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

Authors: Hascup, Kevin N. | Britz, Jesse | Findley, Caleigh A. | Tischkau, Shelley | Hascup, Erin R.

Article Type: Research Article

Abstract: Chronically elevated basal glutamate levels are hypothesized to attenuate detection of physiological signals thereby inhibiting memory formation and retrieval, while inducing excitotoxicity-mediated neurodegeneration observed in Alzheimer’s disease (AD). However, current medication targeting the glutamatergic system, such as memantine, shows limited efficacy and is unable to decelerate disease progression, possibly because it modulates postsynaptic N-methyl-D-aspartate receptors rather than glutamate release or clearance. To determine if decreasing presynaptic glutamate release leads to long-term procognitive effects, we treated Aβ PP/PS1 mice with LY379268 (3.0 mg/kg; i.p.), a metabotropic glutamate receptor (mGluR)2/3 agonist from 2–6 months of age when elevated glutamate levels are first …observed but cognition is unaffected. C57BL/6J genetic background control mice and another cohort of Aβ PP/PS1 mice received normal saline (i.p.) as vehicle controls. After 6 months off treatment, mice receiving LY379268 did not show long-term improvement as assessed by the Morris water maze (MWM) spatial learning and memory paradigm. Following MWM, mice were isoflurane anesthetized and a glutamate selective microelectrode was used to measure in vivo basal and stimulus-evoked glutamate release and clearance independently from the dentate, CA3, and CA1 hippocampal subregions. Immunohistochemistry was used to measure hippocampal astrogliosis and plaque pathology. Similar to previous studies, we observed elevated basal glutamate, stimulus evoked glutamate release, and astrogliosis in Aβ PP/PS1 vehicle mice versus C57BL/6J mice. Treatment with LY379268 did not attenuate these responses nor diminish plaque pathology. The current study builds upon previous research demonstrating hyperglutamatergic hippocampal signaling in Aβ PP/PS1 mice; however, long-term therapeutic efficacy of LY379268 in Aβ PP/PS1 was not observed. Show more

Keywords: Alzheimer’s disease, amyloid-β , cognition, early intervention, glial fibrillary acidic protein, metabotropic glutamate receptor

DOI: 10.3233/JAD-181231

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Goodman, Michelle S. | Zomorrodi, Reza | Kumar, Sanjeev | Barr, Mera S. | Daskalakis, Zafiris J. | Blumberger, Daniel M. | Fischer, Corinne E. | Flint, Alastair | Mah, Linda | Herrmann, Nathan | Pollock, Bruce G. | Bowie, Christopher R. | Mulsant, Benoit H. | Rajji, Tarek K. | for PACt-MD Study Group

Article Type: Research Article

Abstract: While several studies have found that neural oscillations play a key role in the functioning of working memory, the nature of aberrant oscillatory activity underlying working memory impairments in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) remains largely unexplored. These individuals often display structural alterations in brain regions and pathways involved in working memory processes and therefore may also display altered oscillatory activity during memory activation. Electroencephalographic (EEG) activity was recorded during the N-back working memory task in three groups: AD (n  = 29), MCI (n  = 100), and healthy controls (HCs; n  = 40). Theta (4–7 Hz) and alpha (7.5–12 Hz) modulation was …measured in response to the stimulus presentation during correct and incorrect responses. This modulation represents the change in EEG activity associated with the stimulus onset and was measured as a ratio of post stimulus power to pre stimulus power. We also assessed the relationship between this change in oscillatory power and working memory performance. Compared to HCs, the AD group demonstrated the lowest working memory accuracy and a smaller theta ratio for correct responses on the 2-back condition; the MCI group demonstrated a smaller theta ratio for correct responses on the 3-back condition. Finally, we observed that the theta ratio, but not the alpha ratio, was a significant predictor of working memory performance in the three groups for all conditions. Taken together, these behavioral and electrophysiological results suggest that in addition to impairments in working memory performance, modulation of theta, but not alpha power, may be impaired in MCI and AD. Show more

Keywords: Alpha power, Alzheimer’s disease, electroencephalography, mild cognitive impairment, theta power, working memory

DOI: 10.3233/JAD-181195

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

Authors: Zhutovsky, Paul | Vijverberg, Everard G.B. | Bruin, Willem B. | Thomas, Rajat M. | Wattjes, Mike P. | Pijnenburg, Yolande A.L. | van Wingen, Guido A. | Dols, Annemiek

Article Type: Research Article

Abstract: Background: Patients with behavioral variant of frontotemporal dementia (bvFTD) initially may only show behavioral and/or cognitive symptoms that overlap with other neurological and psychiatric disorders. The diagnostic accuracy is dependent on progressive symptoms worsening and frontotemporal abnormalities on neuroimaging findings. Predictive biomarkers could facilitate the early detection of bvFTD. Objective: To determine the prognostic accuracy of clinical and structural MRI data using a support vector machine (SVM) classification to predict the 2-year clinical follow-up diagnosis in a group of patients presenting late-onset behavioral changes. Methods: Data from 73 patients were included and divided into probable /definite …bvFTD (n  = 18), neurological (n  = 28), and psychiatric (n  = 27) groups based on 2-year follow-up diagnosis. Grey-matter volumes were extracted from baseline structural MRI scans. SVM classifiers were used to perform three binary classifications: bvFTD versus neurological and psychiatric, bvFTD versus neurological, and bvFTD versus psychiatric group(s), and one multi-class classification. Classification performance was determined for clinical and neuroimaging data separately and their combination using 5-fold cross-validation. Results: Accuracy of the binary classification tasks ranged from 72–82% (p  <  0.001) with adequate sensitivity (67–79%), specificity (77–88%), and area-under-the-curve (0.80–0.9). Multi-class accuracy ranged between 55–59% (p  <  0.001). The combination of clinical and voxel-wise whole brain data showed the best performance overall. Conclusions: These results show the potential for automated early confirmation of diagnosis for bvFTD using machine learning analysis of clinical and neuroimaging data in a diverse and clinically relevant sample of patients. Show more

Keywords: behavioral variant frontotemporal dementia, classification, magnetic resonance imaging, prognosis, support vector machine

DOI: 10.3233/JAD-181004

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

Authors: Cholerton, Brenna | Weiner, Michael W. | Nosheny, Rachel L. | Poston, Kathleen L. | Scott Mackin, R. | Tian, Lu | Ashford, J. Wesson | Montine, Thomas J.

Article Type: Research Article

Abstract: The study of cognition in Parkinson’s disease (PD) traditionally requires exhaustive recruitment strategies. The current study examines data collected by the Brain Health Registry (BHR) to determine whether ongoing efforts to improve the recruitment base for therapeutic trials in Alzheimer’s disease may be similarly effective for PD research, and whether online cognitive measurements can discriminate between participants who do and do not report a PD diagnosis. Participants enrolled in the BHR (age ≥50) with self-reported PD data and online cognitive testing available were included (n  = 11,813). Associations between baseline cognitive variables and diagnostic group were analyzed using logistic regression. Linear …mixed effects models were used to analyze longitudinal data. A total of 634 participants reported PD diagnosis at baseline with no self-reported cognitive impairment and completed cognitive testing. Measures of visual learning and memory, processing speed, attention, and working memory discriminated between self-reported PD and non-PD participants after correcting for multiple comparisons (p values <  0.006). Scores on all cognitive tests improved over time in PD and controls with the exception of processing speed, which remained stable in participants with PD while improving in those without. We demonstrate that a novel online approach to recruitment and longitudinal follow-up of study participants is effective for those with self-reported PD, and that significant differences exist between those with and without a reported diagnosis of PD on computerized cognitive measures. These results have important implications for recruitment of participants with PD into targeted therapeutic trials or large-scale genetic and cognitive studies. Show more

Keywords: Aging, cognition, neuropsychology, Parkinson’s disease, patient selection, registries

DOI: 10.3233/JAD-181009

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

Authors: Kuhla, Angela | Brichmann, Elaine | Rühlmann, Claire | Thiele, Robin | Meuth, Lou | Vollmar, Brigitte

Article Type: Research Article

Abstract: Epidemiological studies suggest that individuals with diabetes mellitus are at greater risk of developing Alzheimer’s disease. A well-known insulin-sensitizing drug and the most widely prescribed oral medication for diabetes is metformin. There is evidence that metformin acts in a neuroprotective manner via the AMPK/mTOR pathway by inhibiting the tau phosphorylation. In addition, it is known that metformin upregulates Fgf21, which in turn activates the AMPK/mTOR pathway and mediates neuroprotection. Thus, metformin-induced Fgf21 release may be involved in AMPK/mTOR activation. However, some studies reported that metformin causes cognition impairment. Due to the controversial data on the neuroprotective properties of metformin, we …treated Apolipoprotein E deficient (ApoE – /–) mice, a mouse model of tauopathy, with metformin for 18 weeks. Metformin-treated mice revealed increased expression of lipogenic genes, i.e., lxr α and srebp1c . In line with this, metformin caused an increase in plasma triglyceride leading to enhanced gliosis as indicated by an increase of GFAP-positive cells. Although the systemic Fgf21 concentration was increased, metformin did not activate the FgfR1c/AMPK/mTOR pathway suggesting a Fgf21-resistant state. Further, metformin-treated mice showed increased tau phosphorylation and reduced numbers of NeuN-and PSD95-positive cells. Thus, metformin-associated lipogenesis as well as inflammation aggravated neurodegenerative processes in ApoE – /– mice. Consequently, this study supports previous observations showing that metformin causes impairment of cognition. Show more

Keywords: Alzheimer’s disease, ApoE deficiency, Fgf21, metformin, mTOR, neuro-inflammation, pAMPK, tau phosphorylation

DOI: 10.3233/JAD-181017

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

Authors: Klimova, Blanka | Kuca, Kamil | Valis, Martin | Hort, Jakub

Article Type: Research Article

Abstract:  Currently, there is an increase in the number of older people worldwide. Unfortunately, this demographic trend causes a rise in aging diseases, one of which is dementia. Recent research studies have indicated that mild cognitive impairment (MCI) may serve as a predictor of dementia in many patients. At present, there is no pharmacological treatment against MCI. Therefore, there is constant search for novel alternative non-pharmacological approaches to improve MCI. One of the effective complementary emerging approaches seems to be Traditional Chinese Medicine (TCM), which is nowadays becoming quite popular in the treatment of different disorders. The purpose of this study …is to explore the efficacy of TCM as an effective complementary non-pharmacological tool for the improvement and treatment of MCI in older adults. The methods used for this review study included a literature search in the world’s databases: Web of Science, Scopus, PubMed, and Springer. Afterwards, methods of comparison and evaluation of the findings from the selected studies were applied. The results of this review study indicate that TCM might be a beneficial complementary non-pharmacological approach to the improvement and treatment of MCI in older individuals. Nevertheless, more rigorously designed quality randomized clinical trials should be conducted in order to conclusively prove efficacy of TCM on the improvement of MCI among older population groups. In addition, there is an urgent call for a functional collaboration between western and eastern medicinal approaches, which could contribute to the enhancement of the overall quality of life of these aging population groups. Show more

Keywords: Benefits, collaboration, intervention, limitations, mild cognitive impairment, older people, Traditional Chinese Medicine

DOI: 10.3233/JAD-181281

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Heser, Kathrin | Kleineidam, Luca | Wiese, Birgitt | Oey, Anke | Roehr, Susanne | Pabst, Alexander | Kaduszkiewicz, Hanna | van den Bussche, Hendrik | Brettschneider, Christian | König, Hans-Helmut | Weyerer, Siegfried | Werle, Jochen | Fuchs, Angela | Pentzek, Michael | Mösch, Edelgard | Bickel, Horst | Maier, Wolfgang | Scherer, Martin | Riedel-Heller, Steffi G. | Wagner, Michael

Article Type: Research Article

Abstract: Background/Objective: Subjective cognitive decline (SCD) has often been associated with an increased risk for subsequent dementia. However, sex-specific associations are understudied until now. Methods: Cross-sectional and longitudinal associations over a follow-up period of up to 13 years were investigated in a sample of participants without objective cognitive impairment at baseline (n  = 2,422, mean age = 79.63 years). Logistic regression and Cox proportional hazards models were conducted. Results: Women less frequently reported SCD without worries (p  <  0.001), but tended to report more often SCD with worries (p  = 0.082) at baseline compared to men. In models adjusted for age, …education, cognitive status, and depressive symptoms, SCD at baseline increased the risk for subsequent dementia (p  <  0.001), and this effect was less pronounced in males (interaction sex×SCD: p  = 0.022). Stratified analyses showed that SCD increased the risk for subsequent dementia in women (HR = 1.77, p  <  0.001), but not in men (HR = 1.07, p  = 0.682). Similar results were found in analyses with SCD without and with worries, except that SCD with worries also predicted subsequent Alzheimer’s disease (AD) in men (p  = 0.037). Conclusion: At baseline, men reported more SCD without worries and women tended to report more SCD with worries. SCD in women was more strongly associated with subsequent dementia. SCD without and with worries was related to incident dementia and AD in women, whereas in men only SCD with worries increased the risk for AD, but not for all-cause dementia. Show more

Keywords: Alzheimer’s disease, dementia, gender, sex, subjective cognitive decline, subjective memory decline, subjective memory impairment

DOI: 10.3233/JAD-180981

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

Authors: Zhu, Lingyan | Gong, Li | Yang, Tianlun | Xiao, Xiangwei

Article Type: Research Article

Abstract:  Aged people have a high chance to develop two prevalent diseases, diabetes and Alzheimer’s disease (AD), which are characterized with hyperglycemia and neurodegeneration, respectively. Interestingly, recent evidence suggest that diabetes is a predisposing factor for AD. Nevertheless, the mechanisms underlying the association of diabetes with AD remain poorly defined. Here, we studied the effects of diabetes on AD in mice. The APP-PS1 mouse, an AD-prone strain, was administrated with streptozotocin (STZ) to destroy 75% beta cell mass to induce sustained hyperglycemia. We found that STZ-treated APP-PS1 mice exhibited poorer performance in the social recognition test, Morris water maze, and plus-maze …discriminative avoidance task, compared to saline-treated normoglycemic APP-PS1 mice, likely resulting from increases in brain deposition of amyloid-β peptide aggregates (Aβ ). Since formation of Aβ is known to be induced by protein hyperphosphorylation mediated by calpain (CAPN)-induced cleavage of p35 into p25, we examined levels of these proteins in mouse brain. We detected not only increased p35-to-p25 conversion, but also enhanced CAPN1 activity via increased protein but not mRNA levels. The internal CAPN1 inhibitor, calpastatin (CAST), was downregulated in STZ-treated APP-PS1 mouse brain, as a basis for the increase in CAPN1. In vitro , a human neuronal cell line, HCN-2, increased CAPN1 activity and downregulated CAST levels when incubated for 8 days in high glucose level, resulting in increased cell apoptosis. Together, these data suggest that chronic hyperglycemia may promote AD development through downregulating CAST. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide aggregates, calpain 1, calpastatin, diabetes

