bluuebunny/crossref_metadata_2025 huggingface dataset:
Dementia care practice: Integrating medical and caregiver support in a community‐based program
Authors: Templeton Virginia H , Noel Margaret A
Published: December 2020

Background

Dementia is among the most challenging health issues of our time and affects not only the person with dementia (PWD) but their family and other caregivers as well. With no cure or effective disease modifying treatments currently available, having affordable models of care that address caregiver needs as an integral part of medical management of the PWD is widely seen as essential to maximize quality of life, manage safety concerns, plan for future care needs and provide highest quality care. Data is limited regarding cost effectiveness or caregiver and PWD experience of such care models. MemoryCare is a community‐based, out‐patient nonprofit organization serving a largely rural area of western North Carolina for 19 years with a model of care that integrates education, training and support of caregivers with the medical care of persons with Alzheimer’s disease and other types of dementia. Caregivers participate in all clinic visits offering valuable history that informs medical decisions and, with the PWD, contribute to development of care plans. Alongside provision of medical care for the PWD, caregivers receive dementia education, training in behavioral management, resource matching and support specific to their individual needs. In 2019, 1,020 PWD and 3,372 caregivers enrolled at MemoryCare for care services as a supplement to primary care. For the past 5 years, observational data regarding hospitalization rates, 30‐day readmission rates, and ED utilization was collected for PWD seen in MemoryCare’s clinic setting who had been enrolled for at least one year and lived in a defined region where health care utilization could be independently confirmed. Caregiver satisfaction was assessed for the same 5‐year period through anonymous self‐report surveys. Data collected reveal high levels of caregiver satisfaction, increased dementia‐specific knowledge, and perceived improvement in ability to manage dementia‐related behaviors and lengthen time in the home setting. Data shows lower hospitalization and ED visit rates as well as reduced length of stay and readmission rates when compared to published norms. Findings suggest that inclusion of caregivers in the medical model of care for PWD may improve overall outcomes and warrant further study of integration of caregivers into clinical care models.
Modulating SORL1 expression affects endolysosomal trafficking function in hiPSC‐derived models of Alzheimer's disease
Authors: Knupp Allison , Mishra Swati , Martinez Refugio A. , Young Jessica E.
Published: December 2020

Background

The SORL1 gene encodes for the protein SorLA, a sorting receptor involved in retromer‐related endosomal traffic. Many SORL1 genetic variants increase Alzheimer’s disease (AD) risk, and rare loss‐of‐function truncation mutations have been found to be causal of AD. SORL1 is expressed in neurons and glia of the central nervous system and loss of SORL1 has been reported AD tissue.

Method

To model the causal loss‐of‐function mutations, we used CRISPR/Cas9 technology to deplete SORL1 in human induced pluripotent stem cells (hiPSCs) to test the hypothesis that loss of SORL1 (SORL1 KO) contributes to AD pathogenesis by leading to dysfunction in endo‐lysosomal trafficking. In contrast, certain SORL1 variants may be acting in a protective capacity to help prevent AD pathogenesis. To model protective variants, we used a PiggyBac Transposon system to test the hypothesis that overexpression of SORL1 (SORL1 OE) protects against AD pathogenesis and endo‐lysosomal trafficking dysfunction.

Results

We report that loss of SORL1 in hiPSC‐derived neurons leads to early endosome enlargement, a cellular phenotype that is indicative of ‘traffic jams’ and is now considered a hallmark cytopathology AD. We validate defects in endo‐lysosomal traffic in SORL1 KO neurons by showing decreased localization of amyloid‐precursor protein (APP) to the degradative pathway. We confirm decreased function of the degradative pathway in SORL1 KO neurons through experiments using pH‐sensitive pHrodo dyes. Conversely, in SORL1 OE neurons we show nominal early endosome morphology, reduced localization of APP to the degradative pathway, and increased functionality of the degradative pathway. Finally, we determined that defects in endo‐lysosomal trafficking caused by loss of SORL1 affect synapse function by analyzing SORL1 KO neurons on multielectrode arrays.

Conclusion

Collectively, these findings clarify where and how SORL1 links to AD. Moreover, our data, together with recent findings, underscores how sporadic AD pathways that regulate endosomal trafficking, and autosomal‐dominant AD pathways that regulate APP cleavage, independently converge on AD’s defining cytopathology.
Vascular and Alzheimer’s pathology: A mixed affair
Authors: Schneider Julie A
Published: December 2020

Background

In‐vivo indicators of the central pathologies that define Alzheimer’s disease (AD) have transformed research in dementia. The AT(N) framework was proposed to standardize nomenclature when using these biomarkers in the research setting of suspected Alzheimer’s dementia. However, in‐vivo amyloid and tau biomarkers provide an incomplete picture of the brain in persons living with Alzheimer’s dementia, a heterogeneous syndrome that not only includes prominent episodic memory impairment, but often deficits in multiple other cognitive domains, motoric abilities and behavior.

Method

Presentation of human data from autopsy studies that support a role for vascular pathology in accelerating neurodegeneration and worsening cognitive impairment.

Result

Brain vascular disease is extraordinarily common in the aging brain with and without AD pathology and contributes to cognitive impairment. In spite of the prevalence of vascular pathology, most persons have no history of stroke. Vascular brain pathologies include but are not limited to small and large vessel diseases and macro and microscopic tissue injuries. Each vascular pathology adds to cognitive impairment and lowers the threshold for Alzheimer's dementia. In some studies, vascular pathologies contribute to about 1/3 of association between age and dementia. Changes in endothelial cells, the blood brain barrier and the neurovascular unit are also implicated. Moreover, vascular risk factors and vessel diseases may promote or interact with amyloid and/or tau to accelerate tissue injury.

