lifestyle score and either PGS. The effect of PGS on time to dementia was significant with and without adjustment for covariates (age, sex, education, wealth, comorbidities) with higher genetic risk conferring an increased risk for dementia (hazard ratio highest PGS group compared to lowest 1.37 [95% CI [1.17, 1.61]). Individuals with a favorable lifestyle at baseline were significantly less likely to develop dementia adjusting for PGS and covariates (adjusted hazard ratio 0.85 [95% CI, 0.74‐0.99]). Results were similar regardless of which PGS was used. There was no significant interaction between genetic risk and lifestyle.

Conclusion

These findings demonstrate that an unhealthy lifestyle and genetic risk are associated with higher dementia risk. Results from a nationally‐representative sample of older adults in the United States are comparable with those from UK Biobank.
Comparison of baseline characteristics of African‐American/black and non‐Hispanic white family caregivers in Tele‐Savvy: An online psychoeducation program
Authors: Bonds Kalisha , Griffiths Patricia , Higgins Melinda , Nocera Joe R , Epps Fayron , Brewster Glenna S , Hepburn Kenneth
Published: December 2020

Background

Tele‐Savvy is an NIA‐funded 3‐arm randomized controlled longitudinal trial of a fully online psychoeducation program. Tele‐Savvy is specifically designed to promote caregiver mastery by enhancing caregivers’ abilities to manage daily challenges to reduce caregiver distress.

Method

This presentation reports on the baseline characteristics of 209 family caregivers (159 non‐Hispanic White [NHW] and 50 African American/Black [AA] family caregivers). Bivariate analysis was conducted to compare group differences among AA and NHW family caregivers.

Result

AA caregivers reported their persons living with Alzheimer’s disease and related dementias (AD/ADRD; PWD) were more dependent. AA caregivers reported their PWDs had significantly worse performance of activities of daily living (e.g., toileting, grooming) (p < .001) and significantly worse performance of instrumental activities of daily living (e.g., transportation, managing finances) (p = .007). AA caregivers reported their PWDs had significantly more disruptive behaviors (p = .010) and significantly worse neuropsychiatric behaviors (e.g., delusions, disinhibition) (p = .025) than were reported by NHW caregivers regarding their PWDs. In addition, AA caregivers reported better caregiving experiences. AA caregivers reported significantly less personal strain (p = .019), significantly better caregiver competence (p < .001), significantly better management of their caregiving situation (p = .001), and significantly better management of the behavioral symptoms associated with AD/ADRD (p = .009) than NHW caregivers. AA caregivers reported significantly better mindful self‐care in the domain of self‐compassion and purpose (i.e., a sense of meaning when getting through difficult situations) (p = .015) compared to NHW caregivers.

Conclusion

AA caregivers recruited into Tele‐Savvy have reported quantitative baseline characteristics similar to previous caregiving studies, which portray AA caregivers as less distressed and better prepared for AD/ADRD caregiving than NHW caregivers. This longitudinal study will enable us to see if AA and NHW caregivers change on these dimensions over time in similar or different ways. We will interview some of the caregivers to see if AA and NHW caregivers experience similar or different patterns of distress than explained through quantitative measures. Continuation in Tele‐Savvy will provide an opportunity to assess the extent to which both groups respond to the intervention.
Metabolite differences in vascular dementia and control human brain tissue
Authors: Hammond Tyler C. , Xing Xin , Nelson Peter T. , Ham Stephanie , Lin Ai‐Ling
Published: December 2020

Background

Vascular dementia is the second most common cause of dementia worldwide and is characterized by cerebrovascular pathology that presents as an amnestic dementia syndrome like Alzheimer’s disease. The main neuropathological and clinical features for vascular dementia have been described elsewhere, but little is understood about the underlying metabolic processes that may contribute to vascular dementia. Here we measure the metabolites of control brains and brains with cerebrovascular pathology to understand how they differ.

Method

The global biochemical profiles of post‐mortem human brain tissue from the gray matter of Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 52 subjects with cerebrovascular pathology and 46 controls were analyzed and metabolites were compared. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch’s two‐sample t‐test and random forest to rank metabolites in order of importance for predicting cerebrovascular pathology presence in tissue.

Result

Many of the metabolites in the top 20 most important predictors for cerebrovascular pathology overlapped with metabolites deemed important in predicting Alzheimer’s disease, including memantine, sphingadienine, N‐acetylasparagine, N‐acetyl‐aspartyl‐glutamate (NAAG), glycerophosphorylcholine, guanidinoacetate, dimethylglycine, pipecolate, and phosphatidylserine. However, there were quite a few predictors which were unique to predicting cerebrovascular pathology, including 7‐hydroxycholesterol – common to atherosclerotic plaques, methylphosphate – an intermediate of purine and pyrimidine metabolism, 2‐methylcitrate/homocitrate – part of the TCA cycle, tryptophan – a precursor of serotonin and melatonin, 2‐hydroxystearate – a fatty acid, glutamate – the most abundant fast excitatory neurotransmitter, and beta‐hydroxyisovalerate – associated with smoking.

