bluuebunny/crossref_metadata_2025 huggingface dataset:
Vortioxetine use in demented patients
Authors: Valverde Ana H. , Campillo José M. , Godinho Filipe
Published: December 2020

Background

Vortioxetine is a new antidepressant with a distinctive pharmacological profile. It combines inhibition of serotinine transporter with modulation of various serotonine receptors. Its cognitive benefit in adults depressed patients has been previously demonstrated. There is evidence of its antidepressant effect in the elderly but not specifically of its utiliity in demented population. Effects in a group of different types of dementia patients are showed and hypothesis of its efficacy based on its properties are proposed.

Method

A retrospective study was conducted. Eligible patients were those observed in our memory outpatient clinics during 2019. All patients had behavioural symptoms (BPSD), Main symptoms were anxiety, apathy, irritability and restlessness. Thirty‐two patients were reviewed.

Result

32 patients were included, of which 60,6% were women. Median age was 74 years (SD 12,070). Alzheimer´s disease was the most common type of dementia (51.5%), as expected. Median dose of vortioxetine used was 10 mg/day. Symptoms that led to vortioxetine initiation were anxiety (57,6%), apathy (48,5%) and irritability (42,4%). Depreesion was present in 33,3% of cases, but anxiety and apathy were the symptoms that improved the most after vortioxetine introduction. 60,6% of patients were concomitantly treated with antidementia drugs, mostly Rivastigmine (30,3%). Coexistent benzodiazepines or antipsychotics use in patients treated with vortioxetine was not significant (24,2% and 21,2% each one). No side effects were reported.

Conclusion

Vortioxetine may be an useful option for BPSD in dementia population. Available evidence indicates that target receptors for vortioxetine play an important role in brain networks, and this could explain its efficacy regardless the antidepressive effect. No safety concerns were found in this group of patients with doses from 10 to 20 mg/day according with tolerability profile already described. Further studies with a more extensive number of eligible patients and prospective design are needed.
The association between health beliefs and attitudes towards dementia and the intention to change health behavior for dementia risk reduction: A cross‐sectional study in the Netherlands
Authors: Matulesseij Tessa , Joxhorst Tessa , Vrijsen Joyce , Smidt Nynke
Published: December 2020

Background

Approximately one third of the dementia cases are attributed to modifiable risk factors, including physical inactivity, unhealthy diet, excessive alcohol use and smoking (Livingston et al., 2017). Positive health beliefs and attitudes towards dementia (risk reduction) may encourage adopting a healthy lifestyle. We aimed to investigate the association between health beliefs and attitudes towards dementia and the intention‐to‐change health behavior for dementia‐risk‐reduction among the Dutch general population.

Method

A random sample of 4500 residents of the municipality of Groningen (The Netherlands), aged 30 to 80 years, was invited to complete an online survey. Health beliefs and attitudes were measured using the cross‐cultural validated Dutch Motivation to Change Lifestyle and Health Behavior for Dementia‐Risk‐Reduction scale (perceived susceptibility, perceived severity, perceived benefits and barriers, cues to action, general health motivation, self‐efficacy). The intention‐to‐change health behavior (physical activity, diet, alcohol consumption, and smoking) was measured using the stages‐of‐change (contemplation and preparation stage versus pre‐contemplation, action or maintenance stage). We used multiple logistic regression analyses adjusting for potential confounders (age, sex, education, employment).

Results

655 residents participated in the survey (mean(SD) age: 58(13.4) years, 54% female). Sixty percent were physically inactive, 44% were excessive‐alcohol‐users, 13% were smokers and all participants (100%) had a poor‐to‐moderate adherence to the Mediterranean‐DASH‐Intervention‐for‐Neurodegenerative‐Delay (MIND)‐diet. Older participants had higher scores on perceived severity and lower scores on perceived benefits, perceived barriers and self‐efficacy. Participants with a higher education level had higher scores on perceived benefits and self‐efficacy, but lower scores on perceived barriers. Overall, positive attitudes and health beliefs towards dementia‐risk‐reduction are associated with the intention‐to‐change physical activity (OR=1.058; 95%‐CI:1.031,1.087), diet (OR=1.049; 95%‐CI:1.024,1.073) and alcohol use (OR= 1.045; 95%CI:1.006,1.086).

Conclusion

Attitudes and health beliefs towards (dementia) risk reduction in the Netherlands are poor. People with positive health beliefs and attitudes towards (dementia) risk reduction have more often the intention‐to‐change their health behaviors. Dementia prevention should focus on education of the general population to improve their knowledge about dementia in general and the risk and protective factors for dementia. Further research should investigate the effectiveness of improving health beliefs and attitudes towards (dementia) risk reduction on health behavior change.
Stigma of Alzheimer's disease in healthcare professionals: Numbers that still surprise
Authors: Sarmento Ana Luisa Rosas
Published: December 2020

Background

Even in high income countries , the general public and health care professionals still have some stigma about dementia. Despite campaigns people still delay seeking out help advice when they first start to forget and to worry about their own memory or that of a family member.

Method

A simple multiple choice questionnaire, with questions about knowledge about Alzheimer's disease, evolution and prognosis and personal questions about perception, feelings and prejudices about the disease, was applied to physicians in the field of neurology and non‐neurologists. The sample was made up of 5 different groups of health professionals : second and third year neurology residents, general neurology assistants, neurologists specializing in dementia , non‐neurologists and nursing technicians working in a neurology ward.

Result

Doctors are expected to have less prejudice and misconceptions about diseases, however, although rare, we still find some concepts inadequate and mainly, some responses from the questionnaires pointed out a certain stigma in relation to Alzheimer's disease, mainly in the group of non‐neurologists e some nursing technicians.

