Journal of Alzheimer's Disease - Volume 71, issue 2

Authors: Pirker-Kees, Agnes | Dal-Bianco, Peter | Schmidt, Reinhold

Article Type: Research Article

Abstract: Behavioral and psychological symptoms of dementia are common in Alzheimer’s disease (AD) and associated with a more rapid decline in cognitive function. Psychotropic substances are frequently used in AD, but we lack conclusive evidence of their efficacy in this setting. SSRI and trazodone were reported to have positive effects on cognition. Based on the prospective registry of dementia in Austria (PRODEM), we investigated the effects of psychotropic substances on cognition, behavioral symptoms, and caregiver burden (CB) in patients with AD, followed up prospectively over a 12-month period. We used the Mini-Mental State Examination (MMSE), the Neuropsychiatric Inventory (NPI), and the …Zarit caregiver burden interview. The study cohort consisted of 309 patients. Patients taking no psychotropic drugs (NO) or those undergoing consistent monotherapy with a psychotropic drug for 12 months were analyzed further (NO 101 patients, SSRI 22, trazodone 8, atypical neuroleptics or benzodiazepines (ANL/BZD) 18). Additionally, the subgroup of patients who started taking any of the substances during the study period were analyzed further to determine the effects before versus six months after the start of medication. MMSE, NPI, and CB at baseline and during follow-up did not differ between the groups. MMSE and CB declined over 12 months in the overall group (MMSE: 21.2±4 versus 19.7±5, p  = 0.001 and CB 20.3±12 versus 24.7±14.2, p  = 0.007), but no statistically significant changes were registered within groups over 12 months. When trazodone was started, only NPI improved significantly after 6 months (33.4±18 versus 18.9±22.7, p  < 0.01). ANL/BZD or SSRI, when started, did not alter MMSE, NPI, or CB. SSRI had no beneficial effect on cognition. We conclude that trazodone might be helpful in the treatment of behavioral symptoms. Show more

Keywords: Alzheimer’s disease, behavioral, caregiver, psychotropic drugs

DOI: 10.3233/JAD-181102

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 623-630, 2019

Authors: Flores-Rodríguez, Paola | Harrington, Charles R. | Wischik, Claude M. | Ibarra-Bracamontes, Vanessa | Zarco, Natanael | Navarrete, Araceli | Martínez-Maldonado, Alejandra | Guadarrama-Ortíz, Parménides | Villanueva-Fierro, Ignacio | Ontiveros-Torres, Miguel Angel | Perry, George | Alonso, Alejandra D. | Floran-Garduño, Benjamin | Segovia, José | Luna-Muñoz, José

Article Type: Research Article

Abstract: It has been reported that the main function of tau protein is to stabilize microtubules and promote the movement of organelles through the axon in neurons. In Alzheimer’s disease, tau protein is the major constituent of the paired helical filament, and it undergoes post-translational modifications including hyperphosphorylation and truncation. Whether other functions of tau protein are involved in Alzheimer’s disease is less clear. We used SH-SY5Y human neuroblastoma cells as an in vitro model to further study the functions of tau protein. We detected phosphorylated tau protein as small dense dots in the cell nucleus, which strongly colocalize with …intranuclear speckle structures that were also labelled with an antibody to SC35, a protein involved in nuclear RNA splicing. We have shown further that tau protein, phosphorylated at the sites recognized by pT231, TG-3, and AD2 antibodies, is closely associated with cell division. Different functions may be characteristic of phosphorylation at specific sites. Our findings suggest that the presence of tau protein is involved in separation of sister chromatids in anaphase, and that tau protein also participates in maintaining the integrity of the DNA (pT231, prophase) and chromosomes during cell division (TG-3). Show more

Keywords: Alzheimer’s disease, cell cycle, phospho-tau protein, SC35, SH-SY5Y, staurosporine

DOI: 10.3233/JAD-190155

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 631-645, 2019

Authors: Hobel, Zachary | Isenberg, A. Lisette | Raghupathy, Dhvani | Mack, Wendy | Pa, Judy | for the Alzheimer’s Disease Neuroimaging Initiative and the Australian Imaging Biomarkers and Lifestyle flagship study of ageing

