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

Authors: Campos, Jennifer L. | Höbler, Fiona | Bitton, Etty | Labreche, Tammy | McGilton, Katherine S. | Wittich, Walter

Article Type: Research Article

Abstract: Vision impairments are prevalent, but underdiagnosed in individuals with dementia living in long term care (LTC). Effective screening tools could identify remediable vision problems. This scoping review was conducted to identify vision screening tests used with individuals with dementia and assesses their suitability for administration by nurses in LTC. A literature search using the Arksey and O’Malley (2005) method included research articles, conference proceedings, and dissertations. Data was included from participants over 65 years of age with a diagnosis of probable dementia. A panel of vision experts evaluated the suitability of the candidate vision tests. The search yielded 179 publications …that met the inclusion criteria. Of 134 vision tests that were identified, 19 were deemed suitable for screening by nurses in LTC. Tests screened for acuity (12), visual field (1), anatomy (2), color vision (2), and general visual abilities (2). Tests were excluded because of complexity of interpretation (90), need for specialized training (83), use in research only (57), need for specialized equipment (54), not assessing visual function (44), long test duration (21), uncommonness (13), and needing an act reserved for specialists (7). Psychometric properties were not often reported for tests. Few of the tests we identified had been validated for use with individuals with dementia. Based on our review, few tests were deemed suitable for use by nurses to assess this population in LTC. Identifying appropriate tools to screen vision in individuals with dementia is a necessary first step to interventions that could potentially improve functioning and quality of life. Show more

Keywords: Aging, cognition, decline, low vision, nursing, sensory

DOI: 10.3233/JAD-181129

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Wang, Desheng

Article Type: Research Article

Abstract:  Previous studies have shown tumor necrosis factor-alpha (TNF-α ) may impact neurodegeneration in Alzheimer’s disease (AD) by regulating amyloid-β and tau pathogenesis. However, it is unclear whether TNF-α has a role in a cholesterol-fed rabbit model of AD or TNF-α affects the electrophysiological properties of rabbit hippocampus. This study was designed to investigate whether long-term feeding of cholesterol diet known to induce AD pathology regulates TNF-α expression in the hippocampus and whether TNF-α would modulate electrophysiological properties of rabbit hippocampal CA1 neurons. TNF-α ELISA showed dietary cholesterol increased hippocampal TNF-α expression in a …dose-dependent manner. Whole-cell recordings revealed TNF-α altered the membrane properties of rabbit hippocampal CA1 neurons, which was characterized by a decrease in after-hyperpolarization amplitudes; Field potential recordings showed TNF-α inhibited long-term potentiation but did not influence presynaptic function. Interestingly, TNF-α did not significantly affect the after-hyperpolarization amplitudes of hippocampal CA1 neurons from cholesterol fed rabbits compared to normal chow fed rabbits. In conclusion, dietary cholesterol generated an in vivo model of chronic TNF-α elevation and TNF-α may underlie the learning and memory changes previously seen in the rabbit model of AD by acting as a bridge between dietary cholesterol and brain function and directly modulating the electrophysiological properties of hippocampal CA1 neurons. Show more

Keywords: Cholesterol, hippocampus, membrane properties, synaptic plasticity, tumor necrosis factor-alpha

DOI: 10.3233/JAD-190043

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Lim, Yen Ying | Yassi, Nawaf | Bransby, Lisa | Properzi, Michael | Buckley, Rachel

Article Type: Research Article

Abstract: Background: Characterizing the earliest demonstrable cognitive decline in middle-aged adults at risk of Alzheimer’s disease (AD) will allow for the better understanding of the early disease trajectory, and the provision of therapies prior to clinical symptom onset. We developed an online platform— healthybrainproject.org.au (Healthy Brain Project; HBP)— to recruit, assess, and monitor at-risk middle-aged adults. Objective: Describe the HBP methodology and report baseline characteristics and adherence indices of participants. Methods: Between February 2017 and August 2018, 4,000 community-based middle-aged Australian adults with a first or second-degree family history of dementia enrolled at our website (healthybrainproject.org.au). Participants …were directed to complete five modules: “Basics”, “Health History”, “How You Feel”, “How You Live”, and “How You Think”. Of these, 1,816 participants have received a saliva sampling kit for genetic analysis. Results: Participants had a mean (SD) age of 55.5 (6.8) years, 11.8 (3.4) years of education, and annual personal income of AUD$68,830 ($35,044). Participants took 26.4 (49.7) days after enrolment to complete questionnaires and cognitive tests. Most participants were from Victoria (63%), followed by New South Wales (14%). Most participants (74%) were female and 76% identified as Caucasian. Approximately 36% of participants completed all modules (n  = 1,450), and 56% (n  = 2,221) completed 4 out of 5 modules. Most saliva kits (89%) had been returned. Conclusion: The HBP joins a handful of online registries worldwide that assess and monitor a large cohort of individuals at risk of AD. Our study extends on these efforts by focusing on midlife, where the earliest signs of cognitive and pathological changes will manifest. Show more

