bluuebunny/crossref_metadata_2025 huggingface dataset:
Cognitive performance among participants with Alzheimer’s disease and cerebral amyloid angiopathy
Authors: Teylan Merilee , Schwabe‐Fry Kristen , Hughes Timothy M. , Besser Lilah M , Brenowitz Willa D. , Keene C. Dirk , Gauthreaux Kathryn , Culhane Jessica E. , Miller Zachary , Chen Yen‐Chi , Chan Kwun Chuen Gary , Mock Charles , Kukull Walter A.
Published: December 2020

Background

Beta‐amyloid found in Alzheimer’s disease (AD) plaques can also be present in the brain’s blood vessels as cerebral amyloid angiopathy (CAA). Co‐occurrence of AD and CAA is common. We examined the relationship between AD and CAA, and cognitive performance.

Method

Data were obtained from the National Alzheimer’s Coordinating Center. The sample was restricted to those with an autopsy ≤2 years of their last clinic visit and non‐missing data on Braak neurofibrillary tangle stage, neuritic plaque score, and CAA at autopsy. We excluded participants who had autopsy evidence of rare neuropathological diseases. Linear regression models with generalized estimating equations were run comparing CDR® Dementia Staging Instrument sum of boxes (CDR‐SB) and cognitive domain z‐scores across four groups (AD+/CAA+, AD+/CAA‐, AD‐/CAA+, AD‐/CAA‐). AD+ included those with Braak III‐VI and moderate/frequent neuritic plaques. Overall neocortical amyloid angiopathy was assessed for presence of CAA. Models accounted for clustering by center and adjusted for covariates. We also examined the mean differences in CDR‐SB by CAA severity (absent, mild, moderate, severe), stratifying by AD+/‐ and APOE ε4+/‐.

Result

We identified 1723 AD+/CAA+, 547 AD+/CAA‐, 443 AD‐/CAA+, and 741 AD‐/CAA‐ participants. All groups were more likely to be APOE ε4 carriers compared to AD‐/CAA‐. CAA+ participants, regardless if they had AD, were more likely to have arteriolosclerosis. After adjusting for covariates, AD+/CAA+ and AD+/CAA‐ participants had worse CDR‐SB scores compared to AD‐/CAA‐. There was no significant difference in CDR‐SB scores among AD‐ participants with or without CAA. Similar results were seen when examining differences in cognitive domain z‐scores, where AD+ participants performed worse regardless of the presences of CAA when compared to AD‐/CAA‐ participants. We did not observe significant differences in CDR‐SB scores by CAA severity after adjusting for covariates.

Conclusion

These results demonstrate that the presence of AD neuropathologic features appears to be driving the cognitive performance irrespective of the presence or severity of CAA. Our observation that arteriolosclerosis was more likely to be present among those with CAA even in the absence of AD is of note and something to investigate further. Future work should also examine if these differences hold true when examining longitudinal cognitive performance.
Automatic annotation of head movement among elderly people susceptible to Alzheimer's disease
Authors: Helmi Garraoui
Published: December 2020

Background

Several researchers have revealed that sensory and motor changes can predate the cognitive symptoms of Alzheimer's disease (AD) by many years and may signify increased risk of developing AD. Therefore, studying the non‐verbal communication among the elderly susceptible to AD can contribute to a better understanding of their daily needs. Among these non‐verbal communications, we can mention head gestures, hand gestures, etc. This research discusses a new system model of nonverbal language annotation associated to hand gestures among elderly people susceptible to AD.

Method

The proposed approach aims at establishing a longitudinal study based on the use of recurrent neural network as a deep learning technique. We propose an interdisciplinary approach for automatic annotation of hand phases (rest position, preparation, hold, retraction), defined in many existing research works. To perform the classification, we rely on a ground truth, initiated by experts, known as CorpAGEst corpus. The latter is a collect of spontaneous conversations between interviewers and elderly people, which is used to train and test our model

Result

Experimentations show promising results, where the proposed approach succeeded in classifying the hand gesture phases with an 87.5% of precision and recall.

Conclusion

The proposed process focused on the automatic annotation of hand phases, reducing the cost of manual annotations and establishing a back and forth dialog between computer science communities and researchers in AD. The principal impact of this work is to contribute in establishing stronger gesture recognition techniques adapted to the aging population, giving the community of researchers tools to explore specificities in an automated fashion.
Serum cholesterol levels and APOEε4 status potentiate metabolic decline in non‐demented individuals
Authors: Souza João Pedro Ferrari , Pascoal Tharick A. , Povala Guilherme , Brum Wagner Scheeren , De Bastiani Marco Antônio , Benedet Andréa Lessa , Therriault Joseph , das Ros Lucas U. , Bellaver Bruna , Rosa‐Neto Pedro , Zimmer Eduardo R.
Published: December 2020

Background

Epidemiological investigations have shown that midlife elevated total serum cholesterol levels increase the risk of Alzheimer’s disease (AD). However, observational studies in late‐life subjects suggested that high cholesterol levels reduce the risk of dementia. Since hypometabolism is a pivotal marker of AD progression, understanding the impact of peripheral cholesterol levels over the brain’s metabolic state in older adults has become crucial to clarify these seemingly conflicting findings. Therefore, whether high serum cholesterol levels accelerate brain metabolic decline in older subjects remains a key question to be answered. Here, we investigated whether total serum cholesterol levels are associated with cerebral metabolic decline. We hypothesized that elevated total serum cholesterol levels accelerate metabolic decline in AD‐related brain regions.

