Journal of Alzheimer's Disease - Volume 66, issue 1

Authors: Yeo, Si Ning | Lee, Tih Shih | Sng, Wei Theng | Heo, Min Quan | Bautista, Dianne | Cheung, Yin Bun | Zhang, Hai Hong | Wang, Chuanchu | Chin, Zheng Yang | Feng, Lei | Zhou, Juan | Chong, Mei Sian | Ng, Tze Pin | Krishnan, K. Ranga | Guan, Cuntai

Article Type: Research Article

Abstract: Background: Cognitive training has been demonstrated to improve cognitive performance in older adults. To date, no study has explored personalized training that targets the brain activity of each individual. Objective: This is the first large-scale trial that examines the usefulness of personalized neurofeedback cognitive training. Methods: We conducted a randomized-controlled trial with participants who were 60–80 years old, with Clinical Dementia Rating (CDR) score of 0–0.5, Mini-Mental State Examination (MMSE) score of 24 and above, and with no neuropsychiatric diagnosis. Participants were randomly assigned to the Intervention or Waitlist-Control group. The training system, BRAINMEM, has attention, …working memory, and delayed recall game components. The intervention schedule comprised 24 sessions over eight weeks and three monthly booster sessions. The primary outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score after the 24-session training. Results: There were no significant between-subjects differences in overall cognitive performance post-intervention. However, a sex moderation effect (p = 0.014) was present. Men in the intervention group performed better than those in the waitlist group (mean difference, +4.03 (95% CI 0.1 to 8.0), p = 0.046. Among females, however, both waitlist-control and intervention participants improved from baseline, although the between-group difference in improvement did not reach significance. BRAINMEM also received positive appraisal and intervention adherence from the participants. Conclusion: A personalized neurofeedback intervention is potentially feasible for use in cognitive training for older males. The sex moderation effect warrants further investigation and highlights the importance of taking sex into account during cognitive training. Show more

Keywords: Brain-computer interface, cognitive training, older adults, personalized neurofeedback

DOI: 10.3233/JAD-180450

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 127-138, 2018

Authors: Nagata, Tomoyuki | Shinagawa, Shunichiro | Nakajima, Shinichiro | Mimura, Masaru | Shigeta, Masahiro

Article Type: Research Article

Abstract: Background/Objective: To assess associations between improvements in neuropsychiatric symptoms (NPS) and neurocognitive change in patients with Alzheimer’s disease (AD) during treatment using the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer Disease (CATIE-AD) dataset. Methods: AD outpatients with NPS who needed pharmacological treatment (n  = 421) were followed up with antipsychotics, citalopram, or placebo for up to 36 weeks (mean±SD = 252±52 days). The study aim was to investigate associations between improvement in each NPS evaluating scale (by Clinical Global Impression of Change [CGI-C], Neuropsychiatric Inventory [NPI], or Brief Psychiatric Scale [BPRS]) at endpoint (week 36 or early termination [ET], n … = 340) and neurocognitive change (change score in the Mini-Mental State Examination [MMSE] between endpoint and baseline during the treatment). Multiple logistic regression analyses were performed on the associations between each NPS improvement and neurocognitive change as well as socio-clinico-demographic variables of interest. Results: At endpoint, NPS improvement rates were 76.1%, 70.8%, and 58.1% in CGI-C, NPI, and BPRS, respectively, while MMSE score change was –2.3±3.8. NPS improvement was significantly related to more severe psychotic symptoms at baseline and preserved levels of neurocognition (smaller MMSE score change) among several variables. Conclusions: Our findings suggested that neurocognitive preservation may be associated with attaining optimal benefits from any treatment against NPSs in a longitudinal treatment course of patients with AD. Show more

Keywords: Alzheimer’s disease, antipsychotic, CATIE-AD, neurocognitive impairment, neuropsychiatric symptom

DOI: 10.3233/JAD-180304

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 139-148, 2018

Authors: Jütten, Linda Helena | Mark, Ruth Elaine | Wicherts, Jelte Michiel | Sitskoorn, Margriet Maria