Article Type: Research Article

Abstract: Background: APOE ɛ 4 and sex have been linked to increased risk for conversion to Alzheimer’s disease (AD). However, the relationship between APOE ɛ 4 gene dose, sex, and AD biomarkers remains understudied. Objective: To investigate the effect of APOE ɛ 4 dose on AD biomarkers in a sample of older adults with mild cognitive impairment (MCI), and to examine whether APOE ɛ 4 dose modifies AD risk differently in MCI women and men. Methods: We examined cross-sectional AD biomarkers for participants with MCI (n  = 930, 55–96 years old) from three large …aging cohorts. Region of interest MRI volumes, global cognition, and episodic memory were analyzed by number of APOE ɛ 4 alleles and stratified by sex. Results: Across all participants, number of APOE ɛ 4 alleles was associated with smaller hippocampal and amygdala volumes and poorer cognition. When stratified by sex, women showed an APOE ɛ 4 dose effect for bilateral hippocampal and left amygdala volumes and cognition. In contrast, men showed an APOE ɛ 4 dose effect for hippocampal volumes with a trend in amygdala, but cognition did not differ between men with 1 and 2 APOE ɛ 4 alleles. Women with 2 APOE ɛ 4 alleles had poorer memory between 65–69 and poorer global cognition between 70–74 compared to men with 2 APOE ɛ 4 alleles. Conclusion: APOE ɛ 4 confers a dose effect on AD biomarkers in patients with MCI, and the number of APOE ɛ 4 alleles has a greater detrimental impact in women than men, which may be specific to a critical time window. Show more

Keywords: Alzheimer’s disease, APOE, genetics, hippocampus, memory, mild cognitive impairment, MRI, sex effects

DOI: 10.3233/JAD-180859

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 647-658, 2019

Authors: Pavlik, Valory N. | Chan, Wenyaw | Darby, Eveleen

Article Type: Research Article

Abstract: Background: Accurate prediction of Alzheimer’s disease (AD) cognitive and functional outcomes in clinical research requires consistent underlying rates of change over time. Objective: To examine cohort effects in AD progression rate over five years of follow-up using a clinical database of probable AD patients. Methods: Baseline characteristics of three cohorts enrolled from 1995–1999, 2000–2004, and 2005–2009 were compared using ANOVA and chi-square tests. Differences in 5-year decline on the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), the Lawton and Brody Physical Self-maintenance Scale (PSMS), …and Activities of Daily Living Scale (ADL) were assessed using longitudinal mixed effects regression, adjusting for age, sex, education, and other relevant clinical characteristics. Results: Cohorts 1 (n  = 287), 2 (n  = 257), and 3 (n  = 374) did not differ on age, race, APOE genotype, or cognitive and functional measures. Educational attainment increased over time (13.4, 14.1, and 14.5 years, respectively, p  < 0.001). Anti-dementia drug use at baseline was less common in Cohort 1 (32.2% versus 65.0%, and 66.8%, p  < 0.001). The rate of decline in MMSE and CDR-SB did not differ across cohorts. ADAS-Cog scores for Cohort 2 declined more slowly than Cohort 3 (Btime ×cohort2  = -0.91 ± 0.35, p  = 0.009), whereas Cohort 1 did not differ from cohort 3 (reference). Cohorts 1 and 2 differed from Cohort 3 in progression rate on the PSMS, but not the IADL. Conclusions: There were no consistent temporal trends in progression rates over time. Longitudinal data over 15–20 years may be confidently pooled for outcomes analysis, but unexplained variability in rate of decline on some measures may occur. Show more

Keywords: Alzheimer’s disease, cognitive decline, cohort effects, disease progression

DOI: 10.3233/JAD-190661

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 659-669, 2019

Authors: Li, Hui | Luo, Xiao-Bing | Xu, Yan | Hou, Xiao-Yu

Article Type: Research Article

Abstract: Background: Oligomeric amyloid-β peptide (Aβ) is associated with dysfunctional neuronal networks and neuronal loss in the development of Alzheimer’s disease (AD). Ischemic postconditioning protects against post-ischemic excitotoxicity, oxidative stress, and inflammatory process that have also been implicated in the pathogenesis of AD. Evaluating the roles of ischemic postconditioning in oligomeric Aβ-induced neurotoxicity and underlying signal events may provide potential strategy for medical therapy in AD. Objectives: The aim of the present study was to explore whether and how a brief ischemic postconditioning protects against Aβ neurotoxicity in rat hippocampus. Methods: Oligomeric Aβ25-35 (20 nmol/rat) or …Aβ1-42 (5 nmol/rat) was infused by intracerebroventricular injection in adult male Sprague-Dawley rats. Ischemic postconditioning, a brief episode of global brain ischemia (3 min), was conducted at 1, 3, or 7 days after Aβ treatment, respectively. Results: A brief ischemic postconditioning reduced neuronal loss and inhibited the activation of MLK3, MKK3/6, and P38MAPKs in rat hippocampal CA1 and CA3 subfields after Aβ oligomer infusion. An N-methyl-D-aspartate (NMDA) receptor antagonist amantadine, but not non-NMDA receptor antagonist CNQX, reversed the MLK3-MKK3/6-P38MAPK signal events and beneficial effect of ischemic postconditioning on neuronal survival. Such reversion was also realized by NVP-AAM077, a GluN2A-subunit-selective NMDA receptor antagonist. Moreover, posttreatment with low doses of NMDA (5 nmol–40 nmol/rat) suppressed the Aβ-induced P38MAPK signaling and imitated the neuroprotection of ischemic postconditioning against Aβ neurotoxicity. Conclusions: Ischemic postconditioning provides neuroprotection against Aβ neurotoxicity by moderate upregulation of NMDA receptor signaling, especially GluN2A-containing NMDA receptor pathway, and thereafter downregulation of MLK3-MKK3/6-P38MAPK signal events. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, ischemic postconditioning, NMDA receptors, P38MAPKs

