Journal of Alzheimer's Disease - Volume 73, issue 3

Authors: Santos-Mandujano, Rosalía A. | Ryan, Natalie S. | Chávez-Gutiérrez, Lucía | Sánchez-Torres, Carmen | Meraz-Ríos, Marco Antonio

Article Type: Research Article

Abstract: Presenilin 1 gene (PSEN1 ) mutations are the most common cause of familial Alzheimer’s disease (FAD). One of the most abundant FAD mutations, PSEN1 A431E, has been reported to be associated with spastic paraparesis in about half of its carriers, but the determining mechanisms of this phenotype are still unknown. In our study we characterized three A431E mutation carriers, one symptomatic and two asymptomatic, from a Mexican family with a history of spastic paraparesis in all of its affected members. At cognitive assessment and MRI, the symptomatic subject showed an atypical non-amnestic mild cognitive impairment with visuospatial deficits, olfactory …dysfunction and significant parieto-occipital brain atrophy. Furthermore, we found several periventricular white matter hyperintensities whose progression pattern and localization correlated with their motor impairment, cognitive profile, and non-motor symptoms. Together, our data suggests that in this family the A431E mutation leads to a divergent neurological disorder in which cognitive deterioration was clinically exceeded by motor impairment and that it involves early glial and vascular pathological changes. Show more

Keywords: A431E, familial Alzheimer’s disease, posterior cortical atrophy, Presenilin 1, spastic paraparesis, white matter hyperintensities

DOI: 10.3233/JAD-190978

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1075-1083, 2020

Authors: Chamberlain, Stanley | Gabriel, Hoda | Strittmatter, Warren | Didsbury, John

Article Type: Research Article

Abstract: Background: T3D-959 is a chemically unique, brain penetrant, dual PPAR delta/gamma agonist with 15-fold higher PPAR delta selectivity. Ubiquitous brain expression of PPAR delta, its critical role in regulating glucose and lipid metabolism, and the Alzheimer’s disease (AD)-like phenotype of PPAR delta null mice motivated this study. Objective: To determine safety and tolerability of multiple doses of T3D-959 in subjects with mild to moderate AD, examine systemic and central drug pharmacology and in an exploratory manner, perform cognitive assessments. Methods: Thirty-four subjects with mild-to-moderate AD were orally administered 3, 10, 30, or 90 mg of T3D-959 daily …for 14 days. There was no inclusion of a placebo arm. Safety and tolerability were monitored. Systemic drug pharmacology was examined via plasma metabolomics LC-MS-MS analysis, cerebral drug pharmacology via FDG-PET measures of changes in Relative CMRgl (R CMRgl, AD-effected regions relative to brain reference regions), and cognitive function assessed before and after drug treatment and again one week after completion of drug treatment, by ADAS-cog11 and the Digit Symbol Substitution Test (DSST). Results: T3D-959 was in general safe and well tolerated. Single point pharmacokinetics at the Tmax showed dose dependent exposure. Plasma metabolome profile changes showed dose-dependent systemic effects on lipid metabolism and metabolism related to insulin sensitization. Relative FDG-PET imaging demonstrated dose-dependent, regional, effects of T3D-959 on R CMRgl based on the use of multiple reference regions. ADAS-cog11 and DSST cognitive assessments showed improvements with possible ApoE genotype association and pharmacodynamics related to the mechanism of drug action. Conclusions: Exploratory data from this Phase IIa clinical trial supports further clinical investigation of T3D-959 in a larger placebo-controlled clinical study. Show more

Keywords: Alzheimer’s disease, clinical trials, FDG-PET, metabolism, metabolomics, PPAR

DOI: 10.3233/JAD-190864

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1085-1103, 2020

Authors: Xu, Cheng | Guo, Jing | Li, Li | Wang, Xin | Zhou, Qiuzhi | Sun, Dongsheng | Zhang, Shujuan | Li, Shihong | Ye, Jinwang | Liu, Yanchao | Liu, Enjie | Zeng, Peng | Wang, Xiaochuan | Yang, Ying | Wang, Jian-Zhi

