Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Pan, Kuan-Yu | Xu, Weili | Mangialasche, Francesca | Dekhtyar, Serhiy | Fratiglioni, Laura | Wang, Hui-Xin

Article Type: Research Article

Abstract: While the importance of working conditions on cognitive function has been tentatively suggested previously, few studies have considered cumulative effects of exposure throughout the working life. We examined the association between job demand-control status and late-life cognitive decline, taking into account exposure durations. In the population-based cohort study, Swedish National Study on Aging and Care-Kungsholmen, 2,873 dementia-free participants aged 60+ were followed up to nine years. Cognitive function was measured using the Mini-Mental State Examination. The entire working life was outlined through interview and occupations were graded with a psychosocial job-exposure matrix. Multivariate linear mixed-effects models were used. Slower cognitive …decline was observed among people with high job control (β : 0.10, 95% CI: 0.03, 0.19) and demands (β : 0.15, 95% CI: 0.07, 0.22) in the longest-held job. Compared to active job, faster decline was shown in low strain (β : – 0.17, 95% CI: – 0.26, – 0.08), high strain (β : – 0.13, 95% CI: – 0.24, – 0.03), and passive job (β : – 0.22, 95% CI: – 0.34, – 0.11). Longer duration of active jobs was associated with slower cognitive decline (β : 0.24, 95% CI: 0.16, 0.32), whereas faster decline was associated with longer durations of low strain (β : – 0.12, 95% CI: – 0.19, – 0.05), high strain (β : – 0.13, 95% CI: – 0.21, – 0.04), and passive jobs (β : – 0.12, 95% CI: – 0.20, – 0.04). In conclusion, not only psychologically stressful jobs, but also low-stimulating and passive jobs are associated with faster cognitive decline in later life. Duration of exposure may play a role in the psychosocial working condition-cognitive decline association. Show more

Keywords: Cognition, cohort studies, epidemiology, psychosocial work condition, working life

DOI: 10.3233/JAD-180870

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Farlow, Martin R. | Thompson, Richard E. | Wei, Lee-Jen | Tuchman, Alan J. | Grenier, Elaine | Crockford, David | Wilke, Susanne | Benison, Jeffrey | Alkon, Daniel L.

Article Type: Research Article

Abstract: Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer’s disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55–85) with MMSE-2 of 4–15, randomized 1:1:1 into 20 μg and 40 μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p  < 0.1 for primary efficacy, and 2-sided, p  < 0.05 for pre-specified and post hoc exploratory …analyses). Results: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p  = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p  < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant. Conclusion: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin— without memantine— to treat AD. Show more

Keywords: Bryostatin, memantine, neurorestorative, PKC (Protein Kinase C), severe Alzheimer’s disease, severe impairment battery, synaptic growth factors, synaptogenesis

DOI: 10.3233/JAD-180759

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Torrealba, Eduardo | Garcia-Morales, Pilar | Cejudo, Juan Carlos | Diaz, Mario | Rodriguez-Esparragon, Francisco | Fabre, Oscar | Mesa-Herrera, Fatima | Marin, Raquel | Sanchez-Garcia, Florentino | Rodriguez-Perez, Aurelio | Gramunt, Nina

Article Type: Research Article

Abstract: Background: Assessment of hippocampal amnesia is helpful to distinguish between normal cognition and mild cognitive impairment (MCI), but not for identifying converters to dementia. Here biomarkers are useful but novel neuropsychological approaches are needed in their absence. The In-out-test assesses episodic memory using a new paradigm hypothesized to avoid reliance on executive function, which may compensate for damaged memory networks. Objective: To assess the validity of the In-out-test in identifying prodromal Alzheimer’s disease (PAD) in a clinical setting, by comparing this to the Free and Cued Selective Reminding Test (FCSRT) and cerebrospinal fluid biomarkers. …Methods: A cross-sectional study of 32 cognitively healthy, 32 MCI, and 30 progressive dementia subjects. All participants were given both the In-out-test and the FCSRT; 40 of them also received a lumbar puncture. Results: Internal consistency was demonstrated using Cronbach Alpha (r  = 0.81) and Inter-rater reliability with Kappa (k = 0.94). Intraclass correlation (ICC) for test-retest reliability: r  = 0.57 (p  = 0.57). ICC between the In-out-test and FCSRT r  = 0.87 (p  = 0.001). ICC between the In-out-test and Aβ 42 and P-tau/Aβ 42 for controls: 0.73 and 0.75, respectively; P-tau for MCI: 0.77 and total sample: 0.70; Aβ 42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤0.264. AD diagnosis: In-out-test k = 0.71; FCSRT k = 0.49. PAD diagnosis (N = 35): In-out-test k = 0.69; FCSRT k = 0.44. Conclusions: The In-out-test detected prodromal AD with a higher degree of accuracy than a conventional hippocampal-based memory test. These results suggest that this new paradigm could be of value in clinical settings, predicting which patients with MCI will go on to develop AD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, dementia, early diagnosis, episodic memory, mild cognitive impairment, neuropsychological tests, tau proteins

