Journal of Alzheimer's Disease - Volume 69, issue 4

Authors: Fuermaier, Anselm B.M. | Piersma, Dafne | de Waard, Dick | Davidse, Ragnhild J. | de Groot, Jolieke | Doumen, Michelle J.A. | Bredewoud, Ruud A. | Claesen, René | Lemstra, Afina W. | Scheltens, Philip | Vermeeren, Annemiek | Ponds, Rudolf | Verhey, Frans | De Deyn, Peter Paul | Brouwer, Wiebo H. | Tucha, Oliver

Article Type: Research Article

Abstract: Background/Objective: Neurodegenerative disorders impact fitness to drive of older drivers, but on-road driving studies investigating patients with different neurodegenerative disorders are scarce. A variety of driving errors have been reported in patients with Alzheimer’s disease (AD), but it is unclear which types of driving errors occur most frequently. Moreover, patients with other neurodegenerative disorders than AD typically present with different symptoms and impairments, therefore different driving errors may be expected. Methods: Patients with AD (n  = 80), patients with other neurodegenerative disorders with cognitive decline (i.e., vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson’s disease, n  = 59), and healthy …older drivers (n  = 45) participated in a fitness-to-drive assessment study including on-road driving. Results: Patients with AD performed significantly worse than healthy older drivers on operational, tactical, visual, and global aspects of on-road driving. In patients with AD, on-road measures were significantly associated with ‘off-road’ measures. Patients with neurodegenerative disorders other than AD showed large overlap in the types of driving errors. Several driving errors were identified that appear to be characteristic for patients with particular neurodegenerative disorders. Conclusion: Patients from each group of neurodegenerative disorders commonly display tactical driving errors regarding lane positioning, slow driving, observation of the blind spot, and scanning behavior. Several other tactical and operational driving errors, including not communicating with cyclists and unsteady steering, were more frequently observed in patients with non-AD neurodegenerative disorders. These findings have implications for on-road and ‘off-road’ fitness-to-drive assessments for patients with neurodegenerative disorders with cognitive decline. Show more

Keywords: Alzheimer’s disease, automobile driving, cognitive decline, frontotemporal dementia, dementia with Lewy bodies, neurodegenerative diseases, Parkinson’s disease, vascular dementia

DOI: 10.3233/JAD-181095

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1019-1030, 2019

Authors: Matsunaga, Shinji | Fujishiro, Hiroshige | Takechi, Hajime

Article Type: Research Article

Abstract: Background: The efficacy and safety of glycogen synthase kinase 3 (GSK-3) inhibitors in patients with Alzheimer’s disease (AD) is unknown. Objective: A systematic review and meta-analysis of randomized controlled trials (RCTs) to test GSK-3 inhibitors on AD patients. Methods: We included RCTs of GSK-3 inhibitors in AD patients and subjects with mild cognitive impairment (MCI), using cognitive function scores as a primary measure. Results: Five RCTs (three RCTs using lithium and two RCTs using tideglusib) with 568 patients were included. There was no significant difference in cognitive function scores between the GSK-3 inhibitors and …placebo groups [standardized mean difference (SMD) = –0.25, p  = 0.11, I 2  = 55% ]. However, significant heterogeneity remained. A sensitivity analysis revealed that the lithium subgroup was more effective on cognitive function scores than placebo for AD and MCI (lithium subgroup: SMD = –0.41, p  = 0.04; tideglusib subgroup: SMD = –0.02, p  = 0.89). Moreover, a meta-regression analysis showed that the effect size of GSK-3 inhibitors on cognitive function scores was associated with study duration (coefficient, –0.0116). For safety outcomes, tideglusib was associated with a higher incidence of increased aspartate aminotransferase than placebo. There were no significant differences in other secondary outcomes between treatments. Conclusion: Our results suggested that GSK-3 inhibitors were ineffective in treating AD and MCI; however, several studies included in the present meta-analysis were small, and future studies using a larger sample size are needed. Show more

Keywords: Alzheimer’s disease, glycogen synthase kinase 3, lithium, meta-analysis, tideglusib

DOI: 10.3233/JAD-190256

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1031-1039, 2019

Authors: Suijkerbuijk, Sandra | Nap, Henk Herman | Cornelisse, Lotte | IJsselsteijn, Wijnand A. | de Kort, Yvonne A.W. | Minkman, Mirella M.N.