DOI: 10.3233/JAD-190004

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Ayers, Emmeline | Verghese, Joe

Article Type: Research Article

Abstract: Background: Motoric cognitive risk (MCR) syndrome is a cognitive-motor syndrome associated with increased risk of transition to dementia. The clinical phenotype of MCR is not yet established. Objective: To systematically assess clinical gait abnormalities in older adults with MCR. Methods: Of the 522 community-dwelling non-demented adults aged 65 and older enrolled in the Central Control of Mobility in Aging study, 43 were diagnosed with MCR (47% women) based on presence of cognitive complaints and slow gait velocity (MCRv). Four additional subtypes of MCR were defined by substituting slow gait with short stride length (MCRsl, n  = 41), …slow swing time (MCRsw, n  = 21), high stride length variability (MCRslv, n  = 24), and high swing time variability (MCRswv, n  = 25). The prevalence of clinical gait abnormalities (neurological or non-neurological) in MCR overall (n  = 81) and subtypes was studied. We also examined if gait abnormalities predicted further cognitive and functional decline in MCR cases. Results: Most clinical gait abnormalities were mild (walked without assistance) in the five MCR subtypes (44 to 61%). Neurological (range 24 to 46%) and non-neurological gait abnormalities (33 to 61%) were common in all MCR subtypes. Neurological gaits were most frequent in MCRsl (46%) and non-neurological gaits in MCRv (61%). Over a median 3.02 years of follow-up, presence of gait abnormality in MCR cases at baseline predicted worsening disability scores (estimate 0.17, p -value = 0.033) but not decline on cognitive scores (p -value = 0.056). Conclusion: Clinical gait abnormalities are common in MCR syndrome and its subtypes, and are associated with accelerated functional decline. Show more

Keywords: Cognition, gait, motoric cognitive risk syndrome

DOI: 10.3233/JAD-181227

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

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

Authors: Rofes, Adrià | de Aguiar, Vânia | Ficek, Bronte | Wendt, Haley | Webster, Kimberly | Tsapkini, Kyrana

Article Type: Research Article

Abstract: People with primary progressive aphasia (PPA) present language difficulties that require lengthy assessments and follow-ups. Despite individual differences, people with PPA are often classified into three variants that present some distinctive language difficulties. We analyzed the data of 6 fluency tasks (i.e., “F”, “A”, “S”, “Fruits”, “Animals”, “Vegetables”) using random forests to pinpoint relevant word properties and error types in the classification of the three PPA variants: conditional inference trees to indicate how relevant variables may interact with one another and ANOVAs to cross-validate the results. Results indicate that total word count helps distinguish healthy individuals (N = 10) from people with …PPA (N = 29). Furthermore, mean familiarity differentiates people with svPPA (N = 8) from people with lvPPA (N = 10) and nfvPPA (N = 11). No other word property or error type was relevant in the classification. These results relate to previous literature, as familiarity effects have been reported in people with svPPA in naming and spontaneous speech, thus strengthening the relevance of using familiarity to identify a specific group of people with PPA. This paper enhances our understanding of what determines word retrieval in people with PPA, complementing and extending data from naming studies. Show more

Keywords: Category, familiarity, fluency, letter, primary progressive aphasia

DOI: 10.3233/JAD-180990

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

Authors: Robertson, Kayela | Larson, Eric B. | Crane, Paul K. | Cholerton, Brenna | Craft, Suzanne | McCormick, Wayne C. | McCurry, Susan M. | Bowen, James D. | Baker, Laura D. | Trittschuh, Emily H.

Article Type: Research Article

Abstract: Lack of a unitary operational definition of mild cognitive impairment (MCI) has resulted in mixed prevalence rates and unclear predictive validity regarding conversion to dementia and likelihood of reversion. We examined 1,721 nondemented participants aged 65 and older from the Adult Changes in Thought (ACT) community-based cohort. Participants were followed longitudinally through biennial visits (average years assessed = 5.38). Categorization of MCI was based on: 1) deviation of neuropsychological test scores from a benchmark based on either standard or individualized expectations of a participant’s mean premorbid cognitive ability, and 2) cutoff for impairment (1.0 versus 1.5 standard deviations [sd] below benchmark). MCI …prevalence ranged from 56–92%; using individualized benchmarks and less stringent cutoffs produced higher rates. During follow-up, 17% of the cohort developed dementia. Examination of sensitivity, specificity, and predictive validity revealed that the criterion of 1.5 sd from the standardized benchmark was optimal, but still had limited predictive validity. Participants meeting this criterion at their first visit were three times more likely to develop dementia and this increased to seven times if participants had this diagnosis at the second timepoint as well. Those who did not have an MCI diagnosis at their first visit, but did at their second, had a significant increase of risk (but to a lesser extent than those diagnosed at both visits), while those who had an MCI diagnosis at their first visit, but not their second, did not have a significantly increased risk. These results highlight how assessing MCI stability greatly improves prediction of risk. Show more

Keywords: Cognitive dysfunction, dementia, epidemiology, incidence, prevalence

DOI: 10.3233/JAD-180746

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

Authors: Liedes, Hilkka | Lötjönen, Jyrki | Kortelainen, Juha M. | Novak, Gerald | van Gils, Mark | Gordon, Mark Forrest | for the Alzheimer’s Disease Neuroimaging Initiative | and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing

Article Type: Research Article

Abstract: Background: Hippocampal atrophy (HA) is one of the biomarkers for Alzheimer’s disease (AD). Objective: To identify the best biomarkers and develop models for prediction of HA over 24 months using baseline data. Methods: The study included healthy elderly controls, subjects with mild cognitive impairment, and subjects with AD, obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI 1) and the Australian Imaging Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) databases. Predictor variables included cognitive and neuropsychological tests, amyloid-β, tau, and p-tau from cerebrospinal fluid samples, apolipoprotein E, and features extracted from magnetic resonance images (MRI). Least-mean-squares …regression with elastic net regularization and least absolute deviation regression models were tested using cross-validation in ADNI 1. The generalizability of the models including only MRI features was evaluated by training the models with ADNI 1 and testing them with AIBL. The models including the full set of variables were not evaluated with AIBL because not all needed variables were available in it. Results: The models including the full set of variables performed better than the models including only MRI features (root-mean-square error (RMSE) 1.76–1.82 versus 1.93–2.08). The MRI-only models performed well when applied to the independent validation cohort (RMSE 1.66–1.71). In the prediction of dichotomized HA (fast versus slow), the models achieved a reasonable prediction accuracy (0.79–0.87). Conclusions: These models can potentially help identifying subjects predicted to have a faster HA rate. This can help in selection of suitable patients into clinical trials testing disease-modifying drugs for AD. Show more

Keywords: Alzheimer’s disease, atrophy, decision support techniques, disease progression, hippocampus, magnetic resonance imaging, regression analysis, statistical models

DOI: 10.3233/JAD-180484

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Boscher, Emmanuelle | Husson, Thomas | Quenez, Olivier | Laquerrière, Annie | Marguet, Florent | Cassinari, Kevin | Wallon, David | Martinaud, Olivier | Charbonnier, Camille | Nicolas, Gaël | Deleuze, Jean-François | Boland, Anne | Lathrop, Mark | Frébourg, Thierry | FREX Consortium | Campion, Dominique | Hébert, Sébastien S. | Rovelet-Lecrux, Anne

Article Type: Research Article

Abstract: Early-onset Alzheimer’s disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100% . With the exception of rare mutations in APP , PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative …for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1 . This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD. Show more

Keywords: Copy number variants, early-onset Alzheimer’s disease, microRNA, miR-138

DOI: 10.3233/JAD-180940

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

Authors: Baschi, Roberta | Restivo, Vincenzo | Nicoletti, Alessandra | Cicero, Edoardo Calogero | Luca, Antonina | Recca, Deborah | Zappia, Mario | Monastero, Roberto

Article Type: Research Article

Abstract: Neuropsychiatric symptoms (NPS) have been frequently described in Parkinson’s disease (PD), even in the earliest stages of the disease. Recently the construct of mild behavioral impairment (MBI) has been proposed as an at-risk state for incident cognitive decline and dementia. The aim of the present study is to evaluate the prevalence and associated factors of MBI in PD. Cross-sectional data from 429 consecutive PD patients enrolled in the PArkinson’s disease COgnitive impairment Study (PACOS) were included in the study. All subjects underwent neuropsychological assessment, according to the MDS Level II criteria. NPS were evaluated with the Neuropsychiatric Inventory. Multivariate logistic …regression models were used to evaluate clinical and behavioral characteristics, which are associated with PD-MBI. PD-MBI was ascertained in 361 (84.1%) subjects of whom 155 (36.1%) were newly diagnosed patients (disease duration ≤1 year) and 206 (48.0%) had a disease duration >1 year. Furthermore, 68 (15.9%) out of 429 subjects were PDw (without MBI). Across the MBI domains, Impulse Dyscontrol was significantly more prevalent among PD-MBI with disease duration >1 year than newly diagnosed patients. The frequency of Social Inappropriateness and Abnormal Perception significantly increased throughout the entire PD-MBI sample with increasing Hoehn and Yahr (H&Y) stages. PD-MBI in newly diagnosed PD was significantly associated with H&Y stage (OR 2.35, 95% CI 1.05–5.24) and antidepressant drug use (OR 2.94, 95% CI 0.91–9.47), while in patients with a disease duration >1 year was associated with UPDRS-ME (OR 3.37, 95% CI 1.41–8.00). The overall MBI frequency in the PACOS sample was 84% and 36% among newly diagnosed patients. The presence of MBI mainly related to motor impairment and disability. Show more

Keywords: Cognitive impairment, mild behavioral impairment, neuropsychiatric symptoms, Parkinson’s disease, prevalence

DOI: 10.3233/JAD-181117

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Alexopoulos, Panagiotis | Thierjung, Nathalie | Economou, Polychronis | Werle, Lukas | Buhl, Felix | Kagerbauer, Simone | Papanastasiou, Anastasios D. | Grimmer, Timo | Gourzis, Philippos | Berthele, Achim | Hemmer, Bernhard | Kübler, Hubert | Martin, Jan | Politis, Antonios | Perneczky, Robert

Article Type: Short Communication

Abstract: Cost- and time-effective markers of Alzheimer’s disease (AD), reliable and feasible at the population level are urgently needed. Soluble amyloid-β protein precursor β (sAβPPβ) in plasma has attracted scientific attention as a potential AD biomarker candidate. Here we report that plasma sAβPPβ levels in patients with AD dementia and typical for AD cerebrospinal fluid (CSF) biomarker profiles (N = 33) are significantly lower (p  < 0.01) than those of cognitively healthy elderly individuals without AD (N = 39), while CSF sAβPPβ levels did not differ between the studied groups. This provides further evidence for the potential of sAβPPβ in plasma as an AD biomarker candidate.

Keywords: Biomarker candidate, NIA-AA research framework diagnostic criteria, soluble amyloid-β protein precursor β

DOI: 10.3233/JAD-181088

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Langer, Kailey | O’Shea, Deirdre | De Wit, Liselotte | DeFeis, Brittany | Mejia, Andrea | Amofa, Priscilla | Chandler, Melanie | Locke, Dona | Fields, Julie | Phatak, Vaishali | Dean, Pamela | Smith, Glenn

Article Type: Research Article

Abstract: Background: Research has shown that individuals with mild cognitive impairment (MCI) value quality of life (QoL) above and beyond cognitive function or other potential outcomes in MCI. There is evidence supporting the negative impact of poor physical function on QoL ratings. Objective: The study explored whether a modified measure of self-efficacy for managing MCI and education mediated and/or moderated the relationship between physical function and QoL in persons with MCI. Methods: Baseline data from 200 participants with MCI were obtained from a larger study assessing the effectiveness of a behavioral intervention. Physical function was assessed by …the Short Physical Performance Battery. QoL was assessed with the Quality of Life in Alzheimer’s Disease scale. Memory-related self-efficacy was assessed using a modified 9-item version of the Chronic Disease Self-Efficacy Scales. Mediation and moderation analyses tested the hypotheses that self-efficacy and education alter the association between physical function and QoL in individuals with MCI. All analyses were adjusted for age, cognitive severity, and sex. Results: Self-efficacy for managing MCI was a significant mediator of the association between physical function and perceived QoL. Individuals with better physical function reported higher self-efficacy which was associated with higher QoL ratings. Conclusions: Greater self-efficacy for managing MCI mediated the negative association between physical function and quality of life in this exploratory study. Interventions aimed at enhancing memory self-efficacy in MCI may improve perceived QoL, even in the presence of poor physical function. Future research is needed to investigate this further. Show more

Keywords: Activities of daily living, cognitive reserve, life quality, mild cognitive impairment, self-efficacy

DOI: 10.3233/JAD-181020

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: O’Caoimh, Rónán | Gao, Yang | Svendrovski, Anton | Illario, Maddalena | Iaccarino, Guido | Yavuz, Burcu Balam | Kehoe, Patrick Gavin | Molloy, D. William

Article Type: Research Article

Abstract: Background: Visit-to-visit blood pressure (BP) variability (VVV) is increasingly recognized as a marker of cardiovascular risk. Although implicated in cognitive decline, few studies are currently available assessing its effects on established dementia. Objective: To investigate if VVV is associated with one-year rate of decline in measures of cognition and function in patients with mild to moderate Alzheimer’s disease (AD) in the Doxycycline And Rifampicin for Alzheimer’s Disease study. Methods: Patients were included if ≥3 BP readings were available (n  = 392). VVV was defined using different approaches including the coefficient of variation (CV) in BP readings between …visits. Outcomes included rates of decline in the Standardized Alzheimer’s Disease Assessment Scale–Cognitive Subscale (SADAS-cog), Standardized MMSE, Clinical Dementia Rating Scale, the Quick Mild Cognitive Impairment screen and the Lawton-Brody activities of daily living (ADL) scale. Results: Half of the patients (196/392) had a ≥4-point decline in the SADAS-cog over one-year. Using this cut-off, there were no statistically significant associations between any measures of VVV, for systolic or diastolic BP, with and without adjustment for potential confounders including treatment allocation, history of hypertension and use of anti-hypertensive and cognitive enhancing medications. Multiple regression models examining the association between systolic BP CV by quartile and decline over one-year likewise showed no clinically significant effects, apart from a U -shaped pattern of ADL decline of borderline clinical significance.∥Conclusions: This observational study does not support recent research showing that VVV predicts cognitive decline in AD. Further studies are needed to clarify its effects on ADL in AD. Show more

Keywords: Visit-visit-variability, blood pressure variability, blood pressure, cognition, Alzheimer’s disease

DOI: 10.3233/JAD-180774

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Aiello Bowles, Erin J. | Crane, Paul K. | Walker, Rod L. | Chubak, Jessica | LaCroix, Andrea Z. | Anderson, Melissa L. | Rosenberg, Dori | Keene, C. Dirk | Larson, Eric B.