Conclusion

Preventing and treating cognitive impairment requires an integrated understanding of beta‐amyloid, hyperphosphorylated tau, and the vascular pathologies and processes that lead to tissue injury, neurodegeneration, and ultimately cognitive decline.
The features of BECN1 expression in the pyramidal layer of rat hippocampus in chronic cerebral ischemia
Authors: Mednikov Dmitry , Smirnov Alexey Vladimirovich , Tyurenkov Ivan Nikolaevich , Kurkin Denis , Ekova Maria
Published: December 2020

Background

BECN1 is a member of the Bcl‐2 protein superfamily, belonging to the BH3‐proteins subfamily, which performs many functions, including cross‐regulation of autophagy and apoptosis. BECN1 acts as regulator of the formation and maturation of autophagosomes, the development of neurodegenerative processes in the hippocampus and cerebellum in a BECN1‐knockout mice.

Method

Chronic cerebral ischemia modeled in rats by limiting cerebral blood flow with applying ligatures to the carotid arteries. The cognitive sphere, the preservation of reflexes, the ability to remember new objects, the degree of neuronal injury, and the level of BECN1 expression in the pyramidal layer of the hippocampus were evaluated. Immunohistochemical study was performed using polyclonal antibodies to BECN1, visualized using diaminobenzidine.

Result

The most pronounced changes were found in the pyramidal layer of the CA1, where neurons with signs of damage were identified along with unchanged neurons. Dystrophic changes in the pyramidal cells were of different severity, determined by a significant increase in the number of hyperchromic neurons, and in most of them total hyperchromia of the nucleus and cytoplasm was observed, a large number of shadow cells were formed. An immunohistochemical study of the hippocampus using antibodies to BECN1 revealed a uniform positive cytoplasmic reaction, mainly of low intensity. A significant increase in expression was found in the CA1, where the relative area of the immunoreactive material increased by 1.1% compared with the control (p <0.001) and reached 1.5%.

Conclusion

BECN1 is involved in the cross‐regulation of autophagy and apoptosis. According to modern concepts, BECN1 localized intracellularly in the complex with homologs‐proteins of the Bcl‐2 family. With dissociation of the Bcl‐2/BECN1 complex and an increase in free BECN1, autophagy is induced. The observed increase in the expression of BECN1 in CA1 indicates the inclusion of BECN1‐dependent autophagy in this zone in chronic cerebral ischemia.
Preliminary feasibility of technology use in an internet‐delivered intervention: Improving sleep in older adults with mild cognitive impairment
Authors: Mattos Meghan K , Barnes Laura , Davis Eric M , Manning Carol A , Mostafavi Moeen , Quigg Mark S , Perez Hillary , Sollinger Ann , Ritterband Lee M
Published: December 2020

Background

Individuals with mild cognitive impairment (MCI) experience more sleep disturbances than individuals without MCI, and improving sleep in this at‐risk group may delay progression to Alzheimer’s disease. Internet‐based interventions may promote access to treatments for sleep disorders, such as insomnia. However, preliminary studies examining technology use and compliance are needed prior to undertaking large‐scale interventions in this population.

Method

Older adults (≥55 years old) with MCI are recruited from hospital‐based memory and sleep disorders clinics and enrolled in a single‐arm intervention pilot study. An existing Internet‐delivered cognitive behavioral therapy for insomnia (CBT‐I)called Sleep Healthy Using the Internet for Older Adult Sufferers of Insomnia and Sleeplessness (SHUTi OASIS) collects daily sleep diary data and delivers the automated intervention over nine weeks. Wrist‐worn actigraphs are used to collect subject objective sleep data over two 14‐day periods, pre‐ and post‐intervention. SHUTi OASIS sends daily morning emails to remind subjects to complete the sleep diary and wear the actiwatch at night. There are only two in‐person study visits over the 4‐5 month study duration. Care partners are invited to enroll in the study to share their experience observing or assisting their loved one. Descriptive statistics for technology use are presented for the baseline study period.

Result

Seven subjects are enrolled in the ongoing study and are, on average, 76.0±5.4 years of age, mostly female (4/7), with an average MoCA of 22.7±3.1 (19‐28).Four care partners, all spouses, are enrolled. All subjects with MCI completed 10 sleep diaries over 14 days, most accessing the SHUTi OASIS program daily. Actiwatch data show that subjects wore the actiwatch between 5‐14 days.

Conclusion

Consistent daily or every other day sleep diary entry may be in response to viewing the automated e‐mail reminders and immediately logging into SHUTi OASIS to complete their daily entry. Although subjects were accepting of wrist‐worn actigraphy, there was inconsistent wear time at night, which may be related to the early‐morning timing of e‐mail reminders. Incorporating technology for subjective and objective sleep data collection in this population is promising, and future work should consider frequency and timing of reminders with multimodal technology use.
Supporting people with dementia and their family caregivers through a home‐based, dyadic, multisensory stimulation intervention: A feasibility study
Authors: Kor Patrick Pui Kin , Yu Clare , Liu Justina Yat Wa , Cheung Daphne Sze Ki , Kwan Rick Yiu Cho , Leung Angela
Published: December 2020

Background

Multisensory stimulation interventions are commonly used to support people with dementia (PWD). Major attention has only been paid to their beneficial effects on PWD. This study examined the preliminary effects of a home‐based, dyadic, multisensory stimulation intervention on both PWD and family caregivers (CG).