Article Type: Research Article

Abstract: Background: Many psychosocial and behavioral interventions have been developed for informal dementia caregivers. Because existing meta-analyses only focused on a limited number of interventions and outcomes, how effective these interventions are overall and which interventions components are associated with larger effects has yet to be explored. Objective: To provide a comprehensive meta-analysis of the effectiveness of psychosocial and behavioral interventions on burden, depression, anxiety, quality of life, stress, and sense of competence in informal dementia caregivers. In addition, we examined if interventions which utilized more sessions and/or were delivered personally (face-to-face) had larger effect sizes. In …exploratory meta-regressions, we examined seven additional moderators. Methods: The protocol was registered with PROSPERO, number CRD42017062555. We systematically searched the literature to identify controlled trials assessing the effect of psychosocial and behavioral interventions on the six outcome measures, for informal dementia caregivers. We performed six random effects meta-analyses, to assess the pooled effect sizes of the interventions. In addition, we performed separate meta-regressions, for each outcome, for each moderator. Results: The sample consisted of 60 studies. For all outcomes except anxiety, the pooled effects were small and in favor of the intervention group. No moderator was found to systematically predict these effects. There were no indications for publication bias or selection bias based on significance. Conclusion: Overall, the interventions yield significant (small) effects, independent of intervention characteristics. Future research should explore options to enhance the effectiveness of interventions aimed at assisting informal caregivers. Show more

Keywords: Burden, dementia, depression, informal caregivers, interventions, meta-analysis, meta-regression, psychobehavioral, psychosocial

DOI: 10.3233/JAD-180508

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 149-172, 2018

Authors: Ávila-Villanueva, Marina | Maestú, Fernando | Fernández-Blázquez, Miguel A.

Article Type: Research Article

Abstract: Background: Early intervention to prevent, or delay, the transition from healthy cognition to cognitive impairment in older adults is an important goal. In this way, it is critical to find sensitive, reproducible, and early markers to use low cost methods for the detection of that transition. One of those early markers for symptomatic manifestation of AD is subjective cognitive decline (SCD). Objective: To examine the internal consistency of the concept of SCD and to evaluate its clinical significance on the progression through the continuum of AD. Methods: 1,091 cognitively healthy individuals from the Vallecas Project cohort …were followed for three years. Cognitive complaints were systematically collected and analyzed along with clinical data. All participants were classified in three groups at every visit based on specific features of their complaints. Results: Concordance analyses showed a good agreement in longitudinal classification of SCD. The Multi-state Markov Model highlighted a unidirectional transition from the status of no cognitive complaints to SCD. Interestingly, a more severe condition of SCD, namely SCD Plus, showed the highest risk of progression to mild cognitive impairment. Conclusions: The concept of SCD is stable over time when it is operationally defined and consistently assessed. It provides not only a fast identification of individuals at higher risk of future mild cognitive impairment, but also it allows us to track longitudinal trajectories. Show more

Keywords: Aging, Alzheimer’s disease, cognitive symptoms, dementia, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-180307

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 173-183, 2018

Authors: Zupanic, Eva | Kåreholt, Ingemar | Norrving, Bo | Secnik, Juraj | von Euler, Mia | Winblad, Bengt | Religa, Dorota | Kramberger, Milica Gregoric | Johnell, Kristina | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Previous studies have shown that patients with dementia receive less testing and treatment for stroke. Objectives: Our aim was to investigate hospital management of acute ischemic stroke in patients with and without dementia. Methods: Retrospective analysis of prospectively collected data 2010–2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who suffered an acute ischemic stroke (AIS) (n  = 1,356) were compared with matched non-dementia AIS patients (n  = 6,755). Outcomes included length of stay in a stroke unit, total length of hospitalization, and utilization of …diagnostic tests and assessments. Results: The median age at stroke onset was 83 years. While patients with dementia were equally likely to be directly admitted to a stroke unit as their non-dementia counterparts, their stroke unit and total hospitalization length were shorter (10.5 versus 11.2 days and 11.6 versus 13.5, respectively, p  < 0.001). Dementia patients were less likely to receive carotid ultrasound (OR 0.36, 95% CI [0.30–0.42]) or undergo assessments by the interdisciplinary team members (physiotherapists, speech therapists, occupational therapists; p  < 0.05 for all adjusted models). However, a similar proportion of patients received CT imaging (97.4% versus 98.6%, p  = 0.001) and a swallowing assessment (90.7% versus 91.8%, p  = 0.218). Conclusions: Patients with dementia who suffer an ischemic stroke have equal access to direct stroke unit care compared to non-dementia patients; however, on average, their stay in a stroke unit and total hospitalization are shorter. Dementia patients are also less likely to receive specific diagnostic tests and assessments by the interdisciplinary stroke team. Show more