Article Type: Research Article

Abstract:  Although there are promising benefits of supportive technology in dementia care, use of these technologies is still limited. It is challenging for researchers and developers in this field to actively involve people with dementia in development. This review updates and builds on existing knowledge by including a contemporary and relevant perspective. This perspective was gained by including search words and search databases from the field of Human Computer Interaction (HCI) and Design, as these fields were expected to supply novel insights in the complex task of actively involving people with dementia in developing supportive technologies. A total of 49 out …of 3456 studies were included which describe the development of a great variety of technologies. Often people with dementia were involved in the generative or evaluative phase of the development. Interviews and observations were most commonly used methods. In seven articles the people with dementia were co-designers. This literature review reflects that people with dementia can influence the development of technology in regards to content, design, and even the initial idea, although the impact on how they experience their own involvement remains largely unknown. There is a lack of specific knowledge on appropriate methods and materials for active involvement of people with dementia in supportive technology development, even when including articles from the field of HCI and Design. Future research is needed to further appreciate and improve the desired role of people with dementia in meaningful technology development. Show more

Keywords: Co-design, dementia, patient participation, supportive technology

DOI: 10.3233/JAD-190050

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1041-1065, 2019

Authors: Clement, Clare | Selman, Lucy E. | Kehoe, Patrick G. | Howden, Beth | Lane, J. Athene | Horwood, Jeremy

Article Type: Research Article

Abstract: Background: Low participation in clinical trials is a major challenge to advancing clinical Alzheimer’s disease (AD) research and care. Factors influencing recruitment to AD trials are not fully understood. Objective: To identify barriers to, and facilitators of, recruitment in a UK multi-center, secondary care AD trial (Reducing pathology in Alzheimer’s Disease through Angiotensin TaRgeting (RADAR) trial) and implications for improving recruitment to AD trials. Methods: Semi-structured qualitative telephone interviews with a purposive sample of 17 trial site staff explored the RADAR trial recruitment pathway and views and experiences of recruitment. Interviews were analyzed thematically. …Results: Diagnostic and care pathways hindered identifying patients with mild-moderate AD, with a lack of up-to-date patient records and data access problems affecting screening. Research is not routinely embedded in AD care but facilitated recruitment when it was. Clinicians’ and patients’ favorable view of the trial purpose facilitated recruitment, although the complexity of participant information sheets and requirement for study companion created challenges. Conclusion: These findings have important implications for the design of future AD trials and for planning how to best interface with clinical commitments to ensure sufficient and timely recruitment. Challenges to AD trial recruitment can occur at care pathway, clinician, and patient and companion levels. Recruitment can be facilitated by: improving diagnostic processes and systems for recording and sharing patient information, embedding research into routine patient care, collaborating with a range of services to identify and approach eligible patients, training and engaging trial staff, and providing patients with clear and concise study information. Show more

Keywords: Dementia, humans, patient care, qualitative research, randomized controlled trial, research design

DOI: 10.3233/JAD-190146

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1067-1075, 2019

Authors: Liu, Mengyu | Wang, Luwen | Gao, Ju | Dong, Qing | Perry, George | Ma, Xuemei | Wang, Xinglong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) and other tauopathies are characterized by intracellular accumulation of microtubule-associated tau protein leading to neurodegeneration. Calpastatin is the endogenous inhibitor of calpain, a calcium-dependent cysteine protease that has been increasingly implicated in tauopathies. In this study, we generated a neuron specific calpastatin overexpressing knock-in transgenic mouse model and crossed it with the PS19 tauopathy mouse model expressing human P301S mutant tau protein. The forced expression of calpastatin in neurons significantly alleviated tau hyperphosphorylation measured by immunocytochemistry and immunoblot. The genetic inhibition of calpain by calpastatin also greatly suppressed characteristic hippocampal neuron loss and widespread astrogliosis and microgliosis …in PS19 mice. Consistently, PS19 mice with neuronal calpastatin overexpression exhibited remarkably alleviated cognitive deficits, muscle weakness, skeletal muscle atrophy, and neuromuscular denervation, together implying the neuroprotective effects of neuronal calpastatin in PS19 mice of tauopathy. In sum, this study provides additional evidence supporting the pathological role of calpain in neurodegenerative diseases associated with tau pathology, and suggests that targeting calpain is likely a promising therapeutic approach for these devastating diseases. Show more

Keywords: Calpain, calpastatin, cognitive deficits, dementia, motor dysfunction, neurodegeneration, neuroinflammation, neuromuscular junction, tau phosphorylation, tauopathy