Conclusion

Many metabolites differed between the brains with cerebrovascular pathology and control brains. Some metabolite differences were the same as those seen in Alzheimer’s disease, and could be because many of the people in our cohort with cerebrovascular pathology also had Alzheimer’s pathology. Many of the metabolite differences were specific to cerebrovascular pathology including the well‐known lifestyle factors high cholesterol and smoking, and other metabolites which are critical to maintaining brain function, including changes in neurotransmitters, essential amino acids, fatty acids, TCA cycle intermediates, and nucleic acid intermediates. Further studies are needed to examine whether these metabolites are consistently altered in cerebrovascular disease.
HAPPCAP‐AD (Human‐Application Combined Approach for Prevention of Alzheimer's Disease): A novel feasibility study of a personalized midlife intervention to prevent AD
Authors: Ganmore Ithamar , Ravona‐Springer Ramit , Livny Abigail , Matatov Adar , Ziat Adi , Bem‐Moshe Ariela , Beeri Michal Schnaider
Published: December 2020

Background

Developing efficient Alzheimer's disease (AD) prevention strategies is imperative as AD has no cure. Physical inactivity, obesity, type 2 diabetes [T2D], hypertension, smoking, depression, and low educational attainment, are the seven major potentially modifiable risk factors showing consistent association with AD. We have launched a novel, "real‐life", feasibility study of personalized 18‐months intervention for prevention of cognitive decline in middle‐aged individuals at high AD risk due to a parental family history. Our study implements an innovative approach combining a smartphone application (app) with study team guidance through phone‐calls. Our aims are to investigate: 1) The feasibility of our novel intervention and factors associated with adherence to it; 2) Whether our intervention improves AD risk factors and whether greater adherence is associated with larger improvement; and 3) Whether our intervention improves cognition and cerebral blood flow.

Method

We will recruit one hundred 40‐65 years old AD patients' offspring, to two groups (67 at the intervention group and 33 at the passive control). All participants will have at least two risk factors of the seven major modifiable AD risk factors. The 18‐months intervention will include advice for risk factors improvement, interactive follow‐up using a smartphone app and dynamic feedback on risk factors management for its modification, through both the app and the study team.

Result

Recruitment has recently begun, through publishing an online eligibility questionnaire. Thus far, 200 individuals have completed the questionnaire, with 113 fulfilling eligibility criteria‐ among them 86% with physical inactivity, 87% with obesity, 38% with T2D, 17% with hypertension, 13% smoking, and 32% with depression. Thus far 33 participants have been recruited‐ Among them, 10 participants have completed the baseline evaluation, and have been randomized to the study's arms (8 of them had started the active intervention, with an average app‐adherence of 83%). additional 23 participants have completed partial base‐line evaluation.

Conclusion

Results of this study will provide feasibility data on the adherence to the human‐app approach, characteristics of those who adhere, on whether the approach improves risk factors, and will provide initial data on intervention effects on cognition. At AAIC, interim results will be presented.
Are U.S. clinical trial sites in the right places to meet the demand for the population density of those over 60?
Authors: Stanton Sean , Dwyer John , Ward Nichol , Vradenburg George , Taylor James
Published: December 2020

Background

There are approximately 31 drugs in phase 3 and 68 drugs in phase 2 development for memory impairment. It is reported that there are approximately 200 sites in the US that are capable of randomizing 25 subjects per year. The current demand for participants is approximately 25,277 across 55 studies requiring this type of enrollment. That means we would need approximately 505 clinical trials sites capable of randomizing at least 25 subjects per year. Is it possible to meet this demand? Prior to answering this question we researched where in the US the population is located for people >60 years of age. We also researched where clinical trial sites were in relation to this population. And lastly, how many of these sites have done at least 1 memory study in the last 2 years. To determine if the US has sites positioned in the right places to meet the demand from both the patient and the industry/NIH for Alzheimer’s disease. If yes, can we increase capacity to meet the patient enrollment needs? If no, what do we need to do organically to grow sites to meet this demand.

Method

The population was surveyed using the US Census and plotted graphically using. The data can be seen in the graphs. Data on the site locations was compiled though clinical trials.gov. The data on Alzheimer’s sites was also collected from ClinicalTrials.Gov. The data on the Global Alzheimer’s Sites was supplied by GAP. Each data set has scatter plot

Result

The results are plotted on the graphs below.