Keywords: Cohort studies, dementia, hospital management, ischemic stroke

DOI: 10.3233/JAD-180653

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 185-194, 2018

Authors: Panagaki, Theodora | Gengler, Simon | Hölscher, Christian

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones—glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)—have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer’s and Parkinson’s diseases have revealed beneficial effects of these anti-diabetic …agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APPSWE /PS1Δ E9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APPSWE /PS1Δ E9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo . Show more

Keywords: Alzheimer’s disease, APP/PS1 mouse model, autophagy, ER stress, GLP-1/GIP dual agonist, neurotrophins

DOI: 10.3233/JAD-180584

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 195-218, 2018

Authors: Fiorini, Michele | Bongianni, Matilde | Benedetti, Maria Donata | Monaco, Salvatore | Zanusso, Gianluigi

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers are currently included in the diagnostic criteria for Alzheimer’s disease (AD), in particular, decreased concentrations of amyloid-β peptide 1–42 (Aβ42 ) in the CSF, coupled with increased levels of tau and phosphorylated tau proteins, are supportive of AD diagnosis. To date, the quantification of Aβ42 levels with antibody-dependent immunoassay shows a marked variability among different laboratories and is also affected by different pre-analytical factors, suggesting that part of Aβ42 peptides might be aggregated and thus undetected by antibodies. To bypass an antibody-dependent measurement, we determined the Aβ40 and Aβ42 levels by immunoblot. …We analyzed CSF samples from 35 patients with clinical diagnosis of probable AD and from 15 age-matched normal controls; CSF Aβ levels were determined by two different ELISA kits and by immunoblot analysis. Aβ40 levels measured by ELISA were comparable to those obtained by immunoblot, whereas CSF concentrations of Aβ42 measured by ELISA were significantly lower compared to values obtained by immunoblot quantification. Biochemical analysis, following 1D- and 2D-PAGE analysis, showed that the qualitative composition of Aβ peptides in the CSF is similar in AD and controls but different from that of AD brain tissues. Moreover, sedimentation velocity in sucrose gradient of CSF and brain homogenate from AD demonstrated that Aβ42 in CSF is different from Aβ42 in brain in terms of solubility and aggregation state. Show more

Keywords: Aβ1-42, Aβ oligomers, aggregation, Alzheimer’s disease, ELISA

DOI: 10.3233/JAD-180616

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 219-227, 2018

Authors: Fiorenzato, Eleonora | Biundo, Roberta | Cecchin, Diego | Frigo, Anna Chiara | Kim, Jinhee | Weis, Luca | Strafella, Antonio P. | Antonini, Angelo

Article Type: Research Article

Abstract: Background: The pathological processes underlying cognitive impairment in Parkinson’s disease (PD) are heterogeneous and the contribution of cerebral amyloid deposits is poorly defined, particularly in the early stages of the disease. Objective: To investigate regional [18 F]florbetaben binding to amyloid-β (Aβ ) and its contribution to cognitive dysfunction in early stage PD. Methods: A multicenter cohort of 48 PD patients from the Parkinson’s Progression Marker Initiative (PPMI) underwent [18 F]florbetaben positron emission tomography (PET) scanning. Clinical features, including demographic characteristics, motor severity, cerebrospinal fluid (CSF), and cognitive testing were systematically assessed according to the PPMI …study protocol. For the purpose of this study, we analyzed various neuropsychological tests assessing all cognitive functions. Results: There were 10/48 (21%) amyloid positive PD patients (PDAβ +). Increased [18 F]florbetaben uptake in widespread cortical and subcortical regions was associated with poorer performance on global cognition, as assessed by Montreal Cognitive Assessment (MoCA), and impaired performance on Symbol Digit Modality test (SDMT). Further, we found that PDAβ + patients had higher CSF total-tau/Aβ 1 - 42 (p  = 0.001) and phosphorylated-tau/Aβ 1 - 42 in (p  = 0.002) compared to amyloid-negative PD. Conclusion: These findings suggest that multiple disease processes are associated with PD cognitive impairment and amyloid deposits may be observed already in early stages. However, prevalence of amyloid positivity is in the range of literature age-matched control population. Increased cortical and subcortical amyloid is associated with poor performance in attentive-executive domains while cognitive deficits at MoCA and SDMT may identify amyloid-related dysfunction in early PD. Show more