Method

We evaluated 499 cognitively unimpaired and mild cognitive impaired elderly subjects (age>55 years) from Alzheimer's Disease Neuroimaging Initiative (ADNI) with available total serum cholesterol measurements at baseline and longitudinal [18F]FDG‐PET scans. Voxel‐wise general linear modelling was used to assess the baseline association between total serum cholesterol levels and cerebral metabolic rate for glucose (CMRglc), as well as cholesterol’s impact over the 2‐year’s rate of metabolic decline. Age, gender, BMI, cholesterol treatment and diagnostic group were set as covariates for adjustment. APOEε4 genotype was used as both, a covariate or an interaction factor.

Result

No significant associations were observed at baseline. We found a negative correlation between cholesterol levels and the 2‐year CMRglc variation rates in brain regions affected in early stages of AD, which was driven by the interaction with APOEε4 status (Figure 1). Regions affected include the right precuneus (peak t(491) = ‐3.93, p<0.0001) and the right posterior cingulate gyrus (peak t(491) = ‐4.12, p<0.0001). Associations were greater in the right hemisphere.

Conclusion

Our results support the concept that the interaction of higher serum cholesterol levels with APOEε4 genotype accelerate metabolic decline in AD‐related brain regions. These findings complement cross‐sectional studies postulating that, even among older adults, serum cholesterol levels, in association with the APOEε4 status, might be related to brain functional changes similar to those observed in the development of AD.
Preserved cholinergic forebrain structure reduces the impact of strategic lesions to the connectome in mild cognitive impairment
Authors: Berlot Rok , Koritnik Blaž , Pirtošek Zvezdan , Ray Nicola
Published: December 2020

Background

Undetected neurodegeneration is present in many patients with stroke. Clinical consequences of stroke might be partly determined by pre‐existing changes in brain structure. Cortical acetylcholine allows favourable adaptation to pathological changes within the limbic system. However, it remains unclear if it acts more broadly, affecting the configuration of the structural connectome. To test this, we aimed to assess the relationship between nucleus basalis of Meynert (NBM) structure and vulnerability of the connectome to simulated strategic lesions in patients with mild cognitive impairment (MCI).

Method

Twenty patients with MCI and 20 healthy elderly controls underwent 3T structural and diffusion‐weighted MRI. Whole‐brain tractograms were represented as network graphs. Lesions of individual nodes were simulated by removing a node and its connections from the graph. The impact of simulated lesions was measured as the proportional change in global efficiency of the connectome. Relationships between NBM volume, global efficiency of intact connectomes and impacts of individual simulated lesions of network nodes were assessed, controlling for demographic variables and atrophy of individual nodes.

Result

Artificial removal of the thalamus and the hippocampus from the connectome had a lower impact on global efficiency in MCI compared to controls. In MCI, NBM volume was correlated with global efficiency of intact connectomes. Higher NBM volumes were associated with reduced impact of thalamic lesions and lesions of the entorhinal and posterior cingulate cortices. These relationships were not present in other cortical or subcortical nodes or in controls.

Conclusion

Reduced vulnerability to damage of the hippocampus and thalamus in MCI suggests that connections essential for efficient network structure “shift” away from these areas. In MCI, preserved NBM is associated with efficient network topology and has a protective effect against the global impact of simulated strategic lesions. By influencing the configuration of the connectome in MCI, the cholinergic system might have a protective effect against the impact of targeted damage. Structural connectome alterations in response to early neurodegeneration represent a potential mechanism for synergy between neurodegeneration and vascular lesions in post‐stroke cognitive impairment and mixed dementia.
The late‐onset Alzheimer's disease genetic risk factor CD2AP impacts synapses via actin dynamics
Authors: Mirfakhar Farzaneh S. , Almeida Claudia G.
Published: December 2020

Background

In late‐onset Alzheimer’s disease (LOAD) the causal mechanisms of synaptic dysfunction that underlie the memory deficits that lead to dementia are not established. The search for genetic risk factors in LOAD led to the identification of more than 20 genes and three main mechanisms: endocytic trafficking, lipid metabolism and immune response. Here we aim to establish causality between a mutation in CD2AP, one of the endocytic trafficking risk factors, and synaptic dysfunction. Since CD2AP is a regulator of the actin cytoskeleton dynamics which is essential for spine morphology, we hypothesize that a LOAD mutation CD2AP may impact spines by deregulating actin.

Method

We have analyzed synapses and spines density as well as spinal actin in cortical mouse primary neurons either transiently overexpressing wild‐type and mutant CD2AP‐GFP as well as GFP as control or infected with lentivirus expressing GFP and shCD2AP or non‐targeting shRNA as control. Moreover, we investigated CD2AP synaptic localization by immunofluorescence microscopy. We used quantitative single‐cell analysis using ICY and Imaris software.

Result

We discovered that a pool of CD2AP is present in spines; and that both CD2AP wild‐type and mutant are significantly enriched in spines. Spines length decreased with larger spine heads, by CD2AP wild‐type and more pronouncedly by mutant CD2AP overexpression. Indicating that CD2AP might function at synapses, by regulating spine morphology. Indeed, synapses density was reduced by CD2AP knockdown. Mechanistically, we found that spinal F‐actin increased by CD2AP wild‐type and more pronouncedly by mutant CD2AP overexpression compared to control neurons. We are currently investigating whether spinal F‐actin is altered by CD2AP knockdown.