Article Type: Research Article

Abstract:  The three isoforms of 3R-tau are predominantly deposited in neurons bearing neurofibrillary tangles in Alzheimer’s disease (AD), while only 3R-tau accumulation has been detected in Pick’s disease (PiD), suggesting the involvement of 3R-tau in neurodegeneration. However, both the role and the molecular mechanism of 3R-tau in neurodegeneration are elusive. Here, we co-expressed three isoforms of human wild-type 3R-tau in adult mouse hippocampal to mimic the pathologic tau accumulating observed in PiD patients. We found that co-expressing three 3R-tau isoforms induced hyperphosphorylation and accumulation of tau proteins; simultaneously, the mice showed remarkable neuron death with synapse and memory deficits. Further in …vitro and in vivo studies demonstrated that co-expressing 3R-tau isoforms caused oxidative stress evidenced by an increased malondialdehyde, and the decreased superoxide dismutase and glutathione peroxidase; the 3R-tau accumulation also induced significant glial activation and DNA double-strand breaks (DSBs). Notably, the toxic effects of 3R-tau accumulation were efficiently reversed by administration of antioxidants Vitamin E (VitE) and Vitamin C (VitC), respectively. These data reveal that intracellular accumulation of 3R-tau isoforms in adult brain induces significant neuron death and memory deficits with the mechanism involving oxidation-mediated DSBs; and the antioxidants VitE and VitC can efficiently attenuate the toxicities of 3R-tau. Given that no significant cell death has been detected in the currently available wild-type tau-accumulating models, co-expressing 3R-tau isoforms could be a promising model for drug development of tauopathies, such as PiD. Show more

Keywords: 3R-tau, DNA double-strand breaks, oxidative stress, tauopathies

DOI: 10.3233/JAD-191132

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1105-1123, 2020

Authors: Liu, Hanxiang | Reynolds, Gavin P. | Wei, Xianwen

Article Type: Research Article

Abstract: Uric acid (UA) is a major contributor to naturally-occurring antioxidant activity and is thought to have protective effects against neurodegenerative processes. However, UA is also implicated as a risk factor in vascular, including cerebrovascular, disease. Its association with, and role in, dementia and its component diseases including Alzheimer’s disease (AD) and vascular dementia (VaD) remains unclear and inconsistently studied. Changes in blood lipids, particularly cholesterol measures, have also been implicated in dementias although the relationship or interactions with UA have been little studied. We have measured plasma UA and lipids taken from 187 subjects first attending a general hospital …neurology department for symptoms associated with dementia, and from a series of 79 healthy control subjects. Diagnoses of AD and VaD were made following neuroimaging; laboratory measures were compared between dementia and control groups and between AD and VaD subgroups. No overall change in UA was seen in dementia, although a substantial and highly significant reduction was found in the AD patients. Reduced values in total cholesterol, HDL, and LDL were found in dementia, independent of statin treatment. Further investigation found a significant reduction of HDL only in the VaD group, while total cholesterol was significantly reduced in both AD and VaD subjects. These findings indicate that in our Chinese sample, UA deficits are specifically associated with AD, while deficits in HDL cholesterol found in dementia tend to be greater in VaD. Show more

Keywords: Alzheimer’s disease, antioxidant, cerebrovascular disease, cholesterol, HDL, LDL, neurodegeneration, uric acid, vascular dementia

