bluuebunny/crossref_metadata_2025 huggingface dataset:
Well‐being indicators in community‐dwelling elders with dementia
Authors: Alvarez Loreli , Acosta‐Castillo Gilberto Isaac , Sosa‐Ortiz Ana Luisa
Published: December 2020

Background

Due to the high impact of dementia it is a priority to focus on the well‐being of those with this condition, enabling participation, inclusion and better functioning of people with this disease. In the research context it’s increasing the interest on documenting the needs reported by those living with dementia. The aim of this study was to describe well‐being indicators in people living with dementia to construct a composite measure of needs for this group.

Method

We analyze data from the cohort of the 10/66 Dementia Research Group in Mexico.

Results

Our sample consisted in 180 community‐dwelling elders with dementia. There were more women than men, with an average age of 80.8 (7.1) years, 52% had no formal education and 48.3% lived in rural areas. We selected 14 indicators of three dimensions of well‐being (physical health, psychological health and social resources) previously reported in literature. To build a composite measure of well‐being, scores of 0‐2 were assigned to each of the variables studied according to the benefit they represented for the elderly. Our composite measure has a total score of 22 with low scores indicating poor well‐being. We selected the 25th and 75th percentiles to classify subjects in three groups of well‐being (low, moderate, high). Those with higher showed less problems in eyesight, hearing and appetite problems; experience pain less frequently and had fewer comorbidities than the other two groups (low or moderate well‐being); highest well‐being group had less neuropsychiatric symptoms(NPS) and higher global cognitive scores; they attend more frequently to religious services, social activities and need no care according to their informant. The distributions of sleep problems, living alone, contact with relatives and disability showed no difference between the groups (Table1).

Conclusion

Our results show that people with higher well‐being have better physical and psychological health and more social resources compared with those classified with moderate and low well‐being. With our composite measure we can identify needs and possible areas to improve living well in community dwelling dementia patients.
Quantification of small vessel disease in frontal and parietal white matter, genu and splenium
Authors: McAleese Kirsty E. , Dugger Brittany N. , Mifflin Kelsey , Attems Johannes , Jin Lee‐Way , DeCarli Charles
Published: December 2020

Background

Cerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries (lipohyalinosis) and arterioles (arteriolosclerosis) of the white matter (WM) resulting in ischemic WM damage. SVD is commonly assessed using a broad semi‐quantitative (SQ) criterion. We implemented sclerotic index (SI) assessment to quantitatively assess vessel wall thickness in small arteries and arterioles separately in four regions known to exhibit WM changes.

Method

The cohort consisted of 75 cases from the University of California Davis Alzheimer’s Disease Centre Biorepository, neuropathological diagnosed as controls (n=18), intermediate Alzheimer’s disease neuropathologic change (n=13), definite Alzheimer’s disease (n=33), or cerebrovascular disease (n=11). H&E sections that included frontal and parietal WM, genu, or splenium were SQ assessed for SVD and images of small arteries (150‐800μm diameter) and arterioles (40‐150μm diameter) were captured. SI assessment was performed, and mean SI scores were calculated for arteries, arterioles, and an overall total.

Result

Age was not associated with any SQ or SI measure in any region (p>0.106). SI and SQ scores of both arteries and arterioles were highly correlated in all regions (rho >0.551, p<0.0001) validating the SI method. Arteriole‐SI was significantly higher than artery‐SI in both WM regions (p<0.0001) and this was consistent cross controls and disease groups (all p<0.03). Regarding the whole cohort, frontal and parietal WM total‐SI was significantly higher than artery‐SI (P<0.0001) and significantly lower than arteriole‐SI (P<0.0001). Intragroup comparisons between frontal and parietal WM revealed no differences in artery‐ or arteriole‐SI scores (overall cohort p>0.76; subgroups p>0.112), and comparisons between genu and splenium also revealed no difference in arteriole‐SI (overall cohort p>0.41; subgroups p>0.34).

Conclusion

SVD‐associated vessel fibrosis is uniform between the anterior and posterior WM. Separate assessment of arteries and arterioles should be considered given arteriolosclerosis results in more severe vessel occlusion and maybe clinically relevant to ischemic WM changes. A combined SVD assessment may lead to under‐ or overestimation of disease severity.
Transcriptional endophenotypes predicting genetic risk of dementia in Mexican Americans
Authors: Almeida Marcio A ,   South Texas Diabetes and Obesity Institute
Published: December 2020

Background

Dementias are heterogeneous age‐associated neurodegenerative disorders generally included in the broad term, Alzheimer’s disease and related dementias (ADRD). ADRD affects individuals of all ethnicities, but Hispanic individuals show a 1.5‐fold higher risk when compared to non‐Hispanic whites. ADRD is a complex phenotype where both genetic and environmental causal components play significant roles. The identification of early ADRD biomarkers is important and we propose to discover novel non‐invasive endophenotypes using high dimensional multiomic data in an existing Mexican American cohort. The 2000 Mexican American participants are members of large families from the GOBS (Genetics of Brain Structure and Function Study) project from which extensive phenotypic data is available.