Article Type: Research Article

Abstract: Background: Past research has focused on risk factors for developing dementia, with increasing recognition of “resilient” people who live to old age with intact cognitive function despite pathological features of Alzheimer’s disease (AD). Objective: To evaluate demographic factors, mid-life characteristics, and non-AD neuropathology findings that may be associated with cognitive resilience to AD pathology. Methods: We analyzed data from 276 autopsy cases with intermediate or high levels of AD pathology from the Adult Changes in Thought study. We defined cognitive resilience as having Cognitive Abilities Screening Instrument scores >86 within two years of death and no …clinical dementia diagnosis; non-resilient people had dementia diagnoses from AD or other causes before death. We compared mid-life characteristics, demographics, and additional neuropathology findings between resilient and non-resilient people. We used multivariable logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for being resilient compared to not being resilient adjusting for demographic and neuropathology factors. Results: We classified 68 (25%) people as resilient and 208 (75%) as not resilient. A greater proportion of resilient people had a college degree (50%) compared with non-resilient (32%, p  = 0.01). The odds of being resilient were significantly increased among people with a college education (OR = 2.01, 95% CI = 1.01–3.99) and significantly reduced among people with additional non-AD neuropathology findings such as hippocampal sclerosis (OR = 0.28, 95% CI = 0.09–0.89) and microinfarcts (OR = 0.34, 95% CI = 0.15–0.78). Discussion: Increased education and absence of non-AD pathology may be independently associated with cognitive resilience, highlighting the importance of evaluating co-morbid factors in future research on mechanisms of cognitive resilience. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, education, neuropathology

DOI: 10.3233/JAD-180942

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

Authors: Black, Christopher | Lipton, Richard B. | Thiel, Ellen | Brouillette, Matthew | Khandker, Rezaul

Article Type: Research Article

Abstract: The relationship between Alzheimer’s disease (AD) treatment patterns and healthcare costs is unknown. Administrative claims data from the MarketScan Commercial and Medicare databases covering 2010 through 2016 were used to identify the comorbidities, treatment patterns, and healthcare costs in the three years prior to and one year post medical diagnosis of AD in 21,448 patients with no treatment and 57,970 patients with treatment. Pre-index mean annual costs ranged from $14,228 to $26,876, and post-index mean annual costs ranged from $21,052 to $45,685 depending on age and treatment timing. After adjusting for baseline characteristics, patients 50–100 years old who initiated treatment …with an FDA approved drug prior to or concurrent with diagnosis had healthcare costs 9%–19% lower in the year following diagnosis than those who did not receive treatment. Early or concurrent treatment is associated with lower overall healthcare costs in the year following AD diagnosis. Show more

Keywords: Administrative claims, Alzheimer’s disease, delayed diagnosis, health care costs, time-to-treatment

DOI: 10.3233/JAD-180983

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

Authors: Mis, Rachel | Devlin, Kathryn | Drabick, Deborah | Giovannetti, Tania

Article Type: Research Article

Abstract: Heterogeneity of subtle functional difficulties in mild cognitive impairment (MCI) remains poorly understood. We characterized patterns of informant reports of functional abilities among participants with MCI and the relation between functional ability pattern and cognitive abilities and subsequent decline. Data from 4,273 MCI participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set (UDS) were included in latent profile analyses (LPA) of informant responses on the Functional Activities Questionnaire (FAQ). Profiles from the best fitting model were compared on demographic, clinical, and cognitive variables. The best fitting model supported three profiles varying by level and type of difficulty: intact …function (n  = 3,299), intermediate (n  = 769), and high ratings of difficulty (n  = 205). For the Intermediate profile, items related to finances, remembering dates, and travel were rated as most difficult. The High Ratings profile also had elevated ratings on the meal preparation item. Participants with either the Intermediate or High Ratings profile demonstrated a three-fold increase in conversion to dementia as compared to participants with the Intact profile. Demographically, the Intact profile was younger and consisted of a higher proportion of minorities. On cognitive tests, the Intact profile showed the best performance, and the Intermediate profile performed comparably to or better than the High Ratings profile. There is meaningful heterogeneity in informant ratings of function in MCI, though individuals with MCI whose informants report even intermediate-level functional difficulties are more likely to progress to dementia, suggesting that even subtle functional difficulties place individuals at higher risk for future decline. Show more

Keywords: Activities of daily living, alzheimer’s disease, episodic memory, executive function, mild cognitive impairment

DOI: 10.3233/JAD-180975

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

Authors: Sheikh-Bahaei, Nasim | Manavaki, Roido | Sajjadi, S. Ahmad | Priest, Andrew N. | O’Brien, John T. | Gillard, Jonathan H.

Article Type: Research Article

Abstract: Background: Despite the well-documented relationship between lobar cerebral microbleeds (lCMB) and Alzheimer’s disease (AD), there is limited knowledge about the role of lCMB in AD pathology. Objective: To understand the nature of this relationship, we investigated the association between lCMB, amyloid load, perfusion, and metabolism. Methods: Participants with AD, mild cognitive impairment (MCI), and healthy controls were recruited and scanned with 11 C-Pittsburg-Compound B (PiB), Fluorodeoxyglucose (FDG) PET, and susceptibility-weighted MRI. Early PiB-PET frames were used to estimate perfusion. The association between lCMB and PET uptake in each anatomical lobe was measured using multiple regression models. …Results: The presence of lCMB predicted increased total (p  < 0.001) and regional (p  = 0.0002) PiB uptake, as well as decreased cerebral perfusion (p  = 0.03). Cases with lCMB had hypometabolism in their temporal lobe (p  = 0.04). Conclusion: There are significant relationships between lCMBs and various markers of AD pathology. lCMB has a spatial association with Aβ load and a complex effect on perfusion and metabolism. Show more

Keywords: Alzheimer’s disease, cerebral metabolism, cerebral perfusion, FDG-PET, lobar cerebral microbleeds, PiB-PET, susceptibility weighted imaging

DOI: 10.3233/JAD-180443

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Wadhawan, Abhishek | Stiller, John W. | Potocki, Eileen | Okusaga, Olaoluwa | Dagdag, Aline | Lowry, Christopher A. | Benros, Michael E. | Postolache, Teodor T.

Article Type: Review Article

Abstract: Given the increasing rate of death by suicide in the United States, it is imperative to examine specific risk factors and to identify possible etiologies of suicidal behavior in at-risk clinical subpopulations. There is accumulating evidence to support an elevated risk of death by suicide in individuals with a history of traumatic brain injury (TBI). In this review article, after defining terms used in suicidology, we discuss the associations of TBI with death by suicide, suicide attempt, and suicidal ideation. A model for repetitive TBIs, chronic traumatic encephalopathy, is also discussed as a neuroinflammatory process, with discussion about its possible …link with suicide. The review concludes with an overview of interventions to prevent suicidal behavior. Show more

Keywords: Chronic traumatic encephalopathy, death by suicide, inflammation, neuroinflammation, suicidal behavior, traumatic brain injury

DOI: 10.3233/JAD-181055

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-32, 2019

Authors: Boomsma, Jooske M.F. | Exalto, Lieza G. | Barkhof, Frederik | Berg, Esther van den | Bresser, Jeroen de | Heinen, Rutger | Leeuwis, Anna E. | Prins, Niels D. | Scheltens, Philip | Weinstein, Henry C. | van der Flier, Wiesje M. | Biessels, Geert Jan | behalf of the TRACE-VCI study group

Article Type: Research Article

Abstract: Background: Memory clinic patients frequently present with different forms of vascular brain injury due to different etiologies, often co-occurring with Alzheimer’s disease (AD) pathology. Objective: We studied how cognition was affected by different forms of vascular brain injury, possibly in interplay with AD pathology. Methods: We included 860 memory clinic patients with vascular brain injury on magnetic resonance imaging (MRI), receiving a standardized evaluation including cerebrospinal fluid (CSF) biomarker analyses (n  = 541). The cognitive profile of patients with different forms of vascular brain injury on MRI (moderate/severe white matter hyperintensities (WMH) (n  = 398), microbleeds (n  = 368), …lacunar (n  = 188) and non-lacunar (n  = 96) infarct(s), macrobleeds (n  = 16)) was assessed by: 1) comparison of all these different forms of vascular brain injury with a reference group (patients with only mild WMH (n  = 205) without other forms of vascular brain injury), using linear regression analyses also stratified for CSF biomarker AD profile and 2) multivariate linear regression analysis. Results: The cognitive profile was remarkably similar across groups. Compared to the reference group effect sizes on all domains were <0.2 with narrow 95% confidence intervals, except for non-lacunar infarcts on information processing speed (age, sex, and education adjusted mean difference from reference group (β : – 0.26, p  = 0.05). Results were similar in the presence (n  = 300) or absence (n  = 241) of biomarker co-occurring AD pathology. In multivariate linear regression analysis, higher WMH burden was related to a slightly worse performance on attention and executive functioning (β : – 0.08, p  = 0.02) and working memory (β : – 0.08, p  = 0.04). Conclusion: Although different forms of vascular brain injury have different etiologies and different patterns of cerebral damage, they show a largely similar cognitive profile in memory clinic patients regardless of co-occurring AD pathology. Show more

Keywords: Cerebral small vessel diseases, cerebrovascular disorders, cognitive disorders, neuropsychological test

DOI: 10.3233/JAD-180696

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

Authors: Bohlken, Jens | Kostev, Karel

Article Type: Short Communication

Abstract: Little is known about the diagnostic methods currently used in routine care for patients with mild cognitive impairment (PwMCI). We estimated the frequency of diagnostic procedures in incident PwMCI compared to incident patients with dementia (PwD) in 2016-2017. The study is based on the Disease Analyzer database. After matching by age and sex, 4,700 PwMCI and 4,700 PwD were available. The diagnostic procedures were identified on the basis of the related medical fee schedule items. All diagnostic procedures were used more frequently in PwMCI than in PwD. The drafting of a practice-oriented MCI guideline is an important task for the future.

Keywords: Alzheimer’s disease, mild cognitive impairment, preclinical dementia, prevalence, real-world data

DOI: 10.3233/JAD-190012

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2019

Authors: Cao, Long-Long | Guan, Pei-Pei | Liang, Yun-Yue | Huang, Xue-Shi | Wang, Pu

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is reported to be associated with the accumulation of calcium ions (Ca2+ ), which is responsible for the phosphorylation of tau. Although a series of evidence have demonstrated this phenomenon, the inherent mechanisms remain unknown. Using tauP301S and cyclooxygenase-2 (COX-2) transgenic mice and neuroblastoma (n)2a cells as in vivo and in vitro experimental models, we found that Ca2+ stimulates the phosphorylation of tau by activating COX-2 in a prostaglandin (PG) E2 -dependent EP receptor-activating manner. Specifically, Ca2+ incubation stimulated COX-2 and PGE2 synthase activity, microsomal PGE synthase 1 and the synthesis …of PGE2 by activating the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells in n2a cells. Elevated levels of PGE2 were responsible for phosphorylating tau in an EP-1, -2, and -3 but not EP4-dependent glycogen synthase kinase 3-activating manner. These observations were corroborated by results that showed tau was phosphorylated when it colocalized with activated COX-2 in tauP301S and COX-2 transgenic mice or n2a cells. To further validate these observations, treatment of mice with the COX-2 inhibitor rofecoxib decreased the phosphorylation of tau via EP1-3 but not EP4. Collectively, our observations fill the gaps between Ca2+ and the phosphorylation of tau in a COX-2-dependent mechanism, which potentially provides therapeutic targets for combating AD. Show more

Keywords: Alzheimer’s disease, cyclooxygenase-2, EP receptors, prostaglandin E2 , tau

DOI: 10.3233/JAD-181066

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Rosen, Allyson C. | Toy, Leslie | Langston, Ashley

Article Type: Research Article

Abstract: The potential for successful disease modifying treatments for Alzheimer’s disease (AD) opens up the possibility that there will be a large cohort of patients living with late-stage dementia and poor quality of life. There must thus be a parallel effort to leverage restorative therapies that improve quality of life in these patients. With the potential for stopping the onset of new patients with AD must come a commitment to those patients living with this chronic disability for many more years than first thought. Legal and ethical implications surrounding who makes decisions and equity in receiving care will become increasingly important …if AD is no longer a terminal illness. Show more

Keywords: Alzheimer’s disease, dementia, end of life, hospice, neuroethics, therapy

DOI: 10.3233/JAD-181193

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2019

Authors: Strunz, Maximilian | Jarrell, Juliet T. | Cohen, David S. | Rosin, Eric R. | Vanderburg, Charles R. | Huang, Xudong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is an age-related progressive form of dementia that features neuronal loss, intracellular tau, and extracellular amyloid-β (Aβ) protein deposition. Neurodegeneration is accompanied by neuroinflammation mainly involving microglia, the resident innate immune cell population of the brain. During AD progression, microglia shift their phenotype, and it has been suggested that they express matricellular proteins such as secreted protein acidic and rich in cysteine (SPARC) and Hevin protein, which facilitate the migration of other immune cells, such as blood-derived dendritic cells. We have detected both SPARC and Hevin in postmortem AD brain tissues and confirmed significant alterations in transcript …expression using real-time qPCR. We suggest that an infiltration of myeloid-derived immune cells occurs in the areas of diseased tissue. SPARC is highly expressed in AD brain and collocates to Aβ protein deposits, thus contributing actively to cerebral inflammation and subsequent tissue repair, and Hevin may be downregulated in the diseased state. However, further research is needed to reveal the exact roles of SPARC and Hevin proteins and associated signaling pathways in AD-related neuroinflammation. Nevertheless, normalizing SPARC/Hevin protein expression such as interdicting heightened SPARC protein expression may confer a novel therapeutic opportunity for modulating AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β , dendritic cells, Hevin/SPARCL1 protein, macrophages, microglia, SPARC protein

DOI: 10.3233/JAD-181032

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Zhou, Sheng-Lan | Tan, Chen-Chen | Hou, Xiao-He | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: TREM2 (triggering receptor expressed on myeloid cells 2) gene variants were reported to increase the risk of Alzheimer’s disease (AD) and even other neurodegenerative diseases (frontotemporal dementia (FTD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)), but so far, no definite conclusion has been drawn. The aim of our systematic review and meta-analysis was to investigate the role of TREM2 variants in neurodegenerative diseases. A total of 39 papers (including 26 case-control studies and 13 case reports) were retrieved from PubMed, MEDLINE, EMBASE, and the Cochrane library in this study. A fixed effect model was used to pool …results in the analysis. Three variants in TREM2 (rs75932628 (R47H), rs2234255 (H157Y), and rs143332484 (R62H)) were significantly associated with AD risk, but the similar associations between rs104894002 (Q33X), rs2234253 (T96K), rs142232675 (D87N), rs2234256 (L211P), and AD were not proven. Rs75932628 also increased risk of PD in North Americans and FTD, but not PD in Europeans or ALS. In the systematic review, 12 biallelic TREM2 mutations (e.g., rs104894002, rs201258663 (T66M), and rs386834144, etc.) have been described to cause Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) in 14 families. And homozygous mutations also have been reported to cause FTD without typical bone phenotypes in 7 families. This study demonstrates that multiple variants in TREM2 have association with the onset of AD, FTD, and PD in North Americans and also play a key role in the phenotypes of the rare familial genetic disorder. Show more

Keywords: Meta-analysis, neurodegenerative diseases, PLOSL, TREM2 , variant

DOI: 10.3233/JAD-181038

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

Authors: Lee, Sung | Parekh, Trusha | King, Sarah M. | Reed, Bruce | Chui, Helena C. | Krauss, Ronald M. | Yassine, Hussein N.