DOI: 10.3233/JAD-191111

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1125-1131, 2020

Authors: Benussi, Alberto | Dell’Era, Valentina | Cantoni, Valentina | Cotelli, Maria Sofia | Cosseddu, Maura | Spallazzi, Marco | Alberici, Antonella | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Background: The neural correlates of behavioral symptoms in frontotemporal dementia (FTD) are still to be elucidated. Neurotransmitter abnormalities could be correlated to the pathophysiology of negative and positive symptoms in FTD. Objective: To evaluate if the imbalance between inhibitory and excitatory cortical circuits, evaluated with transcranial magnetic stimulation (TMS), correlate with the magnitude of negative and positive symptoms, as measured by Frontal Behavioral Inventory (FBI) scores, in patients with FTD. Methods: Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 186 FTD patients (130 bvFTD, 35 avPPA, 21 svPPA). We applied short …interval intracortical inhibition (SICI – GABAA ergic transmission), intracortical facilitation (ICF – glutamatergic transmission), long interval intracortical inhibition (LICI – GABAB ergic transmission), and short latency afferent inhibition (SAI – cholinergic transmission). Linear and stepwise multiple regression analysis were used to determine the contribution of each neurophysiological measures to the total variance of FBI scores. Results: At the stepwise multivariate analysis, we observed a significant negative correlation between FBI-A scores (negative symptoms) and ICF (β = -0.57, p  < 0.001, adjusted R 2  = 0.32). For FBI-B scores (positive symptoms), we observed a significant positive correlation for SICI (β = 0.84, p  < 0.001, adjusted R 2  = 0.56). Significant correlations were observed for single items of the FBI-A score with ICF and FBI-B scores with SICI, with a medium-large size effect for several items. Conclusions: The present study shows that the imbalance between inhibitory and excitatory intracortical circuits, evaluated with TMS, correlated with the magnitude of negative and positive symptoms in FTD, respectively. Show more

Keywords: Frontal Behavior Inventory, frontotemporal dementia, long interval intracortical inhibition, short interval intracortical inhibition-intracortical facilitation, transcranial magnetic stimulation

DOI: 10.3233/JAD-190986

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1133-1142, 2020

Authors: Fischer, Corinne E. | Ismail, Zahinoor | Youakim, James M. | Creese, Byron | Kumar, Sanjeev | Nuñez, Nicolas | Ryan Darby, R. | Di Vita, Antonella | D’Antonio, Fabrizia | de Lena, Carlo | McGeown, William J. | Ramit, Ravona | Rasmussen, Jill | Bell, Joanne | Wang, Huali | Bruneau, Marie-Andrée | Panegyres, Peter K. | Lanctôt, Krista L. | Agüera-Ortiz, Luis | Lyketsos, Constantine | Cummings, Jeffrey | Jeste, Dilip V. | Sano, Mary | Devanand, D.P. | Sweet, Robert A. | Ballard, Clive

Article Type: Research Article

Abstract: Background: Psychotic symptoms are common in Alzheimer’s disease (AD) and related neurodegenerative disorders and are associated with more rapid disease progression and increased mortality. It is unclear to what degree existing criteria are utilized in clinical research and practice. Objective: To establish research criteria for the diagnosis of psychosis in AD. Methods: The International Society to Advance Alzheimer’s Research and Treatment (ISTAART) Neuropsychiatric Symptoms (NPS) Professional Interest Area (PIA) psychosis subgroup reviewed existing criteria for psychosis in AD and related dementias. Through a series of in person and on-line meetings, a priority checklist was devised to …capture features necessary for current research and clinical needs. PubMed, Medline and other relevant databases were searched for relevant criteria. Results: Consensus identified three sets of criteria suitable for review including those of Jeste and Finkel, Lyketsos, and the Diagnostic and Statistical Manual for Mental Disorders , 5th edition. It was concluded that existing criteria could be augmented by including a more specific differentiation between delusions and hallucinations, address overlap with related conditions (agitation in particular), adding the possibility of symptoms emerging in the preclinical and prodromal phases, and building on developing research in disease biomarkers. Conclusion: We propose criteria, developed to improve phenotypic classification of psychosis in AD, and advance the research agenda in the field to improve epidemiological, biomarker, and genetics research in the field. These criteria serve as a complement to the International Psychogeriatric Association criteria for psychosis in neurocognitive disorders. Show more

Keywords: Alzheimer’s disease, criteria, delusions, hallucinations, mild cognitive impairment, psychosis

