bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylation status and sulfur amino acids as risk factors for cognitive decline over 15 years: A longitudinal, population‐based study
Authors: Hooshmand Babak , Refsum Helga , Smith A David , Grande Giulia , Marseglia Anna , Laukka Erika J , Bäckman Lars , Fratiglioni Laura
Published: December 2020

Background

Impairment of methylation status and raised values of homocysteine and cysteine may be modifiable risk factors for cognitive decline. We aimed to investigate the association of vitamin B12, folate, and sulfur amino‐acids with cognitive decline in a large sample of community dwelling older adults.

Method

From the Swedish National Study of Aging and Care in Kungsholmen (SNAC‐K), 2900 dementia‐free individuals at baseline aged 60‐102 years with comprehensive assessments and Mini‐mental state examination (MMSE) were recruited. A total of 2202 participants underwent repeated MMSE assessments up to 5 occasions over 15 years. The association of baseline vitamin B12, holotranscobalamin, folate, homocysteine, methionine, cystathionine, cysteine, glutathione, and methylation status (defined as serum methionine/homocysteine ratio) with rate of cognitive decline was examined using linear mixed models, adjusted for several potential confounders, including common vascular risk factors.

Result

After adjusting for age, sex, education, creatinine, albumin, smoking status, systolic blood pressure, and APOEε4 status, raised baseline serum total homocysteine and cysteine values were associated with faster rate of cognitive decline: for the highest quartile compared with the lowest, β coefficient and standard error (SE) were ‐0.0058 (0.002) for homocysteine (p=0.004) and ‐0.0051 (0.002) for cysteine (p=0.014) In contrast, a better methylation status was associated with less MMSE decline over 15 years: β (SE) was 0.0058 (0.002) for the highest quartile compared with the lowest (p=0.004). Furthermore, elevated methionine values tended to slow rate of cognitive decline (p=0.079). No relationships were found for other sulfur amino acids, vitamin B12 or folate.

Conclusion

Markers of methylation status and raised cysteine values were related to more rapid cognitive decline over 15 years, suggesting that optimizing homocysteine, cysteine, and methionine values may be important in reducing the risk of cognitive decline in older adults.
Plasma glutamate metabolism correlates with cognitive function and the brain‐adipose axis in a presymptomatic Alzheimer’s cohort
Authors: Fonteh Alfred N. , Arakaki Xianghong , Yu Jianquan , Castor Katherine , Harrington Michael G.
Published: December 2020

Background

In addition to the amyloid hypothesis, it is accepted that neurotransmitter and energy dyshomeostasis may underlie AD pathology. Glutamate (Glu) is one of the most common excitatory neurotransmitters and is the precursor of glutamine (Gln) and pyroglutamine (PGln). Glu signaling intersects with lipid metabolism via neuronal phospholipase A2 activation and the regulation of adiposity. Lipids are a major storage form of energy that is critical to AD pathology. We propose that disturbance in Glu metabolism may interfere with how the brain regulates lipid storage in adipose tissue and its utilization by tissues, and this process can contribute to early AD pathology. Consequently, the aim of our study is to quantify plasma Glu and its metabolites and determine their interaction with lipid metabolism in a pre‐symptomatic AD cohort.

Methods

We collected fasting blood samples from cognitively healthy (CH) study participants with normal cerebrospinal fluid amyloid/ tau ratio (CH‐NAT, n = 36) or with pathological amyloid/tau ratio (CH‐PAT, n = 34), and from AD participants (n = 26). The concentrations of Glu, Gln, and PGln were measured using liquid chromatography‐tandem mass spectrometry. Blood lipids were measured in a clinical laboratory (HMH, Pasadena) and CSF measures of Aβ42 and total tau were determined using an ELISA.

Results

Blood plasma Glu but not Gln and PGln positively correlated with CSF Aβ42/T‐tau ratio, in CH and CH‐NAT (p = 0.02) but not in CH‐PAT (p > 0.05) or AD (p = 0.99) participants. Blood plasma Glu also positively correlated with mean diastolic pressure (p = 0.02), BMI (p = 0.001), plasma triglycerides (p < 0.0001), and VLDL‐cholesterol (p < 0.0001), and negatively correlated with HDL‐cholesterol (p = 0.0003), in all CH study participants. Glu did not correlate with BMI but correlated strongly with VLDL‐cholesterol in CH‐NAT. In contrast, Glu correlated with BMI but not with VLDL‐cholesterol in CH‐PAT.

Conclusions

These data show the differential regulation of blood glutamate metabolism, CSF amyloid/tau, and plasma lipids in pre‐symptomatic AD compared with cognitively healthy participants. We propose that glutamate metabolism and the brain‐adipose interface may be involved in regulating cognitive function and improving its homeostasis may prevent the decline from cognitively healthy to pre‐symptomatic or AD pathology in elderly populations.
Dietary supplementation results in a significant incorporation of DHA into RBC phosphatidylcholine of non‐APOE ε4 allele but not for ε4 carriers
Authors: Solomon Victoria , Smirnova Yelena , Harrington Michael G. , Yassine Hussein N. , Fonteh Alfred N.
Published: December 2020

Background

Alzheimer’s Disease (AD) is commonly characterized by the accumulation of beta‐amyloid plaques in the brain causing neuroinflammation and cognitive decline. Risk for developing AD is associated with the ε4 allele of Apolipoprotein E (ApoE), a cholesterol carrier involved in lipid transport and brain injury repair. Docosahexaenoic Acid (DHA), an omega‐3 polyunsaturated fatty acid, has been shown to decrease ß‐amyloid production and prevent inflammation. The aim of our study is to determine whether DHA incorporation can account for the differences in the efficacy of DHA intervention in carriers of the ApoE ε4 allele (APOE ε4) compared with noncarriers (non‐APOE ε4).