Conclusion

Information is the better way to combat the stigma. More campaigns, more medical information and most importantly, more continuing medical education in dementia needs to be provided to health professionals.
Aβ42 mediated activation of the NLRP3 inflammasome predicts cognitive and gait performance in midlife type 2 diabetes mellitus (T2DM)
Authors: Dyer Adam H. , Batten Isabella , Woods Conor , Gibney James , Bourke Nollaig , Kennelly Sean
Published: December 2020

Background

Midlife Type 2 Diabetes Mellitus (T2DM) is a potent risk factor for later development of dementia. However, putative mechanisms mediating this risk are poorly understood. The NLRP3 inflammasome receptor, which drives strong pro‐inflammatory responses, has been implicated in both T2DM and Alzheimer’s disease (AD) pathogenesis, and can be activated by Amyloid β1‐42 (Aβ42).

Method

Peripheral Blood Mononuclear Cells (PBMCs) were isolated from participants with T2DM (N = 39; 52.04 ± 8.01 years) and matched controls (N = 21; 52.16 ± 7.82 years) without any evidence of cognitive impairment. PBMCs were incubated for 18 hours under the following conditions: (i) Lipopolysaccharide (LPS), (ii) Aβ42, (iii) LPS & Aβ42 and (iv) LPS & Nigericin (potent NLRP3 activator). Cytokine production was measured using ELISA and gene expression using qPCR. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Gait speed was measured under normal and dual‐task conditions (reciting alternate letters of the alphabet). Wilcoxon rank‐sum tests were used for univariate analysis and Poisson and linear regression models used for multivariate analyses, adjusting for important covariates.

Results

Treatment of PBMCs under all four conditions resulted in a significant production of the pro‐inflammatory cytokines IL‐1β and IL‐6, which did not differ between T2DM and healthy controls. Greater IL‐1β production (an NLRP3‐dependent cytokine) under both Aβ‐42 (ii) and LPS & Nigericin (iv) conditions was associated with greater likelihood of error on the MoCA (aIRR 1.01, p = 0.010; aIRR 1.01, p = 0.004). Further, greater IL‐1β production under both LPS & Aβ42 (iii) and LPS & Nigericin (iv) conditions was associated with a greater slowing effect (cost) on the dual‐task (adjusted: β = 0.31, 0.04‐0.58, p = 0.023; 0.029, 0.05 – 0.54, p = 0.019). Effects were seen in the cohort overall, regardless of T2DM status, but were stronger in those with T2DM.

Conclusions

Greater activation of the NLRP3 inflamamsome by Aβ42 was associated with poorer cognitive and gait performance in midlife T2DM. Further work will follow this cohort longitudinally and assess the ability of innate immune NLRP3 activity to predict later cognitive trajectories in those with midlife T2DM.
Prolonged therapy of dementia with Lewy bodies with quaternary ammonium anti‐muscarinic/high‐dose cholinesterase inhibitor (QAAM/HDCI)
Authors: Rich Steven A.
Published: December 2020

Background

Dementia with Lewy Bodies (DLB) is the second most common human neurodegenerative disease and the most reduction in CNS choline acetyl‐transferase. This case series demonstrates beneficial effects from a level inhibition of cholinesterase inhibition that can only be achieved with concurrent peripheral muscarinic blockade.

Method

Patients were selected from those seen in a single geriatric consultation clinic after 2010. DLB was diagnosed by the Consensus criteria of the third report (2005) or fourth (2017) of the DLB consortium by a geriatrician, with concurring neurologist in most cases. Patients received rivastigmine at doses greater that the upper limit of FDA approved dosing. Does greater than 12 mg oral, or 13.3 mg transdermal were paired with glycopyrrolate 1‐4 mg orally twice daily. Concurrent use of carbidopa/levodopa, selegiline was permitted but use of dopamine receptor agonists other than low dose quetiapine, other acetyl‐cholinesterase inhibitors or centrally acting anti‐muscarinic agents was not. Criteria for selection included treatment more than one year, the ability to perform a Mini Mental State Examination (MMSE) at the time of initiation and the availability of follow up data. The MMSE was performed in a standardized format. Functional Assessment Stage (FAST) was determined by nurse and physician after an interview with patient and caregivers.

Result

MMSE values over time were compared to recently published rates of decline of DLB. All patients had MMSE and functional improvement, with most having a reduction in the rate of decline of MMSE scores.

Conclusion

The results show that prolonged symptomatic, cognitive and functional improvement of dementia with Lewy Bodies is possible with the high‐level inhibition of central nervous system cholinesterase achievable when rivastigmine is combined with glycopyrrolate. The discussion correlates these observations with current experimental, clinical and epidemiological evidence regarding the mechanism and treatment of this, and other, neurodegenerative diseases.
Elevated pulse pressure predicts longitudinal accumulation of tau PET in older adults without dementia
Authors: Weigand Alexandra J. , Nation Daniel A. , Delano‐Wood Lisa , Bangen Katherine J. , Galasko Doug R. , Bondi Mark W.
Published: December 2020

Background

Cardiovascular risk is associated with Alzheimer’s disease (AD) pathology, with possible mechanisms including increased blood‐brain barrier permeability, white matter changes, inflammatory cytokine activation, and neuronal vulnerability due to cerebral hypoperfusion. Prior research has linked pulse pressure (PP), an index of arterial stiffening, to abnormal cerebrospinal fluid measures of tau. However, to our knowledge, no research has examined PP in relation to tau PET imaging.