Conclusion

These results indicate that CD2AP regulates spine morphology and thus synapses. A LOAD mutant CD2AP may interfere with its function by dysregulating actin dynamics at spines. Overall CD2AP variants may contribute to LOAD development by directly interfering with synapses. References: (1) Ubelmann, Florent, et al. “Bin1 and CD2AP polarise the endocytic generation of beta‐amyloid.” EMBO reports 18.1 (2017): 102‐122. (2) Hollingworth, Paul, et al. “Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.” Nature genetics 43.5 (2011): 429.
A qualitative analysis of study participant and study partner experiences with the consent process: Assessments guiding the development of an electronic consent (ECONSENT)
Authors: Chin Erin , Croes Kenneth , Dykema Jennifer , Suver Christine , Hamann Jennifer , Truong Amy , Doerr Megan , Lah James J , Goldstein Felicia C , Blazel Hanna , Manzanares Cecelia , Edwards Dorothy Farrar
Published: December 2020

Background

The informed consent process educates potential participants about a research study and guides them to make a decision about participation. Most important, the consent document should meet the needs of the participant so they can make an educated decision. Studies have shown consent documents can be lengthy, redundant and ineffective at enhancing comprehension. We examined the traditional consent process from the perspective of research participants, including people commonly underrepresented in research, and from study partners from the University of Wisconsin‐Madison and Emory University Alzheimer’s Disease Research Centers.

Method

Private interviews were conducted with 15 participants and 8 participant/study partner dyads. The interviews were voluntary and the interviewer was not the same person who consented the participants to avoid any bias or influence over the participant’s response. Each person was asked a series of questions about their overall experience with the informed consent process. In order to evoke prior observations, respondents were encouraged to review the consent form throughout the interview. Responses were recorded, transcribed and coded.

Result

Analysis of the interviews revealed participants were overall satisfied with the consent process. Well‐trained study coordinators made a notable difference in the consent experience. Reported shortcomings highlighted by study partners include the length of the consent form and complex language. Some people felt that both the length and complexity were excessive based on the risks and benefits of participation. Others felt a better explanation was needed to explain more complex procedures and concepts, with one pointing out, “The DNA might pose a little problem for people…depending on how far along the person is with their understanding of medical stuff.” Some recommended using videos or online chats to make it easier for people to understand.

Conclusion

When designing an update for a process as vital as the consent it is imperative to capture the perspective and needs of those it directly affects. Participants and study partners offered recommendations, providing a starting point in the development of an eConsent version. In exploring an electronic approach, we hope to improve comprehension by allowing participants to have control over the order and level of detail of information presented to them.
The Critical Path for Alzheimer’s Disease (CPAD): Pre‐competitive data sharing and generation of innovative high‐impact quantitative tools to support Alzheimer’s disease drug development
Authors: Sivakumaran Sudhir , Romero Klaus , Hanan Nathan J , Sinha Vikram , Haeberlein Samantha Budd , Gold Michael
Published: December 2020

Background

The Critical Path for Alzheimer’s Disease (CPAD) consortium’s primary objective is to promote, support, and manage pre‐competitive data sharing from Alzheimer disease (AD) clinical trials to allow quantification of Alzheimer’s Disease progression across the AD continuum. A quantitative understanding of disease dynamics will drive scientific discovery provided by aggregated and standardized primary clinical trial data. This will provide solutions to optimize the design of clinical trials of AD drugs intended for regulatory review in support of marketing approval. CPAD is a nonprofit, pre‐competitive consortium (https://c‐path.org/programs/cpad/) of the Critical Path Institute (C‐Path) and convenes diverse stakeholders from academia, advocacy groups, industry, and regulators.

Method

As of January 2020, CPAD’s database (www.codr.c‐path.org) contains data contains 38 studies, representing 14,853 individual records and more than 420,000 data points, standardized to the AD CDISC (Clinical Data Interchange Standards Consortium) standards. CPAD’s objective is to collaborate with industry and regulators to leverage their wealth of drug development knowledge by enabling pre‐competitive data sharing from clinical trials in AD. Analysis of datasets (at meta‐data and patient levels) enables generation of tools involving comprehensive disease progression models across the AD continuum, to support successful drug development.

Result

CPAD continues ongoing efforts towards expansion of the CPAD database with contemporary datasets containing patient‐level data from both control and active arms of clinical trials in AD. By aggregating such datasets into our rich clinical trial repository, CPAD will fill existing gaps in our models and generate of quantitative solutions for drug development in AD, in collaboration with the Quantitative Medicine team. Key focus of CPAD in 2020 includes completion of the pre‐dementia model (which has received a Letter of Support from the EMA) and generation of the comprehensive disease progression model. This effort will be based on an evolving workflow initiating with dataset exploration at the level of meta‐data and patient level data and determination of model specifications, resulting in model validation, simulations and regulatory submissions.

Conclusion

Pre‐competitive sharing of contemporary clinical trial data will allow us to develop a comprehensive understanding of the disease continuum in AD, enable a fully informed trial design and advance effective drug development in AD.
The role of intermittent fasting in brain health
Authors: Francis Nikita
Published: December 2020

Background

Despite the continuous efforts to combat dementias, researchers still have not found a pharmaceutical intervention that reliably reverses degeneration or improves cognitive functions. Therefore, lifestyle factors that could potentially aid in healthy brain aging and prevent or delay neurodegenerative diseases are of considerable interest. In particular, the ancient practice of fasting has been the subject of study for potential beneficial effects on longevity, obesity and diabetes, cancers, heart diseases as well as for neurodegenerative diseases. This review examines the health benefits of intermittent fasting (IF) in regard to brain health.

Method

A search employing relevant search terms was conducted in PubMed and Google scholar to produce a comprehensive accounting of the pertinent literature.