Method

We supplied APOE ε4 (n = 15) and non‐APOE ε4 (n = 16) cognitively healthy (CDR ≤ 0.5) participants above the age of 55 with 2 g/day of daily fish oil supplements, for six months. Participants were randomized into either DHA‐treatment or placebo groups. We isolated red blood cells (RBCs) from participants at baseline (T0) and after six months (T6) and used LC/MS‐MS analyses to quantify phospholipid species. We isolated 44 phosphatidylcholine (PC) species and examined changes in DHA contents after supplementation.

Result

We found no significant differences in total PC across treatment groups nor between APOE ε4 and non‐APOE ε4 participants. Acyl DHA‐containing PC species (PC38a:6 and PC40a:6) increased significantly between T0 and T6 (p < 0.02 for all) non‐APOE ε4 participants. In contrast, no significant differences were seen between APOE ε4 carriers after DHA supplementation. No significant differences were found in plasmalogen PC‐DHA (PC40p:6) for any group. The ratio of PC‐DHA to PC‐containing arachidonic acid (C20:4n‐6), an omega‐6 fatty acid known to favor neurodegeneration, was significantly higher (p = 0.0008) for non‐carriers but not for ε4 carriers.

Conclusion

Our data shows that dietary supplementation gives specific incorporation of DHA into acyl‐PC species in RBCs of non‐APOE ε4 carriers but not for ε4 carriers. We propose that the increased risk of AD pathology of ε4 carriers may be due to the inefficient incorporation and transport of DHA. Alternative means are needed to enhance DHA incorporation and transport into blood cells of ε4 carriers to effectively combat cognitive decline even at its earliest stages.
The effect of heat shock protein 72 on cognitive decline and metabolic health in the 5xFAD*Tg30 Alzheimer's disease model
Authors: Marshall Jessica P.S.
Published: December 2020

Background

Heat shock protein 72 (HSP72) has the potential to play a cytoprotective role in Alzheimer’s disease (AD) as previous studies have demonstrated that its elevation inhibits amyloid beta oligomerization and enhances its clearance, restores tau homeostasis and inhibits neuronal apoptosis. BGP‐15 is a compound observed to be a co‐inducer of HSP72, and therefore, we hypothesized that pharmacological activating Hsp72 with this compound or genetically up‐regulating Hsp72 may be advantageous in preventing or delaying AD progression and associated pathology.

Method

We crossed 5xFAD (overexpressing human APP and Presenilin‐1) and Tg30 (overexpressing tau) mice, to create the double transgenic 5xFAD*Tg30. We then crossed the double transgenic mice with HSP72 overexpressing transgenic mice (Hsp72Tg) to create the triple transgenic, 5xFAD*Tg30*HSP72Tg. Double transgenic mice were kept untreated or treated with BGP‐15 in their drinking water in a randomised and blinded study in both male and female mice from the ages of 2‐10months. A comprehensive battery of behavioural and metabolic tests was conducted, and results compared to littermate wildtype mice.

Result

We observed significant declines in Rotarod, Y‐Maze and Novel Object performance in the 5xFAD*Tg30 mice compared to wildtype, however neither HSP72 overexpression or BGP‐15 treatment rescued this decline. HSP72 overexpression was effective in maintaining lean mass in male mice. BGP‐15 was efficacious in significantly increasing body weight specifically in female mice. In males there was a 40% decrease in survival rates by 10months, which was improved by BGP‐15 treatment to a 15% decrease(p=0.08).

Conclusion

BGP‐15 may improve survival rates (male) and increased weight (females) while overexpression of Hsp72 leads to maintenance of lean mass in male5xFAD*Tg30 mice. However, both avenues used to increase Hsp72 were insufficient to protect against cognitive deficits. Further studies analysing the brain pathology of these mice are warranted.
Study of the effect of ascorbic acid on Aβ42 peptide aggregation
Authors: Sampaio Isabella , Quatroni Felipe Domingues , Zucolotto Valtencir
Published: December 2020

Background

Ascorbic acid (AA) is an antioxidant molecule found at high concentrations in the brain. A negative correlation was found in Alzheimer’s disease (AD) patients between the decrease in AA brain levels and the accumulation of amyloid plaques indicating that AA plays some function in amyloid aggregation, however, no studies have elucidated its mechanism of action so far, which can greatly contribute to the development of new therapeutic strategies for AD.

Method

To investigate AA as inhibitor of amyloid aggregation, amyloid‐beta 1‐42 (Aβ42) samples containing or not AA were incubated in pro‐aggregation conditions and analyzed by atomic force microscopy (AFM) and fluorescence spectroscopy using Thioflavin T. The mechanism of action presented by AA was evaluated using isothermal titration calorimetry (ITC) technique to investigate its binding to Aβ42 monomers.

Result

Fluorescence analyses pointed out to a decrease in fibril formation for samples incubated with AA at a concentration found in brains of healthy patients. After 72 h, these samples presented almost 80% fewer β‐sheet structures than samples without the antioxidant molecule. The fluorescence results were corroborated by AFM images, indicating that AA inhibited the amyloid aggregation in the fibrillar form. ITC measurements showed a negative cooperative binding between AA and Aβ42 monomers. In this interaction model for multiple sites, the binding of AA molecule in the first site of Aβ42 decreases the affinity constant (Kd) for the binding in the second site (Kd1>Kd2).