Method

Data were analyzed for 139 older adults without dementia from the Alzheimer’s Disease Neuroimaging Initiative who had at least two tau PET scans. Baseline PP was measured as systolic ‐ diastolic blood pressure (with higher values denoting increased arterial stiffening). Tau PET was measured with the AV‐1451 tracer, intensity normalized, partial‐volume corrected, and parcellated into cortical regions using FreeSurfer. A priori regions of interest (ROIs) included AD‐vulnerable cortical areas across Braak stages I‐V including the entorhinal cortex (EC), the inferior temporal gyrus (ITG), and the inferior parietal lobule (IPL). Iterated re‐weighted least squares regression, robust to the influence of outliers, modeled the association between baseline PP and tau PET accumulation across 12 months within each ROI adjusting for age, sex, cognitive diagnosis (i.e., normal or mild cognitive impairment), APOE status, and baseline tau PET signal.

Result

Higher PP predicted higher baseline tau PET levels only in the ITG (t = 2.09, p = .04), although it was strongly predictive of increased tau PET accumulation over 12 months for all three ROIs (EC t = 3.15, p = .002; ITG t = 2.98, p = .003; IPL t =2.62, p = .01) over and above the effects of covariates.

Conclusion

Results indicate that higher PP is strongly predictive of tau PET accumulation across multiple AD vulnerable regions, whereas it is less predictive of baseline tau PET levels. Further, associations were stronger within earlier Braak regions. Findings confirm prior CSF studies and further suggest that arterial stiffening may be especially associated with a trajectory of increasing tau burden. Although the nature of the relationship between vascular risk and tau PET may be bidirectional, our results highlight the importance of cardiovascular intervention in the context of encroaching AD pathology.
Loss of progranulin leads to dysregulation of innate and adaptive immune cell populations, increased susceptibility to experimental colitis, and brain infiltration of peripheral immune cells
Authors: Keating Cody E. , Houser Madelyn C. , MacPherson Kathryn P. , Herrick Mary K. , Coomes Alexandra , Joers Valerie L. , Oliver Danielle , Johnson Ashlyn G. , Chang Jianjun , McEachin Zachary , Varvel Nicholas H. , Prokop Stefan , Tansey Malu Gamez
Published: December 2020

Background

Mutations in the progranulin gene (GRN) reduce levels of progranulin (PGRN) and granulins (GRNs) causing frontotemporal dementia (FTD), the most common form of early‐onset dementia. PGRN loss in neurons is associated with lysosome dysfunction resulting in diminished cathepsin protease activity. PGRN is also highly expressed in brain‐resident microglia and peripheral immune cells. Therefore, we asked if PGRN loss impacts immune cell profiles and communication in the gut‐brain axis during chronic systemic inflammation.

Methods

We measured lysosomal‐associated proteases in microglia and peripheral immune cells using probes for cathepsin D and pan‐cysteine cathepsins; performed multiplexed RNA & digital spatial protein profiling analyses, immunohistochemistry, and deep‐immunophenotyping by flow cytometry on brain, spleen, and peripheral blood of Grn KO and Grn‐suffficient mice aged 3‐30 months. Furthermore, we exposed mice to experimental colitis to interrogate alterations in the gut‐brain axis.

Results

Highest cathepsin D activity was found amongst Ly6C+, CD11b+ blood monocytes while pan‐cathepsin activity was highest in neutrophils and monocytes. In the spleen of aged Grn KO mice, T cell counts were reduced while Ly6C‐, CD68+ macrophages were increased compared to age‐matched Grn‐sufficient mice. In blood, aberrant T cell and monocyte activation markers in Grn KO mice were evident with minimal increases in inflammatory cytokines in plasma. Aged Grn KO mice exhibited decreased microglia (CD45int, CD11bhi) in the brain relative to Grn‐sufficient mice, with altered MHCII and CD68 expression. Additionally, CD4+ and CD8+ T cells were impacted in the brain of Grn KO mice compared to age‐matched Grn‐sufficient mice. PGRN loss was also associated with increased brain infiltration of activated peripheral monocytes and, interestingly, increased vulnerability to experimental colitis that was mitigated by loss of CCR2 function.

Conclusions

These novel findings suggest that PGRN plays key regulatory functions in innate and adaptive immune cell populations, in central‐peripheral immune cell crosstalk and traffic to the CNS, and in regulating susceptibility to immune challenges that disrupt the gut‐brain signaling axis. Analysis of peripheral immune cells and colonic tissue from patients with Grn mutations or SNPs is ongoing and may shed light on the mechanisms by which GRN haploinsufficiency causes FTD.
Genetic associations with brain amyloidosis
Authors: Raghavan Neha S. , Dumitrescu Logan , Mormino Elizabeth C. , Mahoney Emily R. , Lee Annie , Gao Yizhe , Bilgel Murat , Goldstein David B. , Harrison Theresa M. , Engelman Corinne D. , Saykin Andrew J. , Whelan Christopher , Liu Jimmy , Jagust William J. , Albert Marilyn S. , Johnson Sterling C. , Yang Hyun‐Sik , Johnson Keith A. , Aisen Paul S. , Resnick Susan M. , Sperling Reisa A. , De Jager Philip L. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI), Schneider Julie A. , Bennett David A. , Schrag Matthew , Vardarajan Badri N. , Hohman Timothy J. , Mayeux Richard
Published: December 2020

Background

Genetic studies of Alzheimer’s disease (AD) have focused on the clinical or pathological diagnosis as the primary outcome, but little is known about the genetic basis of the preclinical phase of the disease. Our goal was to identify the underlying genetic bases for brain amyloidosis during the preclinical phase of AD.