Result

The current review specifically focused on the role of IF in neuroinflammation, insulin resistance and autophagy, as they apply to brain health. Studies showed positive effects of IF in reducing neuroinflammation, decreasing insulin resistance and increasing autophagy. Much of the research on the above‐mentioned benefits utilized an alternate day fasting regimen. The current literature indicates that these benefits are more associated with the metabolic switch that occurs during the fasting state than restriction of calories alone. As glucose levels deplete during a fast, insulin levels stay low and ketone bodies are released for cellular fuel. The release of ketone bodies is associated with activating anti‐inflammatory mechanisms as well as activating cellular pathways that induce autophagy.

Conclusion

IF appears to be promising for its potential to protect the brain from the effects of aging and disease. Nevertheless, the mechanisms for these benefits are poorly understood. Additionally, the potential benefits of IF combined with other positive lifestyle factors such as exercise should also be further investigated. Moreover, the effects of long‐term IF and the differences in different IF regiments need to be assessed in animal models as well as clinically.
Astrocyte changes in MRI‐guided immunohistochemistry of white matter hyperintensities in advanced aging
Authors: Roese Natalie E. , Woltjer Randy , Lahna David , Schwartz Daniel L. , Krajbich Victoria , Boespflug Erin L. , Silbert Lisa C.
Published: December 2020

Background

Magnetic Resonance Imaging (MRI) white matter hyperintensities (WMH), a hallmark of subcortical cerebrovascular disease (CVD), are commonly associated with cognitive impairment in older individuals. Glial abnormalities have been reported in subjects with high WMH burden, suggesting a role of astrocyte changes in vascular cognitive impairment. This study aims to use post‐mortem (PM) 7T MRI to specifically target WMH lesions for histopathologic evaluation of markers of astrocytic dysfunction.

Method

Brain tissue from six older Oregon Alzheimer’s Disease Center subjects were included (Table 1). Left brain hemispheres were formalin fixed, sliced into 6mm coronal sections, and scanned using 7 Tesla MRI. Five cassettes (Table 2) were targeted for immunohistochemistry (IHC) from the sliced MR images (Figure 1) and stained with hematoxylin & eosin‐luxol fast blue (HELFB), aquaporin‐1 (AQP1), glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule‐1 (IBA1), and vimentin. Slides were scanned and registered to the corresponding MRI slice. 25 2x2 mm WMH and normal appearing white matter (NAWM) regions of interest were selected on MRI and cropped from corresponding IHC images (Figure 3). Resulting images were assessed semi‐quantitatively by a neuropathologist using a 0‐3 point scale, and quantitatively using mean pixel saturation or thresholded area coverage. Blue pixels were segmented from LFB images and area coverage was quantified. Semi‐quantitative ratings were analyzed using a Wilcoxon signed‐rank test. Quantitative data was analyzed using a pairwise T‐test. Bonferroni correction was conducted within assessment.

Result

LFB area coverage was lower in WMH compared to NAWM (p=0.0003), confirming demyelination as a feature of the WMHs identified. Quantitative assessment of mean pixel saturation values showed decreased AQP1 (p=0.0075) and increased vimentin (p=0.0008) in WMH compared to NAWM. In semi‐quantitative assessments, WMH displayed increased myelin pallor, increased vimentin expression, and decreased GFAP expression (p=0.0038, 0.0004, 0.0452).

Conclusion

PM MRI‐targeted IHC sectioning allows for the comparison of WMH and adjacent NAWM to investigate the nature of astrocyte changes in WM disease and may relate these to myelin and oligodendroglial alterations in age‐associated CVD.
The presence of Alzheimer’s disease pathology in dementia with Lewy bodies is related to increased neocortical α‐synuclein load and different α‐synuclein morphology
Authors: Geut Hanneke , van den Berg Emma , Bank Netherlands Brain , Rozemuller Annemieke J.M. , Lemstra Afina W. , van de Berg Wilma
Published: December 2020

Background

The presence of Alzheimer’s disease (AD) type pathology in dementia with Lewy bodies (DLB) has been linked to a more rapid disease progression. We aimed to examine the relation between load of AD‐type pathology and load and morphology of α‐synuclein pathology in DLB brains.

Method

We included 50 donors from the Netherlands Brain Bank fulfilling clinical criteria for ‘probable DLB’ and limbic or neocortical Lewy body disease. Levels of AD‐type pathology according to NIA‐AA guidelines were either absent to low (pure DLB, n = 15), or intermediate to high (mixed DLB/AD, n = 35). We visually rated α‐synuclein‐positive and amyloid‐β‐positive morphologies, and we quantitatively measured amyloid‐β, hyperphosphorylated tau (HPF‐tau) and α‐synuclein load in fifteen brain regions. Regional amyloid‐β and HPF‐tau levels in DLB donors were compared to eight AD donors without α‐synuclein pathology (pure AD).

Result

Mixed DLB/AD compared to pure DLB donors showed a shorter disease duration (6 ± 3 vs. 8 ± 3 years, p = 0.021), more diffuse intraneuronal α‐synuclein positivity (p = 0.002) but not more glial α‐synuclein positivity, and a higher overall α‐synuclein load (F = 25.7, p < 0.001), specifically in the parietal (p = 0.006), temporal (p = 0.002) and occipital cortex (p = 0.006). Mixed DLB/AD was related to more capillary cerebral amyloid angiopathy (CAA) (49% vs. 7%, p < 0.001). Within cortical regions, α‐synuclein load was most strongly related to amyloid‐β and HPF‐tau load in the temporal (Pearson’s r = 0.38 and 0.50 respectively) and occipital cortex (r = 0.43 and 0.42 respectively). While controlling for age at death, mixed DLB/AD compared to pure AD showed lower HPF‐tau load in frontal (p = 0.043) and parietal cortices (p = 0.002), but not in temporal cortex (p = 0.48), and no differences in amyloid‐β load in the frontal (p = 0.57), parietal (p = 0.56) and temporal cortex (p = 0.10).