Conclusion

Our study revealed that ascorbic acid is able to inhibit the aggregation of Aβ42 peptides into fibrils through the direct binding to the monomers. Based on the thermodynamic parameters, we observed that the interaction is spontaneous and exothermic. This finding highlights ascorbic acid as a potential candidate for Alzheimer’s disease treatment and the mechanism of action provides novel insights for the inhibition of amyloid aggregation.
The role of hypusinated eIF5A in TDP‐43 cytoplasmic sequestration in AD and TDP‐43 related dementia
Authors: Smeltzer Shayna , Quadri Zainnudin , Miller Abraian , Zamudio Frank , Chaput Dale , Lee Daniel C. , Selenica Maj‐Linda B.
Published: December 2020

Background

A wealth of studies have concluded that TAR DNA‐binding protein 43 (TDP‐43) pathology is associated with clinical dementia of including Frontotemporal Disorders (FTD) and Alzheimer’s Disease (AD). Interestingly, TDP‐43 pathology occurs in more than half of clinically diagnosed Alzheimer’s disease (AD) patients (1). These studies were recently complemented by the discovery of limbic‐predominant TDP‐43 encephalopathy (LATE) – underscoring the importance of age‐related TDP‐43 proteinopathy, with or without comorbid AD‐type plaques and tangles. eIF5A is the only known protein to undergo hypusination, a unique post‐translation modification at lysine (K50) (eIF5AhypK50) within the hypusine loop.

Method

We utilized a conditional TDP‐43 HeLa cellular model of sodium arsenite (SA)‐induced stress to investigate the role of hypusinated eIF5A (eIF5AHypK50) in TDP‐43 cytoplasmic mis‐localization and stress granule accumulation. We also performed LC/MS and proteomics analysis combined with Ingenuity and Enrich/GO analysis to identify relevant molecular and biological protein networks. Biochemical and immunocytochemical analysis and cellular microscopy were applied to measure TDP‐43 pathology.

Result

Our proteomics analysis in M17 cellular model provided evidence for the interaction of eIF5A with TDP‐43, while functional data revealed the hypusine‐dependent manner of such interactions. SA treatment promoted co‐localization of TDP‐43 with eIF5AHypK50 both in the cytoplasm and stress granules. Importantly, pharmacological reduction of hypusination or site‐directed mutations of lysine (K) 50 residues decreased phosphorylated and insoluble TDP‐43 levels without effecting “de novo” protein synthesis. Additionally, both proteomic and biochemical analysis identified Ran‐GTP, KPNA1/2 and KPNB1 as interacting partners of eIF5AHypK50.

Conclusion

We demonstrate that modifications in the hypusine loop of eukaryotic initiation factor 5A (eIF5A) reduces hallmarks of TDP‐43 proteinopathy; cytoplasmic mis‐localization, phosphorylation and sequestration. Conversely, pharmacological inhibition of hypusination reduces TDP‐43 accumulation and aggregation in cells. Additionally, we posit that eIF5AhypK50 regulates TDP‐43 cytoplasmic sequestration through interactions with nuclear pore complex (NPC) proteins, particularly importins KPNA2/B1 and Ran‐GTP. These findings elucidate novel pathways and potential therapeutic targets in AD and related dementia and require further investigations.
Higher atherosclerotic cardiovascular disease risk score and pulse pressure are associated with increased cerebrovascular pulsatility in Apolipoprotein E4 carriers
Authors: Kaufman Carolyn S. , Alwatban Mohammed R. , Ward Jaimie L. , Vidoni Eric D. , Morris Jill K. , Burns Jeffrey M. , Billinger Sandra A.
Published: December 2020

Background

Evidence increasingly points to an early role for cerebrovascular dysfunction in the pathogenesis of Alzheimer’s disease (AD). Studies suggest a potential synergistic effect on dementia development between poor systemic vascular health and the strongest known genetic risk factor for AD, the Apolipoprotein E4 (ApoE4) allele. We hypothesized that atherosclerotic cardiovascular disease (ASCVD) risk score and pulse pressure (PP) would be associated with pulsatility index (PI) at rest and during moderate‐intensity exercise in ApoE4 carriers but not non‐carriers.

Methods

We conducted a secondary analysis on data from cognitively‐normal adults (65‐86 years old) who were classified as ApoE4 carriers (n = 15) or non‐carriers (n = 25). For the parent study, individuals were recruited from the University of Kansas Alzheimer’s Disease Center. We calculated the ASCVD risk score from the laboratory values and physiologic measurements obtained for each participant. We used resting brachial artery measurements to calculate pulse pressure (PP = Systolic Blood Pressure – Diastolic Blood Pressure). We recorded middle cerebral artery velocity (MCAv) using transcranial Doppler ultrasound at rest and during 8 minutes of moderate‐intensity exercise. We calculated the PI for each participant (PI = (systolic MCAv – diastolic MCAv) / MCAv mean) during rest and exercise.

Results

No group differences between ApoE4 carriers and non‐carriers were found for age, sex, or body mass index (p > 0.05). A Spearman’s rank‐order correlation showed a significant positive correlation between ASCVD score and exercising PI for ApoE4 carriers (rs
 = 0.614, p = 0.015) but not for non‐carriers (rs
 = ‐0.007, p = 0.974). No association was observed between ASCVD score and resting MCAv. PP showed a positive association with resting PI in ApoE4 carriers (rs
 = 0.531, p = 0.042) but not non‐carriers (rs
 = 0.164, p = 0.432).