Method

We performed genome‐wide association studies of positron emission tomography (PET) amyloid levels and meta‐analyzed the results. Genetic and imaging data were acquired from ten cohorts of primarily non‐demented individuals. The largest cohort, the A4 study (n = 3,154) was a secondary prevention trial designed to slow cognitive decline associated with brain amyloidosis. The other, smaller longitudinal cohort studies, similar in design, provided additional amyloid PET data with existing genetic data (n = 1,160 analyzed and n = 550 currently being analyzed).

Result

We identified a locus for amyloidosis within RBFOX1 in addition to APOE along with several loci nearing significance.

Conclusion

Multiple genetic loci may be associated with brain amyloidosis. Further research into these specific loci and genes will help in our understanding of the molecular bases of amyloid buildup in the brain.
Impact of APOE e4 on cognitive trajectory in early‐onset vs late‐onset Alzheimer’s disease
Authors: Kim Jaeho , Kang Sung Hoon , Kim Ji Sun , Kim Jun Pyo , Woo Sook‐Young , Kim Seonwoo , Na Duk L , Seo Sang Won , Kim Hee Jin
Published: December 2020

Background

Aging and the apolipoprotein E e4 (APOE4) are the two major risk factors for Alzheimer’s disease (AD). Previous reports suggest that the impact of APOE4 on increasing risk for AD differs according to age. However, whether the impact of APOE4 on cognitive trajectories in AD differ according to age is not well established. Thus, we evaluated the impact of APOE4 on cognitive trajectories in early‐onset AD (EOAD) and late‐onset AD (LOAD).

Method

In this retrospective longitudinal study, we collected 807 AD patients who underwent two or more neuropsychological tests after they were diagnosed with AD. We categorized the patients into two groups according to their age at symptom onset: 222 patients with EOAD (age at onset <65 years) and 585 patients with LOAD (age at onset ≥ 65 years). Linear mixed‐effects model analyses were performed to evaluate the effects of APOE4 on cognitive changes after controlling for age, sex, and education in each group.

Result

In LOAD, APOE4 carriers showed more rapid cognitive decline compared to APOE4 noncarriers in language and visuospatial functions. However, in EOAD, APOE4 noncarriers showed more rapid cognitive decline compared to APOE4 carriers in general cognitive function and in all cognitive domains including language, visuospatial, memory, and frontal executive function.

Conclusion

Our data showed that APOE4 is associated with accelerated cognitive decline in LOAD whereas the association is reversed in EOAD. We suggest that in EOAD, there might be other genetic or environmental factors that overshadow the detrimental effects of APOE4.
Visual atrophy scales are not a useful tool to help the clinician in diagnosing clinical or preclinical AD
Authors: Socher Karen LR , Lopes Deborah , Nunes Douglas Mendes , Busatto Geraldo , Nitrini Ricardo , Brucki Sonia MD
Published: December 2020

Background

Visual atrophy scales are useful as auxiliary methods in Alzheimer's disease (AD) diagnosis. Atrophy of temporal medial region is an established risk factor for conversion from mild cognitive impairment (MCI) to AD dementia. Our aims were to compare two visual magnetic resonance imaging (MRI) scales and establish accuracy of these scales in classifying patients in relation to clinical diagnosis and amyloid status

Method

A Brazilian multi ethnic group was analyzed using two visual MRI scale (ERICA for quantification of atrophy in the entorhinal cortex) and MTA scale (medial temporal atrophy). 113 MRI were classified by 2 neurologists trained by a radiologist; all patients had amyloid PET (PIB) and clinical diagnosis as: 31 AD dementia, 52 MCI, and 30 normal cognition.

Result

In this sample, 51(45%) had PIB‐PET positive for amyloid deposition. Visual scales had great to excellent inter‐rater reliability (0.8‐1) by Cohen k analysis. AD patients have higher ERICA scores (mean: 1.92) and MTA score (mean: 1.7) for both hemispheres comparing to subgroups without dementia (p<0.01). MTA has greater specificity and ERICA has greater sensitivity in the DA and MCI groups (above 70%). The accuracy for ERICA and MTA scores were 56.6% and 70% in controls, 53.8% and 59.6% in MCI, 67% and 41% in AD, respectively. The PVV was 84%, for DA group in both scores and NPV were above 68% in non dementia group.

Conclusion

On clinical practice of a neurologist who has no availability of amyloid status tests and would like to monitor visual scales of atrophy as a prognostic biomarker, they have a moderate sensitivity for the MCI and AD subgroup, moderate specificity for controls and MCI, and poor accuracy. These findings could be explained by the fact that atrophy is present in advanced stages of the disease, not allowing an early diagnosis.
The use of second generation RT‐QuIC assay for the diagnosis of Creutzfeldt Jakob disease patients in Brazil
Authors: Barbosa Breno José Alencar Pires , Vieira Tuane C. R. G. , Castrillo Bruno , Alvim Ricardo Pires , Nitrini Ricardo , Smid Jerusa
Published: December 2020

Background

The recent development of IQ‐CSF, the second generation of Real Time Quaking‐Induced Conversion (RT‐QuIC) using cerebrospinal fluid (CSF), for the diagnosis of Creutzfeldt Jakob Disease (CJD) represents a major diagnostic advance in the field. High accuracy results have been reported with encouraging reproducibility among different centers. The aim of this research is to report the pilot use of IQ‐CSF in a small cohort of Brazilian patients with possible or probable CJD, implementing a reference center in the country.

Method

We stored CSF samples from patients with possible, probable or genetic CJD (one case) during the timeframe of December 2016 through June 2018. All CSF samples were processed according to standardized protocols without access to the clinical data. Eight patients presented to our team with a rapidly progressive dementia and typical neurological signs of CJD. We used CSF samples from 8 patients with other neurological conditions as controls.