Method

In this quasi‐experimental study, 72 PWD‐caregiver dyads received either a 15‐week home‐based, dyadic, multisensory stimulation intervention (n=36) or the usual care (n=36). The intervention was delivered 3 times per week (30 minutes each time) by the CG. It consisted of various multisensory stimulation activities (i.e., tasting food, listening to music, singing). Weekly telephone follow‐ups and sharing sessions were also provided. The following outcomes were measured at baseline, immediately post‐intervention, and at the 3‐month follow‐up: the positive aspect of caregiving, stress, depression, burden, and quality of life (QoL) of the CG; and the cognitive function and Behavioral and Psychological Symptoms of Dementia (BPSD) of the PWD. A process evaluation was conducted through focus groups involving 13 pairs of dyads.

Result

Intervention feasibility was established with a high completion rate of 82% (≥60 out of the 90 minutes per week) and a low attrition rate of 5.56%. The average duration of weekly training was 62.5 minutes (S.D.=18.4). The results of the generalized estimating equation indicated that the intervention group experienced a statistically significant improvement in the positive aspect of caregiving (B=‐4.68, 95% confidence interval [CI]=‐7.71, ‐1.65, p=0.002), stress (B=1.75, CI=0.45, 3.06, p=0.009), burden (B=4.86, CI=2.20, 7.52, p<0.001), and QoL (B=‐2.05, CI=‐3.05, ‐1.05, p<0.001) of the CG; and in the BPSD (B=1.80 CI=0.55, 3.05, p=0.005) of the PWD at the post‐test, compared to the controls. Sustainable effects in QoL, positive aspect of caregiving, and BPSD were demonstrated at the 3‐month follow‐up. Focus groups conducted immediately after the intervention revealed three major themes: Impacts on the dyadic relationship, Impacts on the PWD, and Difficulty of implementation.

Conclusion

This study showed that the intervention is acceptable to PWD‐caregiver dyads in Hong Kong. The program not only benefited the PWD but also the caregivers and the dyadic relationship. Further testing of this program with a larger and more diverse sample is needed.
Translational potential of mouse CSF biomarkers in Alzheimer’s disease: Association of CSF neurogranin with tau, NFL and amyloid pathology in APP knock‐in mouse models
Authors: Smailovic Una , Delac Ljerka , Liman Victor , Kvartsberg Hlin , Winblad Bengt , Jelic Vesna , Höglund Kina , Zetterberg Henrik , Blennow Kaj , Nilsson Per
Published: December 2020

Background

Alzheimer’s disease (AD) is characterized by early and progressive synaptic dysfunction and loss that are closely related to cognitive impairment in AD patients. Neurogranin (Ng) has emerged as a potential marker of synaptic dysfunction, with cerebrospinal fluid (CSF) levels specifically increased in AD. In order to investigate the translational potential of CSF Ng, the present study investigated its alterations and relationship to AD‐related pathology (Aβ42, tau and neurofilament light; NFL) in both CSF and brain tissue of novel App knock‐in mouse models.

Methods

CSF and brain tissue were sampled from 12‐months old wild type (WT), AppNL‐F/NL‐F and AppNL‐G‐F/NL‐G‐F mice. CSF and brain (cortex and hippocampus) Ng, Aβ42, t‐tau and NFL protein levels were analyzed using new ultra sensitive digital enzyme‐linked immunosorbent assays on the Simoa platform. Differences in expression of Ng in the brain tissue and its relation to amyloid plaques in App knock‐in mice were investigated by immunohistochemistry (IHC).

Results

CSF Ng, t‐tau and NFL levels were significantly increased in App knock‐in compared to WT mice (p < 0.05). CSF Ng negatively correlated with Ng levels in the cortex and Aβ42 levels in the CSF and positively correlated with CSF t‐tau and NFL levels (p < 0.05). Loss of neurogranin in the dendrites of hippocampal CA1 region of App knock‐in mice was closely associated with the localization of Aβ plaques in double IHC stainings.

Conclusions

App knock‐in mice exhibit synaptic degeneration that is associated with AD neuropathology and remarkably comparable to findings from clinical studies. CSF Ng is potential translational marker of synaptic degeneration in AD.
A‐posteriori‐derived dietary patterns and cognitive function in the SUN project
Authors: Muñoz‐García Mariana I , Martinez‐Gonzalez Miguel Angel , Razquin Cristina , Fernández‐Matarrubia Marta , Guillen‐Grima Francisco , Toledo Estefanía
Published: December 2020

Background

Dementia affected an estimated 44 million persons in 2016 and it is projected to affect 132 million by 2050. Drugs to cure or delay the progression of the disease are not available and are proving difficult to develop. Thus, prevention of cognitive function decline is extremely relevant. Diet is a key and pertinent target for primary prevention, but firm recommendations for dementia prevention are not available yet. Our aim was to address the association between empirically derived dietary patterns (DP) and changes in Spanish Telephone Interview for Cognitive Status (STICS‐m) scores over 6 years in a Mediterranean cohort.

Method

A total of 803 participants from the ‘Seguimiento Universidad de Navarra’ (SUN) Project sub‐study of cognitive function were analyzed using principal component analysis to derive DP. The derived DP were associated with change in STICS‐m scores over 6 years, through adjusted multiple linear regression models.