Conclusion

The presence of AD‐type pathology in DLB was related to more diffuse intraneuronal α‐synuclein positivity, a higher neocortical α‐synuclein load and more capillary CAA. This study provides evidence for different neuropathological profiles in DLB, which may contribute to clinical heterogeneity in this disease.
Binding affinity of Hsp90 for tau protein plays a key role in tau protein degradation
Authors: Calzada Jesus Ismael , Tapia Jose Isabel
Published: December 2020

Background

Deposits of hyperphosphorylated Tau Protein is the main feature of Alzheimer disease and these are closely related with cognitive impairment, aggregates can cause neuronal death. Into cells there are mechanisms responsible for maintaining a balance among synthesis and degradation of proteins, named proteostasis mechanisms, one of them is mediated maily by Hsp90. Due to the presence of intracellular protein deposits in Alzheimer disease it is clear that some of the proteostasis fail or is not too efficient.

Method

SH‐SY5Y cells were transfected independently with two distinct plasmids containing two different forms of tau protein, one which contains a tau with 14 aminoacid changed for alanine in order to prevent phosphorylation and the other containing the same aminoacid changed for glutamate to mimic phosphorylation, Tau protein expression was analyzed by western blot at different times.

The same genes that codified for Tau proteins that were expressed in cell line, were cloned into an expression vector to be expressed in bacteria as recombinant proteins, then protein expression was carried out in E.coli BL21DE3 induced by IPTG, bacterial cells were lysed and recombinant proteins were purified by nickel columns and then quantified. Afterwards overlay assays were developed, various concentrations of the two different types of purified Tau proteins were spotted onto a nitrocellulose membrane. This membrane was incubated with cellular extracts of SHSH‐5Y containing native form of Hsp90. Subsequently, membrane was washed and the protein still bound was detected by inmmunobloting with an antibody recognizing Hsp90. Additionally, Dynamic light scattering light was performed to evaluate if recombinant proteins could produce fibrillation.

Result

We found that diminishing of Tau expression which has glutamates was less than Tau expression containing alanine, at the time of 48h. Overlay assay showed that cellular Hsp90 presented lower binding affinity for recombinant Tau with glutamates. Finally, in Dynamic Light Scattering assay Tau with glutamates presents higher fibrillation than Tau with alanine.

Conclusion

These results suggest that binding affinity of Hsp90 for Tau regulates its degradation, this could be the main reason of its accumulation and agreggation into cell. Moreover, phosphorylation in specific sites is closely related with its fibrillation.
Determinants of caregiver burden in early onset dementia
Authors: Chiari Annalisa , Pistoresi Barbara , Galli Chiara , Tondelli Manuela , Vinceti Giulia , Addabbo Tindara , Zamboni Giovanna
Published: December 2020

Background

Caregivers of patients with early onset dementia (EOD) experience high levels of burden, which is known to be affected by financial and social variables, as well as by psychological features of the caregiver and patient’s symptoms. However, it is not known how all these factors reciprocally interact in determining the burden of caregivers of EOD patients. We investigated multiple determinants of burden in a comprehensive model.

Method

Consecutive eligible patients with EOD and their caregivers were recruited from the Cognitive Neurology Clinic of the Modena University Hospital, Italy. Patients underwent extended clinical, imaging and neuropsychological assessment. Caregivers were interviewed and asked to fill in questionnaires to gain information on patients’ symptoms, caregiver burden (Zarit Burden Interview), caregiver psychological distress (Relative Stress Scale). Patient/caregiver demographics, social and clinical variables were entered in linear multiple regression models and mediation models to explore if the effect on burden is mediated by stress.

Result

Data from 89 EOD patient‐caregiver dyads were examined. Caregiver burden was positively related to female caregiver sex (b=0.44,p=0.0002), severity of patient’s behavioral symptoms (b=0.32,p=0.0004), diagnostic delay (b=0.18,p=0.017) and financial distress of the family (b=0.28, p=0.0008). Significant factors reducing the burden were caregiver perception of patient’s quality of life (b=‐0.20, p=0.005), disease duration (b=‐0.27,p=0.0003), caregiver age (b=‐0.31,p=0.0017), offspring number (b=‐0.25,p=0.0004), patient’s education (b=‐0.15,p=0.022), region of birth (b=‐0.17,p=0.025) and number of days off work (b=‐0.15, p<0.0001) (adjusted‐R2=0.64). While the effect of financial distress, number of caregiver’s days off‐work, patient’s disease duration, and caregiver sex was entirely mediated by the level of caregiver stress, the effect of diagnostic delay and of proxies of family or social network on burden was direct.

Conclusion

Most of the effect of the known determinants of the burden of caregivers is mediated by caregivers’ level of stress, in particular for female caregivers. In particular, the number of days off‐work that the caregiver can take is a variable on which action can be taken to reduce the caregivers’ stress, hence their burden. However, as some determinants are independent from stress, direct actions should be aimed at increasing social networks and shortening diagnostic delay to reduce caregiver burden.
Category‐selective semantic deficit for living things in semantic variant primary progressive aphasia
Authors: Henderson Shalom Kim , Cordella Claire , Dev Sheena Isha , Quimby Megan , Wong Bonnie , Ezzo Rania , Collins Jessica A , Dickerson Brad C
Published: December 2020

Background

Studies of patients with impaired semantic memory have identified cases with a category‐selective semantic deficit (CSSD) for living things—a disproportionate semantic memory loss for animate versus inanimate items. Data are mixed on whether patients with semantic variant primary progressive aphasia (svPPA) exhibit a CSSD, in part because measurement can be confounded by psycholinguistic variables. Furthermore, there exists little consensus regarding the neural substrates of CSSD.Here we examine (1) the effect of animacy on single word comprehension performance in svPPA after accounting for familiarity, frequency, and age of acquisition, and (2) the relationship between cortical atrophy and disproportionate impairment in identifying animate vs. inanimate items.