Conclusion

The site locations do not align cohesively with the population greater the 60 years of age. As the demand of subject enrollment increases there is further pressure on existing sites within overly saturated clinical trial site zones while other zones offer no clinical trial sites within 50 miles. This will continue to lead to low performance and delayed timelines. We will offer answers to expanding site capabilities, organically growing zones in void of clinical trial sites, and also teaching sites interested in stopping Alzheimer’s the dynamics to being successful in clinical trials for Alzheimer’s Disease.
Protocol for a scoping review of the collection, analysis and reporting of variables related to cultural and linguistic diversity in dementia clinical trials and cohort studies
Authors: Sabates Julieta M , Croy Samantha , Lampit Amit , Low Lee‐Fay , Coase Daniel , de Crespigny Fleur , Day Robert , Dobson Annette , Elliott Cerise L , Ellis Stephanie , Etherington Cathy , Geronimo Mary Ann , Hlis Danijela , Maruff Paul T , Moxey Annette , Straiton Nicola , Temple Jeromey , Brijnath Bianca
Published: December 2020

Background

Ethnic minority communities and people living with dementia have been under‐represented in epidemiological studies. Concurrently, there are limited insights into how to analyse and report on a minimum set of variables related to cultural and linguistic diversity in such studies. In light of increased cultural and ethnic diversity in national populations, this review aims to investigate the collection, reporting and analysis of variables related to cultural and linguistic diversity in epidemiological dementia studies, and to identify best practice exemplars to inform recommendations for accurately capturing cultural diversity in future studies

Method

Embase, PsycINFO, Medline, CENTRAL and CINAHL will be searched for peer‐reviewed studies published between January 2000 and January 2020. Selection criteria are: epidemiological dementia research studies (including clinical trials and cohort studies) focusing on cultural and ethnic minorities or cultural and ethnic difference, and undertaken in high‐income countries. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) guidelines will be used to report findings.

Result

Results will describe the variables related to cultural and linguistic diversity, the related measures used, how such variables are treated (e.g. categorical or continuous) and triangulated, what corrections are made (if any) for variables such as time lived in country of settlement, and how these are analysed to inform understanding of dementia among ethnic minorities in high‐income countries.

Conclusion

Based on these findings, best practice exemplars will be identified, and recommendations made for a minimum and consistent set of variables relating to ethnic diversity to be collected and reported. The study addresses methodological uncertainties around which variables to collect and how to bring them together in a robust analysis that accounts for the cultural and pathological heterogeneity often found among ethnic minority study participants living with dementia.

Reference

1Australian Institute of Health and Welfare 2018. Older Australia at a glance. 2L. F., Barcenilla‐Wong, A. L., and Brijnath, B. 2019. Including ethnic and cultural diversity in dementia research. Medical Journal of Australia, 211, 345. 3World Bank Country and Lending groups.https://datahelpdesk.worldbank.org/knowledgebase/articles/906519#High_income. Accessed 14 January 2020.
Self‐efficacy of ADRD caregivers: Results of a pilot survey
Authors: Parsons Kelly Kazee , Gibson Allison , Bardach Shoshana H , Barber Justin M , Johnson Julia , Jicha Gregory A
Published: December 2020

Background

Family members often become informal caregivers of persons diagnosed with Alzheimer’s disease and related dementias (ADRD). Caregiver self‐efficacy is a construct that refers to a belief that a person has about one’s ability to successfully facilitate their caregiving role. However, self‐efficacy can vary across caregiving domains. This pilot study aimed to identify challenges and strengths of caregiver self‐efficacy to inform a caregiving intervention.

Methods

Data collection was administered to ADRD caregivers associated with a southern U.S. Alzheimer’s Disease Research Center. With a focus on motivation, coping, and self‐ efficacy, analysis was conducted with 65 caregivers for ADRD (n=62). The caregiver assessment was conducted as an interview (39 items) and included Zarit’s Caregiver Burden 4‐item screening, REACH II Risk Appraisal, Fortinsky’s Caregiver Self‐Efficacy for Managing Dementia scale, and selected items of Albert’s Care Planning for Individuals with Dementia. Analysis in R identified caregiver efficacy along the continuum of care needs and domains.

Results

Of the 62 respondents, 29 identified as the only caregiver (51.8%) and 51 identified as the primary caregiver (91.1%). The majority of respondents provided daily care (49; 87.5%) without paid assistance (43, 76.8%). Caregivers expressed challenges including frequent trouble sleeping (24; 42.9%) and occasional desire to yell at the persons with ADRD (28; 50.0%). Further, 27 persons with ADRD had access to a weapon (48.2%). Most caregivers “agreed a lot” (26; 44.6%) or “agreed a bit” (18; 32.1%) that providing care made them feel good about themselves. Self‐efficacy and caregiver burden were correlated. ([r(53) = ‐.413, p = .002]). Further, a regression was significant with independent variables level of disease knowledge and caregiver efficacy explaining significant variance in feeling good about providing care ([R2= .141, F(2, 52) = 4.114, p = 0.022]).

Conclusion

Developing strategies to provide specific interventions within the continuum of care is a timely cost effective way to reduce caregiver burden, promote the dyad well‐being, and assist family to age in place. Caregiver interventions should focus on safety in the home (i.e., securing weapons), self‐care for caregivers, and disease education, which can empower caregivers to feel good about themselves in their role as caregivers.