Keywords: Alzheimer’s disease, neuropsychological test, neuropsychology, neuroscience, online systems, psychological test

DOI: 10.3233/JAD-181139

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Moran, Chris | Xie, Kenneth | Poh, Su | Chew, Sarah | Beare, Richard | Wang, Wei | Callisaya, Michele | Srikanth, Velandai

Article Type: Research Article

Abstract: Background: Hypertension is an established risk factor for dementia. However, it is unclear whether there are differential effects of angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blockers (ARB) on brain health. In human observational studies, the evidence for superiority of either agent remains unclear. Objective: To compare brain atrophy and cognitive decline between people treated with ACEi or ARB. Methods: Participants aged 55–90 years without dementia had brain magnetic resonance imaging and neuropsychological assessments performed at 3 time points. The sample was enriched with people with type 2 diabetes (T2D). Multivariable mixed models were used …to examine longitudinal associations of antihypertensive medication class with change in cognition and total brain volume. Results: Of 565 people with longitudinal data, there were 163 on ACEi (mean age 69.9 years, T2D:64% with) and 125 on ARB (mean age 69.6 years, T2D:62%) at baseline. The baseline characteristics of those taking either an ACEi or ARB were similar with regards to age, sex, blood pressure control, and vascular risk factors. The mean duration of follow up was 3.2 years. The baseline association of ACEi and ARB use with total brain volume was similar in both groups. However, those taking an ARB had a slower rate of brain atrophy than those taking an ACEi (p  = 0.031). Neither ACEi nor ARB use was associated with baseline cognitive function or cognitive decline. Conclusions: These results support the theory that ARB may be preferable to ACEi to reduce brain atrophy. The mechanisms underlying this differential association warrant further investigation. Show more

Keywords: Angiotensin-converting enzyme inhibitors, antihypertensive agents, blood pressure, cognition, dementia

DOI: 10.3233/JAD-180943

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Robens, Sibylle | Heymann, Petra | Gienger, Regine | Hett, Andreas | Müller, Stephan | Laske, Christoph | Loy, Roland | Ostermann, Thomas | Elbing, Ulrich

Article Type: Research Article

Abstract: The digital tree drawing test (dTDT) is a newly developed screening tool for the early detection of Alzheimer’s disease. It is performed with a digitizing pen, recording each pen stroke with temporal and spatial precision. It was hypothesized that movement characteristics recorded during the painting process contribute to the identification of patients with mild cognitive impairment (MCI) and early dementia of the Alzheimer type (eDAT). The study population consisted of 187 participants (67 healthy controls, 64 MCI, and 56 eDAT patients) with a mean age of 68.6±10.6 years. Between-group comparisons of the dTDT-variables were conducted with analysis of variance. The …diagnostic power of dTDT variables was analyzed with stepwise logistic regressions and areas under curve (AUC) of receiver operating control curves. Cognitively impaired persons used less colors and line widths and changed them less often than healthy subjects (p -values ≤0.05). Compared to control, eDAT patients had larger not-painting periods, were slower, and their pictures had less contrast, image size, and complexity (p -values ≤0.01). Logistic regression models of stepwise selected dTDT variables resulted in an AUC of 0.84 (95% confidence interval (CI) [0.79, 0.90], sensitivity = 0.78, specificity = 0.77) for discriminating healthy subjects from all cognitive impaired, an AUC of 0.77. (95% CI [0.69; 0.85], sensitivity = 0.56, specificity = 0.83) for discriminating healthy controls from MCI patients and an AUC of 0.90 (95% CI [0.84, 0.96], sensitivity = 0.86, specificity = 0.82) for discriminating controls from eDAT patients. The results suggest that digital recording of pen-stroke data during the drawing process can contribute to the screening of cognitive impaired patients. Show more