Methods

21 individuals with svPPA completed the Cambridge Semantic Battery‐Word Picture Matching (CSB‐WPM) task, which includes 32 animate and 32 inanimate items. Using a multiple regression model, we assessed the effects on CSB‐WBM accuracy of familiarity, frequency, age of acquisition, and animacy (i.e., animate, inanimate). Cohen’s d was used to measure effect size. We then estimated CSSD per individual (% inanimate correct ‐ % animate correct). For each ROI, we ran a linear regression assessing the relationship between cortical thickness and CSSD, covarying for overall semantic impairment.

Results

The main effect of animacy remained significant (t = 4.6, p < .001) even after including all psycholinguistic variables in the model [F(4,56) = 13.8, p < .001] (Cohen’s d=1.1). After controlling for overall semantic impairment, greater cortical atrophy was associated with greater CSSD in the right posterior superior temporal gyrus (STG) (β = ‐.41, t = ‐2.38, p = .031). Relationships between CSSD and the right entorhinal/perirhinal cortex (β = ‐.39, t = ‐1.88, p = .081) and right posterior fusiform gyrus (β = ‐.39, t = ‐2.08, p = .056) also trended in this direction.

Conclusions

Results provide support for an animacy CSSD in svPPA, with individuals showing greater deficits for animate compared with inanimate items even after controlling for familiarity, frequency, and age of acquisition. The right temporal lobe, especially the posterior STG, entorhinal/perirhinal cortex, and the posterior fusiform gyrus, may also play a critical role in the representation of animate items.
Characterizing the cognitive phenotype of Parkinson’s disease
Authors: Tipton Philip W. , Bulbul Nazli G. , Crook Julia E. , Uitti Ryan J. , Wszolek Zbigniew , Ertekin‐Taner Nilufer
Published: December 2020

Background

Parkinson’s disease (PD) is a complex neurodegenerative disease in which combinations of motor and non‐motor symptoms result in a wide range of phenotypic presentations and disease progression. Precise characterization of these clinical endophenotypes can guide clinical practice. Such endophenotypes can also be powerful to identify genetic factors for complex diseases, like PD. Given the prevalence and impact of cognitive impairment in PD, we aimed to characterize cognitive endophenotypes in a cohort of PD patients with longitudinal assessments.

Method

We reviewed the medical records of 1028 individuals diagnosed with PD by a movement disorders specialist at our institution. We extracted scores from all available Mini‐Mental Status Examinations (MMSE). We fit proportional odds models with patient specific random effects to estimate odds ratios for higher versus lower cognition in association with age, sex and follow‐up time.

Result

Among the 237 patients with at least one MMSE, 108 had ≥2 time points and 118 were cognitively impaired (MMSE<27). The mean age was 71 years, 63 (27%) were female and the mean follow‐up time was 2.56 years. Overall, females with PD had higher MMSE scores than males with an odds ratio at age 70 of 2.43 (95% CI: 1.29, 4.97). However, MMSE scores decline with age at a faster rate in females than males (p=0.002) with ORs for a 1 year of 0.85 (0.79, 0.91) and 0.94 (95%CI: 0.91, 0.97), respectively. Within patients, declines in MMSE per year had an OR of 0.76 (0.60, 0.97) for females and 0.85 (0.75, 0.95) for males though this difference was not statistically significant. Corresponding expected MMSE trajectories are shown in the figure.

Conclusion

Our findings demonstrate sex differences in the cognitive phenotypes of PD. In particular, cognitive scores tend to be higher in females compared to males, but decline faster in females. These findings have clinical implications regarding counseling of patients with PD. We are currently expanding this approach to specific cognitive domains, other validated tests of cognition, and investigating the influence of genetic risk factors, such as APOE on cognitive decline in PD.
Pilot study of MRI white matter tissue properties in Alzheimer’s, vascular and mixed dementias
Authors: Lee Hyunwoo , Wiggermann Vanessa , Rauscher Alexander , Beg Mirza Faisal , Popuri Karteek , Tam Roger , Lam Kevin , Jacova Claudia , Sossi Vesna , Pettersen Jacqueline , Benavente Oscar R. , Hsiung Ging‐Yuek Robin
Published: December 2020

Background

Alzheimer’s disease (AD) with cerebrovascular disease is known as ‘mixed’ dementia (MixD).[Wang_2012][Langa_2004] MixD can have heterogeneous clinical/imaging presentations. This makes it difficult to distinguish MixD from AD or vascular dementia (VaD) using structural markers such as atrophy or white matter hyperintensity (WMH) volumes. [Suri_2014] We explored whether WM tissue properties on MRI, represented by R2* and diffusion‐tensor (DTI) images, could distinguish MixD from AD or VaD.