Method

We applied a mean‐based endophenotype ranking value (ERV) method tailored for relatively rare diseases and extended pedigrees. A set of 70 GOBS subjects were diagnosed as ADRD cases. The estimated heritability is high (h2= 0.75, p = 2.6×10‐5) supporting a major role for genes influencing ADRD risk. The ADRD cases have 363 1st, 2nd, 3rd, and 4th degree relatives currently not suffering from dementia. To identify transcriptional endophenotypes that are genetically correlated with ADRD, we contrasted this group of relatives to 839 unaffected individuals without affected relatives. We constructed a genetic risk vector and tested its correlation to the expression level of each gene. (Figure 1).

Result

We tested the validity of our proposal by limiting ourselves to a set of 113 genes previously associated with ADRD. We observed a clear enrichment for significant effects over that expected under the null hypothesis (p=3.3×10‐10). Several cytokine genes (TNF, IL1B, and IL1A) exhibited reduced expression in relatives of cases versus controls (Table 1). Notably, the APBB1 gene showed increased expression in relatives of ADRD cases. This gene regulates the amyloid precursor protein playing a central role for ADRD development.

Conclusion

The observed statistical enrichment of previously ADRD associated genes serves as a positive control for our approach. The ERV method is especially powerful for rare diseases when large human families are available. Candidate genes identified will be extensively annotated to aid the detection of relevant early ADRD genes highly correlated with ADRD risk.
A comparison of cerebral small vessel disease severity between autopsy cohorts in the northeast of England and Sacramento County in California, USA
Authors: McAleese Kirsty E. , Dugger Brittany N. , Mifflin Kelsey , Jin Lee‐Way , Attems Johannes , DeCarli Charles
Published: December 2020

Background

Cerebral small vessel disease (SVD) encompasses progressive fibrosis/hyalinosis of the small arteries and arterioles of the white matter (WM) resulting in ischemic WM damage. Few studies have compared SVD between different cohorts. Using a sclerotic index (SI) measurement, we quantitatively assessed vessel wall fibrosis in the frontal and parietal WM of human brains donated to brain banks in the UK and the USA.

Method

64 cases from the University of California Davis (UCD) Alzheimer’s Disease Centre Biorepository and 55 cases from the Newcastle Brain and Tissue resource (NBTR) were included. Cases were neuropathological diagnosed as controls (UCD n=18; NBTR n=25), intermediate Alzheimer’s disease (AD) neuropathologic change (UCD n=13; NBTR n=4), and definite AD (UCD n=33; NBTR n = 26). In the UCD cohort, 49 identified racially as White, 9 as Black African American, 3 as Chinese and 1 as Indian Asian. All cases from the NBTR identified racially as White. Using H&E sections, images of approximately eight arteries/arterioles from the frontal and parietal WM were captured and SI assessment performed. Mean SI score was calculated per region, per cases.

Result

No intergroup differences in age were observed and age was not associated with SI score in either cohort. In the UCD cohort, race was not associated with neuropathological diagnosis (Chi‐sq = 8.39, p>0.211) and no differences were seen in SI scores between White and Black African Americans (p>0.69). Intergroup comparisons revealed that SI scores in both WM regions were significantly higher in the overall UCD cohort compared to the overall NBTR cohort (p>0.006) and this was consistent across controls (frontal p=0.0001; parietal p=0.045), intermediate AD neuropathological change (p=0.001), and AD (frontal p=0.001) cases.

Conclusion

SVD‐associated vessel occlusion is more severe in the USA cohort from Sacramento compared to the UK cohort from Newcastle. This may reflect differences in cardiovascular disease and lifestyle of individuals enrolled in the two brain donation programmes.
Elucidating the relationship between TGF‐β signaling and Alzheimer’s disease
Authors: Croft Cara L. , Liu Xuefei , Ryu Daniel H. , Ceballos‐Diaz Carolina , Tejeda Giancarlo , Marrero Marc , Moran Corey , Cruz Pedro E. , Ladd Thomas , Moore Brenda D. , Golde Todd E.
Published: December 2020

Background

The TGF‐β signaling pathway represents a complex family and network of ligands and receptors. A body of evidence suggests that in Alzheimer’s Disease this signaling network may be perturbed and could contribute to disease development and progression. Other studies have shown a role for TGF‐β signaling in both Aβ clearance and deposition, as well as, in neuroprotection and neurotoxicity. It remains to be determined precisely the contributions of TGF‐β signaling to mechanisms underlying Alzheimer’s disease and other dementias and whether targeting TGF‐β may lead to suitable novel therapies.

Methods

To interrogate the contributions of TGF‐β signaling to Aβ and tau pathology in AD we developed several recombinant adeno‐associated virus (rAAV) constructs to express TGF‐β family ligands and decoy receptors. APP overexpressing (TgCRND8) mice were injected with rAAVs at postnatal day 0 or after 3 months of aging to examine contributions of the TGF‐β family prior to and during Aβ deposition. We also examined how TGF‐β family ligands and decoy receptors affect the development of tau pathology in tau brain slice culture (BSC) models.