DOI: 10.3233/JAD-190281

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1077-1087, 2019

Authors: Aarons, Toby | Bradburn, Steven | Robinson, Andrew | Payton, Antony | Pendleton, Neil | Murgatroyd, Chris

Article Type: Research Article

Abstract: Background: Brain-derived neurotrophic factor (BDNF) is essential for neurogenesis and has been implicated in Alzheimer’s disease (AD). However, few studies have investigated together the epigenetic, transcriptional, and translational regulation of this peptide in the brain in relation to AD. Objective: To investigate mechanisms underlying how BDNF is possibly dysregulated in the brain in relation to aging and AD neuropathology. Methods: Prefrontal cortex tissues were acquired from the Manchester Brain Bank (N = 67). BDNF exon I , and exon IV -containing transcripts and total long 3’ transcript gene expression were determined by quantitative PCR and bisulfite pyrosequencing …was used to quantify DNA methylation within promoters I and IV . Protein concentrations were quantified via ELISA. Results: BDNF exon IV and total long 3’ isoform gene expression levels negatively associated with donor’s age at death (IV : r  = –0.291, p  = 0.020; total : r  = –0.354, p  = 0.004). Expression of BDNF exon I- containing isoform was significantly higher in Met-carriers of the rs6265 variant, compared to Val-homozygotes, when accounting for donor ages (F = 6.455, p  = 0.014). BDNF total long 3’ transcript expression was significantly lower in those with early AD neuropathology, compared to those without any neuropathology (p  = 0.021). There were no associations between BDNF promoter I and IV methylation or protein levels with ages, rs6265 genotype or AD neuropathology status. Conclusion: Prefrontal cortex BDNF gene expression is associated with aging, rs6265 carrier status, and AD neuropathology in a variant-specific manner that seems to be independent of DNA methylation influences. Show more

Keywords: Alzheimer’s disease, BDNF, DNA methylation, prefrontal cortex

DOI: 10.3233/JAD-190049

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1089-1097, 2019

Authors: Rouch, Isabelle | Dorey, Jean-Michel | Padovan, Catherine | Trombert-Paviot, Béatrice | Benoit, Michel | Laurent, Bernard | PACO group (appendix) | Boublay, Nawèle | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Premorbid personality could play a role in the onset of behavioral and psychological symptoms (BPS) in Alzheimer’s disease (AD) but prospective studies are lacking. Objective: The present study aimed at prospectively assessing the influence of premorbid personality traits on BPS evolution in a population of patients with prodromal or mild AD. Methods: We used a multicenter prospective cohort study of 237 patients followed-up for 18 months. The influence of personality traits on BPS evolution, measured with Neuropsychiatric Inventory (NPI), was assessed using linear mixed-effect models. Results: A principal components analysis of the 12 …NPI behavioral domains yielded five factors labelled as psychotic symptoms, affective symptoms, behavioral dyscontrol, apathy/appetite symptoms, and sleep disorders. During the follow-up, higher neuroticism was significantly associated with a higher progression of affective symptoms (p  < 0.0001), apathy/appetite symptoms (p  = 0.002), sleep disorders (p  = 0.001) as well as global NPI scores (p  < 0.0001). Greater conscientiousness was related to a lower evolution of psychotic (p  = 0.002), affective (p  = 0.02) and apathy/appetite symptoms (p  = 0.02), and global NPI score (p  < 0.0001). Higher openness was associated with lower affective symptoms evolution (p  = 0.01). A significant relationship was found between higher extraversion, lower affective symptoms (p  = 0.02), and higher behavioral dyscontrol (p  = 0.04). Conclusion: The present analysis suggests that premorbid personality may influence the evolution of BPS in prodromal or mild AD. Given these results, it seems important to give more importance to personality assessment in early AD, in order to better identify and manage patients at risk of adverse behavioral changes. Show more

Keywords: Alzheimer’s disease, behavior, dementia, neuropsychiatry

DOI: 10.3233/JAD-190183

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1099-1108, 2019

Authors: Andrews, Shea J. | McFall, G. Peggy | Booth, Andrew | Dixon, Roger A. | Anstey, Kaarin J.