Keywords: Digital device, digital tree drawing test, drawing characteristics, early alzheimer’s disease, logistic regression, mild cognitive impairment, neuropsychological drawing test, screening test

DOI: 10.3233/JAD-181029

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Sacco, Guillaume | Ben-Sadoun, Grégory | Bourgeois, Jérémy | Fabre, Roxane | Manera, Valeria | Robert, Philippe

Article Type: Research Article

Abstract: Background: Neuropsychological tests are particularly important for the clinical evaluation and Alzheimer’s disease (AD) diagnosis. However, the tests currently employed for neuropsychological assessment have been developed several decades ago, and thus they do not fully exploit the potential provided by modern digital tools. One of the tests most commonly employed to assess attention and executive functions is the Trail Making Test (TMT). Objective: The aim of this study was to evaluate whether the TMT developed and used for the serious exergame X-Torp (TMTX-Torp ) can be used to evaluate cognitive functions such as mental flexibility. …Methods: Adjusted multivariate mixed model was used to compare performances in the TMTX-Torp to performances in the standard variant (TMTs ) in three populations. 21 participants with AD (78.6y±8.5 y), 27 with mild cognitive impairment (MCI) (76.8y±8.5 y), and 27 healthy (HEC) (71.8y±7.4 y) were included. Results: A difference was observed for the TMT A between AD and HEC and for the TMT B between AD and MCI and between AD and HEC. Whatever the variant of the TMT, we found a positive linear correlation between the time to complete the TMTX-Torp and the TMTs for HEC (TMT A: r  = 0.75, p  < 0.001; TMT B: r  = 0.52, p  = 0.008) and MCI participants (TMT A: r  = 0.53, p  = 0.005; TMT B: r  = 0.48, p  = 0.025) but not for AD participants. Conclusion: Although these versions of the TMT were not identical, the results showed that both versions were able to discriminate between HEC, MCI, and AD populations. Show more

Keywords: Alzheimer’s disease, executive function, neurocognitive disorders, serious games

DOI: 10.3233/JAD-180396

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Soeda, Yoshiyuki | Saito, Marino | Maeda, Sumihiro | Ishida, Kohki | Nakamura, Akira | Kojima, Shuichi | Takashima, Akihiko

Article Type: Research Article

Abstract: Alzheimer’s disease pathology is characterized by extracellular deposits of amyloid-β (Aβ) and intracellular inclusions of hyperphosphorylated tau. Although genetic studies of familial Alzheimer’s disease suggest a causal link between Aβ and disease symptoms, the failure of various Aβ-targeted strategies to slow or halt disease progression has led to consideration of the idea that inhibition of tau aggregation might be a more promising therapeutic approach. Methylene blue (MB), which inhibits tau aggregation and rescue memory deficits in a mouse model of tauopathy, however, lacked efficacy in a recent Phase III clinical trial. In order to gain insight into this failure, the …present study was designed to examine the mechanism through which MB inhibits tau aggregation. We found that MB inhibits heparin-induced tau aggregation in vitro , as measured by thioflavin T fluorescence. Further, MB reduced the amount of tau in precipitants recovered after ultracentrifugation of the aggregation mixture. Atomic force microscopy revealed that MB reduces the number of tau fibrils but increases the number of granular tau oligomers. The latter result was confirmed by sucrose gradient centrifugation: MB treatment was associated with higher levels of granular tau oligomers (fraction 3) and lower levels of tau fibrils (fractions 5 and 6). We previously demonstrated that the formation of granular tau oligomers, rather than tau fibrils, is essential for neuronal death. Thus, the fact that MB actions are limited to inhibition of tau fibril formation provides a mechanistic explanation for the poor performance of MB in the recent Phase III clinical trial. Show more

Keywords: Alzheimer’s disease, clinical trial, granular tau oligomer, inhibitor, methylene blue, oligomer, protein aggregation, tau protein

DOI: 10.3233/JAD-181001

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Meguro, Kenichi | Dodge, Hiroko H.