Result

7 out of 9 suspected cases had positive tests; among controls, there was 1 false‐positive (a CSF sample from a 4‐year‐old child with leukemia under treatment). The occurrence of a false positive in one of the negative control samples raises the possibility of the presence of interfering components in the CSF sample from patients with non‐neurodegenerative pathologies.

Conclusion

Our pilot results illustrate the feasibility of having CJD CSF samples tested in Brazilian centers and highlight the importance of inter‐institutional collaboration to pursue a higher diagnostic accuracy in CJD in Brazil and Latin American.
Endothelial APP expression exacerbates cerebral amyloid angiopathy in AD model mice
Authors: Tachida Yuriko , Ogasawara Naomi , Saito Takashi , Shindo Akihiro , Kawaguchi Yasushi , Tomimoto Hidekazu , Saido Takaomi C. , Kitazume Shinobu
Published: December 2020

Background

Most AD patients show accumulation of Ab peptides in both brain parenchyma and blood vessels. We recently found that brain vascular endothelial cells specifically express APP770 and produces Ab40/42. We then expect endothelial APP770 could contribute to cerebral amyloid angiopathy (CAA).

Method

We first generated conditional transgenic mice harboring loxP‐neo(R)‐loxP‐APP770NL, (APP770(flox)), then crossed with the mice with Tie2‐Cre mice that specifically express Cre recombinase in their endothelial cells. We then crossed the mice with AD model mice, AppNL‐F.

Result

We found that aged endothelial APP770NL expressing mice exhibit Ab deposition in brain vessels but not the parenchyma. Remarkably, not all but some of the aged transgenic mice show cerebral hemorrhage. By crossing this CAA model mice with AD model mice, massive CAA pathology was observed.

Conclusion

These findings highlight the contribution of endothelial APP770 to vascular Ab deposition.
Relation of neuroticism to frontal cortical transcriptome and Alzheimer’s disease
Authors: De Jager Celine H. , Bennett David A. , Ma Yiyi
Published: December 2020

Background

Prior studies have shown that certain personality traits are associated with differences in aging‐related cognitive decline and incidence of Alzheimer’s disease (AD). Neuroticism, proneness to pscyhological distress, worsens cognitive decline while conscientiousness is protective. However, the molecular composition of these personality traits and the series of molecular events that lead from personality traits to AD in the brain is unknown.

Method

We examined data from 1419 participants in one of two longitudinal studies of cognitive aging with prospectively collected brains at autopsy: the Religious Order Study and the Rush Memory & Aging Project (ROSMAP). We accessed RNA sequence data (>13,000 genes) from the dorsolateral prefrontal cortex (DLPFC); linear regression adjusting for age, sex, and education. We performed a mediation analysis to assess whether certain modules mediate the association of neuroticism to cognitive decline.

Result

We first confirmed that neuroticism contributes to accelerated cognitive decline and AD onset (p=6.75x10‐7) while conscientiousnessis protective (p=4.34x10‐4). We then evaluated the 6 gene modules previously associated with cognitive decline (p<0.001) and found that three of them displayed some association with neuroticism (p<0.05). Mediation modeling suggests that these three modules of co‐expressed genes are altered by in individual’s with greater neuroticism. Neurotic is associated with higher m7 which in turn is related to cognitive decline (p=0.008) than its direct causal effect on cognitive decline which is not mediated through m7 (p=0.042).

Conclusion

We demonstrate neuroticism is associated widespread differences in RNA profiles and that these differences contribute to the onset of AD. Although results need further investigation, they identify a new gene signature that could be used to develop new therapies that minimize the risk of AD in individuals with a neurotic personality.
Severe multimorbidity is prevalent in those with cognitive decline, which challenges neurologists and family physicians: A clinical decision‐support software (CDSS) platform provides guidance
Authors: Zelek Mark C , Walker John Q , Sabbagh Marwan N
Published: December 2020

Background

Multimorbidity is the concurrent occurrence of two or more chronic diseases, with severe multimorbidity (abbreviated here as SMM) meaning three or more. Patients have chronic diseases that fall into different domains (e.g., cardiovascular or endocrine), and many of these diseases themselves, such as diabetes, contribute to the onset and progression of cognitive decline. Chronic diseases may interact, curtailing compensatory mechanisms and increasing the likelihood of physical and cognitive decline. Physicians often miss diagnoses of cognitive decline when addressing SMM, while cognitive decline, in turn, can reduce a person’s ability to manage SMM. This becomes a vicious cycle.

Method

uMETHOD Health has developed a CDSS platform to address cognitive decline (i.e., dementia, MCI, and mild AD) through the creation of personalized, multidomain treatment plans. Across a population of 2,079 individual 65 years or older, the platform evaluated 19 chronic disease conditions (the three most frequent: CKD, hypertension, and dyslipidemia), plus diseases detected in CBC serum analysis (such as macrocytosis and thrombocytopenia) and CMP serum analysis (such as hypercupremia and hypernatremia). Disease status was determined by physicians’ diagnoses or by the software, through analyzing lab reports, vital signs, medications, and medical status.

Result

In this population, 7.2% individuals had no comorbid chronic diseases. 64.5% had three or more chronic diseases (that is, SMM), with two people having 14 concurrently (mean: 3.85 chronic diseases, std: 2.63). 64.3% of the 2,079 had cognitive decline. A symmetry (by coincidence) emerged when considering cognitive decline: 75% of those with SMM had cognitive decline; 75% of those with cognitive decline had SMM. Lastly, the percentage of people with cognitive decline increased as the number of concurrent chronic diseases increased.