Result

Two main DP were identified. The first resembled a Western diet (WDP)— high in sugar, fat, processed foods and red meat— and the second one a Mediterranean diet (MDP)— high in vegetable, fruit, nuts, fish and olive oil (table 1). Baseline characteristics of participants are shown in table 2. Highest adherence to the WDP (tertile 3 vs tertile 1) was associated with a non‐significant decrease in STICS‐m after 6 years of ‐0.65 points (95% CI ‐1.36, 0.06, p‐value=0.07) (figure 1). On the other hand, results for the MDP were showed a 0.73 point increase in STICS‐m after 6 years (95% CI 0.18, 1.27, p‐value=0.008), comparing tertile 3 vs tertile 1 (figure 2).

Conclusion

A healthy, prudent, Mediterranean‐like DP was associated with less decline in cognitive function and, thus, could help to lower dementia incidence. Western‐type diets could be associated with a faster decline in cognitive performance and higher dementia incidence. Our results are compatible with previous studies in other populations and can have an impact in future public health recommendations to decrease the risk of developing dementia.
Cognitive impairment in physicians suffering burnout syndrome: A matter of moral Injury
Authors: Martino Gabriel Gerardo , Rojas Galeno , Zuin Daniel , Persi Gabriel Gustavo , Leis Adriana , Macri Ana Macarena , Camino María Victoria , Parisi Virginia Laura , Silva Nahuel Pereira , Gatto Emilia , Aldinio Victoria , Guillen Jonathan Cubas , Boccazzi Julián Fernández
Published: December 2020

Background

Burnout syndrome (BOS) is frequently described in physicians, being characterized by exhaustion and long‐term loss of interest generally at work. It is associated with lower effectiveness, lower job satisfaction, and a decrease in commitment to work. It’s been recently hypothesized that BOS could lead to cognitive impairment (CI), leading to serious consequences for health care professionals. Primary objective: to determine the impact that BOS has on subjective memory (SM) in physicians compared to general population in other occupations (OthOcc). Secondary objective: to compare how BOS is linked to anxiety, depression and SM impact in physicians and OthOcc.

Method

We performed an observational multicenter cross‐sectional study using a custom‐made survey (using Maslach Burnout Inventory [MBI], Hospital Anxiety and Depression Scale, and a SM scale of our own elaboration), sent digitally, distributed nationally. Risk of BOS (BOS‐R) was defined when 1‐2/3 MBI subscales were altered and BOS when all 3 were. Statistical analysis was performed with parametric and non‐parametric tests.

Result

We obtained 215 responses (111 physicians and 104 OthOcc). The average age of the physicians, was 34.23 years, women were 62.16% (n=69). In physicians, prevalence of BOS‐R was 62.16% (n=69) and of BOS was 20.72% (n=23); 33.33% (n=37) presented anxiety; and 9.91% (n=11), depression. We found a relationship between BOS‐R/BOS and lower SM scores (p=0.011). Physicians had worse SM scores when compared to OthOcc, being the mean for physicians with BOS‐R 11.32 (SD 6.36) and for OthOcc 9.75 (SD 6.54); for physicians with BOS 11.52 (SD 6.56) and for OthOcc 8.23 (SD 4). Physicians with BOS‐R/BOS presented anxiety (p<0.001) and depression (p=0.001), OthOcc also presented anxiety (p=0.019) and depression (p=0.001).

Conclusion

The impact of BOS in physicians is alarming, and is associated with cognitive impairment and anxiety/depression. It has serious personal consequences, negatively affecting health care quality. We believe physicians are suffering what has been coined as ‘moral injury’, something beyond BOS, that is also affecting our health care system and our patients.
Association of tau tangle burden with depressive symptoms in community‐dwelling older adults: A longitudinal study
Authors: Gatchel Jennifer R. , Marshall Gad A. , Locascio Joseph J. , Yang Hyun‐Sik , Donovan Nancy J. , Buckley Rachel F. , Properzi Michael J. , Quiroz Yakeel T. , Rabin Jennifer S. , Vannini Patrizia , Amariglio Rebecca , Chhatwal Jasmeer P. , Rentz Dorene , Blacker Deborah , Sperling Reisa A. , Johnson Keith A. , Hanseeuw Bernard J
Published: December 2020

Background

Depressive symptoms are thought to be among the earliest behavioral changes in preclinical Alzheimer's disease (AD). However, the association between AD pathology and depressive symptoms in preclinical AD remains poorly understood. In the current study we examined the impact of pathology burden (amyloid‐β and tau) on longitudinal change in depressive symptoms in cognitively unimpaired adults.

Method

252 adults (age: 70.8 ±8.2; 61% females) from the Harvard Aging Brain Study completed annual assessment with the 30‐item Geriatric Depression Scale (GDS) (average follow‐up=5.87 annual visits). All were cognitively normal, without clinically significant depression at study entry (mean GDS=3.19±3.12; range: (0‐16)). All underwent tau (18F‐Flortaucipir) and amyloid‐β (11C‐Pittburgh Compound B) PET at study year 3 or 4 to derive measures of inferior temporal (IT) and entorhinal cortex (EC) tau and cortical amyloid. A mixed model was employed with dependent variable GDS (for each annual study visit), a random intercept and slope for each participant, and fixed predictors: tau (IT or EC, at study year 3/4), cortical amyloid (at year closest to tau), time (time of tau PET), covariates: age, sex, education; and the interaction of predictors with time.