Keywords: Amyloid, cerebrospinal fluid, cognition, cognitive dysfunction, dementia, neuropsychology, Parkinson’s disease, positron emission tomography, synuclein

DOI: 10.3233/JAD-180390

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 229-237, 2018

Authors: Katz, Mindy J. | Wang, Cuiling | Derby, Carol A. | Lipton, Richard B. | Zimmerman, Molly E. | Sliwinski, Martin J. | Rabin, Laura A.

Article Type: Research Article

Abstract: Background: The relation of pre-dementia stages to mortality has not been fully explored. Previous work examining subjective cognitive decline (SCD) and mortality is limited and mixed regarding methods used and consistency of findings. Objective: To examine SCD and mortality in a longitudinal, community-based cohort, using item response theory (IRT) methodology to form a composite SCD measure. Also, to assess whether this relationship was independent of clinical cognitive status. Methods: The Einstein Aging Study is a diverse longitudinal cohort of adults aged ≥70. SCD items were extracted from baseline CERAD questionnaires and a composite score was formed …using IRT methodology. A total of 1,741 participants with complete data were clinically diagnosed as cognitively normal, or as having amnestic mild cognitive impairment (aMCI), nonamnestic mild cognitive impairment (naMCI), or dementia. 645 deaths occurred over a period of 8,912 person-years of follow-up. Cox proportional hazard models predicted time to death adjusting for covariates. Results: A one standard deviation unit increase in level of SCD was associated with >20% higher risk of mortality. However, when models were adjusted for clinical cognitive status, the association was no longer significant. Both dementia and aMCI predicted mortality. Furthermore, when analyses focused only on those without cognitive impairment, SCD level did not predict mortality. Conclusions: The association of SCD with mortality may be due to the association of SCD with clinical cognitive status. Thus, SCD may be used as a community-based screen to initially identify those with cognitive impairment who may be at greatest risk for death. Show more

Keywords: Dementia, IRT methodology, mild cognitive impairment, mortality, subjective cognitive decline

DOI: 10.3233/JAD-180335

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 239-248, 2018

Authors: Minn, Yang-Ki | Choi, Seong Hye | Suh, Young Ju | Jeong, Jee Hyang | Kim, Eun-Joo | Kim, Jong Hun | Park, Kyung Won | Park, Moon Ho | Youn, Young Chul | Yoon, Bora | Choi, Seok-Jin | Oh, Youn Kyung | Yoon, Soo Jin

Article Type: Research Article

Abstract: Background: There is a lack of research on the effects of physical activity (PA) on the progression of Alzheimer’s disease (AD). Objectives: We investigated whether PA is associated with progression of dementia and mortality in AD. Methods: In the present study, 934 patients with mild-to-moderate AD were included. PA was evaluated using a questionnaire written by the caregiver. The outcome measures were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living (S-IADL), Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), a global composite score of neuropsychological subtests, and mortality. They were evaluated annually and received a maximum …of three follow-up examinations. Results: Between-group differences compared with the no PA group in the change of CDR-SB scores were –0.431 (95% CI = –0.824∼–0.039; p  = 0.031) for the moderate PA group (150–750 minutes per week of moderate intensity PA), and –1.148 (–1.656∼–0.639; p  < 0.001) for the high PA group (>750 minutes per week). As PA increased, there was a significant trend to slow the rate of increase in the CDR-SB, S-IADL, and CGA-NPI scores. The patients with ≥150 minutes per week for each of non-recreational and recreational PAs had a lower risk of mortality compared to those with <150 minutes per week for each of the PAs (hazard ratio 0.22, 95% CI = 0.05∼0.88; p  = 0.033). Conclusion: More PA is associated with slower progression of dementia severity, functional decline, and abnormal behavior, and with a lower risk of mortality in AD. Show more

Keywords: Alzheimer’s disease, dementia, physical activity, progression, mortality

DOI: 10.3233/JAD-180333

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 249-261, 2018