Article Type: Research Article

Abstract: Cerebral beta-amyloidosis (CA) is a condition in which amyloid-β (Aβ) proteins are deposited in the cerebral cortex and is a predictor of Alzheimer’s disease (AD). The Aging Brain Study (ABS) investigated risk factors for CA in persons with diabetes and dyslipidemia. In the ABS, we identified that greater levels of LDL cholesterol and lower level of HDL cholesterol were associated with increased CA. Low-density lipoprotein (LDL) particles comprise multiple species of varying size, density, and protein composition. For example, within a lipoprotein profile characteristic for persons with obesity and diabetic dyslipidemia, larger LDL particles have a greater ApoE to ApoB …ratio, enhancing their binding affinity to LDL receptors. The goal of this study was to identify LDL particles that associate with CA in ABS. LDL particle size fractions were measured by ion mobility in plasma samples of 58 participants (40 women and 18 men). CA was assessed using Pittsburgh Compound B index-Positron Emission Tomography (PiB-PET) imaging. Among the LDL subfractions, greater plasma levels of large LDL particles were significantly associated with greater cerebral amyloidosis and lower hippocampal volumes independent of LDL cholesterol or triglyceride levels. Since Aβ is cleared by the LDL receptor family, such as lipoprotein-like receptor 1 (LRP1), one potential mechanism for our findings is competition between ApoE enriched larger LDL particles and brain-derived Aβ on hepatic Aβ clearance and degradation. We conclude that assessing larger LDL particles in persons with atherogenic dyslipidemia may provide a mechanistic biomarker for the extent of CA. Show more

Keywords: Alzheimer’s disease, apolipoproteins lipids, lipoproteins, receptors

DOI: 10.3233/JAD-181252

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Wang, Ya-Juan | Wan, Yu | Wang, Hui-Fu | Tan, Chen-Chen | Li, Jie-Qiong | Yu, Jin-Tai | Tan, Lan | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Two CD33 common variants, rs3826656 and rs3865444, have been identified to be correlated with Alzheimer’s disease (AD). Our study examined the effects of the two AD-related CD33 common variants (rs3826656 and rs3865444) on the chosen AD-related brain regions (including hippocampus, amygdala, parahippocampus, middle temporal, entorhinal cortex, and total brain volume) in non-demented elders recruited from the Alzheimer’s Disease Neuroimaging Initiative database at baseline and during four-year follow-up. We further tested the effects in an Aβ-positive group (including preclinical and prodromal stage of AD) and an Aβ-negative group. In the total non-demented elderly population, no associations reached significant levels …after FDR correction. In the Aβ-positive group, we found that rs3826656 was associated with hippocampal and amygdala volumes (Hippocampus-R: pc  = 0.0022; Amygdala-L: pc  = 0.0044; Amygdala-R: pc  = 0.0066), and rs3865444 was associated with right entorhinal volume (pc  = 0.0286). The associations of rs3826656 with hippocampal and amygdala volumes in the Aβ-positive group were successfully replicated in the prodromal AD group (Hippocampus-R: pc  = 0.0022; Amygdala-L: pc  = 0.0022; Amygdala-R: pc  = 0.0088). These changes became more obvious over time during four-year follow-up. No associations were found between the two CD33 variants and neuroimaging biomarkers in the Aβ-negative and preclinical AD groups after FDR correction. These results suggested that the two CD33 common variants (rs3826656 and rs3865444) influenced volumes and atrophy rates of AD-related brain regions in non-demented elders. Subgroup analyses showed the effects mainly existed in the Aβ-positive group instead of the Aβ-negative group, and the effects began in the prodromal AD stage. Show more

Keywords: Alzheimer’s disease, brain structure, CD33, neuroimaging, non-demented elders, polymorphism

DOI: 10.3233/JAD-181062

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

Authors: Hollinger, Kristen R. | Alt, Jesse | Rais, Rana | Kaplin, Adam I. | Slusher, Barbara S.

Article Type: Short Communication

Abstract: Studies over the past two decades report significant reductions in brain N-acetylaspartyl glutamate (NAAG) levels in neurodegenerative diseases with associated cognitive impairment, including Alzheimer’s disease (AD). Because NAAG is cleaved by glutamate carboxypeptidase II (GCPII), restoration of brain NAAG levels via GCPII inhibition is a potential therapeutic strategy for AD. Herein, studies were conducted to identify an appropriate murine model of AD that recapitulates human brain NAAG changes in order to preclinically evaluate the therapeutic benefit of GCPII inhibition. Our opposing findings of brain NAAG changes in human and mouse AD highlights the limited predictive value of AD mouse models.

Keywords: Alzheimer’s disease, animal models, drug discovery, mass spectrometry

DOI: 10.3233/JAD-181251

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Musaeus, Christian Sandøe | Nielsen, Malene Schjønning | Høgh, Peter

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is associated with clinical progression to Alzheimer’s disease (AD) but not all patients with MCI convert to AD. However, it is important to have methods that can differentiate between patients with MCI who progress (pMCI) and those who remain stable (sMCI), i.e., for timely administration of disease-modifying drugs. Objective: In the current study, we wanted to investigate whether quantitative EEG coherence and imaginary part of coherency (iCoh) could be used to differentiate between pMCI and sMCI. Methods: 17 patients with AD, 27 patients with MCI, and 38 older healthy controls were …recruited and followed for three years and 2nd year was used to determine progression. EEGs were recorded at baseline and coherence and iCoh were calculated after thorough preprocessing. Results: Between pMCI and sMCI, the largest difference in total coherence was found in the theta and delta bands. Here, the significant differences for coherence and iCoh were found in the lower frequency bands involving the temporal-frontal connections for coherence and parietal-frontal connections for iCoh. Furthermore, we found a significant negative correlation between theta coherence and the Addenbrooke’s Cognitive Examination (ACE) (p  = 0.0378; rho = –0.2388). Conclusion: These findings suggest that low frequency coherence and iCoh can be used to determine, which patients with MCI will progress to AD and is associated with the ACE score. Low-frequency coherence has previously been associated with increased hippocampal atrophy and degeneration of the cholinergic system and may be an early marker of AD pathology. Show more

Keywords: Coherence, dementia, EEG, mild cognitive impairment, progression

DOI: 10.3233/JAD-181081

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

Authors: Hackney, Madeleine E. | McCullough, Lauren E. | Bay, Allison A. | Silverstein, Hayley A. | Hart, Ariel R. | Shin, Ryan J. | Wharton, Whitney

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disease resulting in memory loss and a severe reduction in ability to perform activities of daily living. The role of caring for someone with AD frequently falls to female family members, often daughters. The burden of caregiving can increase stress and anxiety and cause health decline in the caregiver. The combination of ethnicity-related genetic factors promoting the development of dementias among African-Americans (AA) and the increased risk among women for developing AD means that AA women who are caregivers of a parent with AD are at great risk for developing dementias including …AD. The proposed study would compare the cognitive, motor, and psychosocial benefits of a well-established 12 week, 20-lesson adapted Argentine Tango intervention (N = 30) to a no-contact control group (N = 10) in middle-aged (45–65 years) AA women who are caregivers of a parent with AD in the metro Atlanta area. Show more

Keywords: African American, Alzheimer’s disease, caregiver, clinical trial, dance, inflammation

DOI: 10.3233/JAD-181130

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Ngabirano, Laure | Samieri, Cecilia | Feart, Catherine | Gabelle, Audrey | Artero, Sylvaine | Duflos, Claire | Berr, Claudine | Mura, Thibault

Article Type: Research Article

Abstract: Background: The links between diet and the risk of dementia have never been studied considering the possibility of protopathic bias (i.e., reverse causation). Objective: We aimed to examine the relationship between consumption frequency of meat, fish, fruits, and vegetables and long-term risk of dementia and Alzheimer’s disease (AD), by taking into account this possibility. Methods: We analyzed data of 5,934 volunteers aged 65 and over from the Three-city study who were followed every 2 to 4 years for 12 years. Dietary habits were assessed at inclusion using a brief food frequency questionnaire. The presence of symptoms …of dementia was investigated at each follow-up visit. To limit the risk of protopathic bias, a 4-year lag window between exposure and disease assessment was implemented by excluding from the analyses all dementia cases that occurred during the first four years after inclusion. Analyses were performed using a Cox proportional hazard model and were adjusted for socio-demographic, lifestyle, and health factors. Results: The average follow-up time was 9.8 years. During this period, 662 cases of dementia, including 466 of AD, were identified. After adjustment, only low meat consumption (≤1 time/week) was associated with an increased risk of dementia and AD compared with regular consumption (≥4 times/week) (HR = 1.58 95% CI = [1.17–2.14], HR = 1.67 95% CI = [1.18–2.37], respectively). No association was found between the consumption of fish, raw fruits, or cooked fruits and vegetables and the risk of dementia or AD. Conclusion: These findings suggest very low meat consumption increases the long-term risk of dementia and AD, and that a protopathic bias could have impacted finding from previous studies. Show more

Keywords: Cohort, dementia, fish, meat, protopathic bias, reverse causation

DOI: 10.3233/JAD-180919

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Abu-Rumeileh, Samir | Giannini, Giulia | Polischi, Barbara | Albini-Riccioli, Luca | Milletti, David | Oppi, Federico | Stanzani-Maserati, Michelangelo | Capellari, Sabina | Mantovani, Paolo | Palandri, Giorgio | Cortelli, Pietro | Cevoli, Sabina | Parchi, Piero

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in idiopathic normal pressure hydrocephalus (iNPH) with the aim of a better differential diagnosis, but the pathophysiological mechanisms underlying CSF biomarker changes and the relationship between biomarker levels and clinical variables are still a matter of debate. We evaluated CSF amyloid-β (Aβ)42 and Aβ40 , total (t)-tau, phosphorylated (p)-tau, total prion protein (t-PrP), and neurofilament light chain protein (NfL) in healthy controls (n  = 50) and subjects with iNPH (n  = 71), Alzheimer’s disease (AD) (n  = 60), and several other subtypes of dementia (n  = 145). Patients with iNPH showed significantly lower levels of …Aβ42 , Aβ40 , t-tau, and p-tau compared to controls. Similarly, t-PrP values showed a trend toward lower levels in iNPH patients than in controls. At variance, NfL levels were increased in iNPH as in all other neurodegenerative dementias, with no significant difference between “pure” iNPH cases and those with vascular or AD comorbidities. Aβ42 /Aβ40 ratio showed higher diagnostic value than Aβ42 alone in the differential diagnosis between iNPH and AD. There were no clinically relevant associations between neuroimaging markers, scores at clinical and cognitive scales/tests, or rates of response at tap test and CSF biomarker results. In summary, the CSF biomarker signature in patients with iNPH is mainly characterized by reduced CSF concentrations of Aβ- and tau-related proteins. The assessment of CSF neurodegenerative biomarker profile in iNPH, including the Aβ42 /Aβ40 ratio, contributes to the differential diagnosis with AD and other dementias but shows poor associations with clinical variables. Show more

Keywords: Aβ42/Aβ40 ratio, Alzheimer’s disease, amyloid, dementia with Lewy bodies, frontotemporal dementia, neurofilament light chain protein, prion protein, tau, vascular dementia

DOI: 10.3233/JAD-181012

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

Authors: Manca, Chloé | Hopes, Lucie | Kearney-Schwartz, Anna | Roch, Véronique | Karcher, Gilles | Baumann, Cédric | Marie, Pierre-Yves | Malaplate-Armand, Catherine | Rivasseau Jonveaux, Thérèse | Verger, Antoine

Article Type: Research Article

Abstract: Background/Objective: The aim of this study was to assess, in routine, the rates with which an amyloid deposition was documented by 18 F-florbetaben PET in patients with suspected Alzheimer’s disease (AD) but with isolated increases in cerebrospinal fluid (CSF) tau-protein concentrations, and the subsequent impact of these PET results on medical management. Methods: This prospective study included 34 patients with mild neurocognitive disorders (MND) and suspected AD (73±9 years, 16 women) and with abnormal CSF concentrations in total-tau (T-tau) and/or phosphorylated-tau (P-tau) proteins but normal Aβ42 concentration and Aβ42 /Aβ40 ratio. These patients were referred to …8 F-florbetaben PET from which the PET-related changes in the confidence for AD diagnosis (low, intermediate, or high) and treatments were reported. Results: The PET examinations were positive for amyloid deposition (brain amyloid plaque load, BAPL score >1) in none of the 9 patients with an increase in only T-tau proteins and in 8 among the 25 (32%) with an increase in P-tau proteins (one BAPL score of 2 and seven BAPL scores of 3). Knowledge of the PET results was associated with subsequent changes in diagnostic confidence in 44% of patients (15/34) and in the intention-to-treat with a cholinesterase inhibitor drug in 18% (6/34). Conclusion: In patients with suspected AD and isolated increase in CSF tau protein concentrations, an amyloid deposition is documented by 18 F-florbetaben PET in as much as one third of cases when the concentration of P-tau is abnormal, and PET results are associated with significant further changes in medical management. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid, positron emission tomography

DOI: 10.3233/JAD-181146

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Paroni, Giulia | Bisceglia, Paola | Seripa, Davide

Article Type: Research Article

Abstract: The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer’s disease (IAD). However, despite the complete neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, amyloid-β (Aβ) peptides production and AP formation are physiological aging processes resulting from a systemic …age-related decrease in the efficiency of the proteins catabolism/clearance machinery. Aβ peptides also act as neurotoxic molecules, but only above a critical concentration [Aβ]c . A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c . In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing [Aβ] anabolism, such as amyloid precursor protein (APP ), presenilin 1 (PSEN1 ), and presenilin 2 (PSEN2 ) gene mutations, and/or catabolism/clearance could contribute to overcoming [Aβ]c , being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c . The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD. Show more

Keywords: Alpha-secretase, Alzheimer’s disease, amyloid hypothesis, amyloid plaque, amyloid-alpha peptide, amyloid-beta peptide, amyloid precursor protein, apolipoprotein E, beta-secretase, inherited Alzheimer’s disease, non-inherited Alzheimer’s disease

DOI: 10.3233/JAD-180802

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

Authors: Yang, Hyun-Sik | Chhatwal, Jasmeer P. | Xu, Jishu | White, Charles C. | Hanseeuw, Bernard | Rabin, Jennifer S. | Papp, Kathryn V. | Buckley, Rachel F. | Schultz, Aaron P. | Properzi, Michael J. | Gatchel, Jennifer R. | Amariglio, Rebecca E. | Donovan, Nancy J. | Mormino, Elizabeth C. | Hedden, Trey | Marshall, Gad A. | Rentz, Dorene M. | Johnson, Keith A. | De Jager, Philip L. | Sperling, Reisa A.