Result

Baseline tau burden was associated with increasing GDS over time. In the model with predictor EC tau, EC tau X time was a significant predictor of GDS (β=0.48; t=3.80; 95% CI (0.23, 0.73); p=0.0002). Findings were similar for IT tau:(β = 0.71; t=3.67; 95% CI (0.33, 1.1); p=0.0002). By contrast, amyloid was not a significant predictor of longitudinal GDS in tau models: (β=‐0.14; t=‐1.58; 95% CI(‐0.23, ‐0.08); p=0.11).

Conclusion

Baseline tau, but not amyloid, is independently associated with increasing depressive symptoms over time. Future research incorporating longitudinal tau PET and individuals with more severe depressive symptoms is needed to delineate the temporal sequence of rising depressive symptoms and increasing tauopathy in preclinical AD.
White matter texture abnormalities are associated with delusional severity in a cognitively mixed sample of older adults
Authors: Venkatesh Saanika , Bahsoun Mohamad‐Ali , Arezza Giordano , Digregorio Justin , Schweizer Tom A. , Churchill Nathan W , Munoz David G. , Fischer Corinne E. , Khademi April
Published: December 2020

Background

Delusions in older adults correlate with white matter lesion burden [1], though the relationship with white matter texture (WMT) is unclear. White matter texture is the tissue organization in normal‐appearing brain matter (NABM) related to overall diffusion capabilities.

Method

Using NPI‐Q scores from the ADNI data set, a cognitively mixed sample of patients with delusions was extracted. Delusional severity was ranked from 1‐3 (1 being the lowest severity) based on the NPI‐Q scores along with downloads of FLAIR MRI volumes for each subject. Subjects and volumes were analyzed in each severity group. Normal‐appearing brain matter of FLAIR images were extracted with validated in‐house brain extraction and intensity standardization algorithms [2]. Volume texture maps representing the correlation in the NABM for each FLAIR image were generated as per Khademi et. al [3].

Result

Boxplots for the NABM texture measures are shown for groups 1, 2 and 3 in Figure 1. Subjects with high delusional severity (group 3) had the most noticeable change in WMT relative to lowest delusional severity (group 1). Group 3 had a higher spatial correlation value of 6.0947 e+03 +/‐ 592.6178 than group 1 with values of 5.7630 e+03 +/‐ 832.5040. A higher value indicates more spatial correlation among pixels. This suggests that there are larger regions that are smooth in Group 3 compared to Group 1, indicating less WM “structure” in the more severe delusion group.

Conclusion

The severity of delusions in a cognitively diverse sample of older adults correlates with abnormalities in white matter texture, though further research is required to further validate our findings. References: [1] K. Misquitta, M. Dadar, D. L. Collins and M. C. Tartaglia and Alzheimer’s Disease Neuroimaging Initiative, White matter hyperintensities and neuropsychiatric symptoms in Alzheimer’s disease and mild cognitive impairment, bioRxiv, 2019. [2] A. Khademi, B. Reiche, G. Arezza, Method and System for Standardized Processing of MR Images, PCT Patent Application No. PCT/CA2018/051606, Filed.US. December 2018. [3] A. Khademi, D. Hosseinzadeh, A. Venetsanopoulos and A. Moody, "Nonparametric statistical tests for exploration of correlation and nonstationarity in images," 2009 16th International Conference on Digital Signal Processing, Santorini‐Hellas, 2009, pp 1‐6.
Results and drug development summary for Xanamem, a potent inhibitor of the 11β‐HSD1 enzyme
Authors: Ritchie Craig W. , Miller Tamara , Ketelbey John W.
Published: December 2020

Background

Xanamem™ is a potent and selective 11β‐HSD1 inhibitor. 11β‐HSD1 amplifies cortisol in brain regions, including the hippocampus. There is abundant evidence from animal and clinical studies linking elevated cortisol with hippocampal dysfunction, leading to poor learning, recall, and objective memory impairment. Thus, interventions that reduce cortisol levels may improve cognition and have long‐term benefits in reducing the risk of glucocorticoid toxicity and thereby reducing the risk of development and/or progression of dementia; Xanamem™ also has potential to treat additional indications beyond AD.

Method

The development strategy for Xanamem™ will be outlined including all pre‐clinical and clinical studies. Additionally, many independent studies have concluded that higher plasma cortisol is significantly related to lower hippocampal and gray matter volume, and that chronically elevated cortisol could exacerbate pathological processes associated with the onset and progression of AD.

Result

The development of Xanamem™ will be discussed, inclusive of: Pre‐clinical Studies; Phase II XanADu Study; Phase I XanaHES Study ‐including statistically significant results achieved in the Cogstate NTB in XanaHES; Target Occupancy program ‐ including new data on human and in vitro binding studies; Quantitative Systems Pharmacology (QSP) Modelling Outcomes ‐ including new data on QSP and PBPK models; and Complementary research endorsing the cortisol hypothesis.

Conclusion

Xanamem™ provides a mode of action wherein it inhibits cortisol production; the results achieved to date further endorses this scientifically robust target for both symptomatic treatment and disease course modification in AD and potentially non‐AD dementias and other neurodegenerative disorders.
Effect of increased physical activity on cognitive function in individuals with mild cognitive impairment: A pilot study
Authors: Nickerson Gasong Yun , Shade Kate
Published: December 2020

Background

Studies suggest physical activity reduces risk of dementia and aerobic exercise improves global cognitive function in people with Mild Cognitive Impairment (MCI). Commercial wearable activity trackers tested in neurological studies have shown excellent reliability with older adults and are valid measures of daily step count. The primary objective of this pilot study was to determine if increased physical activity improved cognitive function in individuals with MCI. The secondary objective was to evaluate the feasibility of the use of an activity tracker with individuals with MCI.