Results

We have successfully expressed TGF‐β family ligands and decoy receptors to determine their contributions to Aβ clearance and deposition in vivo in APP overexpressing mice, as well as, effects on tau pathology in ex vivo tau BSC models. Stimulating and blocking TGF‐β signaling cascades appears to have opposing effects on AD‐relevant pathology. Using this rAAV approach we can rapidly dissect how complex signaling cascades may contribute to the progression and development of human AD and how targeting these pathways may be therapeutically rewarding.

Conclusions

These findings suggest that interventions targeting TGF‐β signaling may be a novel therapeutic approach to AD. This data also enforces that pathways involved in immune function can have significant effects on the healthy and diseased brain and should be explored further in order to understand the development and progression of AD. Using a systems approach (NIH U01AG046139) we identified perturbed networks regulating innate immunity in the AD brain and have now validated how intervening with TGF‐β signaling may provide therapeutic benefit.
Electroencephalography (EEG) reveals a decrease in speed of animacy processing in mild cognitive impairment and an alteration in neural response patterns
Authors: Karimi Hamed , Marefat Haniye , Khanbagi Mahdiyeh , Kalafatis Chris , Vahabi Zahra , Razavi Seyed‐Mahdi Khaligh
Published: December 2020

Background

Electroencephalography (EEG) has been commonly used to measure the brain alterations in the early stages of Alzheimer's Disease. However, the reported measures are limited to the univariate changes, including activation level and frequency bands. To look beyond the activation level, we used a task‐based EEG and applied multivariate pattern analysis (MVPA) to study the changes in the pattern of information processing.

Method

We recruited 18 participants with mild cognitive impairment (MCI), and 22 age‐matched healthy controls (HC). We acquired EEG data from all participants, while they were doing the integrative cognitive assessment (ICA) test (Khaligh‐Razavi et al., 2019). ICA is a rapid visual categorization task, in which participants are presented with a sequence of natural images of animals and non‐animals, and are asked to respond as quickly and accurately, whether images contained an animal. To analyze the EEG data, we took advantage of MVPA techniques to measure how accurately EEG signals can discriminate between brain representations of animals and non‐animals.

Result

Univariate analysis showed a significant decline in the activation level of the right temporal lobe in MCI compared to HC. In the left parietal lobe, we found that the pattern of EEG responses to the presented visual stimuli was significantly different between HC and MCI, in the absence of any difference in their level of activation. Furthermore, we found that animacy information (animal vs. non‐animal categorization) emerges later in the brain of patients with MCI (t = 67 ms ± 33 SE of mean; p‐value ≤ 0.03) compared to HC.

Conclusion

We demonstrated that in addition to the level of activation (i.e., mean ERP response), the pattern of EEG responses to visual stimuli also carries information about the status of the disease. In particular, we see that in some of the brain areas where the mean activation shows no difference between HC and MCI, patterns of EEG responses are significantly different and can be used to discriminate MCI from HC. Furthermore, the results also suggest a delay or impairment in the speed of processing animacy information in MCI patients.
11C‐PBR28 brain PET imaging with lipopolysaccharide challenge for the study of microglia function in Alzheimer’s disease
Authors: Salardini Arash , Hillmer Ansel T , Mecca Adam P , Hashemi‐Aghdam Arsalan , Laltoo Emily , Savoia Sarah , O'Dell Ryan S , Harris Joanna E , Godek Tyler A. , Nabulsi Nabeel B , Lim Keunpoong , Ropchan Jim R , Huang Yiyun , Cosgrove Kelly , Carson Richard E , Strittmatter Stephen M , van Dyck Christopher H
Published: December 2020

Background

The study of neuroimmune function in Alzheimer’s disease (AD) has been challenging, partly because the underlying mechanisms are still incompletely understood. Here we present the results of a novel imaging study in human subjects to assess microglial activity in cognitively normal (CN) participants compared to participants with mild cognitive impairment (MCI) or mild dementia (MD) due to AD.

Method

This pilot study used positron emission tomography (PET) imaging with the radioligand 11C‐PBR28, which is specific for the 18 kDa‐translocator protein (TSPO), a marker sensitive to acute immune effects of lipopolysaccharide (LPS). The 11C‐PBR28 volume of distribution (VT) was measured from two scans, one at baseline and a second at 180 minutes after intravascular administration of lipopolysaccharide (LPS‐ 0.4 ng/Kg). We calculated microglia activation reserve index (MARI) as the proportional increase in binding of 11C‐PBR28, 180 minutes after the administration of the LPS: MARI = [(VT,LPS‐VT,Baseline)/ VT,Baseline] x 100.

Results

CN participants had a significantly higher global cerebral MARI of 35% (SD 13%, n=5) compared to the AD group (MARI=15%, SD 15%, n=5, p=0.030). We found no significant differences between global 11C‐PBR‐28 VT at baseline in CN participants compared to the AD group. MARI values correlated with clinical dementia rating (CDR) ‐ sum of boxes (CDR‐SB) score (R2=0.55, p=0.013), but not with MOCA scores. Conversely baseline 11C‐PBR‐28 VT correlated with MOCA scores (R2=0.44, p=0.025) but not CDR‐SB. TSPO gene polymorphism (high vs. medium affinity binding) did not make a difference in the response pattern. Measurements of serum cytokines indicated that the response differences between the two groups were central and not related to the peripheral immune response.