Method

N=17 participants (cross‐sectional; 7 MixD/5 Subcortical VaD/5 AD; Sex: 11M/6F; Age: 75±8yrs) were scanned on a 3T Philips Achieva. WMHs were segmented on 3D‐Fluid Attenuated Inversion Recovery images. T1‐weighted MP‐RAGE images were segmented into the grey/white‐matters using SPM12. These outputs were combined to construct WMH and normal‐appearing WM (NAWM) masks. DTI images were processed using FSL. R2* images were computed using in‐house software. For each participant, the average R2*, fractional anisotropy (FA) and mean diffusivity (MDf) values were calculated within the WMH and NAWM masks.

Result

Average WMH volumes were (mean±SD) AD: 5191±4693mm3, MD: 34680±17059mm3 (p<.05 compared to AD), SVaD: 20896±14920mm3 (p>.05 compared to MixD or AD). A linear model was used to predict the measured R2*, FA or MDf values from the diagnosis subtypes, adjusting for age and sex. R2* results: Pairwise t‐tests revealed significantly lower R2* values within the WMHs compared to NAWM (all subtypes p<0.0005). MixD had significantly lower WMH R2* values compared to AD (p=0.01) or VaD (p=0.02) subgroups. DTI results: Pairwise t‐tests revealed significantly higher MDf values within the WMHs compared to NAWM (all subtypes p<0.009). FA values were significantly lower within the WMHs compared to NAWM for the MixD (p=0.0002) and VaD (p=0.03) but not the AD (p=0.09) subtype.

Conclusion

Our MixD cohort was characterized by potentially disrupted fiber integrity (represented by decreased FA) and increased water content (represented by lower R2*) within the WMH areas. These abnormalities likely represent etiologies caused by both neurodegenerative and cerebrovascular factors. Future studies that incorporate measures of neurodegeneration or neuroinflammation, such as biofluid markers, may help to further characterize WM tissue abnormalities in MixD compared to those found in ‘pure’ AD or VaD.
Deletion of neuronal BACE1 causes mice memory deficits
Authors: Hu Xiangyou , Darboe Mabintou , Yan Riqiang
Published: December 2020

Background

The β‐site APP cleaving enzyme 1 (BACE1) was initially identified as a transmembrane aspartyl protease cleaving amyloid precursor protein.

Methods

Behavioral test (open field, water maze, Y‐maze and fear conditioning test), western blotting and LTP.

Results

We crossed Thy1‐cre line with BACE1 conditional knockout (BACE1fl/fl) mice to obtain Thy1‐cre;BACE1fl/fl mice to delete BACE1 in neurons. These mice at 8 months were conducted behavioral tests which includes open field, Y maze, water maze, and fear conditioning. In the open field, we found that the total moving distance were similar between Thy1‐cre;BACE1fl/fl and BACE1fl/fl controls. However, the Thy1‐cre;BACE1fl/fl
mice spent more time in the corner area and less time in the center area. In the Y maze test, we found that the spontaneous alteration was significantly reduced in Thy1‐cre;BACE1fl/fl
mice, suggesting deleting neuronal BACE1 affects mice spatial working memory. In water maze test, we found that Thy1‐cre;BACE1fl/fl
mice spent more time to reach the platform compared to the age‐matched controls, which indicates that deleting neuronal BACE1 also causes mice reference memory deficit. This phenomenon was only observed in the male Thy1‐cre;BACE1fl/fl
mice. In fear conditioning test, the freeze time (%) was significantly reduced in day 2 for contextual memory test and day 3 for cue memory test in male Thy1‐cre;BACE1fl/fl
mice, but not in the females. To explore what reason causing gender difference in the cognition deficit in both water maze and fear conditioning tests, we did western bolt and found that BACE1 level was significantly reduced in the hippocampus and the cerebral cortex in Thy1‐cre;BACE1fl/fl
mice, and the BACE1 level was ever lower in the males than in the females. We also conducted LTP recording on Thy1‐cre;BACE1fl/fl
hippocampal slices, and found that the amplitudes of field excitatory postsynaptic potentials (fEPSPs) were significantly reduced in Thy1‐cre;BACE1fl/fl
mice compared to age‐matched BACE1fl/fl
mice.

Conclusion

These data reveal that only deletion of BACE1 in neurons affects mice learning and memory.
Glucose metabolism mainly reflects local atrophy and tau pathology at symptomatic stages of Alzheimer’s disease
Authors: Strom Amelia , Iaccarino Leonardo , Edwards Lauren , Lesman‐Segev Orit H. , Soleimani‐Meigooni David N. , Jagust William J. , Miller Bruce L. , Rabinovici Gil D. , Joie Renaud La
Published: December 2020

Background

We assessed the relative contributions of four potential mechanisms associated with [18F]‐Fluorodeoxyglucose (FDG)‐PET hypometabolism in the posterior cingulate cortex (PCC) and inferior parietal (IP) lobe, two primary regions of hypometabolism in AD: 1) local (amyloid and tau) pathology and atrophy, 2) pathology in functionally connected regions, 3) deafferentation from the degenerating medial temporal lobe (MTL), and 4) vascular injury in the white matter (Figure 1).

Method

Eighty‐five patients with MCI or AD dementia underwent MRI and PET with FDG for glucose metabolism, [11C]‐Pittsburgh Compound B (PIB) for amyloid, and [18F]‐Flortaucipir (FTP) for tau within one year (Table 1). SUVR were calculated using tracer‐specific reference regions: pons for FDG, cerebellar cortex for PIB, and inferior cerebellar cortex for FTP. ROIs and volume of white matter hyperintensities (WMH) were defined in native space using FreeSurfer. Regions with high or low connectivity to PCC/IP were defined based on task‐free fMRI data from cognitively normal participants from neurosynth.org (Figure 2). Imaging variables were transformed into age‐adjusted z‐scores using demographic‐matched modality‐specific control groups (Table 1). Multiple regression analyses were run to identify variables associated with FDG‐SUVR, using a composite disease severity score combining Mini‐Mental State Examination and Clinical Dementia Rating scores as a covariate.