Method

This pilot was a one‐group pretest‐posttest study and included 16 community‐dwelling older adults diagnosed with MCI who met inclusion and exclusion criteria. Participants were patients of the memory clinic in Sacramento, CA during 2018‐2019. One wrist wearable activity tracker was issued to each participant, along with a free downloadable software application to pair the tracker with a device. Daily step count was measured by an activity tracker. Change in cognitive function was measured with a pretest and posttest using the Montreal Cognitive Assessment (MoCA). Timed Up and Go (TUG) assessed risk for fall as an exclusion criteria and to measure any change in physical fitness. Participants were encouraged to increase their physical activity for 12 weeks. The primary investigator contacted the participants every 2 weeks to check their progress.

Result

Increased step count was positively correlated with an improvement in cognitive function (p‐value of 0.04) with a moderate effect size (r = 0.55). The group of participants showing MoCA score improvement had a higher average daily step count than those that did not show score improvement at a confidence level of 90% (p‐value of 0.09).

Conclusion

5,500 steps or more per day is recommended to help improve cognitive function in individuals with MCI. It is feasible for individuals with MCI to wear an activity tracker reliably. The results of this pilot suggest the need for a randomized controlled trial with a larger sample. Further study is also recommended to identify covariates, such as activity intensity or history of regular exercise that predict improvement in cognitive function after a 12‐week intervention.
Translation and cultural adaptation of iSupport in Brazil
Authors: Oliveira Deborah , Jacinto Alessandro Ferrari , Gratao Aline Cristina Martins , Ottaviani Ana Carolina , Ferreira Camila Rafael , Monteiro Diana Quirino , Barham Elizabeth Joan , Orlandi Fabiana de Souza , de Cruz Keila Cristianne Trindade , Correa Larissa , Zazzeta Marisa , Pavarini Sofia Cristina Iost
Published: December 2020

Background

Most people with dementia are living in low‐ and middle‐income countries and are being cared for at home by their families. This task can negatively affect the mental and physical health of carers. However, public health initiatives to support family carers are still scarce. This study aimed to translate and culturally adapt the iSupport programme from World Health Organization for use by carers of people with dementia in Brazil.

Methods

The translation of the programme from English to Brazilian Portuguese was conducted by a professional translator. The translated content was discussed and checked for relevance, clarity and accuracy by a multidisciplinary team of researchers in Brazil. Next, 16 focus groups (n=48) were conducted with family carers of people with dementia and health and social care professionals in Sao Carlos‐SP, Brasilia‐DF and Sao Lourenco‐MG. Discussions were aimed at exploring whether the content of the translated version of iSupport was both clear and relevant to the needs of carers of people with dementia in Brazil. Representatives of the Brazilian Ministry of Health and Alzheimer’s Associations also contributed to this assessment.

Results

Overall, all participants had positive views of the iSupport material. In addition to researchers and translators, carers and professionals helped refine the text to make it clearer and more tuned to the Brazilian context. In general, participants found the material clearly written and culturally relevant. A few changes were suggested with regards to terminology and examples given in the modules to better fit the Brazilian culture and health systems, and links to relevant web pages of the Brazilian Alzheimer Association were included. Although further information could be added, the existing material was seen as sufficient.

Conclusion

The translation and cultural adaptation of iSupport included inputs from four categories of participants and showed that the programme was considered easy to understand and culturally relevant for carers of people with dementia in Brazil. The next step will be to pilot the translated and culturally adapted programme with carers in Brazil to establish its efficacy and usability.
Diagnosis of Alzheimer's disease with eye examination
Authors: Lü Yang , Qin Zhang Jin
Published: December 2020

Background

To evaluate the retinal changes in patients with Alzheimer's disease(AD) by combining pattern visual evoked potential(PVEP) and optical coherence tomography(OCT) and to study their diagnostic effects on AD.

Method

31 patients with AD and 37 normal elderly were involved in the study. The patients with AD were diagnosed in the First Affiliated Hospital of Chongqing Medical University between August 1, 2018 and November 30,2019, and the normal elderly were recruited from the local community. PVEP and OCT were performed on all subjects, and then the latency and amplitude of P100 wave in PVEP, the pRNFL thickness of each quadrant in OCT were recorded, and the difference between AD and HC(Health Control) was analyzed to study its diagnostic value for AD.

Result

Compared with the HC group, the amplitude of P100 wave in the AD group was significantly lower (p<0.05), and there was no difference in latency of P100 wave (p>0.05);The thickness of pRNFL was significantly thinner in the nasal, superonasal, superotemporal and Inferotemporal quadrant(p<0.05), and there was no difference in the temporal and Inferonasal quadrant(p>0.05). And by ROC curve analysis, it was found that the AUC of a single parameter of either retinal function or structure was lower than the AUC of multiple parameter combinations.

Conclusion

The amplitude of P100 wave combined with pRNFL thickness of superonasal and superotemporal has a high diagnostic efficiency for identifying patients with or without AD. This suggests that the combination of PVEP and OCT provides a good clinical biomarker for the diagnosis of AD.
Increased excess short‐ and long‐term mortality following infections in dementia: A prospective nationwide and registry‐based cohort study
Authors: Janbek Janet , Taudorf Lærke , Musaeus Christian Sandøe , Frimodt‐Møller Niels , Laursen Thomas Munk , Waldemar Gunhild
Published: December 2020

Background

The role of infections in dementia remains to date insufficiently explored. Studies have reported that pneumonia and sepsis were either an immediate cause of death or increased mortality in people with dementia. However, it is unknown whether association with mortality is long‐term and whether it is dependent on the type of infection. We aimed to investigate the association between several infections and the short‐ and long‐term mortality in people with and without dementia.