Conclusion

Our experiment presents preliminary human data on reduced brain microglial activity in AD.. Our novel method provides a unique opportunity to test the dynamic response of microglia in vivo. However, further investigations with larger sample sizes are required for better understanding of the role of microglia in AD.
For the sake of informed participation: Development of two audio‐visual aids for informed consent to a dementia prevalence study through participatory action research
Authors: Fadda Marta , Fiordelli Maddalena , Ibnidris Aliaa , Albanese Emiliano
Published: December 2020

Background

The limits of traditional informed consent are well known. Its goal should be to support individual autonomy and provide assurance that potential research participants are neither deceived nor coerced. For these reasons, they should be designed to give potential research participants control over the amount of information they receive and the opportunity to rescind consent already given. However, most informed consent forms are excessively long and use a technical jargon that is hard to understand for lay people. As part of an epidemiological study on dementia and its impact, we set out to develop two visual aids for informed consent (a video and a printed infographic) through participatory action research.

Method

We conducted four focus groups with people aged 65 or older and resident in the Italian‐speaking Canton of Switzerland (N=30). Participants were shown a preliminary version of the visual aids and were asked to provide feedback on information quality and appeal (speed, duration, color, font etc.). Focus groups were tape‐recorded, transcribed and analyzed to inform refinement of the visual aids before each subsequent focus group.

Result

The two visual aids complied with good clinical practice (GCP) guidelines of informed consent. We adapted the videos to the participants’ demand for lower speed and longer duration. We re‐arranged information according to a question‐and‐answer format displayed within the same graphical sequence. Information deemed too complex by participants was simplified using an advanced readability assessment tool (READ–IT), which combines traditional raw text features with lexical, morpho‐syntactic and syntactic information.

Conclusion

Participatory action research is crucial for the development of tailored tools to support informed consent in epidemiological research. Further research is warranted to test if compared to traditional informed consents, the use of audio‐visual aids developed with potential participants to epidemiological research promotes research participation, and in a better informed fashion.
Association of brain amyloid accumulation and glucose hypometabolism with cognition domain of language
Authors: Huang Qi , Ren Shuhua , Huang Lin , Li Junpeng , Jiang Donglang , Wang Ying , Guan Yihui , Guo Qihao , Xie Fang
Published: December 2020

Background

Amyloid is the main pathology for Alzheimer’s disease (AD), amyloid and glucose metabolism alternation are very important to investigate the progress of Alzheimer’s disease. However, not so many results were reported in Chinese population. In this study, we try to figure out the brain structure, function alternation and brain network alternation in Chinese subjective cognitive decline (SCD), mild cognition impairment (MCI) and Alzheimer’s disease (AD) from the data of Chinese preclinical Alzheimer’s disease (C‐PAS), which is initiated by us.

Method

200 participants were enrolled in this study, including 93 normal cognition (NC) healthy volunteers, 37 SCD, 34 MCI and 36 AD patients.6 types of neuropsychological tests from 3 cognitive domains and MMSE, Moca B were performed. FDG and amyloid PET (18F‐Flortabetapir) were conducted in these participants. 18F‐FDG and 18F‐Flortabetapir PET images were coregistered to the individual structural MRI images and then spatially normalized into MNI space.To assess the regional pattern of the 4 groups, one‐way ANOVA followed by two sample t test for post hoc analysis were performed, The statistical level was set at p<0.05 with FDR[hq1] correction and a minimum cluster extent Ke>20 voxels.

Results

In Chinese population, changed glucosemetabolism were present in Superior temporalcortex, inferior temporal cortex, superior occipital cortex, precuneus, frontal cortex, supra‐marginal gyrus, anterior cingulate cortex, insula in a multiple comparison of AD MCI, SCD, and NC. And amyloid plaque were found in temporal cortex, frontal cortex, middle occipital cortex, inferior parietal cortex, insular, lingual gyrus, calcarine fissure and surrounding cortex, cingulate gyrus, fusiform gyrus, gyrus rectus, angular gyrus in these participants. Most of these changes were from AD patients, but slight hypometabolism, and amyloid accumulation were found among NC, SCD, MCI.

Conclusion

Cortex and cingulate gyrus were the main regions for amyloid accumulation and glucose hypometabolism for Chinese AD patients. However, slight change was observed in NC, SCD, MCI participants.
Astrocyte activation and neurovascular function in a diet‐based model of vascular contributions to cognitive impairment and dementia (VCID)
Authors: Sompol Pradoldej , Edelmann Stephanie E. , Lin Ruei‐Lung , Gant Christopher C. , Kraner Susan D. , Weiss Blaine E. , Farr N. Drew , Gollihue Jenna L. , Thibault Olivier , Wilcock Donna M. , Norris Christopher M.
Published: December 2020

Background

Vascular contributions to cognitive impairment and dementia (VCID) are highly comorbid with Alzheimer’s disease (AD) pathology and may accelerate the progression of dementia and/or reduce the clinical efficacy of anti‐AD treatments. Neurotoxic astrocyte activation linked to aberrant calcineurin/NFAT signaling is a shared mechanism between VCID and AD. Recently, hyperhomocysteinemia, a major risk factor for VCID and a variety of other vascular‐related diseases, was linked to astrocyte dysfunction and calcineurin/NFAT hyperactivation. However, causal relationships between astrocytes and neurovascular dysfunction under hyperhomocysteine conditions has yet to be determined. Here, we investigate the hypothesis that diet‐induced hyperhomocysteinemia disrupts cerebrovascular function, in part, through an astrocyte‐based calcineurin/NFAT mechanism.