Conclusions

Poor systemic cardiovascular health was associated with higher pulsatile flow in the cerebral vasculature in ApoE4 carriers but not non‐carriers. These findings provide evidence for the connection between poor systemic vascular health and poor cerebral vascular function in ApoE4 carriers. These data highlight the importance for maintaining good cardiovascular health, particularly for those at highest genetic risk of AD.
The aging rhesus macaque as a potential model for Alzheimer's disease/dementia: An in vivo study of [11C]PIB, [11C]UCB‐j, [18F]MK‐6240 and working memory performance
Authors: Fang Xiaotian T. , Williams Graham , Castner Stacy , Holden Daniel , Zheng Ming‐Qiang , Najafzadeh Soheila , Ropchan Jim R. , Arnsten Amy F.T. , Horvath Tamas , Carson Richard E.
Published: December 2020

Background

Nonhuman primates (NHPs) exhibit age‐related cognitive impairments, synaptic loss, and accumulation of tau and amyloid in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In a cohort of NHPs with longitudinal cognitive data, we perform SV2A ([11C]UCB‐J), amyloid ([11C]PIB), and tau ([18F]MK‐6240) PET. We aim to 1) investigate in vivo relationships and age‐related change in amyloid, tau, and synaptic density (SV2A) and 2) to relate these to cognition in NHPs.

Method

Middle‐aged (n = 5, 10.4 ± 0.5 y.o.) and old (n = 17, 19.9 ± 2.7 y.o.) NHPs were dynamically PET scanned (FOCUS 220) following i.v. injection of each of [18F]MK‐6240 (173 ± 12 MBq), [ 11C]PIB (131 ± 52 MBq), and [11C]UCB‐J (105 ± 34 MBq). Structural MR scans were acquired for registering PET to template space. Outcome measures were SUVR40‐60 for [11C]PIB, SRTM2‐derived DVR for [11C]UCB‐J, and SUVR90‐110 for [18F]MK‐6240. Cerebellum was used as reference ([11C]PIB, [11C]UCB‐J), and cerebellar gray matter for [18F]MK‐6240. A subset of the old NHPs (n = 15) were tested with the spatial‐delayed response task to assess working memory performance. Outcome measures: number‐of‐wells, time‐delay, and combined score (number‐of‐wells × time‐delay); higher score indicates better memory performance.

Result

No regional mean differences were observed in amyloid or SV2A between middle‐aged and old NHPs, though old NHPs exhibited higher variance for all tracers; mean tau was elevated in dlPFC (p = 0.0031) and hippocampus (HC, p = 0.011) in old NHP compared with middle‐aged (Figure 1). In ERC, a positive relationship was found between tau and amyloid), and in HC, a negative correlation was found between tau and SV2A (Figure 2A). Synaptic density displayed a positive relationship with combined score both in dlPFC (p = 0.0055, R2 = 0.46) and HC (p = 0.029, R2 = 0.32) (Figure 2B). Tau had a negative relationship with number‐of‐wells in dlPFC (p = 0.05, R2 = 0.40), and combined score in HC (p = 0.015, R2 = 0.40).

Conclusion

NHPs exhibit age‐related changes in canonical AD biomarkers as seen by PET. PET markers of SV2A, tau, and amyloid in known early‐pathology regions (dlPFC, HC) correlate appropriately with working memory performance. These studies demonstrate the potential of NHPs as a highly useful model for human AD.
Mitochondrial translocator protein (TSPO) ligand attenuates neuroinflammation and reduces complement component C1Q in a mouse model of tauopathy
Authors: Fairley Lauren H. , Sahara Naruhiko , Suhara Tetsuya , Higuchi Makoto , Barron Anna M.
Published: December 2020

Background

The mitochondrial translocator protein (TSPO) has been widely investigated as a positron emission tomography (PET) detectable biomarker of neuroinflammation, as well as a potential therapeutic target for the treatment of neurodegenerative disease. In transgenic mouse models of AD, we and others have shown that TSPO ligands attenuate inflammation and beta amyloid burden (Barron et al., 2013). However, the effect of TSPO ligands on tauopathy‐induced inflammation has not yet been investigated. Here, we analysed the effects of the prototypic TSPO ligand, Ro5‐4864, on the progression of tauopathy, gliosis and atrophy in the rTg4510 tau transgenic mouse model (TauTg).

Method

TauTg and WT control mice were treated with Ro5‐4864 or vehicle for 4 months. Brain atrophy was assessed using volumetric magnetic resonance imaging, while tauopathy and neuroinflammation were assessed by PET using 11C‐PBB3 and 18F‐FEBMP tracers, respectively. To corroborate in vivo findings, immunohistochemistry was performed in sections from scanned mice to measure phosphorylated tau (AT8), inflammation (IBA1, complement component 1q, C1q) and neuronal loss (NeuN).

Result

Ro5‐4864 treatment reduced markers of neuroinflammation, as well as expression of the neuronal ‘eat me’ signal, C1q in rTg4510 mice. In vitro experiments using the immortalized microglial cell line, BV2, confirmed the TSPO ligands, Ro5‐4864, reduced expression of C1q in response to inflammatory stimuli.

Conclusion

These findings support a protective role for TSPO ligands in reducing tauopathy‐induced neuroinflammation.
A pilot study exploring factors influencing delivery of individual cognitive stimulation therapy in the Indian context
Authors: Adhikari Dimple , Faqurudheen Hena , Dasgupta Jayashree
Published: December 2020

Background

Elderly with dementia in India is expected to increase to 7.6 million by 2030, however, availability of therapeutic services like Individual Cognitive Stimulation Therapy (iCST) remain limited. In order to bridge this gap, we culturally adapted the iCST modules for use with dementia patients in India and report preliminary findings from a pilot study exploring factors influencing session delivery.