Conclusion

Treatment plans for cognitive decline are already multivariable, and must address multidomain SMM as part of their coverage. Neurologists need processes for developing comprehensive care plans that address cognitive decline and comorbidities in concordance, and coordinating care with other physicians simultaneously caring for a given patient. This CDSS platform generates effective and highly‐usable guidelines for identifying and prioritizing concurrent chronic diseases, and giving guidance on the total picture: what needs to happen, how, and when.
Associated factors with mortality at three‐year follow‐up in a population‐based Mexican elderly cohort study
Authors: Rodríguez Nallely Solano , Santiago Brenda Margarita Carrillo De , Ibarrola Mariana Longoria , Acosta‐Castillo Gilberto Isaac , Sosa‐Ortiz Ana Luisa
Published: December 2020

Background

The highest proportion of deaths occurs in people over 65 years. Factors related to mortality differ between clinical and community population. In Mexico there are few population‐based studies that explore sociodemographic factors, comorbidities, cognitive status and disability, associated with mortality in community elders.

Method

This is a secondary analysis of the 10/66 Dementia Research Group cohort study, after three years of follow‐up. The participants were evaluated with the protocols of the Dementia Research Group 10/66 Mexico, in 2006 (baseline) and in 2009. We identified two groups deceased and survivors participants and 1,570 participants were selected. Summary and variability measures were calculated, comparing the distribution of both groups. The association of the sociodemographic and clinical variable of interest, with mortality at three years of follow‐up was estimated using multivariate models’ analyses.

Result

The factors associated with mortality at 3 years of follow‐up were: male gender, being 80 years of age or older, zero education, 3 or less goods or services at home (BSD), presence of dementia, cognitive impairment (CI ), DM ‐2, disability and having suffered 2 or more falls in the last year (table 1). Of the 12 neuropsychiatric symptoms evaluated, only : hallucinations, depression, psychomotor agitation and appetite disturbances, showed significant associations; in the multivariate adjustment the persistent associations were: male gender, dementia, CI and disability (table 2).

Conclusion

Male gender, the presence of dementia, CI and disability were the factors associated with mortality in Mexican older adults in this analysis. This information contributes to the evidence of relevant factors associated to mortality in Mexican elders. Dementia and CI exceeded the mortality risk of other chronic diseases. In the epidemiological reports , dementia and CI do not appear within the first 10 causes of mortality, probably because they are under‐diagnosed and under‐documented.
Multipredictor risk models for predicting individual risk of Alzheimer’s disease
Authors: Yu Jin‐Tai , Hou Xiao‐He , Suckling John , Shen Xue‐Ning , Liu Yong , Zuo Chuantao , Huang Yu‐Yuan , Wang Hui‐Fu , Tan Chen‐Chen , Cui Mei , Dong Qiang , Tan Lan ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

Background

We aimed to develop and validate risk models for predicting AD onset at the individual level.

Method

Participants were included from Alzheimer's Disease Neuroimaging Initiative. Least Absolute Shrinkage and Selection Operator Cox regression was applied for candidate predictors selection and model construction.

Result

In the prediction of individual risk of prodromal AD in cognitively normal (CN) individuals, the AUC of the final CN model was 0.81 within five years. The final MCI model predicted individual risk of AD dementia in MCI patients with an AUC of 0.92 within five years. The models were also associated with longitudinal change of Mini‐Mental State Examination (p<0.001). An ATN model was developed which could predict the Alzheimer’s continuum for individuals with normal AD biomarkers within three years with high accuracy (AUC=0.91).

Conclusion

Risk models were able to provide personalized risk for AD onset at each year after evaluation, which could improve early diagnosis.
Analyses mutations in GSN, CST3, TTR and ITM2B genes in Chinese patients with Alzheimer’s disease
Authors: Jiang Yaling , Jiao Bin , Liao Xinxin , Xiao Xuewen , Shen Lu
Published: December 2020

Background

Amyloid protein deposition is a common mechanism of hereditary amyloidosis (HA) and Alzheimer’s disease (AD). Mutations in gelsolin (GSN), cystatin C (CST3), transthyretin (TTR) and integral membrane protein 2B (ITM2B) genes can lead to HA. But the relationship is unclear between these genes and AD.

Method

Genes targeted sequencing (GTS), including GSN, CST3, TTR and ITM2B, was performed in a total of 636 patients with clinical AD and 365 normal controls from China.

Result

According to American College of Medical Genetics and Genomics (ACMG) guidelines, two novel likely pathogenic frame‐shift mutations (GSN: p.K346fs and GSN: p.P3fs) were detected in five patients with AD, whose initial symptom was memory decline, accompanied with psychological and behavioral abnormalities later. Interestingly, the patient with K346fs mutation, presented cerebral β‐amyloid protein deposition, had an early onset (48 years) and experienced rapid progression, while other four patients with P3fs mutation had a late onset ((Mean ± SD): 69.50 ± 5.20 years) and a long course of illness ((Mean ± SD): 9.24 ± 4.86 years).