Method

Wild type mice (2‐3 months‐of‐age) received intracortical injections of adeno associated virus (AAV) equipped with an astrocyte‐specific promoter to target astrocytes with EGFP (control) or VIVIT‐EGFP, to inhibit the calcineruin/NFAT pathway. A chronic, glass cranial window was then installed for longitudinal multiphoton imaging of astrocytes and cerebrovascular parameters in barrel cortex. Three weeks post‐surgery, mice were fed with control or hyperhomocysteinemia‐inducing diet (low levels of folate, vitamins B6 and B12 and enriched with methionine) for 12 weeks. Astrocytic EGFP volume, microvessel leakage, and functional hyperemia (during whisker stimulation) were measured in the same brain region before and after 12 weeks of diet treatment.

Result

Upregulation of astrocytic EGFP volume developed during hyperhomocysteinemia consistent with astrocyte activation. This change was attenuated by CN/NFAT inhibition with VIVIT, similar to previous observations in amyloidogenic mice. Hyperemic capillary responses to whisker stimulation in barrel cortex were also reduced with the development of hyperhomocysteinemia, suggesting an impairment of cerebrovascular function. Microvessel integrity (leakage) and the role of astrocytic NFATs are currently under investigation.

Conclusion

The results indicate that hyperhomocysteinemia, a major risk factor for VCID, may trigger a neurotoxic activated astrocyte phenotype leading to neurovascular injury, and ultimately cognitive decline.
Relationship between state‐level administrative school quality data, years of education, cognitive decline and dementia risk
Authors: Avila Justina F , Murchland Audrey R , Glymour M Maria , Manly Jennifer J
Published: December 2020

Background

We examined indicators of state‐level administrative school quality as predictors of cognitive decline and dementia risk in later life across racial/ethnic by sex/gender groups.

Method

Participants included 2,446 men and women enrolled in the Washington Heights/Inwood Columbia Aging Project (WHICAP) who attended elementary school in the U.S., including 858 non‐Hispanic Whites (NHWs) and 1,588 non‐Hispanic Blacks (Blacks) followed up to 21 years. Cognitive outcomes were memory and language trajectories. A school quality indicator was created using U.S. census microsample data to combine historical measures of state compulsory schooling (mandatory enrollment age, minimum drop out age, and minimum work permit age) and school quality (term length, student‐teacher ratio, and percent attendance) on a scale corresponding to years of education via regression. The school quality indicator values were linked to WHICAP individual data via birth state, birth year, sex/gender, and race/ethnicity (black or NHW). Multiple‐group growth curve modeling and multiple‐group Cox regressions analyses were used to examine associations between school quality, cognitive decline, and dementia risk across racial/ethnic by sex/gender groups.

Result

After adjusting for age, childhood SES, and state of childhood residence, higher quality of early‐life education was associated with level and change in language performance across groups, level of memory performance in Black women, and change in memory for NHWs and Black women. Higher quality of education was associated with lower risk of dementia for NHW women, Black men and women. Quality of education was not associated with dementia risk for NHW men after accounting for covariates. When years of education was included in the models, the influence of school quality on dementia risk and level and change in memory and language performance was fully attenuated for Black men and partially attenuated for NHWs and Black women.

Conclusion

Quality of early‐life education positively impacts cognitive outcomes and dementia risk later in life. Our results suggest an indirect relationship of school quality to late‐life cognitive outcomes through enabling additional years of educational attainment. Associations also varied across racial/ethnic by sex/gender groups. These findings provide evidence that later life brain health is influenced by early‐life state educational policies.
The legal capacity of patients with Alzheimer's disease
Authors: Mroczko Piotr
Published: December 2020

Background

As human life extends, problems affecting people over the age of 60 are becoming an important challenge for scientists. One of the biggest threats to these people is the risk of Alzheimer's disease. This is not only a medical, but also a sociological, psychological and legal problem. One of the most important problems in legal sciences is the issue of legal capacity. It defines when a particular person has the ability to acquire rights and incur obligations under civil law. Usually a person achieves legal capacity at the age of majority. Another factor that affects having legal capacity is the occurrence of a mental illness. The progressive symptoms of Alzheimer's disease, such as memory loss or lack of awareness about one's life situation, significantly limit patient competence to knowingly acquire rights and incur obligations.

Methods

The research was carried out using the method of analyzing scientific literature in the field of medicine, medical law and civil law.