Method

Modules were reviewed by two experienced geriatric care specialists and modified to include culturally appropriate content, images and activities such as music, cinema, games, food and festivals. To ensure appropriateness of content, inputs were taken from senior citizens. Sessions were piloted with 4 older adults who had a diagnosis of dementia by a neurologist/psychiatrist and corroborated with the Hindi Mental Status Examination (range of scores between 14 to 21 indicating initial and moderate stage of dementia). A trained care‐specialist delivered the sessions at home (3 participants) or clinic setting (1 participant). Participants were assessed on a 5‐point Likert scale for interest, mood, enjoyment, communication and anxiety for each session. Session notes were maintained to document observations and feedback was obtained from family members that was qualitatively analyzed for acceptability and feasibility.

Result

Participants were between 60‐85 years of age, with postgraduate education, retired from private or government jobs. Qualitative data from session notes and family feedback was analyzed using thematic analysis. Feedback indicated the following benefits: setting up a meaningful daily routine, improving socialization and providing respite for primary caregivers during sessions. Clients showed improvements in learning new information, self‐confidence and self‐motivation. Modules on food, faces/scenes and number games were most enjoyable. Participant interest in sessions fluctuated according to changes in medication and mood of the client, (usually impacted by day‐to‐day on goings within the family), which the specialist had to factor into session delivery. Two participants discontinued iCST, one due to development of aphasia and another due to denial of the illness by spouse and refusal to continue sessions.

Conclusion

Although iCST has several benefits, several contextual factors influence delivery of sessions, highlighting the importance of increasing public awareness for better delivery.
Sleep disturbance is associated with higher plasma Aβ: A population‐based cross‐sectional study
Authors: Gao Yao
Published: December 2020

Background

Growing evidence suggest that sleep disturbance is a risk factor for Alzheimer’s disease (AD). Amyloid‐β (Aβ) deposition in the brain is a main pathophysiology of AD. Although peripheral Aβ clearance is associated with brain Aβ deposition, but the relationship between sleep disturbance and plasma Aβ levels is unclear.

Method

This was a population‐based cross‐sectional study. A total of 1459 participants from a village in the suburbs of Xi’an, China were enrolled from January 3 to March 26, 2017. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI), and good sleep quality defined as PSQI score<5 points, poor sleep quality defined as PSQI score >10. Cognitive function was assessed with the mini‐mental state examination (MMSE). Fasting venous blood was taken in the morning and plasma Aβ levels were measured by ELISA. The relationships between plasma Aβ levels and sleep quality was analyzed using multiple linear regressions.

Result

Among 1459 participants, 231 had poor sleep quality (15.83%). The log‐transformed Aβ40 level had significant difference among different sleep groups (F=3.216, p=0.040). log‐transformed Aβ40 level was higher in poor sleep quality group than that in general sleep quality group [87.17 (73.42,107.34) vs. 89.69 (74.81,125.79) pg/ml, p=0.016]. In bivariate analysis, sleep quality was negatively associated with plasma log‐transformed Aβ40 level (β=‐0.025, p=0.011).

Conclusion

In the cognitively normal population, the poorer sleep quality is associated with higher plasma Aβ40 level. These indicated that sleep disturbance may relate to peripheral Aβ clearance.
Is there still a rationale for BACE‐inhibition in Alzheimer’s disease? A quantitative systems pharmacology analysis
Authors: Geerts Hugo , Spiros Athan
Published: December 2020

Background

So far all clinical trials with BACE inhibitors have failed to generate a cognitive benefit and many have demonstrated a reversible cognitive worsening. Lack of understanding of the biological reason for this clinical effect hampers the study of which patient subpopulations might still benefit from lower levels of target exposure.

Method

We present computer‐based Quantitative Systems Pharmacology (QSP) simulations of cognitive ADAS‐Cog readouts to identify relevant PD‐PD interactions between comedications, common genotype variants, disease state and amyloid modulating agents, in particular BACE inhibition. This platform is based on a computer model of biophysically realistic neuronal cortical microcircuit with 35 CNS targets and calibrated for ADAS‐Cog. Long and short amyloid peptides affect glutamate and nAChR neurotransmission differentially that reproduces three clinical datasets. APOE, COMTVal158Met and 5‐HTTLPR rs23351 genotype are introduced using human imaging studies.

Result

The 5‐HTTLPR rs23351 L/L genotype defines a set of responders that are more resilient to amyloid increase with a 3‐4 point smaller worsening on ADAS‐Cog. Differential interaction with tau pathology can further reduce the effect with up to a 0.5 point. When simulating 2 year BACE‐I treatment in MCI, the platform predicts a worsening of up to 3 points compared to baseline on ADAS‐Cog for subjects with 5‐HTTLPR s/s genotype and slow amyloid progression while placebo deteriorates only 2 points. Conversely, BACE‐I is anticipated to improve cognition by about 0.4 point compared to baseline in subjects with 5‐HTTLPR L/L genotype and fast amyloid progression with placebo deteriorating 0.1 point. Lower levels of target engagement slightly improve the effect of BACE‐I but only in subjects with already elevated amyloid baseline levels. This is likely because of the beneficial effect of low doses of short amyloid forms that are also reduced by BACE‐I.