DOI: 10.3233/JAD-190828

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1143-1156, 2020

Authors: Cao, Qing | Tan, Chen-Chen | Xu, Wei | Hu, Hao | Cao, Xi-Peng | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Dementia is a severe neurodegenerative disorder and it can be categorized into several subtypes by different pathogenic causes. We sought to comprehensively analyzed the prevalence of dementia from perspectives of geographic region (Asia, Africa, South America, and Europe/North America), age, and gender. We searched PubMed and EMBASE for relevant articles on dementia published from January 1985 to August 2019. In these studies, analyses were stratified by geographic region, age, and gender. Meta-regression was conducted to identify if there were significant differences between groups. We included forty-seven studies. Among the individuals aged 50 and over in the community, the pooled prevalence …for all-cause dementia, Alzheimer’s disease, and vascular dementia were 697 (CI95%: 546–864) per 10,000 persons, 324 (CI95%: 228–460) per 10,000 persons, and 116 (CI95%: 86–157) per 10,000 persons, respectively. In our study, the prevalence of all-type dementia in individuals aged 100 years and older (6,592 per 10,000 cases) is 244 times higher than in those aged 50–59 (27 per 10,000 cases). The number of people living with dementia approximately doubles every five years. The prevalence was greater in women than in men (788 cases versus 561 cases per 10,000 persons) in overall analysis. In individuals aged 60 to 69 years, AD prevalence in females was 1.9 times greater than that in males (108 cases versus 56 cases per 10,000 persons), while the prevalence of VaD was 1.8 times greater in males than in females (56 cases versus 32 cases per 10,000 persons). Prevalence rate was higher in Europe and North America than in Asia, Africa, and South America. Show more

Keywords: Alzheimer’s disease, dementia, prevalence, vascular dementia

DOI: 10.3233/JAD-191092

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1157-1166, 2020

Authors: Devyatkin, Vasiliy A. | Redina, Olga E. | Kolosova, Nataliya G. | Muraleva, Natalia A.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and age-related macular degeneration (AMD) are two complex incurable neurodegenerative disorders the common pathogenesis of which is actively discussed. There are overlapping risk factors and molecular mechanisms of the two diseases; at the same time, there are arguments in favor of the notion that susceptibility to each of these diseases is associated with a distinct genetic background. Here we identified single-nucleotide polymorphisms (SNPs) that are specific for senescence-accelerated OXYS rats, which simulate key characteristics of both sporadic AD and AMD. Transcriptomes of the hippocampus, prefrontal cortex, and retina (data of RNA-Seq) were analyzed. We detected SNPs in …genes Rims2 , AABR07072639.2 , Lemd2 , and AABR07045405.1 , which thus can express significantly truncated proteins lacking functionally important domains. Additionally, 33 mutations in genes—which are related to various metabolic and signaling pathways—cause nonsynonymous amino acid substitutions presumably leading to disturbances in protein structure or functions. Some of the genes carrying these SNPs are associated with aging, neurodegenerative, and mental diseases. Thus, we revealed the SNPs can lead to abnormalities in protein structure or functions and affect the development of the senescence-accelerated phenotype of OXYS rats. Our data are consistent with the latest results of genome-wide association studies that highlight the importance of multiple pathways for the pathogenesis of AD and AMD. Identified SNPs can serve as promising research objects for further studies on the molecular mechanisms underlying this particular rat model as well as for the prediction of potential biomarkers of AD and AMD. Show more

Keywords: Age-related macular degeneration, aging, Alzheimer’s disease, senescence-accelerated OXYS rats, SNP

DOI: 10.3233/JAD-190956

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1167-1183, 2020

Authors: Palmer, Jennifer C. | Tayler, Hannah M. | Dyer, Laurence | Kehoe, Patrick G. | Paton, Julian F.R. | Love, Seth

Article Type: Research Article

Abstract: Cerebral blood flow is reduced in Alzheimer’s disease (AD), which is associated with mid-life hypertension. In people with increased cerebral vascular resistance due to vertebral artery or posterior communicating artery hypoplasia, there is evidence that hypertension develops as a protective mechanism to maintain cerebral perfusion. In AD, amyloid-β (Aβ) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system. The level of endothelin-1 in brain tissue correlates positively with Aβ load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of Aβ40 exacerbated pre-existing …hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of Aβ40 on blood pressure and heart rate and their variability; carotid flow; endothelin-1; and markers of cerebral oxygenation, in the (normotensive) Wistar rat, and the modulatory influence of the endothelin A receptor antagonist Zibotentan (ZD4054). Cerebral infusion of Aβ caused progressive rise in blood pressure (p  < 0.0001) (paired t -test: increase of 3 (0.1–5.6) mmHg (p  = 0.040)), with evidence of reduced baroreflex responsiveness, and accumulation of Aβ and elevated endothelin-1 in the vicinity of the infusion. Oral Zibotentan (3 mg/kg/d, administered for 31 d) abrogated the effects of Aβ40 infusion on baroreflex responsiveness and blood pressure, which declined, although without reduction in carotid blood flow, and Zibotentan caused uncoupling of the positive linear relationship between endothelin-1 and vascular endothelial growth factor, which as a sensor of tissue oxygenation would be expected to increase if there were hypoperfusion. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, endothelin, hypertension, Zibotentan