Article Type: Research Article

Abstract: Background: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele’s effect on hippocampal neurodegeneration needs to be examined. Objective: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults. Methods: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from …population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n  = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis. Results: rs3846455G was associated with greater PACC decline (β= –0.087/year, 95% CI –0.169 to –0.005, p  = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= –57.3 mm3 /year, 95% CI –102.8 to –11.9, p  = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = –0.014, 95% CI –0.032 to –6.0×10–4 , p  = 0.039). Conclusion: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults. Show more

Keywords: Alzheimer’s disease, amyloid plaques, cognitive reserve, genetics, hippocampus, neuroimaging

DOI: 10.3233/JAD-180788

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

Authors: Boccia, Maddalena | Di Vita, Antonella | Diana, Sofia | Margiotta, Roberta | Imbriano, Letizia | Rendace, Lidia | Campanelli, Alessandra | D’Antonio, Fabrizia | Trebbastoni, Alessandro | de Lena, Carlo | Piccardi, Laura | Guariglia, Cecilia

Article Type: Research Article

Abstract: Spatial navigation tasks reveal small differences between normal and pathological aging and may thus disclose potential neuropsychological predictors of neurodegenerative diseases. The aim of our study was to investigate which navigational skills are compromised in the early phase of pathological aging as well as the extent to which they are compromised. We performed an extensive neuropsychological evaluation based on working memory and learning tasks (i.e., Corsi Block-Tapping Test and Walking Corsi Test) involving both reaching and navigational vista spaces. We also assessed spatial navigation skills in the real world by asking participants to perform route-learning and landmark-recognition tasks. We conducted …a cross-sectional study on nineteen patients with a diagnosis of mild cognitive impairment (MCI) who displayed either an isolated memory deficit (single-domain amnestic MCI, MCIsd; N = 3) or a memory deficit associated with deficits in other cognitive functions (multi-domain MCI, MCImd; N = 16) as well as on nineteen healthy control participants. The groups’ performances were compared by means of mixed factorial ANOVA and two-sample t -tests. We found that patients with MCI performed worse than controls, especially when they were required to learn spatial positions within the navigational vista space. Route-learning within the real environment was also impaired whereas landmark-recognition was spared. The same pattern of results emerged in the MCImd subgroup. Moreover, single case analyses on MCIsd patients revealed a dissociation between learning of spatial positions within navigational vista space and within reaching space. These results suggest that topographical learning is compromised in the early phase of MCIsd and MCImd and that spatial navigation tasks may be used to better characterize topographical disorientation in MCI patients as well as for the early diagnosis of pathological aging. Show more

Keywords: Alzheimer’s disease, environmental navigation, mild cognitive impairment, topographical memory

DOI: 10.3233/JAD-180890

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

Authors: Groussard, Mathilde | Chan, Tyler G. | Coppalle, Renaud | Platel, Hervé

Article Type: Review Article

Abstract: Through this review of 25 clinical and experimental works on long-term musical memories in Alzheimer’s disease (AD) patients, we attempt to clarify the conceptual understanding of musical memories, identify their evolution across the stages of the pathology, and propose possible explanations concerning the neural and cognitive mechanisms that underpin the preservation and impairment of certain musical memories. After clarifying the different kind of musical memories, we investigated their alterations throughout AD’s progression from mild to severe stages. Both procedural and retrograde semantic memory seem relatively spared in AD, while episodic memory appears to be impaired early. Moreover, partial preservation of …music encoding in AD can be revealed through paradigms that are especially designed for AD patients (relying on behavioral cues, using adapted settings, etc.). Although seldomly used, they would definitely help understanding the preserved capacities in every stage of AD. However, more research is needed to better understand this phenomenon and assess its specificity to music or other types of supports. These findings could lead to multiple applications in care settings and research designs, bringing more nuanced understanding of how long-term musical memory degrades throughout the course of AD, and should encourage us to prioritize patients’ preserved cognitive abilities in current AD recreational and care programs. Show more

Keywords: Alzheimer’s disease, care, memory, music, neuroimaging, preservation

DOI: 10.3233/JAD-180474

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-27, 2019

Authors: Nakajima, Madoka | Kuriyama, Nagato | Miyajima, Masakazu | Ogino, Ikuko | Akiba, Chihiro | Kawamura, Kaito | Kurosawa, Michiko | Watanabe, Yoshiyuki | Fukushima, Wakaba | Mori, Etsuro | Kato, Takeo | Sugano, Hidenori | Tange, Yuichi | Karagiozov, Kostadin | Arai, Hajime

Article Type: Research Article

Abstract: Background: Patients with idiopathic normal-pressure hydrocephalus (iNPH) are typically older adults with multiple comorbidities that are associated with a reduction in the efficacy of iNPH treatment via cerebrospinal fluid (CSF) shunt placement. Objective: The present study aimed to investigate the effectiveness of CSF shunt for iNPH using data from a nationwide epidemiological survey in Japan. Methods: We examined 1,423 patients (581 women) aged ≥60 years (median age [25%–75%]: 77 [73–80] years) who were diagnosed with iNPH following a hospital visit in 2012. Patients who experienced an improvement of at least one modified Rankin Scale (mRS) grade …after the CSF shunt were classified as “improvement” while the remaining patients were classified as “non-improvement.” The efficacy of the shunt intervention (n  = 842) was analyzed using a binomial logistic regression analysis. Results: An analysis of risk factors associated with shunt placement in patients with mRS grade 2 at study entry revealed an association between comorbid chronic ischemic lesions (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.11–4.67; p  = 0.025) and cervical spondylosis (OR, 3.62; 95% CI, 1.15–11.34; p  = 0.027). Patients with mRS grade 3 at study entry had an association with comorbid Alzheimer’s disease (OR, 3.02; 95% CI, 1.44–6.31; p  = 0.003). Conclusions: The results presented here showed that any age-related risk is minimal and should not be cause for rejection of surgical treatment options. Clinical decisions regarding CSF shunt should be individualized to each patient, with adequate consideration of the relative risks and benefits, including maximizing a healthy life expectancy. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid shunt, geriatric care, healthy life expectancy, normal pressure hydrocephalus

DOI: 10.3233/JAD-180955

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

Authors: Somers, Charisse | Lewczuk, Piotr | Sieben, Anne | Van Broeckhoven, Christine | De Deyn, Peter Paul | Kornhuber, Johannes | Martin, Jean-Jacques | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Despite decades of research on the optimization of the diagnosis of Alzheimer’s disease (AD), its biomarker-based diagnosis is being hampered by the lack of comparability of raw biomarker data. In order to overcome this limitation, the Erlangen Score (ES), among other approaches, was set up as a diagnostic-relevant interpretation algorithm. Objective: To validate the ES algorithm in a cohort of neuropathologically confirmed cases with AD (n  = 106) and non-AD dementia (n  = 57). Methods: Cerebrospinal fluid (CSF) biomarker concentrations of Aβ1-42 , T-tau, and P-tau181 were measured with commercially available single analyte ELISA kits. Based …on these biomarkers, ES was calculated as previously reported. Results: This algorithm proved to categorize AD in different degrees of likelihood, ranging from neurochemically “normal”, “improbably having AD”, “possibly having AD”, to “probably having AD”, with a diagnostic accuracy of 74% using the neuropathology as a reference. Conclusion: The ability of the ES to overcome the high variability of raw CSF biomarker data may provide a useful diagnostic tool for comparing neurochemical diagnoses between different labs or methods used. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, dementia, harmonization, standardization, tau

DOI: 10.3233/JAD-180563

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Orr, Adam L. | Kim, Chaeyoung | Jimenez-Morales, David | Newton, Billy W. | Johnson, Jeffrey R. | Krogan, Nevan J. | Swaney, Danielle L. | Mahley, Robert W.

Article Type: Review Article

Abstract: Apolipoprotein (apo) E4, the major genetic risk factor for Alzheimer’s disease (AD), alters mitochondrial function and metabolism early in AD pathogenesis. When injured or stressed, neurons increase apoE synthesis. Because of its structural difference from apoE3, apoE4 undergoes neuron-specific proteolysis, generating fragments that enter the cytosol, interact with mitochondria, and cause neurotoxicity. However, apoE4’s effect on mitochondrial respiration and metabolism is not understood in detail. Here we used biochemical assays and proteomic profiling to more completely characterize the effects of apoE4 on mitochondrial function and cellular metabolism in Neuro-2a neuronal cells stably expressing apoE4 or apoE3. Under basal conditions, apoE4 …impaired respiration and increased glycolysis, but when challenged or stressed, apoE4-expressing neurons had 50% less reserve capacity to generate ATP to meet energy requirements than apoE3-expressing neurons. ApoE4 expression also decreased the NAD+ /NADH ratio and increased the levels of reactive oxygen species and mitochondrial calcium. Global proteomic profiling revealed widespread changes in mitochondrial processes in apoE4 cells, including reduced levels of numerous respiratory complex subunits and major disruptions to all detected subunits in complex V (ATP synthase). Also altered in apoE4 cells were levels of proteins related to mitochondrial endoplasmic reticulum–associated membranes, mitochondrial fusion/fission, mitochondrial protein translocation, proteases, and mitochondrial ribosomal proteins. ApoE4-induced bioenergetic deficits led to extensive metabolic rewiring, but despite numerous cellular adaptations, apoE4-expressing neurons remained vulnerable to metabolic stress. Our results provide insights into potential molecular targets of therapies to correct apoE4-associated mitochondrial dysfunction and altered cellular metabolism. Show more

Keywords: Alzheimer’s disease, ApoE4, mitochondrial respiration, neurodegeneration, neuronal metabolism, protein expression

DOI: 10.3233/JAD-181184

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2019

Authors: Lee, Cecilia S. | Larson, Eric B. | Gibbons, Laura E. | Latimer, Caitlin S. | Rose, Shannon E. | Hellstern, Leanne L. | Keene, C. Dirk | Crane, Paul K. | for the Adult Changes in Thought (ACT) Study

Article Type: Research Article

Abstract: Background: The aging eye offers unique opportunities to study and understand the aging brain, in particular related to Alzheimer’s disease (AD) and dementia. However, little is known about relationships between eye diseases and dementia-related neurodegeneration. Objective: To determine the potential association between three age-related eye diseases and AD and dementia-related neuropathology. Methods: We reviewed autopsy data from the prospective longitudinal Adult Changes in Thought (ACT) cohort. ICD-9 codes were used to identify diagnoses of diabetic retinopathy, glaucoma, and age-related macular degeneration. Multivariate regression models were used to determine odds ratios (OR) of neuropathology features associated with …dementia, including Braak stage, Consortium to Establish a Registry for AD (CERAD score), Lewy bodies, hippocampal sclerosis, and microvascular brain injury, in addition to quantitative paired helical filament (PHF)-tau levels for people with and without each eye condition. We also evaluated interactions between eye conditions and dementia related neuropathologic findings were evaluated. Results: 676 autopsies were included. Diabetic retinopathy was significantly associated with increased risk of deep cerebral microinfarcts (OR = 1.91 [95% confidence interval (CI) 1.11, 3.27], p  = 0.02). No other significant association or interaction between eye diseases and neuropathology was found. When PHF-tau quantity was evaluated in 124 decedents, the OR for the association between PHF-tau in the occipital cortex and glaucoma was 1.36 (95% CI 0.91, 2.03, p  = 0.13). No statistical correction was made for multiple comparisons. Conclusion: Increased risk of deep cerebral microinfarcts was found in participants diagnosed with diabetic retinopathy. Eye diseases such as glaucoma may increase susceptibility to neurofibrillary tangles in the occipital cortex. Show more

Keywords: Alzheimer’s disease, diabetic retinopathy, glaucoma, macular degeneration, neuropathology

DOI: 10.3233/JAD-181087

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Wright, Lauren M. | Stein, Thor D. | Jun, Gyungah | Chung, Jaeyoon | McConnell, Kate | Fiorello, Marissa | Siegel, Nicole | Ness, Steven | Xia, Weiming | Turner, Kelley L. | Subramanian, Manju L.

Article Type: Research Article

Abstract: Background: The eye may serve as source for diagnostic testing for early detection of Alzheimer’s disease (AD). Examination of amyloid-β (Aβ) and tau protein content in human vitreous and its correlation to neuro-cognition may improve ocular-based AD detection methods. Objective: To evaluate levels of Aβ and tau protein in human vitreous humor and investigate the clinical predictive role of these proteins as early diagnostic markers of AD. Methods: A prospective, single-center, multi-surgeon cohort study. Vitreous humor samples from 80 eyes were measured quantitatively for Aβ42 , pTau, and tTau. Linear regression was used to test associations …between AD biomarker levels, Mini-Mental State Exam (MMSE), and serum apolipoprotein E (APOE) allele status, with adjustment for age, sex, and education level of patients. Results: Lower MMSE scores were significantly associated with lower levels of vitreous Aβ40 (p  = 0.015), Aβ42 (p  = 0.0066), and tTau (p  = 0.0085), and these biomarkers were not associated with any pre-existing eye conditions. Presence of the ɛ 4 allele and the ɛ 2 allele approached significance with reduced Aβ40 level (p  = 0.053) and increased p-Tau level (p  = 0.056), respectively. Conclusion: Patients with poor cognitive function have significantly lower vitreous humor levels of AD-related biomarkers Aβ40 , Aβ42 , and tTau. These biomarkers do not correlate with underlying eye conditions, suggesting their specificity in association with cognitive change. This is the first study to our knowledge to correlate cognition with AD-related proteins in the vitreous humor. Results suggest ocular proteins may have a role for early dementia detection in individuals at risk for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia, Mini-Mental State Exam, ocular biomarkers, tau, vitreous

DOI: 10.3233/JAD-181104

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

Authors: Nunes, Paula Villela | Schwarzer, Monise Caroline | Leite, Renata Elaine Paraizo | Ferretti-Rebustini, Renata Eloah de Lucena | Pasqualucci, Carlos Augusto | Nitrini, Ricardo | Rodriguez, Roberta Diehl | Nascimento, Camila Fernandes | Oliveira, Katia Cristina de | Grinberg, Lea Tenenholz | Jacob-Filho, Wilson | Lafer, Beny | Suemoto, Claudia Kimie

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms (BPSD) can be a prodrome of dementia, and the Neuropsychiatric Inventory (NPI) is widely used for BPSD evaluation. Objective: To compare the prevalence of BPSD according to cognitive status, and to determine NPI cutoffs that best discern individuals with mild cognitive impairment (MCI) and dementia from those without dementia. Methods: We included 1,565 participants (mean age = 72.7±12.2 years, 48% male). BPSD and cognitive status were assessed with the NPI and the Clinical Dementia Rating (CDR). We used multivariable logistic regression models to investigate the association of BPSD with cognitive status. The area …under the curve (AUC) was used to assess model discrimination, and to determine the best NPI cutoff for MCI and dementia. Results: Participants were cognitively normal (CDR = 0; n  = 1,062), MCI (CDR = 0.5; n  = 145), or dementia (CDR≥1.0, n  = 358). NPI symptoms were more frequent in dementia and MCI when compared to cognitively normal. Higher odds for delusions, hallucinations, disinhibition, and psychomotor alterations were found among participants with dementia and MCI than in those who were cognitively normal. The best NPI cutoff to discern participants with dementia from those cognitively normal was 11 (AUC = 0.755). Poor discrimination (AUC = 0.563) was found for the comparison of MCI and those cognitively normal. Conclusions: We found an increase in BPSD frequencies across the continuum of cognitive impairment. BPSD severity and frequency in MCI was more similar to individuals cognitively normal than with dementia. NPI scores≥to 11 in individuals with no diagnosis of dementia can support the decision for further investigation of dementia. Show more

Keywords: Behavioral and psychological symptoms, dementia, mild cognitive impairment, Neuropsychiatric Inventory

DOI: 10.3233/JAD-180641

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

Authors: Abner, Erin L. | Nelson, Peter T. | Jicha, Gregory A. | Cooper, Gregory E. | Fardo, David W. | Schmitt, Frederick A. | Kryscio, Richard J.