Conclusion

QSP is a hypothesis‐generating engine based on mechanistic, integrative and quantitative modeling of pharmacological and biological data and is particular informative at the individual patient level. The platform explains the reversible worsening of cognition with high exposure levels of BACE‐I in prodromal AD. Further simulations suggest that BACE inhibition can have modest benefits at lower levels of target engagement and in well‐defined patient populations.
Which tau target to select for drug discovery? Insights from an advanced quantitative systems pharmacology model
Authors: Spiros Athan , Geerts Hugo
Published: December 2020

Background

Although tau pathology is a major driver of Alzheimer’s Disease (AD) pathology and remains a very interesting target, the mere complexity of tau biology significantly hampers the identification and validation of the most impactful target.

Method

We developed a Quantitative Systems Pharmacology (QSP) platform integrating diverse preclinical and clinical knowledge about tau biology processes in an actionable computer model. The computer model includes tau species diversity, activity‐dependent tau secretion, tau binding to HSPG at the synaptic cleft and along the axonal membrane following a diffusion gradient and subsequent internalization, slow axonal transport over microtubules, intracellular degradation and templating of monomeric tau by seed‐competent tau into aggregates and insoluble Neurofibrillary Tangles. Polysynaptic progression is implemented by modeling secretion into the second synapse and subsequent uptake in the second axon.

Result

The platform was calibrated with preclinical experiments from in‐vitro cellular assays and injected brain extract in transgene mouse models. The model reproduced experimentally determined in vivo monomeric tau progression speeds at 0.25 mm/day; the rate of oligomerization was estimated to not less than 58 nM/year and the presence of each additional synapse reduces the peak of oligomeric tau about tenfold. We modified the platform to reproduce clinical AD pathology, based on stationary levels of seed‐competent tau from experimental measures in post‐mortem brains at diverse Braak stages. Using sensitivity analysis on this in silico platform we rank ordered various possible therapeutic interventions on the accumulation of seed‐competent tau in distal regions such as passive immunization using antibodies with different epitopes on the tau protein, reduced binding to HSPG, reduction of oligomerization, decreased secretion and increased degradation and identified interesting synergistic interactions. Interestingly this order was not the same as for the simulated conditions of injected brain extract in mouse models, possible identifying another problem of translationability.

Conclusion

Advanced computer modeling allows to ‘humanize’ preclinical experiments and can be an additional tool to support innovative disease modifying tauopathy R&D projects.
Assessing the longitudinal relationship between theta‐gamma coupling and working memory performance
Authors: Brooks Heather J. , Wang Wei , Kumar Sanjeev , Goodman Michelle S. , Zomorrodi Reza , Blumberger Daniel M. , Daskalakis Zafiris J. , Mulsant Benoit H. , Voineskos Aristotle N. , Rajji Tarek K.
Published: December 2020

Background

Individuals with a history of depression exhibit cognitive deficits and are at high‐risk for developing dementia. In particular, they show deficits in prefrontal cortical function, e.g. executive functioning and working memory. Theta‐gamma coupling (TGC) is a neurophysiologic marker of prefrontal cortical function. In cross‐sectional studies, TGC is associated with performance on several prefrontal cortex dependent cognitive tasks. Thus, it is a promising target for interventions to enhance cognition and possibly prevent cognitive decline. However, the relationship between change in TGC and change in cognitive performance is not yet characterized. The aim of this study is to determine whether change in TGC over repeated assessments is associated with change in working memory performance at these assessments.

Methods

Twenty‐seven older individuals with a history of depression (mean age = 66.18, SD = 5.43) completed the N‐back, a working memory task, at three time‐points (T0, T1 (2 weeks post T0) and T2 (90 days post T0). TGC was recorded using electroencephalography during the N‐back task. Change in TGC and N‐back performance among the three time‐points was calculated for each participant. Regression analyses were run, with change in N‐back dprime as the dependent variable, change in TGC as the independent variable, and time‐point as the fixed factor. To control for any effect of change in theta and gamma oscillations, we included also changes in theta and gamma powers as covariates.

Results

We found a positive association between change in TGC and change in N‐back dprime (B = 96.5, p = 0.006), but no association between change in theta (B = 7.66e‐6, p = 0.28) or gamma (B = 1.96E‐6, p = 0.93) power. There was also no effect of time‐point (B = ‐0.32, p = 0.07), and no interaction between time‐point and TGC (B = ‐67.17, p = 0.23).

Conclusion

Our results suggest enhancing TGC could enhance working memory performance irrespective of whether this enhancement happens over days or weeks. They also further support the use of TGC as a target for intervention to enhance prefrontal cortical function in individuals at high‐risk for cognitive decline, and potentially prevent decline and dementia.
Genetic analysis of biobank data: Familial history aggregation‐based tests (FHAT) with application to Alzheimer's disease
Authors: Wang Yanbing , Chen Han , Peloso Gina M. , Destefano Anita L. , Dupuis Josée
Published: December 2020

Background

Biobanks provide great resources for genetic association analysis. To increase power of genetic association analysis, we propose a novel approach to exploit family history of disease that is often available in biobanks. While methods have been proposed to incorporate family history in single variant analysis, methods to incorporate this information in gene‐based tests, such as the Sequence kernel association test (SKAT), are not available. The goal of this project is to develop a familial history aggregation‐based test (FHAT) to improve power to detect rare variant associations in gene‐based tests, and to apply this method to detect genes associated with Alzheimer’s Disease (AD).