Result

Local gray matter volume (GMV) and FTP‐SUVR, but not PIB‐SUVR, were independently associated with FDG‐SUVR in PCC (R2=.603, βGMV=0.353, βFTP=‐0.374) and IP (R2=.702, βGMV=0.419, βFTP=‐0.361) in a model that included disease severity (Table 2). Models including PIB/FTP in connected regions did not outperform models with disease severity and local GMV/FTP alone. Results were similar when including measures of pathology in non‐connected regions. Similarly, models including MTL volume did not outperform models with disease severity and local GMV/FTP alone. Volume of WMH was weakly associated with FDG‐SUVR in PCC but not IP.

Conclusion

Hypometabolism reflected local atrophy and tau pathology. A weak association between WMH volume and PCC hypometabolism was seen, suggesting that white matter damage may also be a driver of hypometabolism. Our data did not support hypotheses of a detrimental effect of pathology in connected regions or MTL volume in the symptomatic stage of AD.
Alzheimer's disease GWAS weighted by multi‐omics and endophenotypes identifies novel risk loci
Authors: Ma Yiyi , Vardarajan Badri N. ,   CHARGE ADSP FUS, Bennett David A. , Fornage Myriam , Seshadri Sudha , Destefano Anita L. , De Jager Philip L.
Published: December 2020

Background

We have increasing information on the role of certain genetic variants in a wide variety of molecular traits and endophenotypes of Alzheimer’s disease (AD), but their impacts on the prioritization of AD risk gene are unknown.

Method

Based on the summary statistics of the genome‐wide association study (GWAS) of AD published by the International Genomics of Alzheimer’s Project (IGAP) consortium (Kunkle et al., 2019), we have weighted each SNP by their associations with traits of eQTL (RNA expression), mQTL (DNA methylation), haQTL (histone acetylation), brain phosphorylated tangles (TAU), β‐amyloid protein (Aβ), and cognitive decline derived from the ROS‐MAP samples of postmortem dorsal‐lateral prefrontal cortex of AMP‐AD. Then, we collapsed all of the weighted SNPs found in each gene using the SKATO test, based on the 1000 reference genome.

Result

38∼43% of genes (n = 12,899) have an increase in their statistical significance level after incorporating the weights of their genetic effects on omic molecular traits and AD endophenotypes. A subset of these gene‐level assessments reach the trait‐specific Bonferroni corrected genome‐wide significance threshold (P < 0.05/number of genes for each trait). The burden of TAU pathology has the strongest effect with RASGRF2, FCF1, ZCWPW1, C6orf10, VAC14, ADGRF2, ACP2, DDB2, and CR1L being prioritized. Similarly, we have results prioritized by weighting by (1) Amyloid β: FCF1, NRXN1, PLCB1, and DLG2; (2) cognitive decline: AKAP13, CR1L, KIAA1671, and CR2; and (3) eQTL: TRIT1, RAPSN, and C6orf10. The latter also emerges from the haQTL analysis, and no results emerge from the mQTL analysis.

Conclusion

Weighting by omic molecular traits and endophenotypes leading to AD is able to prioritize additional genes that could contribute to AD susceptibility. Functional validation is ongoing.
Investigating the role of blood metabolites as biomarkers of cognitive function and dementia in the MRC 1946 British Birth Cohort
Authors: Green Rebecca
Published: December 2020

Background

Decline in cognitive function in late midlife is indicative of dementia. Identifying early markers in this key phase is critical for identifying those at risk and guiding effective interventional strategies. As blood metabolites closely reflect the physiological status of an individual, they show promise as minimally invasive markers for population‐level implementation. Using the MRC 1946 British Birth Cohort, we aim to: 1) Identify blood metabolites associated with early cognitive changes relevant to dementia 2) Tease apart mediating life course factors to address key aetiological questions 3) Employ a network approach, weighted coexpression network analysis (WGCNA), to glean insights into underlying biology.

Method

At age 60‐64, levels of 1019 metabolites were quantified using liquid chromatography‐mass spectrometry (N=1740). At the same age and 5‐9 years later, four aspects of cognitive function were assessed: short‐term and delayed verbal memory, processing speed, and the Addenbrook’s Cognitive Examination‐IIII (ACE‐III). Using WGCNA, 14 modules of highly connected metabolites were identified. Linear regression models evaluated associations between metabolites/metabolite modules and cognitive outcomes, sequentially adjusting for sex, childhood cognitive ability, education, socioeconomic status (SES), lipid medication and lifestyle factors. To infer biological function, pathway analyses were conducted to identify enriched pathways within metabolite modules

Result

After correcting for multiple testing, 154 metabolites were associated with cognitive outcomes. Many associations attenuated after adjusting for early life cognition and SES, with seven metabolites belonging to lipid, amino acid and xenobiotic families remaining. WGCNA revealed two modules, enriched in vitamin A and sphingolipid metabolism, to be positively associated with cognitive outcomes. However, after adjusting for education and childhood cognition, these associations were largely reduced. Two modules, enriched in amino acid and fatty acid metabolism, were negatively associated with cognitive outcomes, with associations of the fatty acid metabolism module remaining after adjusting for life course factors.

Conclusion

These results provide support for a role for metabolites in reflecting early changes relevant to dementia, revealing insights into underlying biological mechanisms and lifelong interplay. It is hoped that these insights can be utilised to inform early diagnosis and the development of disease‐modifying treatments and interventions.