Article Type: Research Article

Abstract: Tobacco smoking was examined as a risk for dementia and neuropathological burden in 531 initially cognitively normal older adults followed longitudinally at the University of Kentucky’s Alzheimer’s Disease Center. The cohort was followed for an average of 11.5 years; 111 (20.9% ) participants were diagnosed with dementia, while 242 (45.6% ) died without dementia. At baseline, 49 (9.2% ) participants reported current smoking (median pack-years = 47.3) and 231 (43.5% ) former smoking (median pack-years = 24.5). The hazard ratio (HR) for dementia for former smokers versus never smokers based on the Cox model was 1.64 (95% CI: 1.09, 2.46), while the HR for …current smokers versus never smokers was 1.20 (0.50, 2.87). However, the Fine-Gray model, which accounts for the competing risk of death without dementia, yielded a subdistribution hazard ratio (sHR) = 1.21 (0.81, 1.80) for former and 0.70 (0.30, 1.64) for current smokers. In contrast, current smoking increased incidence of death without dementia (sHR = 2.38; 1.52, 3.72). All analyses were adjusted for baseline age, education, sex, diabetes, head injury, hypertension, overweight, APOE ɛ 4, family history of dementia, and use of hormone replacement therapy. Once adjusted for the competing risk of death without dementia, smoking was not associated with incident dementia. This finding was supported by neuropathology on 302 of the participants. Show more

Keywords: Competing risks, dementia, dementia free death, lifetime smoking

DOI: 10.3233/JAD-181119

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Brett, Benjamin L. | Wilmoth, Kristin | Cummings, Peter | Solomon, Gary S. | McCrea, Michael A. | Zuckerman, Scott L.

Article Type: Research Article

Abstract: This work critically reviews chronic traumatic encephalopathy (CTE), with a specific focus on the single criterion necessary and sufficient for diagnosis. Herein, CTE is compared to other well-established neurodegenerative entities including Alzheimer’s disease and dementia with Lewy bodies. Each neurodegenerative disorder is reviewed in five pertinent areas: 1) historical perspective, 2) guideline formation process, 3) clinical diagnostic criteria, 4) pathological diagnostic criteria, and 5) validation of previously described diagnostic criteria (e.g., sensitivity and specificity). These comparisons indicate that CTE is a disease in the earliest stages of formation and has yet to undergo rigorous development and refinement similar to other …neurodegenerative diseases. Suggested future revisions to the diagnostic criterion of CTE include establishing a lower threshold for accumulation of pathology, as well as accounting for the presence of concomitant neuropathology and comorbid neurodegenerative disorders. Currently, while initial efforts have been attempted, agreed upon antemortem clinical criteria do not exist. As has been the scientific standard with similar neurodegenerative disorders, antemortem diagnostic guidelines should first be refined through subcommittees of neuroscientists from diverse institutional backgrounds with a subclassification of levels of diagnostic certainty (possible, probably, and definite). Validation studies should then assess the predictive value and accuracy of proposed antemortem diagnostic criteria in relation to potential pathological criteria. Show more

Keywords: Chronic traumatic encephalopathy, concussion, football, neurodegenerative diseases, sports, traumatic brain injury

DOI: 10.3233/JAD-181058

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

Authors: Cortés, Nicole | Guzmán-Martínez, Leonardo | Andrade, Víctor | González, Andrea | Maccioni, Ricardo B.

Article Type: Review Article

Abstract: The cyclin-dependent kinase 5 (CDK5) is known as an exceptional component of the CDK family, due to its characteristic regulatory pathways and its atypical roles in comparison to the classical cyclins. Despite its functional uniqueness, CDK5 shares a great part of its structural similarity with other members of the cyclin-dependent kinase family. After its discovery 26 years ago, a progressive set of cellular functions has been associated with this protein kinase, ranging from neuronal migration, axonal guidance, and synaptic plasticity in diverse stages of brain development, including specific and complex cognitive functions. More than 30 substrates for CDK5 have been …found in different cellular pathways. Together with its essential physiological roles, a major discovery was the finding twenty years ago that CDK5 participates in neurodegenerative diseases responsible for tau hyperphosphorylations, and, as a consequence, it becomes a neurotoxic factor. This review focuses on the wide roles of CDK5 in the central nervous system, its implications in neurodegeneration, and provides an integrative insight of its involvement in pain modulation, Alzheimer’s disease, and other contexts. Show more

Keywords: Alzheimer’s disease, CDK5, chemoreception, nervous system, tau

DOI: 10.3233/JAD-180792

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

Authors: Brandt, Jason | Buchholz, Alison | Henry-Barron, Bobbie | Vizthum, Diane | Avramopoulos, Dimitrios | Cervenka, Mackenzie C.

Article Type: Research Article

Abstract: Ketone bodies, the products of fat metabolism, are a source of energy for the brain and are available even when glucose supplies are inadequate (such as with severe carbohydrate deprivation) or its metabolism is faulty (as it is in Alzheimer’s disease). This phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (MAD) to induce ketogenesis in persons with mild cognitive impairment (MCI) or early AD, and the effect of this diet on memory and other clinical outcomes. In the first 2.5 years of active recruitment, only 27 eligible and willing patients enrolled. After extensive assessment …and education, they and their study partners were randomly assigned for 12 weeks to either the MAD or the National Institute on Aging (NIA) recommended diet for seniors. As of April 2018, 9 patients in the MAD arm and 5 in the NIA arm have completed the trial. In spite of extensive teaching, coaching, and monitoring, adherence to both diets was only fair. Among those in the MAD arm who generated at least trace amounts of urinary ketones, there was a large (effect size = 0.53) and statistically significant (p  = 0.03) increase in Memory Composite Score between the baseline and week-6 assessment. MAD participants also reported increased energy between baseline and week-6 assessment. Despite challenges to implementing this trial, resulting in a small sample, our preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in very early AD. Show more

Keywords: Carbohydrates, clinical trial, cognitive function, diet, ketone bodies, memory, neuropsychological tests

DOI: 10.3233/JAD-180995

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

Authors: Kaczynski, Anika | Michalowsky, Bernhard | Eichler, Tilly | Thyrian, Jochen René | Wucherer, Diana | Zwingmann, Ina | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: People with dementia (PwD) suffer from coexisting medical conditions, creating complex clinical challenges and increasing the risk of poor outcomes, which could be associated with high healthcare cost. Objective: To describe the prevalence of comorbidity in PwD and to analyze the association between comorbidity in dementia diseases and healthcare costs from a payer’s perspective. Methods: This cross-sectional analysis was based on n  = 362 PwD of the DelpHi trial (Dementia: Life-and person-centered help in Mecklenburg-Western Pomerania). Comorbidity was assessed using the Charlson comorbidity index (CCI) and was categorized into low, high, and very high comorbidity. Healthcare …resource utilization and unit costs were used to calculate costs. Multivariable regression models were applied to analyze the association between comorbidity and costs. Results: Comorbidity was highly prevalent in the sample. 47% of PwD had a very high, 37% a high, and 16% a low comorbidity in addition to dementia. The most prevalent co-existing comorbidity were diabetes mellitus (42% ), peripheral vascular disease (28% ) and cerebrovascular disease (25% ). Total costs significantly increased by 528€ (SE  = 214, CI95  = 109–947, p  = 0.014) with each further comorbidity, especially due to higher significantly higher cost for medication and medical aids. Compared with a low comorbidity, a very high comorbidity was significantly associated with 818€ (SE  = 168, CI95  = 489–1147, p  <  0.001) higher medication costs and 336€ (SE  = 161.21, CI95  = 20–652, p  = 0.037) higher cost for medical aids. There were no significant association between a higher comorbidity and cost for formal care services. Conclusions: Comorbidity in PwD represents a substantial financial burden on healthcare payers and is a challenge for patients, healthcare providers, and the health systems. Innovative approaches are needed to achieve a patient-oriented management of treatment and care in comorbid PwD to reduce long-term costs. Show more

Keywords: Alzheimer’s disease, comorbidity, dementia, economics, health care costs, health resources

DOI: 10.3233/JAD-180896

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Smith, Carr J. | Ashford, J. Wesson | Perfetti, Thomas A.

Article Type: Review Article

Abstract: Inheritance of a single copy of the apolipoprotein E (APOE) ɛ 4 allele increases risk of Alzheimer’s disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to ɛ 3 allele homozygosity. There is a decreased risk associated with the APOE ɛ 2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous ɛ 4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily …young subjects, we have reviewed a representative body of literature on ɛ 4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the ɛ 4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral ɛ 4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing ɛ 3 allele, at the expense of decreased fitness in old age, which is substantially improved by the ɛ 3 allele. However, possession of the ɛ 4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, ɛ4 allele, improved performance, youth

DOI: 10.3233/JAD-181089

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-39, 2019

Authors: Sato, Kenichiro | Mano, Tatsuo | Ihara, Ryoko | Suzuki, Kazushi | Tomita, Naoki | Arai, Hiroyuki | Ishii, Kenji | Senda, Michio | Ito, Kengo | Ikeuchi, Takeshi | Kuwano, Ryozo | Matsuda, Hiroshi | Iwatsubo, Takeshi | Toda, Tatsushi | Iwata, Atsushi | Alzheimer’s Disease Neuroimaging Initiative, and Japanese Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Effect of serum calcium level to the incidence of mild cognitive impairment (MCI) conversion to early Alzheimer’s disease (AD) remains uncertain. Objective: To investigate association between baseline serum calcium and the MCI conversion in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI) study cohort. Methods: In this sub-analysis of J-ADNI study, we reviewed data from MCI participants at baseline regarding their conversion to early AD during the 3 years of observation period and assessed the associated factors including serum calcium level. In addition, we compared our results from the J-ADNI study with the corresponding results from …the North American (NA)-ADNI. Results: Of 234 eligible MCI participants from the J-ADNI cohort, 121 (51.7% ) converted to AD during the first 36 months of observation. Using univariate analysis, being female, having shorter years of education, and lower serum calcium level were correlated with increased risk of MCI-to-AD conversion exclusively in J-ADNI cohort. The lower corrected serum calcium level remained as one of conversion-associated factors in the J-ADNI cohort even after adjustment for multiple confounding variables, although this was not observed in the NA-ADNI cohort. Conclusion: Our findings suggest that lower serum calcium may be associated with an increased risk of MCI conversion to AD in Japanese cohorts. The reason for this correlation remains unclear and further external validation using other Asian cohorts is needed. It would be interesting for future AD studies to obtain serum calcium levels and other related factors, such as vitamin D levels, culture-specific dietary or medication information. Show more

Keywords: Alzheimer’s disease, calcium, conversion, Japanese Alzheimer’s Disease Neuroimaging Initiative, mild cognitive impairment

DOI: 10.3233/JAD-181115

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Rosso, Andrea L. | Metti, Andrea L. | Faulkner, Kimberly | Redfern, Mark | Yaffe, Kristine | Launer, Lenore | Elizabeth Shaaban, C. | Nadkarni, Neelesh K. | Rosano, Caterina

Article Type: Research Article

Abstract: Background: Performance on complex walking tasks may provide a screen for future cognitive decline. Objective: To identify walking tasks that are most strongly associated with subsequent cognitive decline. Methods: Community-dwelling older adults with Modified Mini-Mental State (3MS) >85 at baseline (n  = 223; mean age = 78.7, 52.5% women, 25.6% black) completed usual-pace walking and three complex walking tasks (fast-pace, narrow-path, visuospatial dual-task). Slope of 3MS scores for up to 9 subsequent years (average = 5.2) were used to calculate a cognitive maintainer (slope ≥0) or decliner (slope <0) outcome variable. Logistic regression models assessed associations between gait speeds and being …a cognitive decliner. A sensitivity analysis in a subsample of individuals (n  = 66) confirmed results with adjudicated mild cognitive impairment (MCI) or dementia at 8-9 years post-walking assessment. Results: Cognitive decliners were 52.5% of the sample and on average were slower for all walking tasks compared to maintainers. In models adjusted for demographic and health variables, faster fast-pace (OR = 0.87 per 0.1 m/s, 95% CI: 0.78, 0.97) and dual-task (OR = 0.84 per 0.1 m/s, 95% CI: 0.73, 0.96) gait speeds were associated with lower likelihood of being a cognitive decliner. Usual-pace gait speed was not associated (OR = 0.96 per 0.1 m/s, 95% CI: 0.85, 1.08). Results were nearly identical in analyses with adjudicated MCI or dementia as the outcome. Conclusion: Fast-pace and dual-task walking may provide simple and effective tools for assessing risk for cognitive decline in older individuals with high cognitive function. Such screening tools are important for strategies to prevent or delay onset of clinically meaningful change. Show more

Keywords: Cognitive disorders, epidemiology, geriatrics, walking speed

DOI: 10.3233/JAD-181140

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Medoro, Alessandro | Bartollino, Silvia | Mignogna, Donatella | Marziliano, Nicola | Porcile, Carola | Nizzari, Mario | Florio, Tullio | Pagano, Aldo | Raimo, Gennaro | Intrieri, Mariano | Russo, Claudio

Article Type: Short Communication

Abstract: Certain proteases are involved in Alzheimer’s disease (AD) and their erroneous control may contribute to the pathology onset and progression. In this study we evaluated the cerebral expression of eight proteases, involved in both AβPP processing and extracellular matrix remodeling. Among these proteases, ADAM10, ADAMTS1, Cathepsin D, and Meprin β show a significantly higher mRNAs expression in sporadic AD subjects versus controls, while ADAMTS1, Cathepsin D, and Meprin β show an increment also at the protein level. These data indicate that transcriptional events affecting brain proteases are activated in AD patients, suggesting a link between proteolysis and AD.