Article Type: Review Article

Abstract: Vascular mild cognitive impairment (MCI) is a critical disease. Its prognosis includes not only onset of vascular dementia, but also death by cardiovascular disease. The vascular risk factors for vascular MCI are treatable, and appropriate treatment can prevent or delay the progression to dementia. Therefore, this group is an excellent candidate for secondary prevention. However, community-dwelling older adults with vascular MCI are often undetected and are not clinically identified until they develop frank dementia. Furthermore, older adults with undetected vascular MCI often have decreased ability to follow their medication regimens and this poor medication adherence worsens their vascular comorbidities. This …vicious cycle needs to be prevented through community-based interventions. There is evidence that treatment of hypertension or diabetes mellitus could lead to a reduced incidence of vascular MCI and dementia. In this review article, we first explain the background and etiology of vascular MCI. We then summarize phenotype of subcortical vascular dementia which is often unrecognized or “hidden” in the community. Then we introduce the Osaki-Tajiri and Kurihara Projects which have been conducted in Northern Japan, as an example of prevention projects aimed to identify early-stage vascular MCI in the community, reduce the risk factors and facilitate their treatment. Early identification of vascular MCI in the community could lead to a large reduction in the dementia burden worldwide. The outreach efforts presented here could be useful in developing secondary prevention strategies targeted to vascular MCI. Show more

Keywords: Community, kurihara project, mild cognitive impairment, tajiri project, vascular dementia, vascular MCI

DOI: 10.3233/JAD-180899

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Patel, Hamel | Dobson, Richard J.B. | Newhouse, Stephen J.

Article Type: Research Article

Abstract: Background: Microarray technologies have identified imbalances in the expression of specific genes and biological pathways in Alzheimer’s disease (AD) brains. However, there is a lack of reproducibility across individual AD studies, and many related neurodegenerative and mental health disorders exhibit similar perturbations. Objective: Meta-analyze publicly available transcriptomic data from multiple brain-related disorders to identify robust transcriptomic changes specific to AD brains. Methods: Twenty-two AD, eight schizophrenia, five bipolar disorder, four Huntington’s disease, two major depressive disorder, and one Parkinson’s disease dataset totaling 2,667 samples and mapping to four different brain regions (temporal lobe, frontal lobe, parietal …lobe, and cerebellum) were analyzed. Differential expression analysis was performed independently in each dataset, followed by meta-analysis using a combining p -value method known as Adaptively Weighted with One-sided Correction. Results: Meta-analysis identified 323, 435, 1,023, and 828 differentially expressed genes specific to the AD temporal lobe, frontal lobe, parietal lobe, and cerebellum brain regions, respectively. Seven of these genes were consistently perturbed across all AD brain regions with SPCS1 gene expression pattern replicating in RNA-Seq data. A further nineteen genes were perturbed specifically in AD brain regions affected by both plaques and tangles, suggesting possible involvement in AD neuropathology. In addition, biological pathways involved in the “metabolism of proteins” and viral components were significantly enriched across AD brains. Conclusion: This study identified transcriptomic changes specific to AD brains, which could make a significant contribution toward the understanding of AD disease mechanisms and may also provide new therapeutic targets. Show more

Keywords: Alzheimer’s disease, gene expression, human, mental disorders, meta-analysis, microarray analysis, neurodegenerative disorders, neuropathology

DOI: 10.3233/JAD-181085

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2019

Authors: Wuttke-Linnemann, Alexandra | Baake, Ricarda | Fellgiebel, Andreas

Article Type: Review Article

Abstract: Patients with dementia (PWD) and their caregivers experience long-term stress, leading to accelerated disease progression and to stress-related morbidity. Previous research focused on intrapersonal biopsychological stress responses. Quite recently, dyadic interrelations between caregivers and PWD and their effects on stress and caregiver burden have received more attention, giving rise to dyadic intervention studies. However, while it is of importance to consider both the patient and the caregiver from a dyadic point of view, evaluation of these dyadic interventions considering underlying mechanisms is still lacking. We therefore extend the current literature on dyadic processes between PWD and caregivers by transferring the …knowledge about underlying stress-modulating dyadic processes in healthy couples to the dementia patient-caregiver constellation. By targeting dyadic stress co-regulation between PWD and caregivers, we expect significant therapeutic effectiveness. The aims of this article are two-fold: 1) We aim to provide a rationale for incremental benefits of considering dyadic processes among caregivers and PWD by means of elucidating underlying mechanisms and 2) we aim to emphasize the need to evaluate these underlying mechanisms by means of objective physiological stress markers in both PWD and caregivers. Knowledge on these underlying mechanisms will ultimately help developing dyadic interventions tailored to the needs of both PWD and their caregivers. Show more

Keywords: Cortisol, dementia care management, hypothalamic-pituitary-adrenal axis, stress physiology, systemic approach

DOI: 10.3233/JAD-181025

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019