DOI: 10.3233/JAD-190207

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 671-684, 2019

Authors: Rogojin, Alica | Gorbet, Diana J. | Hawkins, Kara M. | Sergio, Lauren E.

Article Type: Research Article

Abstract: Background: Cognitive-motor integration (CMI) involves concurrent thought and action which requires the interaction of large brain networks. Given that early-stage dementia involves neural network dysfunction, deficits in CMI may prove useful for early dementia detection. Objective: Our research objective was to investigate sex-related differences in the ability to integrate rules into action. Methods: Based on family medical history, we recruited male and female participants both with and without dementia risk factors. Participants did not demonstrate cognitive impairment at the time of testing. Participants were tested on four increasingly dissociated visuomotor tasks (eye and hand movements were …made in different spatial planes and/or visual feedback was reversed). Results: We observed significantly greater hand movement endpoint error scores and corrective path lengths in at-risk females compared to at-risk males in the most complex CMI condition (plane-change + feedback reversal). Multiple regression analyses revealed both sex and family history as significant predictors of worse performance in a CMI condition requiring visual feedback reversal. Further, the regression analyses provided preliminary evidence that having an APOE ɛ 4 allele was a significant predictor of poorer CMI performance in the two plane-change CMI conditions. Conclusion: These data suggest that underlying brain networks controlling simultaneous thought and action may differ between the sexes in ways that may be clinically relevant in dementia progression. Preliminary data also suggest an important connection between APOE variant and CMI performance in individuals at risk of developing dementia. Show more

Keywords: Aging, alzheimer’s disease, apolipoprotein E4, dementia risk, geriatric assessment, motor skills, movement, visuomotor integration

DOI: 10.3233/JAD-190403

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 685-701, 2019

Authors: Stirland, Lucy E. | Russ, Tom C. | Ritchie, Craig W. | Muniz-Terrera, Graciela | EPAD Consortium

Article Type: Research Article

Abstract: Background: Multimorbidity (the co-occurrence of multiple chronic conditions) is increasingly common, especially among people with dementia. Few neuroimaging studies have explored amyloid biomarkers in people with multimorbidity. Objective: We aimed to conduct the first study of the association between multimorbidity and cerebrospinal fluid amyloid-β42 (CSF Aβ). Method: The European Prevention of Alzheimer’s Dementia (EPAD) Longitudinal Cohort Study V500.0 dataset includes volunteers aged ≥50 years from 12 sites. Participants undergo detailed phenotyping, including CSF measures and a self-reported medical history. Using logistic and linear regression analyses, we explored the association between multimorbidity and continuous chronic condition …count with CSF Aβ positivity (Aβ42 <1000pg/ml) and continuous CSF Aβ concentration. All models were adjusted for age, sex, APOE status, education, and family history of dementia. Results: Among 447 eligible participants without dementia, the mean (SD) age was 66.6 (6.6) years, 234 (52.3%) were women, and 157 (35.1%) were amyloid positive. With chronic conditions regarded as pseudo-continuous, each additional condition carried a decreased likelihood of amyloid positivity (OR = 0.82, 95% CI: 0.68–0.97; p  = 0.026). With CSF Aβ as a continuous variable, each additional condition was associated with an increase of 54.2 pg/ml (95% CI: 9.9–98.5, p  = 0.017). Having ≥2 conditions was inversely associated with amyloid positivity (OR 0.59, 95% CI: 0.37–0.95, p  = 0.030) compared to one or none. Conclusion: Our findings suggest that the established association between multimorbidity and dementia may be due to a pathway other than amyloid. However, this cross-sectional study does not allow us to make causal inferences. Longitudinal work is required to confirm the inverse association found. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, multimorbidity

DOI: 10.3233/JAD-190222

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 703-711, 2019

Article Type: Correction

DOI: 10.3233/JAD-199008

Citation: Journal of Alzheimer's Disease, vol. 71, no. 2, pp. 713-713, 2019