Results

There is no doubt that in the first phase of Alzheimer's disease the patient has legal capacity. The patient's situation in the third phase, i.e. dementia due to Alzheimer's disease, is also clear ‐ he no longer has legal capacity. The second phase, i.e. Mild cognitive impairment, is problematic from a legal point of view. It is difficult to unequivocally assess the patient's competence to consciously acquire rights and incur obligations. Each time in such a situation, a court that assesses a person's legal capacity should seek the opinion of expert neurologists and psychiatrists to determine the person's state of consciousness.

Conclusions

Alzheimer's disease affects a person's legal capacity. The assessment of whether a person is able to consciously acquire rights and incur obligations should always belong to the doctors and lawyers cooperating with each other.
Plasma soluble TREM2 and inflammatory markers in Alzheimer’s disease
Authors: Weber Grace E. , Khrestian Maria , Shao Yvonne , Tuason Elizabeth D. , Rao Stephen M. , Pillai Jagan A. , Leverenz James B. , Bekris Lynn M.
Published: December 2020

Background

Triggering receptor expressed on myeloid cells 2 (TREM2) activation is involved in several cellular functions such as cell survival, phagocytosis and cytokine production. TREM2 genetic variants have been shown to increase risk for AD and other neurodegenerative disorders. Leukocyte TREM2 mRNA has been described as elevated in AD. However, the cleaved, soluble protein (sTREM2) is not elevated in AD plasma suggesting that plasma sTREM2 is less likely to play a significant a role in AD. As TREM2 mRNA is elevated in AD, it is also possible that membrane bound TREM2 plays a more important role in AD, by inhibiting certain cytokine or chemokines. We therefore hypothesized that plasma sTREM2 positively correlates with certain plasma cytokines and chemokines in cognitively normal controls, but not in AD.

Method

We investigated this hypothesis in a study of adults with AD, mild cognitive impairment (MCI), and age‐matched cognitively normal controls (HC). A panel of 38 immune factors and sTREM2 were measured in plasma utilizing the Luminex platform. Hierarchical clustering and correlation analyses were used to demonstrate differing relationships between sTREM2, cytokines and chemokines in AD or MCI, compared to HC.

Result

We observed a relationship between plasma sTREM2 and cytokines in our cohort that varied by disease status.

Conclusions

Our results suggest that plasma sTREM2 is related to an aberrant peripheral inflammatory profile in AD. Increased levels of sTREM2 correlated positively with anti‐inflammatory, regulatory, and pro‐inflammatory cytokines in plasma. This study provides a basis for future studies investigating peripheral sTREM2 and the development of AD.
What am I measuring? Disentangling cognitive status from sensory impairment
Authors: Nichols Emma , Swenor Bonnielin K , Deal Jennifer A , Abraham Alison , Carlson Michelle C , Ramulu Pradeep , Resnick Susan M , Gross Alden L
Published: December 2020

Background

Sensory impairment in hearing or vision affects 55% of older adults aged 60+. Some studies have shown sensory impairment is associated with impaired cognitive test performance, however tests rely to varying degrees on hearing, vision, or both. We hypothesized that scores for cognitive tests whose administration or instructions depend on vision (e.g., Trail Making) or hearing (e.g., word‐list learning) are biased among those with vision or hearing impairment, respectively, after controlling for underlying cognitive performance.

Method

We leveraged cross‐sectional data from a comprehensive neuropsychological battery on N=658 men and women from the Baltimore Longitudinal Study of Aging (BLSA) and N=1,008 participants from the Atherosclerosis Risk in Communities study (EyeDOC ancillary study), all of whom had objective diagnostic hearing and vision assessed. We used item response theory methods to test for differential item functioning (DIF) by hearing (PTA>25 db in 4 speech frequencies) and visual acuity (20/40) impairment.

Result

The BLSA sample was 55.7% female and 66.3% white. The EyeDoc sample had a higher proportion of women (63.4%) but fewer white participants (54.3%). Overall, we found more evidence of DIF in the EyeDoc study, a sample with lower cognitive performance and a higher number of comorbidities, as compared to the BLSA. No DIF by visual impairment was observed in BLSA, but in EyeDoc we observed DIF by visual impairment for the Delayed Word Recall Task such that the task was harder for those with visual impairment. A larger number of tests showed DIF by hearing impairment in both BLSA and EyeDoc, including the Delayed Word Recall Task in EyeDoc and the Digit Symbol Substitution Task in BLSA.

Conclusion

We identified DIF by hearing impairment for tests that do not rely on hearing and DIF by vision impairment for tests that do not rely on vision. Based on these findings, if bias is found in cognitive tests independent of characteristics of the test administration or instructions, cognitive load may be playing a larger role than previously acknowledged. Future investigation is warranted to determine how sensory impairment impacts completion of cognitive testing, as this study was limited to participants who successfully completed cognitive testing.
Safety monitoring in the U.S. study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (US POINTER)
Authors: Williams Benjamin J , Felton Deborah M , Nichols John E , Espeland Mark A , Baker Laura D
Published: December 2020

Background

US POINTER is a multisite randomized clinical trial funded by the Alzheimer's Association. It is designed to evaluate whether different lifestyle interventions (exercise, nutrition, and cognitive and social stimulation) protect cognitive function over a 2‐year period in approximately 2000 older adults.