DOI: 10.3233/JAD-190630

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1185-1199, 2020

Authors: Schultz, Nina | Byman, Elin | the Netherlands Brain Bank | Wennström, Malin

Article Type: Research Article

Abstract: Background: Previous studies have used immunohistology to demonstrate Alzheimer’s disease (AD) characteristic accumulation of amyloid-β (Aβ) in the retina of AD patients, a finding indicating retina examination as a potential diagnostic tool for AD pathology. Objective: To further explore this idea by investigating whether levels of Aβ42 and Aβ40 in retina are associated with corresponding levels in hippocampus, neuropathological assessments, apolipoprotein E (APOE ) genotype, and levels of islet amyloid polypeptide (IAPP). Methods: Levels of high molecular weight (HMW) Aβ42 , Aβ40 , and IAPP in ultra-centrifuged homogenates of retina and hippocampus from patients …with AD, multiple sclerosis, AD with Lewy bodies, and non-demented controls were analyzed using Mesoscale Discovery electrochemiluminescence technology employing immunoassay and enzyme-linked immunosorbent assay. Results: Higher levels of retinal and hippocampal Aβ42-HMW , Aβ40-HMW , and IAPP-HMW were found in individuals with high neuropathological scores of Aβ plaques and in individuals carrying the APOE ɛ 4 allele. The retinal levels of Aβ42-HMW and Aβ40-HMW correlated with corresponding levels in hippocampus as well as with neurofibrillary tangles (NFT) and Aβ scores. Retinal IAPP-HMW correlated with retinal levels of Aβ42-HMW and with NFT and Aβ scores. Conclusion: These results show that different isoforms of Aβ can be detected in the human retina and moreover support the growing number of studies indicating that AD-related pathological changes occurring in the brain could be reflected in the retina. Show more

Keywords: Alzheimer’s disease, amyloid-β, hippocampus, IAPP, retina

DOI: 10.3233/JAD-190868

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1201-1209, 2020

Authors: Ezzati, Ali | Harvey, Danielle J. | Habeck, Christian | Golzar, Ashkan | Qureshi, Irfan A. | Zammit, Andrea R. | Hyun, Jinshil | Truelove-Hill, Monica | Hall, Charles B. | Davatzikos, Christos | Lipton, Richard B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Amyloid-β positivity (Aβ+) based on PET imaging is part of the enrollment criteria for many of the clinical trials of Alzheimer’s disease (AD), particularly in trials for amyloid-targeted therapy. Predicting Aβ positivity prior to PET imaging can decrease unnecessary patient burden and costs of running these trials. Objective: The aim of this study was to evaluate the performance of a machine learning model in estimating the individual risk of Aβ+ based on gold-standard of PET imaging. Methods: We used data from an amnestic mild cognitive impairment (aMCI) subset of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) …cohort to develop and validate the models. The predictors of Aβ status included demographic and ApoE4 status in all models plus a combination of neuropsychological tests (NP), MRI volumetrics, and cerebrospinal fluid (CSF) biomarkers. Results: The models that included NP and MRI measures separately showed an area under the receiver operating characteristics (AUC) of 0.74 and 0.72, respectively. However, using NP and MRI measures jointly in the model did not improve prediction. The models including CSF biomarkers significantly outperformed other models with AUCs between 0.89 to 0.92. Conclusions: Predictive models can be effectively used to identify persons with aMCI likely to be amyloid positive on a subsequent PET scan. Show more

Keywords: Alzheimer’s disease, amyloid imaging, machine learning, mild cognitive impairment, predictive analytics

DOI: 10.3233/JAD-191038

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1211-1219, 2020

Authors: Rundek, Tatjana | Gardener, Hannah | Dias Saporta, Anita Seixas | Loewenstein, David A. | Duara, Ranjan | Wright, Clinton B. | Dong, Chuanhui | Levin, Bonnie | Elkind, Mitchell S.V. | Sacco, Ralph L.