DOI: 10.3233/JAD-171007

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Bonvicini, Cristian | Scassellati, Catia | Benussi, Luisa | Di Maria, Emilio | Maj, Carlo | Ciani, Miriam | Fostinelli, Silvia | Mega, Anna | Bocchetta, Martina | Lanzi, Gaetana | Giacopuzzi, Edoardo | Ferraboli, Sergio | Pievani, Michela | Fedi, Virginia | Defanti, Carlo Alberto | Giliani, Silvia | Frisoni, Giovanni Battista | Ghidoni, Roberta | Gennarelli, Massimo

Article Type: Research Article

Abstract: Background: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. Objective: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE ) and prion protein (PRNP ) genes were also assessed. Methods: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation …Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. Results: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN , VCP , MAPT , FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP ), and one did not show any risk mutation/variant. Overall, 69% (n  = 9) of our early onset Alzheimer’s disease (EAOD) patients, compared with 34% (n  = 13) of sporadic late onset Alzheimer’s disease (LOAD) patients and 27% (n  = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. Conclusion: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD. Show more

Keywords: Alzheimer’s disease, common variants, early onset dementia, frontotemporal dementia, Lewy body dementia, next generation sequencing, rare mutations

DOI: 10.3233/JAD-180482

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: de Macêdo Medeiros, André | Silva, Regina Helena

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that drastically compromises patients’ and relatives’ quality of life, besides being a significant economic burden to global public health. Its pathophysiology is not completely elucidated yet, hence, the current therapies are restricted to treating the symptoms. Over the years, several epidemiological studies have shown disproportionalities in AD when sex is considered, which has encouraged researchers to investigate the potentiality of sex as a risk factor. Studies in rodent models have been used to investigate mechanistic basis of sex differences in AD, as well as the development of possible new sex-specific therapeutic strategies. However, …full knowledge on factors related to this sexual dimorphism remains to be unraveled. Some findings point to differences in genetic and developmental backgrounds either earlier in life or in the aging brain. Herein we summarize the multisystemic framework behind the sex differences in AD and discuss the possible mechanisms involved in these differences raised by the literature so far in an integrative perspective. Show more

Keywords: Aging, animal models, hormones, humans, immune system, oxidative stress, stress

DOI: 10.3233/JAD-180213

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2018

Authors: Hvidsten, Lara | Engedal, Knut | Selbæk, Geir | Wyller, Torgeir Bruun | Jūratė Šaltytė, Benth | Kersten, Hege

Article Type: Research Article

Abstract: Background: Cross-sectional studies of quality of life (QOL) of people with young-onset dementia shows diverging results. Objective: To identify factors associated with QOL in people with young-onset Alzheimer’s (AD) and frontotemporal dementia (FTD) and explore development in QOL over a two-year period, including differences between the two subtypes. Methods: A two-year cohort study of 88 community-dwelling people with young-onset AD and FTD recruited from Nordic memory clinics. QOL was assessed using the proxy version of the Quality of Life – Alzheimer’s Disease questionnaire, dementia severity was rated with the Clinical Dementia Rating scale, depressive symptoms by …the Cornell Scale for Depression in Dementia, awareness with the Reed anosognosia scale, and needs using the Camberwell Assessment of Needs in the Elderly questionnaire. Factors associated with QOL and development in QOL over time were explored with growth mixture model trajectories and mixed model analyses. Results: We identified two groups of people following trajectories with better (n  = 35) versus poorer (n  = 53) QOL. People with more depressive symptoms at baseline had higher odds of belonging to poorer QOL group, OR 1.2 (CI 1.1; 1.5, p  = 0.011). Having Alzheimer’s disease was associated with significantly better QOL (p  = 0.047 at baseline, p  = 0.009 at T1 and p  = 0.033 at T2). Increasing number of unmet needs was significantly associated with poorer QOL at baseline (p  = 0.007), but not later in follow-up. Conclusion: Early assessment and treatment based on dementia subtype, depression, and individual needs may enhance quality of life in young-onset dementia. Show more

Keywords: Alzheimer’s disease, depression, frontotemporal dementia, quality of life, young-onset

DOI: 10.3233/JAD-180479

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Almansoub, Hasan A.M.M. | Tang, Hui | Wu, Ying | Wang, Ding-Qi | Mahaman, Yacoubou Abdoul Razak | Wei, Na | Almansob, Yusra A. M. | He, Wei | Liu, Dan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases that is characterized by progressive memory loss and two main pathological hallmarks, including the extracellular amyloid plaques and intracellular neurofibrillary tangles. The microtubule-related protein tau is involved in the pathogenesis of many neurological diseases commonly known as tauopathies and is found to be abnormally hyperphosphorylated in AD and accumulated in neurons. Besides hyperphosphorylation, tau also undergoes abnormal glycosylation, ubiquitination, glycation, and other posttranslational modifications. These abnormalities lead to the aberrant aggregation of tau in the synaptic loci in AD. In this review, we highlighted the most recent studies about …how tau is abnormally regulated and how those abnormalities play important roles in the pathogenesis of AD. Show more