Keywords: ADAMTS1, α-secretase, Alzheimer’s disease, cancer, Cathepsin D, Meprin β, RT-PCR, western blot

DOI: 10.3233/JAD-181284

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Marksteiner, Josef | Oberacher, Herbert | Humpel, Christian

Article Type: Research Article

Abstract: Diagnosis of Alzheimer’s disease (AD) is still a challenge. Salivary analysis could produce an easily accessible and inexpensive possibility to study metabolic changes in AD. In the present pilot study, we show for the first time using targeted metabolomics that acyl-alkyl phosphatidylcholines (PCae C34:1-2; Pcae C36:1-2-3; PcaeC38:1c3; Pcae C40:2-3) are significantly reduced in saliva of AD patients (n  = 25) compared to healthy controls (n  = 25). Saliva levels of Pcae C36Λ 1-2-3) were also decreased in patients with mild cognitive impairment (n  = 25). No changes were seen for saliva diacyl-phosphatidylcholines, lyso-acyl-phosphatidylcholines, and sphinogomyelins. These data suggest specific lipid changes in the …saliva of AD patients, thus salivary measures could establish new biomarkers. However, these preliminary results have to be established in larger scale studies. Show more

Keywords: Alzheimer’s disease, biomarkers, diagnosis, metabolomics, phosphatidylcholines, saliva

DOI: 10.3233/JAD-181278

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Liu, Jia | Wang, Qianqian | Jing, Donglai | Gao, Ran | Zhang, Jing | Cui, Chunlei | Qiao, Hongwen | Liang, Zhigang | Wang, Chaodong | Rosa-Neto, Pedro | Wu, Liyong | Jia, Jianping | Gauthier, Serge

Article Type: Research Article

Abstract: For early-onset Alzheimer’s disease (EOAD) cases with unclear family history, most cases are sporadic. Some cases are positive in genetic findings, that is, either incomplete penetrance or de novo mutation. We aimed to focus on EOAD cases with de novo mutations. Case reports and literature review were performed. The implication for diagnostic approach of early-onset dementia with negative family history was developed. We reported two Chinese EOAD cases with de novo mutations. The genotype PSEN1 G206S appeared to correlate with the phenotype of EOAD with pure cognitive problems. The second case had a PSEN1 M233V mutation with …an earlier age of onset of 25 with cognitive decline, parkinsonism, and epilepsy. Although EOAD due to de novo mutations is not common, it should be considered in patients with a phenotype of progressive cognitive decline and amyloid positivity on PET or CSF analysis. Show more

Keywords: De novo PSEN1 mutation, diagnostic approach, early-onset Alzheimer’s disease, early-onset dementia with negative family history

DOI: 10.3233/JAD-181108

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Tiiman, Ann | Jelić, Vesna | Jarvet, Jüri | Järemo, Petter | Bogdanović, Nenad | Rigler, Rudolf | Terenius, Lars | Gräslund, Astrid | Vukojević, Vladana

Article Type: Research Article

Abstract: Background: Biomarkers are central to current research on molecular mechanisms underlying Alzheimer’s disease (AD). Their further development is of paramount importance for understanding pathophysiological processes that eventually lead to disease onset. Biomarkers are also crucial for early disease detection, before clinical manifestation, and for development of new disease modifying therapies. Objective: The overall aim of this work is to develop a minimally invasive method for fast, ultra-sensitive and cost-effective detection of structurally modified peptide/protein self-assemblies in the peripheral blood and in other biological fluids. Specifically, we focus here on using this method to detect structured amyloidogenic oligomeric aggregates …in the blood serum of apparently healthy individuals and patients in early AD stage, and measure their concentration and size. Methods: Time-resolved detection of Thioflavin T (ThT) fluorescence intensity fluctuations in a sub-femtoliter observation volume element was used to identify in blood serum ThT-active structured amyloidogenic oligomeric aggregates, hereafter called nanoplaques, and measure with single-particle sensitivity their concentration and size. Results: The concentration and size of structured amyloidogenic nanoplaques are significantly higher in the blood serum of individuals diagnosed with AD than in control subjects. Conclusion: A new method with the ultimate, single-particle sensitivity was successfully developed. The proposed approach neither relies on the use of immune-based probes, nor on the use of radiotracers, signal-amplification or protein separation techniques, and provides a minimally invasive test for fast and cost-effective early determination of structurally modified peptides/proteins in the peripheral blood, as shown here, but also in other biological fluids. Show more

Keywords: Alzheimer’s disease, amyloidogenic aggregates, β-pleated sheet, blood serum, early diagnosis, florescence intensity fluctuation analysis, fluorescence correlation spectroscopy, single-molecule sensitivity, Thioflavin T

DOI: 10.3233/JAD-181144

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Pentikäinen, Heikki | Savonen, Kai | Ngandu, Tiia | Solomon, Alina | Komulainen, Pirjo | Paajanen, Teemu | Antikainen, Riitta | Kivipelto, Miia | Soininen, Hilkka | Rauramaa, Rainer

Article Type: Research Article

Abstract: Background: Previous studies have found positive associations between cardiorespiratory fitness (CRF) and cognitive performance in older people but data are inconsistent and have methodological limitations. Objective: Our aim was to study the longitudinal associations of CRF with executive functions, processing speed and memory as well as with the overall cognitive function in older people at risk for cognitive impairment. Methods: Participants (n  = 421), mean age 69.0, were a sub-sample of The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). To be eligible, individuals were required to be 60–77 years old with a CAIDE …(Cardiovascular Risk Factors, Aging and Dementia) Dementia Risk Score of at least 6 points and cognition at mean level or slightly lower than expected for age. CRF was assessed as peak oxygen uptake (VO2peak , L/min) measured directly in a symptom-limited maximal exercise test on cycle ergometer at baseline and at 24 months. Cognitive performance was assessed using an extensive neuropsychological test battery (NTB) at baseline and at 24 months. NTB data were standardized to Z scores, and analyzed with the linear mixed model. Results: Over two years, VO2peak was associated with NTB total score (β= 0.12, p  = 0.01), executive functions (β= 0.16, p  = 0.01), and processing speed (β= 0.25, p  < 0.001), but not with memory (β= 0.11, p  = 0.12). Conclusion: Over two years follow-up, CRF was associated with executive functions and processing speed, and was related also to the overall cognitive function. Show more

Keywords: Aged, cardiorespiratory fitness, cognition, executive function, memory

DOI: 10.3233/JAD-180897

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Regland, Björn | McCaddon, Andrew

Article Type: Research Article

Abstract: The ‘amyloid hypothesis’ dominates Alzheimer’s disease (AD) research but has failed to deliver effective therapies. Amyloid precursor protein (APP ) and presenilin-1 (PSEN1 ) genetic mutations are undoubtedly pathogenic, albeit by unclear mechanisms. Conversely, high dose B-vitamins convincingly slow brain atrophy in a pre-stage state of sporadic AD. Here we suggest a link between sporadic and genetic AD: 1) Increased serum homocysteine, a marker of B-vitamin deficiencies, is a significant risk factor for sporadic AD. It also correlates with elevated levels of antichymotrypsin, a serine protease inhibitor. 2) Family members with codon 717 APP mutations and dementia have low …serum vitamin B12 values. Overexpression of the APP domain coding for a Kunitz type serine protease inhibitor might explain this. 3) PSEN1 mutations disrupt lysosomal function due to reduced proteolytic activity. They also trap cobalamin (B12 ) within lysosomes, leading to intracellular deficiency of the vitamin. In summary, APP and PSEN1 mutations both confer a risk for reduced protease activity and B12 bio-availability. Comparably, sporadic AD features a constellation of increased protease inhibition and B-vitamin deficiencies, the central part of which is believed to be B12 . These concordant observations in three disparate AD etiologies suggest a common neuropathogenic pathway. This hypothesis is evaluable in laboratory and clinical trials. Show more

Keywords: Alzheimer’s disease, amyloid, proteolysis, vitamin B12 deficiency

DOI: 10.3233/JAD-181007

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2019

Authors: Marcum, Zachary A. | Hohl, Sarah D. | Gray, Shelly L. | Barthold, Doug | Crane, Paul K. | Larson, Eric B.

Article Type: Short Communication

Abstract: We administered a mixed-method survey to 1,661 patients in a large health system to assess preferences toward antihypertensive use for dementia prevention. If a specific antihypertensive medication was shown to prevent or delay dementia, the vast majority (>90%) of respondents currently taking an antihypertensive reported that they would be willing to take that specific antihypertensive starting as early as mid-life. Concerns reported were potential side effects, lack of evidence of effectiveness, blood pressure being normal or low, and medication cost. Analysis of free-text responses revealed themes of concerns regarding evidence of effectiveness and health priorities.

Keywords: Alzheimer’s disease, antihypertensive agents, dementia, primary prevention

DOI: 10.3233/JAD-181080

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Ameen-Ali, Kamar E. | Simpson, Julie E. | Wharton, Stephen B. | Heath, Paul R. | Sharp, Paul | Brezzo, Gaia | Berwick, Jason

Article Type: Research Article

Abstract: The role of cellular changes in the neurovascular unit is increasingly being investigated to understand the pathogenesis of Alzheimer’s disease (AD). The aim of the current study was to determine the time course of recognition memory impairment in the J20 mouse model of AD, in relation to neuroinflammatory responses and the pathology of amyloid-β (Aβ). Male hAPP-J20 and wild-type mice were assessed at 3, 6, 9, and 12 months of age. The spontaneous object recognition (SOR) task provided a measure of memory, with assessment of both a short delay (1 min) and a long delay (4 h). Immunohistochemistry was used to characterize …Aβ deposition, and quantify astrocyte and microglial responses. At all ages tested, J20 mice had impaired long-term, but preserved short-term, recognition memory. Wild-types demonstrated preserved long-term memory up to 9 months of age, and preserved short-term memory at all ages tested. Plaque pathology in the J20 mice was present from 6 months onwards, with co-localization of reactive microglia and activated astrocytes. Reactive microglia and astrocyte activation in the hippocampus were significantly greater in the J20 mice at 9 months, compared to wild-types. This study contributes to our understanding of the pathological and cognitive mechanisms at play in AD. J20 mice showed impairment in retaining information over longer periods from an early age, preceding the deposition of Aβ and glial activation. Defining early physiological changes in relation to cognitive decline could provide insight into new therapeutic targets early in the disease process, when intervention is most likely to effectively slow disease progression. Show more

Keywords: Alzheimer’s disease, amyloid, astrocytes, hAPP-J20, microglia, recognition memory

DOI: 10.3233/JAD-181238

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Becker, Robert E. | Greig, Nigel H.

Article Type: Research Article

Abstract: Neuronal death is the final step in the progression of preclinical Alzheimer’s disease (AD) pathologies into clinically evident AD and its profound dementia. As such, a drug candidate proposed to be effective in AD must successfully prevent neuronal losses. The lack of preclinical demonstrated abilities to prevent neuronal programmed cell death may explain the recent failure of 300–400 AD drug candidates, identify a flaw in the Amyloid Hypothesis, and a risk for subsequent drug candidate interventions against AD. We propose that investigators use either animal models or small early translational clinical trials to test for AD drug candidates’ efficacy against …clinically critical features of the disease, such as prevention of neuronal death. Such stringent testing would more effectively shelter AD patients from being recruited into clinical trials that are destined to fail in Phase II or III. Show more

Keywords: Alzheimer’s disease, amyloid hypothesis, animal models, clinical trial failures, neuronal death, programmed cell death, traumatic brain injury

DOI: 10.3233/JAD-181300

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: Umstead, Andrew | Vega, Irving E.

Article Type: Short Communication

Abstract: The accumulation of tau protein aggregates is a pathological hallmark in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the identity of the toxic tau conformation that propagates and induces neurodegeneration is still unknown. Anti-tau antibodies are a common tool used to differentiate between normal and pathological-associated tau forms or as passive immunotherapy in the quest to interfere with tau-mediated neurodegeneration. Here, we show that Tau13, a tau N-terminal antibody, preferentially enriches high molecular weight tau species produced in a tauopathy mouse model and AD. The data suggest that Tau13 has higher affinity to specific tau conformation presence in higher …molecular weight tau species. Show more

Keywords: Aggregation, Alzheimer’s disease, tau, tauopathy

DOI: 10.3233/JAD-181187

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2019

Authors: Mandal, Pravat K. | Shukla, Deepika | Tripathi, Manjari | Ersland, Lars

Article Type: Editorial

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting millions of people worldwide. The actual cause of AD is still unknown. Oxidative stress is believed to be important player in AD. Glutathione (GSH) is a major antioxidant, and it is already known that GSH is depleted significantly in the hippocampal regions in mild cognitive impairment and AD patients compared to healthy old subjects. Hence there is a serious discussion to improve the brain GSH level by supplementation. This editorial highlights the need for GSH supplementation for the cognitive enhancement in mild cognitive impairment (MCI) and AD.

DOI: 10.3233/JAD-181054

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Peters, Ruth | Ee, Nicole | Peters, Jean | Booth, Andrew | Mudway, Ian | Anstey, Kaarin J.

Article Type: Research Article

Abstract: Background: Both air pollution and dementia are current and growing global issues. There are plausible links between exposure to specific air pollutants and dementia. Objective: To systematically review the evidence base with respect to the relationship between air pollution and later cognitive decline and dementia. Methods: Medline, Embase, and PsychINFO® were searched from their inception to September 2018, for publications reporting on longitudinal studies of exposure to air pollution and incident dementia or cognitive decline in adults. Studies reporting on exposure to tobacco smoke including passive smoking or on occupational exposure to pollutants were excluded. …Using standard Cochrane methodology, two readers identified relevant abstracts, read full text publications, and extracted data into structured tables from relevant papers, as defined by inclusion and exclusion criteria. Papers were also assessed for validity. CRD42018094299 Results: From 3,720 records, 13 papers were found to be relevant, with studies from the USA, Canada, Taiwan, Sweden, and the UK. Study follow-up ranged from one to 15 years. Pollutants examined included particulate matter ≤2.5 μ (PM2.5 ), nitrogen dioxide (NO2 ), nitrous oxides (NOx ), carbon monoxide (CO), and ozone. Studies varied in their methodology, population selection, assessment of exposure to pollution, and method of cognitive testing. Greater exposure to PM2.5 , NO2 /NOx , and CO were all associated with increased risk of dementia. The evidence for air pollutant exposure and cognitive decline was more equivocal. Conclusion: Evidence is emerging that greater exposure to airborne pollutants is associated with increased risk of dementia. Show more

Keywords: Air pollutants, cognitive decline, dementia, particulate matter

DOI: 10.3233/JAD-180631

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: de la Monte, Suzanne M. | Tong, Ming | Daiello, Lori A. | Ott, Brian R.