Article Type: Research Article

Abstract: Background: Modifiable vascular risk factors (VRF) have been implicated in cognitive impairment. Objective: We compared the prediction of cognitive performance between the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score, a validated tool to estimate dementia risk using VRF, and the Northern Manhattan Study (NOMAS) global vascular risk score (GVRS), created to predict vascular events. Methods: The CAIDE and GVRS scores were calculated based on baseline VRF among 1,290 stroke-free participants in the prospective population-based NOMAS MRI cohort (mean age 64±8 years, 60% women; 66% Hispanic, 17% Black, 15% White; 46% completed …high school). Domain-specific Z-scores were derived for episodic and semantic memory, executive function, and processing speed, and averaged to calculate global cognition. Results: The CAIDE score was associated with worse global cognition at initial assessment (Beta per SD = –0.347, p  < 0.0001), and with greater decline over time (Beta per SD = –0.033, p  = 0.02). These associations were largely due to age and education, and the association with cognitive decline was not significant after adjusting for age, sex, and education. The GVRS was inversely associated with global cognition at initial testing (Beta per SD = –0.247, p  < 0.0001) and greater decline over time (Beta per SD = –0.127, p  < 0.0001), which persisted after adjusting for sociodemographics. The associations for both scores with initial cognitive performance were driven by executive function and processing speed, and the GVRS was associated with decline in episodic memory and processing speed. Conclusions: The GVRS was a stronger predictor of cognitive decline than the CAIDE in a multi-ethnic urban cohort. The inclusion of glucose and smoking in the GVRS, which are absent in CAIDE, likely explains the better performance of the GVRS. Show more

Keywords: Cognition, dementia, epidemiology, risk score, vascular risk factors

DOI: 10.3233/JAD-190925

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1221-1231, 2020

Authors: McMichael, Alan J. | Zafeiridi, Evi | Passmore, Peter | Cunningham, Emma L. | McGuinness, Bernadette

Article Type: Research Article

Abstract: Background: Understanding factors associated with mortality after a dementia diagnosis can provide essential information to the person with dementia, their family, and caregivers. To date very little is known about the factors associated with mortality after a dementia diagnosis in Northern Ireland. Objective: To determine how demographic and other factors such as deprivation and comorbidity medications influence mortality rates after a dementia diagnosis in Northern Ireland and whether these factors are influenced through nursing home transitions. Methods: 25,418 people prescribed anti-dementia medication were identified through the enhanced prescribing database between 2010 and 2016. The impact of …covariates including age, gender, marital status, deprivation measure, urban/rural classification, and comorbidity medications were examined using cox proportional hazard models with hazard ratios (HR) and 95% confidence intervals. Results: Between 2010 and 2016, 12,129 deaths occurred, with 114 deaths/1,000 person years. Males had significantly higher mortality rates in comparison to females (HR = 1.28; 95% CI = 1.23–1.33); this was true regardless of whether the person with dementia transitioned to a nursing home. People prescribed anti-dementia drugs living with lower levels of deprivation had significantly lower mortality rates in comparison to people living with the highest levels of deprivation (HR = 0.93; 95% CI = 0.89–0.97). Diabetic (HR = 1.18; 95% CI = 1.07–1.29) and anti-arrhythmic (HR = 2.44; 95% CI = 1.01–5.91) medication in particular significantly influenced mortality. Conclusion: Male gender, higher comorbidity medications, and living in areas of higher deprivation significantly increased mortality rates for people prescribed anti-dementia drugs in our study population. When comorbidity medications were classified, only anti-arrhythmia and diabetic medications significantly increased mortality. Future research should continue to investigate factors which influence mortality after a dementia diagnosis. Show more

Keywords: Cohort studies, dementia, epidemiology, mortality

DOI: 10.3233/JAD-190751

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1233-1242, 2020

Authors: Lampela, Pasi | Tolppanen, Anna-Maija | Koponen, Marjaana | Tanskanen, Antti | Tiihonen, Jari | Hartikainen, Sirpa | Taipale, Heidi