Method

We assume that participants’ genotypes, and phenotypes of participants’ and their relatives, such as parents, are available from a large cohort. We first assess the association between participants’ genotypes and their phenotypes. Then we evaluate the association between participants’ genotypes and a set of relatives’ disease status conditional on the participants’ disease status. We use a weighted meta‐analysis to combing the score statistics from probands and their relatives. We evaluate the FHAT in simulations, and we apply our novel method to detect associations of gene regions with Alzheimer’s Disease (AD) in the UK Biobank data incorporating parental disease history.

Result

Our simulation results showed that the type I error of FHAT is well controlled with disease prevalence of 10% and 20%. We obtained corrected type I error rate at various alpha levels using 10,000 simulation replicates with a sample size of 5,000. Out of seven genes previously implicated in AD susceptibility, six showed evidence of association using FHAT in UK Biobank. These six genes had improved significance after incorporating parental phenotype information.

Conclusion

We proposed a novel approach to include family history, as is often available from medical charts, and showed improved power to detect aggregates of rare variant genetic associations with AD in large cohorts or biobanks.
Best practices for rehabilitation for older adults with dementia
Authors: McGilton Katherine S , Vellani Shirin , Zheng Nancy , Wang Daniel , Yeung Lydia , Escrig‐Pinol Astrid
Published: December 2020

Background and Objectives

Despite emerging evidence that older adults with cognitive impairment including those with dementia can be rehabilitated following a hip fracture, there is a paucity of research on strategies staff use and the support required to effectively rehabilitate this cohort. This qualitative study explores healthcare professionals’ perspectives of providing rehabilitation for older adults with cognitive impairment.

Methods

An in‐depth qualitative exploration of one site selected for its excellent outcomes in rehabilitation of older adults with cognitive impairment. Sixteen healthcare professionals with various backgrounds (occupational therapists, nurses, physiotherapists, and one social worker) were purposively sampled using a maximum diversity sampling strategy. Four focus groups were conducted to explore the experiences of professionals providing rehabilitation to this population. A hybrid inductive‐deductive approach was used to analyze the data.

Results

Participating healthcare professionals acknowledged that older adults with cognitive impairment deserved a chance at inpatient rehabilitation and favourable outcomes were achievable; however, their knowledge, skills, and attitudes required reframing. Analysis identified three essential components to rehabilitating this cohort: i) staff’s need for education, mentorship, and support to facilitate positive outcomes for persons with dementia, as well as for the healthcare team ; ii) the importance of knowing each patient to individualize rehabilitation approaches that encourages participation in rehabilitation; and iii) the need for care partner involvement by making contributions to rehabilitation care while in the hospital as well as continue to support recovery when they returned home, with support and education from the rehabilitation staff.

Conclusions

Rehabilitation of older adults with cognitive impairment is achievable and healthcare professionals can learn how to modify their practices to achieve positive patient outcomes. However, support and involvement of management to help create a vision for success is essential.
Are life events differentially associated with dementia risk by gender?
Authors: Kim Alice J. , Beam Christopher R.
Published: December 2020

Background

Gender differences in the association between life events and dementia have rarely been explored. Mixed findings exist regarding the role of gender in stress exposure, generation, and reactivity. Gender may affect the pathways through which different life events correlate with dementia risk. We hypothesized that life events would differentially associate with dementia risk by gender via both familial confounding and causal processes in a sample of older Swedish adults.

Method

We analyzed data from 885 twin families (>= 50 years; 57.81% women; N = 1,742) in the Swedish Adoption/Twin Study of Aging. Six life event domains were constructed from variables measuring ever‐occurrence of life events through 1990 (general loss, negative child events, self‐illness, family strife, negative spousal events, positive life events). Models were run separately by gender. Dementia diagnoses occurring after 1990 were made via clinical assessment and national registry linkage (15.06% diagnosed). Biometric regression models were used to evaluate confounding and quasi‐causal effects of life events on dementia status.

Result

For women, the total effect of life events on dementia was detected for general loss (B = 0.19, SE = 0.06, p = .001); for men, family strife was associated with dementia (B = 0.22, SE = 0.10, p = .027). After adjusting for shared genetic and environmental factors, there were no associations between these life events and dementia, indicating little evidence for quasi‐causal effects. The associations were best explained by familial confounding.

Conclusion

Gender differences were found in the association between life events and dementia such that general loss in women and family strife in men were predictors of dementia risk. Familial confounding explained these associations. Rather than attempting to minimize dementia incidence by mitigating impacts of life events, future research could examine the kinds of genotypes and environments that increase the risk of experiencing both negative life events and dementia by gender (e.g., for men, social environments inducing hostility may engender risk of both family strife and dementia). By preventing or intervening in impacts of these mechanisms, it may be possible to decrease the incidence of both negative life events and dementia.
CSF p‐Tau/AΒ40 ratio adjusts for the variance of CSF production and predicts brain tau accumulation in Alzheimer’s disease
Authors: Guo Tengfei , Korman Deniz , Shaw Leslie M. , Trojanowski John Q , Jagust William J. , Landau Susan M. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

Alzheimer’s‐related tauopathy can be measured with CSF p‐Tau and tau PET, but the associations between them as well as in relation to prospective tau PET and cognition are not well understood. Furthermore, recent studies observed CSF p‐Tau is positively associated with CSF Aβ42 in the normal range, which presumably reflects individual differences in CSF production rather than pathology and adds noise to CSF p‐Tau measurements.