Method

We conducted a nationwide registry‐based prospective cohort study using data from Danish national registries. Follow up was from 1 January 2000 or the 65‐year birthday (whichever came later) until death, immigration or 31 December 2015. Primary exposure was incident dementia and a first infection post start of follow‐up. The primary outcome was all‐cause mortality. Mortality rate ratios (MRR) were calculated in all exposure groups (Dementia/Infection; Infection before or after dementia, Dementia/No Infection, No Dementia/Infection and with No Dementia/No Infection as the reference group) and stratified by sex and infection site categories. MRRs were also calculated by time since first infection and by infection site.

Result

A total of 1,496,436 people were followed with a total of 12,739,135 person years. A total of 575,260 people died during follow‐up (82,573 with dementia). MRR for the Dementia/Infection group (infection after dementia) was 6.52 (95% CI: 6.43 to 6.61) times higher compared with the reference group and was higher in men. MRRs for the Infection groups in all of the site categories were markedly higher in the Dementia than No Dementia group (highest ratios for sepsis and lowest for ear infections). MRRs were highest the first 30 days after onset of first infection in the Dementia group and remained higher than the No Dementia group until 10 years after first infection (similar trends in the analyzed infection site categories).

Conclusion

Mortality is substantially increased in people with dementia following infections of all sites. Excess mortality is both short‐ (within 30 days) and long‐term (after10 years). Our findings identify people with dementia and infections as a vulnerable group who need clinical attention.
What can lipidomics tell about patho‐mechanisms at the early phases of Alzheimer’s disease?
Authors: Sakr Fatemah A. , Dybra Martin , Gräler Markus , Teipel Stefan J. , Braeuer Anja
Published: December 2020

Background

“Precision medicine” is an emerging concept in the field of Alzheimer’s disease research, allowing for individual risk stratification based on the specific biological/molecular signature. Hence, extensive “Omics” studies exploring different biological molecules were run in order to retrieve molecular‐cellular pathways reflecting the full spectrum of the disease. Lipidomics seems to be one promising approach, as it reveals a number of bioactive molecules regulating patho‐physiological mechanisms. In this study, we explored Lipidomics‐derived data to identify relevant predictors of diagnostic sensitivity in the early phases of AD.

Method

We used data provided by ADNI and ran initial exploratory analyses followed by a logistic regression approach with elastic‐net regularization for selecting pertinent lipids discriminating between people from the AD spectrum and amyloid negative healthy controls. We defined three different models; 1‐ null model, only lipids were included as predictors 2‐ Fixed factors adjusted model, where Age, Gender and BMI were included as covariates and 3‐ APOE4 & Fixed factors adjusted model, which were further tested by adding continuous CSF‐pTAU values.

Result

In our analysis investigating CSF‐Aβ‐ NC (n=63) and CSF‐Aβ+ MCI (n=134), the best performance was achieved by the third model with an estimated cross‐validation accuracy, area under the curve (AUC), negative (NPV) and positive predictive value (PPV) of 0.76, 0.83, 0.67 and 0.80 respectively. Analogously, on investigating individuals at preclinical stage (CSF‐Aβ+ cognitively normal, n=39) against CSF‐Aβ‐ NC, the third model was the only model with acceptable performance with estimated CV accuracy, AUC, NPV and PPV of 0.66, 0.70, 0.68 and 0.64, respectively. This performance was further improved by combining the lipids with pTAU yielding 0.72, 0.74, 0.73 and 0.72 for the accuracy, AUC, NPV and PPV, respectively. The comparison between all models’ performance is summarized in Table. 1 for theNC versus preclinical analysis and displayed in terms of AUC values in Fig. 1 for NC versus MCI analysis. Additional results will be presented at the conference.

Conclusion

Lipid profiling can be a useful tool to reflect the pathological changes in early phases of AD. We plan to replicate these findings on a locally recruited cohort from our specialized memory clinic.
Studies on ApoE in the neurobiology of Alzheimer’s disease
Authors: Konings Sabine C. , Martinsson Isak , Gouras Gunnar K.
Published: December 2020

Background

ApoE4, the most important genetic risk factor for Alzheimer’s disease (AD), is mainly produced by astrocytes, to some extent by microglia, and under stress also by neurons. Under healthy conditions ApoE transports lipids from astrocytes to neurons, where it binds to receptors and is internalized. ApoE4 was reported to impair normal receptor recycling, modulates synaptic receptors and associates with enlarged endosomes in AD. ApoE4 target replacement (TR) mice in the absence of AD mutations show neuronal hyperactivity. However, precise mechanisms, cell types and targets of ApoE relating to AD remain unclear. Previous studies from our lab reported endosomal Aβ accumulation and Aβ‐induced endosome enlargement. Here we aim to elucidate the cellular mechanisms of different ApoE isoforms on neurobiological AD changes, including intraneuronal Aβ accumulation, endosomal alterations and synaptic dysfunction.

Method

Cortical and hippocampal mouse astrocytes and neurons are derived from ApoE KO, ApoE3‐TR and ApoE4‐TR mice. Human ApoE is obtained from various sources, including conditioned media of ApoE‐TR astrocytes or recombinant ApoE protein, among others. Wild‐type C57BL/6JRj, APP/PS1 and APP KO mouse neurons and mouse N2a cells are treated for different durations with ApoE3, ApoE4, ApoE KO or vehicle control, and analyzed by immunofluorescence, western blot and live cell calcium imaging.