Conclusion

To our knowledge, we firstly report AD phenotype with GSN mutations in patients with AD in Chinese cohort. Although mutations in GSN gene are rare, it may explain a small portion of clinically diagnosed AD.
Biomarkers of agitation in moderate‐to‐severe Alzheimer's disease patients enrolled in an RCT with nabilone
Authors: Ruthirakuhan Myuri , Herrmann Nathan , Andreazza Ana C. , Verhoeff Nicolaas Paul L.G. , Gallagher Damien , Black Sandra E. , Lanctot Krista L.
Published: December 2020

Background

Brain cholesterol metabolism, neuroinflammation, and oxidative stress are processes altered during Alzheimer’s disease (AD), which may impede endocannabinoid signaling, and thus worsen agitation. We assessed whether the brain cholesterol metabolite, cerebrocholesterol (Cchol), proinflammatory cytokine, tumor necrosis factor (TNF), and oxidative stress marker, 4‐hydroxynonenal (4‐HNE) were associated with agitation severity and response to nabilone.

Method

Serum Cchol, TNF and 4‐HNE, were collected from AD patients enrolled in a 14‐week, double‐blind cross‐over trial comparing 6 weeks of nabilone to placebo, at the start and end of each phase. We assessed the relationship between agitation (Cohen Mansfield Agitation Inventory (CMAI)) and baseline (BL) biomarker levels; the relationship between change in agitation and BL biomarker levels within each phase; and the relationship between change in agitation and change in biomarker levels within each phase. Exploratory analyses included adjustments for BL cognition (Mini‐Mental Status Exam (MMSE)), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation.

Result

Serum was collected from thirty‐eight participants (mean±SD age=87±10, 77% male, CMAI=68±18, MMSE=6.3±6.3). Cchol was not associated with CMAI cross‐sectionally or longitudinally, before and after adjusting for MMSE. However, BL Cchol was negatively correlated with BL CMAI IPA (F(1,36)=4.95, p=.03). In placebo only, lower BL Cchol was associated with increases in CMAI IPA (b=‐35.2, p=.02), and decreases in Cchol were associated with increases in CMAI IPA (b=‐20.94, p=.03). After adjusting for MMSE, BL TNF was positively correlated with BL CMAI (F(2,25)=3.69, p=.04), and predicted improvements in CMAI during nabilone only (b=‐1.14, p=.045). Decreases in TNF were associated with improvements in CMAI during nabilone only (b=1.12, p=.006). BL 4‐HNE was positively correlated with BL CMAI (F(1,35)=6.41, p=.02), and predicted worsening in CMAI during placebo only (b=0.01, p=.01). Changes in 4‐HNE were not associated with changes in CMAI in either phase.

Conclusion

Cchol, TNF, and 4‐HNE may be markers of agitation severity in AD. Though neither Cchol nor 4‐HNE predicted response to nabilone and did not change over time with nabilone, these markers may be associated with changes in agitation severity. Findings with TNF suggest that this marker predicts treatment response, and decreases with nabilone treatment.
Higher digit ratio (2D:4D) associated with dementia in women
Authors: Jiang Joanne , Young Katherine , Pike Christian J
Published: December 2020

Background

Women have higher prevalence and risk for developing Alzheimer’s disease (AD) than men. The reason(s) underlying this sex difference in AD has not been definitively established but has been theorized to reflect sex‐specific patterns in age‐related depletion of sex steroid hormones, primarily the loss of estrogens in women. Not well considered is the possible role of developmental actions of sex steroids, which drive sexual differentiation of the brain. We investigated the hypothesis that early life differences in sex hormone exposure yield a female brain that is inherently more vulnerable to AD and related dementias.

Method

Relative group differences in prenatal sex steroid hormone exposure were indirectly assessed by the ratio of the index (2nd digit) and ring (4th digit) fingers (2D:4D). The subjects were a community sample of non‐demented and demented men (N=66; 31 non‐demented, 35 demented) and women (N=73; 39 non‐demented, 34 demented) aged >65 years. Subjects’ right hands were scanned, finger length determined by caliper measurement, and 2D:4D calculated. Data were analyzed by two‐way ANOVA with sex and dementia status as the variables.

Result

There were no significant differences in age between men (age range: 65‐97 years; mean age=82.8 years) and women (age range: 65‐104 years; mean age=84.5). Men had a significantly lower mean 2D:4D than women (0.948 versus 0.964; p=0.006), which is expected since relatively higher androgen exposure in utero has been linked with lower 2D:4D. Among men, there was no significant difference in 2D:4D between non‐demented and demented subjects (0.954 versus 0.943; p=0.57). Importantly, women with dementia showed a significantly higher 2D:4D than non‐demented women (0.979 versus 0.951; p=0.005).

Conclusion

The data demonstrate a higher (more feminine) 2D:4D in women with dementia in comparison to non‐demented women. Similar effects were not observed in men. These results suggest that developmental events that yield relatively more feminine phenotypes increase vulnerability of women to dementia. The findings support the hypothesis that the female bias in AD risk is due in part to developmental sex differences. (Support: RF1AG058068 [NIH] and SAGA‐17‐419408 [Alzheimer’s Association].)
Altered regional cerebral blood perfusion in mild cognitive impairment patients with dizziness
Authors: Im Jooyeon Jamie , Jeong Hyeonseok.s , Lee Eek‐Sung , Lee Tae‐Kyeong , Chung Yong‐An , Song In‐Uk , Na Seunghee
Published: December 2020

Background

Dizziness is a common symptom presenting with lightheadedness, vertigo, or disequilibrium. Previous studies reported that the prevalence of feeling dizziness is increased with age and chronic dizziness including vestibular vertigo and orthostatic hypotension may be associated with cognitive impairment and psychiatric illness. The aim of this study was to examine regional cerebral blood flow (rCBF) in mild cognitive impairment patients with or without dizziness using single‐photon emission computed tomography (SPECT).

Method

A total of 50 patients with MCI were recruited. All participants underwent brain SPECT and completed the dizziness handicap inventory (DHI, 0‐100 points, higher scores indicating more severe handicap). Participants divided into a dizziness group (DHI ≥ 1, n = 18) and a non‐dizziness group (DHI = 0, n = 32).