Keywords: Aggregation, Alzheimer’s disease, hyperphosphorylation, post-translational modifications, tau

DOI: 10.3233/JAD-180868

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2018

Authors: Zammit, Andrea R. | Muniz-Terrera, Graciela | Katz, Mindy J. | Hall, Charles B. | Ezzati, Ali | Bennett, David A. | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery. Objective: Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS. …Methods: MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS. Results: LCA resulted in a 5-class model: Mixed-Domain Impairment (n  = 71, 4.3%), Memory-specific-Impairment (n  = 274, 16.5%), Average (n  = 767, 46.1%), Frontal Impairment (n  = 222, 13.4%), and a class of Superior Cognition (n  = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer’s disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer’s disease when compared to the Average class. Conclusions: Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests. Show more

Keywords: Alzheimer’s disease, dementia, latent class analysis, neuropsychological profiles

DOI: 10.3233/JAD-180737

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Reed, May J. | Damodarasamy, Mamatha | Pathan, Jasmine L. | Chan, Christina K. | Spiekerman, Charles | Wight, Thomas N. | Banks, William A. | Day, Anthony J. | Vernon, Robert B. | Keene, C. Dirk

Article Type: Research Article

Abstract: Little is known about the extracellular matrix (ECM) during progression of AD pathology. Brain ECM is abundant in hyaluronan (HA), a non-sulfated glycosaminoglycan synthesized by HA synthases (HAS) 1–3 in a high molecular weight (MW) form that is degraded into lower MW fragments. We hypothesized that pathologic severity of AD is associated with increases in HA and HA-associated ECM molecules. To test this hypothesis, we assessed HA accumulation and size; HA synthases (HAS) 1–3; and the HA-stabilizing hyaladherin, TSG-6 in parietal cortex samples from autopsied research subjects with not AD (CERAD = 0, Braak = 0– II, n  = 12–21), intermediate AD (CERAD = 2, Braak = III–IV, n … = 13–18), and high AD (CERAD = 3, Braak = V–VI, n  = 32–40) AD neuropathologic change. By histochemistry, HA was associated with deposits of amyloid and tau, and was also found diffusely in brain parenchyma, with overall HA quantity (measured by ELSA) significantly greater in brains with high AD neuropathology. Mean HA MW was similar among the samples. HAS2 and TSG-6 mRNA expression, and TSG-6 protein levels were significantly increased in high AD and both molecules were present in vasculature, NeuN-positive neurons, and Iba1-positive microglia. These results did not change when accounting for gender, advanced age (≥ 90 years versus <90 years), or the clinical diagnosis of dementia. Collectively, our results indicate a positive correlation between HA accumulation and AD neuropathology, and suggest a possible role for HA synthesis and metabolism in AD progression. Show more

Keywords: Alzheimer’s disease, extracellular matrix, hyaluronan, TSG-6

DOI: 10.3233/JAD-180797

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Deckers, Kay | Nooyens, Astrid | van Boxtel, Martin | Verhey, Frans | Verschuren, Monique | Köhler, Sebastian

Article Type: Research Article

Abstract: Background: Several modifiable risk factors for cognitive decline have been identified, but whether differences by gender and educational level exist is unclear. Objective: The present study aims to clarify this by prospectively investigating the relationship between health- and lifestyle factors and cognitive functioning in different subgroups defined by gender and educational level. Methods: 2,347 cognitive healthy individuals (mean age = 54.8, SD = 6.8, range: 41–71; 51.8% female; 26.2% low education) from the Doetinchem Cohort Study were examined for cognitive function at baseline, and at 5- and 10-year follow-up. Health- and lifestyle factors were captured by a poly-environmental risk score …labelled ‘LIfestyle for BRAin Health’ (LIBRA). This score consists of 12 modifiable risk and protective factors for cognitive decline and dementia, with higher scores indicating greater risk (range: –2.7 to +12.7). Heterogeneity in associations between LIBRA and decline in verbal memory, cognitive flexibility, and mental speed between males and females and individuals with different levels of education were assessed in linear mixed models. Results: Overall, higher LIBRA scores predicted faster decline in verbal memory, cognitive flexibility, and mental speed over 10 years. Higher LIBRA scores were further associated with increased risk for incident cognitive impairment (one-point increase in LIBRA: HR = 1.09, 1.04–1.14, p  = 0.001). In general, these effects were similar across gender and educational level. Conclusion: A composite risk score comprising unhealthy lifestyle and relatively poor health in midlife is significantly associated with a worse course of cognition 10 years later. These associations were for the most part unrelated to gender or educational differences. Show more

Keywords: Aging, cognition, dementia, education, gender, lifestyle, modifiable risk factors, prevention

DOI: 10.3233/JAD-180492

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018