Method

We have designed a web‐based safety tracking system (STS) that meets the complexity of this trial that involves oversight of participants as they carry out the interventions by community partners at 5 trial sites.

Result

In US POINTER, participants interact with community interventionists as well as research clinic staff and clinicians. All personnel are charged with documenting potential safety events. We designed the STS to allow timely and accurate collection of safety data by study personnel regardless of their role in the study or the location of their contact with the participant. This ensures that safety data are complete. Health events entered by interventionists and clinical trial staff are reviewed by local site clinicians to determine if the event meets criteria for an adverse event (AE). If so, the clinician then determines the expectedness, relatedness, and risk of harm of the AE. These determinations are captured on the STS. Safety reporting is then reviewed and adjudicated by the central Safety Manager and the trial Safety Officer and, if needed, by the Safety Committee. The STS facilitates these processes and ensures the accuracy and consistency of safety data reporting throughout the trial. Importantly, the trial design requires that study personnel, Safety Manager, Safety Officer, and the Data Coordinating Center remain masked or unmasked as to study interventions and outcomes. The STS was designed so that access to the STS is restricted by study role in order to maintain the intervention assignment mask. These attributes of the STS help to maintain the rigor and integrity of the trial.

Conclusion

The innovation of the POINTER STS is that it allows for reporting of AEs obtained during any point of contact between the participant, community partners and study personnel, and allows for a multi‐level review of safety events in a centralized, efficient and timely manner thus ensuring participant’s ongoing safety throughout the trial.
Infocaregiver: Co‐conception of an information campaign on assistive technology solutions to support informal caregivers of older adults with neurocognitive disorders in priority areas of needs
Authors: Pino Maribel , Laabar Amal , Rigaud Anne‐Sophie , Damnee Souad , Cantegreil‐Kallen Inge , Benveniste Samuel
Published: December 2020

Background

Informal caregivers of older adults with neurocognitive disorders participate in essential tasks in the life of their loved one, ranging from household chores to following complex medical treatments or coordinating home care and services. Caregivers report a strong lack of support regarding this role which can lead to high levels of stress and depression, musculoskeletal disorders and general exhaustion. The access to information on assistive technology (AT) resources, could help caregivers improve quality of life and care. Particularly, since AT could provide them with an affordable and effective daily support. However, in France, many caregivers lack of information regarding AT. A consequence of this situation is the limited AT use.

Method

The objective of the InfoCaregiver project is to create and distribute 6 information packs (animation videos and flyers) for informal caregivers regarding the use of AT to support caregiving tasks. The conception process of this information campaign includes: a literature review, a need’s assessment study regarding AT use among caregivers using a questionnaire, interviews and focus groups, and an iterative process involving caregivers and professionals for the definition of the scripts and video scenarios and their production. A particular attention will be paid to the provision of neutral and accessible information. These packs will be then freely distributed (Creative Commons license).

Result

Six main priority themes have been identified for the AT information campaign : 1) The caregiver role and the general benefits for caregivers of using AT, 2) the use of AT for improving security at home, 3) the use of AT for promoting social life and communication, 4) the use of AT for the coordination of home care services, 5) the use of AT for leisure activities, and 6) the use of AT for providing psychosocial support to caregivers. Video and print material is currently under development

Conclusion

Involving caregivers in the design process allows the creation of useful, acceptable and ethical AT information. Caregivers reached by our AT information campaign will gain a better knowledge of AT possibilities. It is expected that this action will lead to an increased use of AT in France.
Genetics, diet, and sex interact to modulate cognitive decline in Alzheimer’s disease
Authors: Dunn Amy R. , O'Connell Kristen M.S. , Kaczorowski Catherine C.
Published: December 2020

Background

Alzheimer’s disease (AD) etiology is complex, with disease risk and progression mediated by individual genetic and environmental factors. Additionally, there are significant sex differences in aging, brain metabolism, and AD risk. This complexity adds challenges to understanding disease mechanisms and developing treatment strategies that will be effective across the AD population; human studies have been limited in understanding these interacting effects due to human genome complexity and difficulty controlling environmental factors, such as diet.

Method

We recently developed a population of genetically diverse mice carrying the 5XFAD transgene (AD‐BXDs; Neuner, et al. 2019). Because they model human genetic heterogeneity, AD‐BXDs are ideally suited to investigate translationally‐relevant gene‐environment and sex interactions. Here, we used AD‐BXDs to determine how genetics, diet, and sex interact to modify AD‐related symptoms. We fed a chronic 45% high fat diet (HFD) starting at ∼2.5mo of age to 39 strains of AD‐BXDs and nontransgenic littermates (Ntg‐BXD). We monitored hippocampus‐dependent cognitive function using y‐maze (working memory) and contextual fear conditioning (short‐ and long‐term memory) across their lifespan.