Article Type: Research Article

Abstract: Background: Asthma and chronic obstructive pulmonary disease (COPD) are common comorbidities in persons with Alzheimer’s disease (AD). However, pharmacotherapy of these diseases may have opposite mechanisms of action; anticholinergics in asthma/COPD and acetylcholinesterase inhibitors (AChEI) in AD. Objective: To investigate whether existing asthma/COPD affects the choice of AD medication, and the survival of the patients with AD. Methods: In this retrospective cohort study, data from the MEDALZ-study, which includes all community-dwelling persons with AD during 2005–2011 in Finland (n  = 70718) was utilized. Persons with asthma/COPD (N = 7211) were defined as having a special reimbursement for asthma/COPD, or …long-term use (≥250 days) of inhaled anticholinergics, inhaled corticosteroids, or leukotriene antagonists during the year before AD diagnosis. We compared persons with and without asthma/COPD regarding the choice of the initial antidementia medication (AChEI versus memantine) with logistic regression and mortality with Cox regression model during the follow-up (up to end of 2015). Results: Memantine was favored over AChEIs as first-line treatment to AD in persons with asthma/COPD compared to those without asthma/COPD (odds ratio 1.23, 95% confidence interval (CI) 1.15–1.31). Memantine was also more commonly used among those who used multiple asthma/COPD medications (7.9% of memantine initiators used ≥3 asthma/COPD medications compared with 5.5% of those who initiated with AChEI). Mortality was higher in persons with asthma/COPD compared to those without asthma/COPD (adjusted hazard ratio 1.10, 95% CI 1.07–1.13). Conclusion: More frequent use of memantine instead of AChEI may result from an attempt to prevent possible worsening of asthma/COPD by AChEIs. Vulnerable persons with both AD and asthma/COPD need individually assessed pharmacotherapy for their medical conditions. Show more

Keywords: Alzheimer’s disease, anticholinergics, asthma, cholinesterase inhibitors, chronic obstructive pulmonary disease, dementia, older person

DOI: 10.3233/JAD-190850

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1243-1251, 2020

Authors: Alzubaidi, Hamzah | Saidawi, Ward | Hussein, Amal | Hasan, Sanah

Article Type: Research Article

Abstract: Background: The global prevalence of Alzheimer’s disease (AD) and its treatment costs are projected to increase significantly, placing increasing pressure on health systems to create new models of care. Community pharmacists are well-positioned to provide medication management for people with AD. In Arabic-speaking countries, little is known about pharmacists’ knowledge and practices in caring for people with AD. Objective: To evaluate community pharmacists’ knowledge of AD and its management, counseling skills, and dispensing patterns when caring for people with AD and their caregivers in the United Arab Emirates (UAE). Methods: A large-scale cross-sectional survey of community …pharmacists was conducted in three cities in the UAE using stratified random sampling. The questionnaire comprised of validated tools to measure knowledge and open-ended questions. A logistic regression model was conducted to predict counseling comprehensiveness. Results: A total of 325 community pharmacists completed the questionnaire. The mean knowledge scores about AD and its pharmacotherapy were 57.0% and 67.6%, respectively. Major shortcomings in pharmacists’ practices were identified; history-taking, adherence assessment, and counseling were provided by 2.2%, 9.3%, and 17.3%, respectively. A minority provided comprehensive counselling; the multivariate analysis yielded new insights into pharmacist characteristics associated with such counseling. Conclusion: Pharmacists did not provide structured patient-centered care for people with AD. Community pharmacists did not provide adequate counseling, did not assess adherence-related issues appropriately, and had deficient knowledge. To develop patient-centered pharmacy-based services for Arabic-speaking communities, a multifaceted approach is required that goes beyond improving pharmacy workforce knowledge and communication skills to address broader sociocultural, legislative, and financial factors. Show more

Keywords: Alzheimer’s disease, Arabs, community pharmacy services, counseling, knowledge, medication therapy management

DOI: 10.3233/JAD-190804

Citation: Journal of Alzheimer's Disease, vol. 73, no. 3, pp. 1253-1264, 2020