Result

There were no significant differences between the two groups in terms of demographics. Patients with dizziness had a mean DHI score of 16.3 ± 14.6. SPECT analysis revealed decreased rCBF in the left superior temporal gyrus, left lateral orbital gyrus, and right middle frontal gyrus in patients with dizziness compared with those without dizziness. There were no significant clusters of increased rCBF in patients with dizziness compared with those without dizziness.

Conclusion

MCI patients with dizziness revealed frontal and left temporal hypoperfusion compared with the patients without dizziness. This finding is similar to those of the patients with persistent postural perceptual dizziness, the representative functional dizziness. Our result suggested that the altered rCBF in the left temporal and frontal cortices might be reflecting the negative impact of dizziness in patients with MCI.
Association of antihypertensive medications and Alzheimer’s disease neuropathology
Authors: Xu Chenjia , Apostolova Liana G. , Oblak Adrian L , Gao Sujuan
Published: December 2020

Background

Previous research has reported that antihypertensive medications are associated with reduced risk of Alzheimer’s disease (AD). The objective of this study is to determine the association between antihypertensive medication use and its subclasses of medications with AD neuropathological measures.

Methods

Autopsy data were obtained from National Alzheimer's Coordinating Center (NACC). This analysis included data from 4,368 individuals. Braak stage for neurofibrillary degeneration, CERAD score for neuritic and diffuse plaques, and cerebral amyloid angiopathy were used as separate outcomes in proportional odds models. Vascular pathology, defined as the total of vascular conditions noted on autopsy forms was also used an outcome in proportional odds models. Any antihypertensive medication use and seven antihypertensive subclasses of medications (antiadrenergic agents, ACE inhibitors, angiotensin II inhibitors, beta‐blockers, calcium channel blocking agents, diuretics, and vasodilators) were independent variables in separate models for each neuropathological outcome while adjusting for age, sex, education, race and other vascular conditions (hypertension, heart disease, diabetes and stroke), blood pressure measures and APOE status.

Results

Mean age at death for this sample was 80.6 (SD=11.6) and 54.0% were male. Sixty percent reported a history of hypertension, 91% of whom were on antihypertensive medications. Any antihypertensive medication use was associated with lower Braak stage of neurofibrillary tangles (proportional OR=0.82, p=0.0085) and lower cerebral amyloid angiopathy (OR=0.80, p=0.0063) while adjusting for demographic variables and other vascular conditions. Among antihypertensive subclass of medications, diuretics were associated with lower Braak stage (OR=0.71, p<0.0001), lower CERAD neuritic plaque density (OR=0.77, p=0.0007), lower CERAD diffused plaque (OR=0.74, p<0.0001), and cerebral amyloid angiopathy (OR=0.75, p<0.0001) while adjusting for demographic variables, other vascular conditions, blood pressure, and APOE. The associations between diuretics and lower pathological measures were unchanged after further adjusting for vascular pathology.

Conclusions

Antihypertensive medication use is associated with decreased AD neuropathology in this large sample of individuals with autopsy. In particular, individuals on diuretics were associated with lower AD pathology after adjusting for blood pressure and APOE. This association appears to be independent of other vascular conditions and is not mediated by vascular neuropathology findings. The mechanism underlying these associations requires further investigation.
Exacerbation of tau pathology by pre‐existing amyloidosis in novel transgenic mice
Authors: Lewis Jada , Xu Guilian , Ulm Brittany , Howard John , Fromholt Susan , Borchelt David R.
Published: December 2020

Background

Numerous mouse models have been created to recapitulation of AD pathology; however, mouse models featuring Aβ‐related transgenes and mutations has been imperfect, resulting in Aβ plaques, synaptic and other AD‐related changes, but failing to fully recapitulate the downstream tau pathology. Conversely, mouse models with mutant tau demonstrate neurofibrillary tangle formation and neurodegeneration, while failing to demonstrate amyloid β pathology. While we and others have created model systems in which APP and tau pathologies were driven by concurrent expression of amyloid and tau transgenes or through the use of proteinaceous seeds, those systems failed to test the age‐associated, sequential nature of amyloidosis, and tauopathy as is suggested by the amyloid cascade hypothesis. In the current study, we have introduced late stage tau expression onto a background of pre‐existing amyloidosis to determine if this accelerated the development secondary tauopathy.

Method

We crossed APPswe/PS1dE9 amyloidosis mice with rTg4510 conditional tauopathy mice to determine if inducing mutant human tau expression in aged brains of APPswe/PS1dE9/rTg4510 mice with pre‐existing amyloidosis accelerates “secondary” tauopathy. Mice were raised on doxycycline (to suppress transgenic tau expression) until ∼14 months of age, at which time transgenic tau expression was induced through the withdrawal of doxycycline in the diet. We evaluated the aggregation of phosphorylated tau and the activation of glia through immunohistochemistry.

Result

We found that inducing mutant tau expression at 14‐15 months of age, in a background of substantial amyloid deposition, produced robust tau pathology by 20‐21 months of age as compared to rTg4510 transgenic mice lacking the amyloid pathology. In the triple transgenic model, neurofibrillary tangle pathology was evident throughout the cortex and hippocampus. Unexpectedly, the level of glial activation between triple transgenic and APPswe/PS1dE9 mice was similar with no obvious increase by the combination of amyloid and tau pathology.

Conclusion

These data demonstrate that pre‐existing amyloidosis can exacerbate tauopathy and highlights the utility of delayed tau expression in modeling the amyloid cascade hypothesis.