Method

We analyzed 345 participants with Aβ PET, 18F‐flortaucipir PET, and CSF measurements and from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We observed that the use of a CSF p‐Tau/Aβ40 ratio to define CSF tauopathy reduced noise related to the presumably artifactual positive correlation between CSF p‐Tau and Aβ42 among Aβ PET‐ individuals (Fig.1). We investigated inter‐relationships associations between continuous and dichotomous Aβ PET, CSF p‐Tau/Aβ40 and flortaucipir as well as their prediction of subsequent flortaucipir increase and cognitive decline.

Result

The CSF p‐Tau/Aβ40 ratio also increased associations (relative to p‐Tau alone) with flortaucipir uptake across 34 Freesurfer‐defined cortical regions and amygdala. The highest CSF p‐Tau/Aβ40 associations were observed primarily in Temporal‐metaROI (Fig.2), so this region was selected to detect tau deposition for further analyses. Among Aβ+ participants (who drove all associations), Aβ PET was associated (p<0.001) with both CSF p‐Tau/Aβ40 and flortaucipir, and “abnormal CSF p‐Tau/Aβ40 only” were 4 times more prevalant (p<0.001) than “abnormal tau PET only” (Fig.3); in multivariate analyses predicting longitudinal flortaucipir and cognitive changes, CSF p‐Tau/Aβ40 was the strongest predictor of subsequent flortaucipir increase while flortaucipir was the strongest predictor of longitudinal cognitive change(Fig.4).

Conclusion

In summary, we found that CSF p‐Tau/Aβ40 may reduce individual variability related to CSF production and improve the accuracy of tau detection in CSF. Our findings support a model in which Aβ PET positivity precedes abnormal CSF p‐Tau/Aβ40 and is subsequently followed by abnormal Temporal‐metaROI tau PET and cognitive decline. The temporal sequence of abnormal tau biomarker changes may provide insight into pathological changes that precede cognitive decline in Alzheimer’s disease.
Anemia, mild cognitive impairment, and dementia among rural‐dwelling older adults: A population‐based study
Authors: Jiang Ziying , Han Xiaolei , Wang Yongxiang , Hou Tingting , Cong Lin , Tang Shi , Qiu Chengxuan , Du Yifeng
Published: December 2020

Background

Evidence has emerged that anemia is associated with cognitive impairment and dementia in older people. However, their relationship has been rarely examined among people in low‐ and middle‐income countries. We aimed to investigate the associations of anemia and hemoglobin with mild cognitive impairment (MCI) and dementia among rural‐dwelling Chinese older adults.

Method

This population‐based cross‐sectional study included 4,838 participants (age ≥65 years; 57.0% women) who were living in the rural communities in western Shandong Province. Data on demographics, lifestyle, clinical conditions, and cognitive function were collected through face‐to‐face interviews, physical examinations, and laboratory tests. Anemia was defined as hemoglobin levels <13 g/dl in men and <12 g/dl in women. Cognitive function was evaluated using the Mini‐Mental State Examination (MMSE) and neuropsychological test battery. We defined MCI using Petersen’s criteria and dementia according to the DSM‐IV criteria. Data were analyzed using multiple multinomial logistic and general linear regression models.

Results

The overall prevalence of anemia was 20.1%, with the prevalence in people with normal cognition, MCI, and dementia being 19.2%, 22.8%, and 26.3%, respectively. Anemia was associated with a multiple‐adjusted odds ratio of 1.28 (95% CI: 1.04‐1.57) for MCI and 1.27 (95% CI: 0.87‐1.85) for dementia, and a multiple‐adjusted β‐coefficient of ‐0.60 (95% CI: ‐0.94 to ‐0.27) for MMSE score. Furthermore, a higher hemoglobin level was significantly associated with a greater C‐MMSE score (P for trend <0.001), but not with dementia.

Conclusions

Anemia is associated with MCI and poor global cognitive performance, but not with dementia among rural‐dwelling Chinese older adults. Furthermore, a higher hemoglobin level is correlated with better cognitive performance.
Memory clinics as vehicles of research into dementia: The NACC example
Authors: Kukull Walter A. ,   National Alzheimer's Coordinating Center
Published: December 2020

Background

Alzheimer’s Disease Research Centers (ADRC) in the U.S, (N∼30) all enroll participants through similar clinical settings while applying a variety of active and passive recruitment methods. Thus, the voluntary enrollment and other characteristics of participants may resemble many referral‐based memory clinics not at ADRCs. In most cases however, the enrollee may not reflect the composition of the general population. When standardized clinical examination and data are applied across these independent case series valuable research data can be collected and both cognitively normal and cognitively impaired groups can be compared cross‐sectionally and longitudinally. The National Alzheimer’s Coordinating Center (NACC) receives, curates, stores and distributes the aggregate data to researchers on request. https://www.alz.washington.edu

Method

The Uniform Data Set (UDS) was established in 2005 and applied in the clinics of the ADRCs. By December 2019, data from 42,022 participants were included; 6,056 of those participants had also died and completed standardized neuropathology exam and data collection. In addition 28,519 UDS participants have data on 2 or more clinic visits.

Result

This conglomerate “case series” is comprised of cognitively normal through demented individuals etiologically classified by underlying disease (e.g., AD, VaD, LBD et al). The value of common data collection is also highlighted as DNA are made available for genomic studies resulting in new genetic associations with disease. In addition the overall data have led researchers to produce some 500 research publications.

Conclusion

Combination of standardized data across independent memory clinic settings can lead to valuable research findings. While population‐based research is still most valuable for inferring the occurrence of various conditions in the community, these clinic‐based case‐series can provide valuable insights and comparisons to further our knowledge of Alzheimer’s disease and related dementias.