Result

Astrocytes from ApoE3‐TR and ApoE4‐TR mice secrete high levels of human ApoE. Recombinant ApoE3 and ApoE4 bind to neurites, seemingly preferentially to synaptic terminals of neurons. ApoE‐TR mouse neurons express endogenous human ApoE in vitro, potentially related to stress associated with culture conditions. Internalized recombinant and endogenous ApoE and internalized synthetic and endogenous Aβ show a mostly vesicular but non‐overlapping pattern of labeling.

Conclusion

Endogenous and internalized ApoE are present in a vesicular pattern, which however does not significantly overlap with internalized Aβ. In addition, particularly exogenous synthetic ApoE appears to preferentially bind to synapses. We hypothesize that determining the biology of ApoE within neurons, as well as its effects on endosomes, intraneuronal Aβ and synapses, can help to better understand the role of ApoE in neurons and can provide new insights on the role of ApoE in Alzheimer’s pathogenesis.
Improving patient care through a national memory clinic network
Authors: Bouwman Femke H , Pel‐Littel Ruth , Hoogendoorn Tanja , Devries Kerst , Schipper Annemieke C , Driesen Jan , VanStek‐Smits Vera CJ , Sterrenburg Anje , VanderKroon Hester , Oudega Mardien L , van Der Flier Wiesje , Hofman Cynthia
Published: December 2020

Background

Memory clinics and their practising professionals may hide a treasure of clinical experience and knowledge. In addition, neuroscientists are seeking a way to bring their scientific results swiftly to clinical practice.

Objective

To optimize patient care in Dutch memory clinics (>100) by stimulating and facilitating its members to learn together, innovate and share knowledge and experience.

Methods

In November 2016 the Dutch Memory clinic Network (Nederlands Geheugenpoli Netwerk, NGN) was initiated after consulting the four national academic Alzheimer clinics (Amsterdam, Rotterdam, Maastricht, Nijmegen) and the Dutch Alzheimer Association (Alzheimer Nederland). The primary goal ‐ sharing knowledge – is achieved by: 1) Maintaining the NGN Website with information on educational opportunities, ongoing clinical research, guidelines, list of associated memory clinics, etc., 2) Sending out newsletters (4 times a year), 3) Organizing yearly conferences on various topics relevant to memory clinic professionals and researchers, 4) Facilitating professionals to discuss complex patients via the Siilo groups app (a protected messenger, to be used only by care professionals, checked through a national registration number: BIG).

Results

Of >100 memory clinics 77 listed themselves at the website (Fig 1). In the last nine months the website generated >4000 pageviews. Topics that are most frequently visited on the website are educational podcasts on trending topics in the field of dementia presented by clinicians several times a year. The newsletter topics vary: ‘ current research projects’, reports of recent relevant conferences, agenda of relevant conferences for memory clinics. Currently we have 430 subscribers for the newsletter. For the conference the number of attendants has increased over the past four years from 90 in 2016 till 220 in 2019. The Siilo groups app started November 2019, and currently counts 30 participants, increasing every month. Complex patients are discussed as well as news on memory clinics in the media.

Conclusion

With the growing number of page views, newsletter‐subscribers, attendants at the conference and members of the Siilo groups app, the NGN serves the dense network of memory clinic professionals in the Netherlands, with the ultimate goal to improve patient care for cognitively impaired patients.
Micronutritional biological status and dementia risk
Authors: Samieri Cécilia
Published: December 2020

Background

Optimal nutrition may prevent dementia; several nutrients have been associated with dementia risk, yet randomized controlled trials (RCT) testing the efficacy of nutrient supplementation for the prevention of dementia have remained largely disappointing so far. One of the reasons for the inability of RCT to demonstrate the efficacy of nutrient supplementation may be their failure to take into account basal nutritional status (as supplementation may benefit only people with nutrient deficiency). Epidemiology is a unique tool to understand and define the basal nutritional deficiencies that may primarily deserve correction with (multi)‐nutrient supplementation. We leveraged the large prospective French Three‐City (3C) cohort study, with multiple nutrient biomarkers measured at study entry and 17 years of follow‐up for the incidence of dementia, to define a micro‐nutritional biological status (MNBS) score that is associated with subsequent dementia risk.

Method

We included n=666 participants from the 3C study not demented and with blood measurements of 22 nutrients (12 fatty acids, 6 carotenoids, vitamin D, 2 forms of vitamin E, and vitamin A) at baseline, who were followed for up to 17 years for incidence of dementia. To construct our MNBS score, we: (1) defined the primary nutrients of interest, based on both literature review and 3C data; (2) defined plasma concentration thresholds, based on both existing thresholds (eg, existing recommendations, as for vitamin D) and 3C data (modeling each individual nutrient with dementia risk using Cox models with penalized splines); (3) computing a summary MNBS score and estimating its multivariable association with dementia risk.

Result

Our MNBS score included 3 nutrient groups significantly associated with dementia risk in our cohort: 25(OH)D; EPA+DHA; total carotenoids. Each component was divided into 3 biological levels (low, 0 point; intermediate, 1 point; high, 2 points), and the total score ranged from 0 to 6 points (Figure 1). Each increase of 1 point of the score was associated with a 20% reduction of dementia risk (p=0.002) (Figure 2).

Conclusion

A biological score assessing micro‐nutritional status globally is strongly associated with dementia risk. B vitamins may increase the predictive performance of the score and will be incorporated shortly.