Result

Gene‐by‐diet interactions accounted for a significant proportion of variance in cognitive phenotypes across the population of AD‐BXDs and Ntg‐BXDs, and the effect of HFD differed depending on sex. We saw a protective effect of HFD in female AD mice on working memory through middle age that was not seen in male mice. By 14mo, female Ntg – but not AD – mice on HFD experienced significantly worse cognitive decline than those on chow—an effect that again was not seen in males.

Conclusion

Our results suggest that diet affects AD risk and progression differentially based on sex and genetic background: intriguingly, HFD may be protective in female AD mice while being detrimental to cognitive function in “normal” aging. These findings in the AD‐BXDs demonstrate individual variation in how diet affects AD risk and cognitive aging, and that the mechanisms underlying this variation are ripe for discovery. Future analyses will build upon these data to identify genetic and molecular targets contributing to AD pathogenesis sensitized by sex and HFD that may be exploited to delay, prevent or treat AD.
Do senescent cells play a role in Alzheimer’s disease?
Authors: Walker Lauren , Jacobs Eleanor , McAleese Kirsty E. , Johnson Mary , Attems Johannes
Published: December 2020

Background

Cellular senescence, the irreversible arrest of the cell cycle, is a common occurrence in ageing. Astrocytes have been shown to demonstrate a senescent phenotype, which is increased in ageing, and in Alzheimer’s disease (AD) (as evidenced by p16INK4a expression). Recently, a causal link was established between p16INK4a expression and hyperphosphorylated tau (HPT) pathology in the MAPTP301SPS19 mouse model of tauopathy, where treatment with a senolytic agent removed senescent p16INK4a positive astrocytes, prevented aggregation of HPT, and preserved cognitive function, suggesting senescent astrocytes may play a role in HPT deposition observed in AD. However, data in human post‐mortem tissue from AD cases (inclusive of Aβ pathology) is lacking.

Method

Frontal cortex (BA9) from 10 AD and 10 control cases were double immunolabelled for GFAP and p16INK4a. A mean number of p16INK4a positive astrocytes (identified by the presence of co‐localisations) was determined at 6 regions of interest across each section. HPT and Aβ were quantified by percentage area of immunopositivity in the same region.

Result

AD cases had significantly more p16INK4a positive astrocytes compared to controls (p<0.05). We observed a positive association between number of p16INK4a positive astrocytes and HPT load in AD cases (p<0.05). No association was observed between the mean number of p16INK4a positive astrocytes and Aβ load.

Conclusion

We found a positive association was found between p16INK4a positive astrocytes and HPT. This area of research warrants further investigation to determine whether the development of senolytic therapies are a viable option for the treatment of AD and other tauopathies.
Disease progression modeling‐based prediction of cognitive decline
Authors: Ghazi Mostafa Mehdipour , Sørensen Lauge , Pai Akshay , Cardoso Jorge , Modat Marc , Ourselin Sebastien , Nielsen Mads
Published: December 2020

Background

The objective of this study is to investigate decline prediction of cognitive test scores in stable and converting mild cognitive impairment (MCI) subjects using both nonparametric and parametric Alzheimer’s disease (AD) progression modeling methods trained on data including cognitive tests, CSF measures, and neuroimaging biomarkers.

Method

The study dataset consisted of yearly visits (2005‐2017) for 782 Alzheimer’s Disease Neuroimaging Initiative (ADNI) subjects with normal cognition, MCI, or AD, including FreeSurfer‐based T1‐weighted brain MRI volumes (ventricles, hippocampus, whole brain, fusiform, and entorhinal cortex, all normalized with intracranial volume), cognitive tests (MMSE, CDR‐SB, ADAS‐Cog‐13, FAQ, and RAVLT‐immediate‐recall), CSF measures (Amyloid‐beta and p‐tau), and FDG‐PET. Two state‐of‐the‐art disease progression modeling methods, a nonparametric using LSTMs (Ghazi, M. M., et al., Medical Image Analysis 53, 39‐46, 2019) and a parametric using regression (Jedynak, B. M., et al., Neurobiology of Aging 36, 178‐184, 2015), were trained on 632 subjects and subsequently applied to predict month 24 to 96 MMSE scores for 150 independent test subjects using only their baseline and month 12 data.

Result

The predictive power and prognostic capability of the AD progression modeling methods were assessed using the per‐visit mean absolute error (MAE) and area under the ROC curve (AUC) of predicted MMSE scores for stable MCI (sMCI) and converting MCI (cMCI) test subjects. The average MAE results for month 24 to 96 MMSE scores were as follows: nonparametric 1.39 to 1.04 (sMCI), 2.41 to 3.62 (cMCI); parametric 1.46 to 4.00 (sMCI), 2.42 to 2.53 (cMCI). The average AUC results for month 24 to 96 obtained based on the predicted MMSE scores were as follows (two‐sample t‐test, p < 0.001 in all cases): nonparametric 0.79 to 0.73; parametric 0.83 to 0.69.

Conclusion

In almost all cases, the nonparametric method outperforms the parametric model in predicting MMSE scores. Moreover, predictions from both nonparametric and parametric methods can significantly discriminate between sMCI and cMCI groups. Though, the discrimination capability of the nonparametric method is superior in long‐term prediction of cognitive decline.