Article Type: Research Article

Abstract: The association of Apolipoprotein E (APOE ) with late-onset Alzheimer’s disease (LOAD) and cognitive endophenotypes of aging has been widely investigated. There is increasing interest in evaluating the association of other LOAD risk loci with cognitive performance and decline. The results of these studies have been inconsistent and inconclusive. We conducted a systematic review of studies investigating the association of non-APOE LOAD risk loci with cognitive performance in older adults. Studies published from January 2009 to April 2018 were identified through a PubMed database search using keywords and by scanning reference lists. Studies were included if they were …either cross-sectional or longitudinal in design, included at least one genome-wide significant LOAD risk loci or a genetic risk score, and had one objective measure of cognition. Quality assessment of the studies was conducted using the quality of genetic studies (Q-Genie) tool. Of 2,466 studies reviewed, 49 met inclusion criteria. Fifteen percent of the associations between non-APOE LOAD risk loci and cognition were significant. However, these associations were not replicated across studies, and the majority were rendered non-significant when adjusting for multiple testing. One-third of the studies included genetic risk scores, and these were typically significant only when APOE was included. The findings of this systematic review do not support a consistent association between individual non-APOE LOAD risk and cognitive performance or decline. However, evidence suggests that aggregate LOAD genetic risk exerts deleterious effects on decline in episodic memory and global cognition. Show more

Keywords: Alzheimer’s disease, cognition, genetic predisposition to disease, single nucleotide polymorphism

DOI: 10.3233/JAD-190342

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1109-1136, 2019

Authors: Cui, Hailun | Ren, Rujing | Lin, Guozhen | Zou, Yang | Jiang, Lijuan | Wei, Zhengde | Li, Chunbo | Wang, Gang

Article Type: Research Article

Abstract: Background: Repetitive transcranial magnetic stimulation (rTMS) is thought to be effective in alleviating cognitive symptoms in patients with amnestic mild cognitive impairment (aMCI), but the mechanisms related to network modification are poorly understood. Objective: Here we tested rTMS efficacy and explored the effect of rTMS-induced changes in the default mode network (DMN) and their predictive value for treatment response. Methods: Twenty-one subjects clinically diagnosed with aMCI were recruited to complete a 10-session randomized and sham-controlled rTMS treatment targeting the right dorsolateral prefrontal cortex. Resting-state functional magnetic resonance imaging in tandem with neuropsychological assessments were administered before …and after the intervention. Changes in functional connectivity of the DMN and relevant brain regions, as well as the correlations between baseline functional connectivity and clinical rating scales were calculated in order to elucidate the mechanism of treatment response to rTMS therapy. Results: Compared to the sham group, the rTMS group achieved improvement of neuropsychological performance and significant functional connectivity changes within the DMN. Group×Time interactions were found between posterior cingulate gyrus and right fusiform gyrus (F (1,19)   = 17.154, p  = 0.001), and also left anterior cingulate gyrus (F (1,19)   = 3.908, p  = 0.063), showing an rTMS-induced deactivation of functional connectivity within the DMN. Baseline functional connectivity analysis of seeds within the DMN in the rTMS group revealed negative correlation with AVLT-Recognition score changes. Conclusion: rTMS-induced hypoconnectivity within DMN is associated with clinical cognitive improvements in patients with aMCI. Further, pre-rTMS baseline activity of the DMN at rest may be a predictor for favorable rTMS treatment response. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, default mode network, repetitive transcranial magnetic stimulation, resting-state functional MRI

DOI: 10.3233/JAD-181296

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1137-1151, 2019

Authors: Stanley, Karen | Whitfield, Tim | Kuchenbaecker, Karoline | Sanders, Oliver | Stevens, Tim | Walker, Zuzana

Article Type: Research Article

Abstract: Background: There is only limited information available about the effect of age on course of cognitive decline in patients with onset of Alzheimer’s disease (AD) over the age of 64 years. Objective: We compared the rate of, and factors affecting, cognitive decline in patients with AD aged < 65 years (young-onset AD), 65–74 years (middle-onset AD), and ≥75 years (late-onset AD). Method: The study used longitudinal data from the Essex Memory Clinic which included a total of 305 participants; 56 had YOAD, 73 had MOAD, and 176 had LOAD. The rate of cognitive decline was measured using scores …from the Mini-Mental State Examination (MMSE), and the data were examined using multilevel models analysis. Results: There was evidence of a difference in cognitive decline across the age groups with the YOAD group declining 2.8 MMSE points per year, those with MOAD declined 2.0 MMSE points per year, and the LOAD group declined 1.4 MMSE points per year. Conclusions: Patients with LOAD have a better prognosis than YOAD and MOAD. However, even between the MOAD and LOAD groups, age is a significant predictor of cognitive decline, with older patients having a more benign course. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia, rate of decline, young-onset

DOI: 10.3233/JAD-181047

Citation: Journal of Alzheimer's Disease, vol. 69, no. 4, pp. 1153-1160, 2019