Article Type: Research Article

Abstract: Background: Brain insulin resistance is a well-recognized abnormality in Alzheimer’s disease (AD) and the likely mediator of impaired glucose utilization that emerges early and progresses with disease severity. Moreover, the rates of mild cognitive impairment (MCI) or AD are significantly greater in people with diabetes mellitus or obesity. Objective: This study was designed to determine whether systemic and central nervous system (CNS) insulin resistant disease states emerge together and thus may be integrally related. Methods: Insulin-related molecules were measured in paired human serum and cerebrospinal fluid (CSF) samples from 19 with MCI or early AD, and …21 controls using a multiplex ELISA platform. Results: In MCI/AD, both the CSF and serum samples had significantly altered mean levels of C-peptide (both elevated), Visfatin, incretins, PAI-1, ghrelin, and leptin, whereas only CSF showed a significant reduction in insulin and only serum had increased glucagon levels. Although the overall CSF and serum responses reflected insulin resistance together with insulin deficiency, the specific alterations measured in CSF and serum were different. Conclusion: In MCI and early-stage AD, CNS and systemic insulin-related metabolic dysfunctions, including insulin resistance, occur simultaneously, suggesting that they are integrally related and possibly mediated similar pathogenic factors. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, insulin resistance, mild cognitive impairment, neurodegeneration, serum

DOI: 10.3233/JAD-180906

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Roda, Alejandro R. | Montoliu-Gaya, Laia | Villegas, Sandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), the most common type of dementia worldwide, is characterized by high levels of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein. Genetically, the ɛ 4 allele of apolipoprotein E (ApoE) has been established as the major risk factor for developing late-onset AD (LOAD), the most common form of the disease. Although the role ApoE plays in AD is still not completely understood, a differential role of its isoforms has long been known. The current review compiles the involvement of ApoE isoforms in amyloid-β protein precursor transcription, Aβ aggregation and clearance, synaptic plasticity, neuroinflammation, lipid metabolism, mitochondrial function, …and tau hyperphosphorylation. Due to the complexity of LOAD, an accurate description of the interdependence among all the related molecular mechanisms involved in the disease is needed for developing successful therapies. Show more

Keywords: Aβ clearance, Aβ aggregation, AβPP transcription, AICD generation, Alzheimer’s disease, amyloid-β, apolipoprotein E, lipid metabolism, mitochondrial damage, neuroinflammation

DOI: 10.3233/JAD-180740

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

Authors: Marjańska, Małgorzata | McCarten, J. Riley | Hodges, James S. | Hemmy, Laura S. | Terpstra, Melissa

Article Type: Research Article

Abstract: This study’s objective was to increase understanding of biological mechanisms underlying clinical Alzheimer’s disease (AD) by noninvasively measuring an expanded neurochemical profile and exploring how well this advanced technology distinguishes AD from cognitively normal controls. We measured concentrations of 14 neurochemicals using ultra-high field (7 T) ultra-short echo time (8 ms) magnetic resonance spectroscopy (MRS) in 16 participants with mild to moderate clinical AD and 33 age- and gender-matched control participants. MRS was localized to the posterior cingulate cortex (PCC), a region known to be impacted by AD, and the occipital cortex (OCC), a control region. Participants with AD were recruited …from dementia specialty clinics. Concentration of the antioxidant ascorbate was higher (p  < 0.0007) in both brain regions. Concentrations of the glial marker myo -inositol and the choline-containing compounds involved in membrane turnover were higher (p ≤0.0004) in PCC of participants with AD. Ascorbate and myo -inositol concentrations were strongly associated, especially in the PCC. Random forests, using the 14 neurochemicals in the two regions, distinguished participants with AD from controls: same-sample sensitivity and specificity were 88% and 97%, respectively, though out-of-sample-values would be lower. Ultra-high field ultra-short echo time MRS identified the co-occurrence of elevated ascorbate and myo -inositol in the PCC as markers that distinguish participants with mild to moderate AD from controls. While elevated myo -inositol may be a surrogate marker of neuroinflammation, the unexpected elevation of the antioxidant ascorbate may reflect infiltration of ascorbate-rich leukocytes. Show more

Keywords: Ascorbate, myo-inositol, neurochemical profile, neuroinflammation, posterior cingulate cortex, ultra-high field, ultra-short echo time

DOI: 10.3233/JAD-180861

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

Authors: McFall, G. Peggy | McDermott, Kirstie L. | Dixon, Roger A.

Article Type: Research Article

Abstract: Background: Non-demented cognitive aging trajectories are characterized by vast level and slope differences and a spectrum of outcomes, including dementia. Objective: The goal of AD risk management (and its corollary, promoting healthy brain aging) is aided by two converging objectives: 1) classifying dynamic distributions of non-demented cognitive trajectories, and 2) identifying modifiable risk-elevating and risk-reducing factors that discriminate stable or normal trajectory patterns from declining or pre-impairment patterns. Method: Using latent class growth analysis we classified three episodic memory aging trajectories for n = 882 older adults (baseline M age=71.6, SD =8.9, range = 53-95, …female=66%): Stable (SMA; above average level, sustained slope), Normal (NMA; average level, moderately declining slope), and Declining (DMA; below average level, substantially declining slope). Using random forest analyses, we simultaneously assessed 17 risk/protective factors from non-modifiable demographic, functional, psychological, and lifestyle domains. Within two age strata (Young-Old, Old-Old), three pairwise prediction analyses identified important discriminating factors. Results: Prediction analyses revealed that different modifiable risk predictors, both shared and unique across age strata, discriminated SMA (i.e., education, depressive symptoms, living status, body mass index, heart rate, social activity) and DMA (i.e., lifestyle activities [cognitive, self-maintenance, social], grip strength, heart rate, gait) groups. Conclusion: Memory trajectory analyses produced empirical classes varying in level and slope. Prediction analyses revealed different predictors of SMA and DMA that also varied by age strata. Precision approaches for promoting healthier memory aging—and delaying memory impairment—may identify modifiable factors that constitute specific targets for intervention in the differential context of age and non-demented trajectory patterns. Show more

Keywords: Biomarkers, dementia prevention, memory trajectories, protective factors, risk factors, Victoria Longitudinal Study

DOI: 10.3233/JAD-180571

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

Authors: Kasahara, Hiroo | Ikeda, Masaki | Nagashima, Kazuaki | Fujita, Yukio | Makioka, Kouki | Tsukagoshi, Setsuki | Yamazaki, Tsuneo | Takai, Eriko | Sanada, Etsuko | Kobayashi, Ayumi | Kishi, Kazuhiro | Suto, Takayuki | Higuchi, Tetsuya | Tsushima, Yoshito | Ikeda, Yoshio

Article Type: Research Article

Abstract: Neuroimages of cerebral amyloid-β (Aβ) accumulation and small vessel disease (SVD) were examined in patients with various types of cognitive disorders using 11 C-labeled Pittsburgh Compound B-positron emission tomography (PiB-PET) and magnetic resonance imaging (MRI). The mean cortical standardized uptake value ratio (mcSUVR) was applied for a quantitative analysis of PiB-PET data. The severity of white matter lesions (WML) and enlarged perivascular spaces (EPVS) on MRI were assessed to evaluate complicating cerebral SVD using semiquantitative scales. In homozygous apolipoprotein E ɛ 3/ɛ 3 carriers, the incidence of more severe WML and EPVS was higher in PiB-positive than PiB-negative patients, indicating …that WML and EPVS might be associated with enhanced Aβ accumulation. An association study between PiB-PET and MRI findings revealed that higher WML grades significantly correlate with lower mcSUVRs, especially in the frontal area, indicating that more severe ischemic MRI findings are associated with milder Aβ accumulation among patients with Alzheimer’s disease. In these patients SVD may accelerate the occurrence of cognitive decline and facilitate early recognition of dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia, Pittsburgh Compound B, positron emission tomography, white matter lesion

DOI: 10.3233/JAD-180939

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Damulina, Anna | Pirpamer, Lukas | Seiler, Stephan | Benke, Thomas | Dal-Bianco, Peter | Ransmayr, Gerhard | Struhal, Walter | Hofer, Edith | Langkammer, Christian | Duering, Marco | Fazekas, Franz | Schmidt, Reinhold

Article Type: Research Article

Abstract: Background/Objective: Higher white matter hyperintensity (WMH) load has been reported in Alzheimer’s disease (AD) patients in different brain regions when compared to controls. We aimed to assess possible differences of WMH spatial distribution between AD patients and age-matched controls by means of lesion probability maps. Methods: The present study included MRI scans of 130 probable AD patients with a mean age of 73.4±8.2 years from the Prospective Dementia Registry Austria Study and 130 age-matched healthy controls (HC) from the Austrian Stroke Prevention Family Study. Risk factors such as hypertension, diabetes mellitus, hypercholesterolemia, coronary artery disease, and smoking were …assessed. Manually segmented FLAIR WMH masks were non-linearly registered to a template and voxel-based probability mapping was performed. Results: There were no significant between group differences in cardiovascular risk factors and WMH volume. AD patients showed a significantly higher likelihood of having WMH in a bilateral periventricular distribution than controls before and after correcting for age, sex, cardiovascular risk factors, and ventricular volume (p ≤0.05; threshold-free cluster enhancement corrected). There was no significant association between the periventricular WMH volume and cognitive decline of AD patients. Conclusion: In AD, WMH were preferentially found in a periventricular location but the volume of lesions was unrelated to cognitive decline in our study irrespective of lesion location. Show more

Keywords: Alzheimer’s disease, magnetic resonance imaging, periventricular white matter, white matter hyperintensities

DOI: 10.3233/JAD-180982

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Rawlings, Andreea M. | Sharrett, A. Richey | Mosley, Thomas H. | Wong, Dean F. | Knopman, David S. | Gottesman, Rebecca F.

Article Type: Short Communication

Abstract: We examined associations between cognitive reserve and late-life amyloid-β deposition using florbetapir positron emission tomography (PET). We used data from the Atherosclerosis Risk in Communities (ARIC) and ARIC-PET Study. 330 dementia-free participants underwent PET scans. Mean global cortical standardized uptake value ratio (SUVR) >1.2 was defined as elevated. Midlife cognition was significantly associated with late-life cognition, but not with late-life elevated SUVR; education was not associated with late-life SUVR, but was strongly associated with late-life cognition. Cognitive reserve may reduce dementia risk by mitigating the impact of Alzheimer’s disease pathology on the clinical expression of dementia, rather than by altering …its pathogenesis. Show more

Keywords: Amyloid, cohort study, education, epidemiology, human, PET imaging

DOI: 10.3233/JAD-180785

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Nordheim, Johanna | Häusler, Andreas | Yasar, Sevil | Suhr, Ralf | Kuhlmey, Adelheid | Rapp, Michael | Gellert, Paul

Article Type: Research Article

Abstract: Background: Psychosocial interventions may improve the quality of life of both people with dementia (PWD) and their family caregivers. However, research is inconclusive and focused primarily on the quality of life of either the PWD or the caregiver, rather than on both. Objective: Our aim was to evaluate the effect of couple-based interdisciplinary psychosocial intervention in patients with mild-to-moderate dementia on quality of life of both partners. Methods: 108 community-dwelling PWD and their caregiving partners were enrolled in this pragmatic randomized controlled trial. The intervention consisted of 7 sessions at participants’ homes led by a psychotherapist …and a social worker. Quality of life was evaluated at baseline, one, and six-month follow-up for patients and their partners. Mixed effects models have been applied. Results: Intervention allocation was not associated with an improvement in quality of life in either the patients or their partners. In subgroup analyses, intervention was negatively associated with caregiver performance. However, this was only present in those reporting poor relationship quality. Patients in the intervention group who reported good relationship quality were found to have decreased cognitive decline. Conclusion: A couple-based interdisciplinary intervention did not yield improvements in quality of life. This may be the result of a bias caused by an increased awareness due to the intervention. Relationship quality and support in the long-term should be considered when designing and implementing interventions for PWD and their partners. Show more

Keywords: Caregiving, coping with illness/disability, dementia, family, psychosocial intervention, quality of life

DOI: 10.3233/JAD-180812

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

Authors: Devanarayan, Priya | Devanarayan, Viswanath | Llano, Daniel A. | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The 2018 NIA-AA research framework proposes a classification system with Amyloid-β deposition, pathologic Tau, and neurodegeneration (ATN) for diagnosis and staging of Alzheimer’s disease (AD). Data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database can be utilized to identify diagnostic signatures for predicting AD progression, and to determine the utility of this NIA-AA research framework. Profiles of 320 peptides from baseline cerebrospinal fluid (CSF) samples of 287 normal, mild cognitive impairment (MCI), and AD subjects followed over a 3–10-year period were measured via multiple reaction monitoring mass spectrometry. CSF Aβ42 , total-Tau (tTau), phosphorylated-Tau (pTau-181), and hippocampal volume were also …measured. From these candidate markers, optimal signatures with decision thresholds to separate AD and normal subjects were first identified via unbiased regression and tree-based algorithms. The best performing signature determined via cross-validation was then tested in an independent group of MCI subjects to predict future progression. This multivariate analysis yielded a simple diagnostic signature comprising CSF pTau-181 to Aβ42 ratio, MRI hippocampal volume, and low CSF levels of a novel PTPRN peptide, with a decision threshold on each marker. When applied to a separate MCI group at baseline, subjects meeting these signature criteria experience 4.3-fold faster progression to AD compared to a 2.2-fold faster progression using only conventional markers. This novel 4-marker signature represents an advance over the current diagnostics based on widely used markers, and is easier to use in practice than recently published complex signatures. This signature also reinforces the ATN construct from the 2018 NIA-AA research framework. Show more

Keywords: Biomarker, mild cognitive impairment, PTPRN, receptor-type tyrosine-phosphatase-like N

DOI: 10.3233/JAD-180905

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

Authors: Griffith, Chelsea M. | Macklin, Lauren N. | Cai, Yan | Sharp, Andrew A. | Yan, Xiao-Xin | Reagan, Lawrence P. | Strader, April D. | Rose, Gregory M. | Patrylo, Peter R.

Article Type: Research Article

Abstract: Several studies have demonstrated that mouse models of Alzheimer’s disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-β plaques; Aβ) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1–3 months and 6–8 months old) and post-pathology (16–18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. …Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD. Show more

Keywords: 3xTg-AD, AKT, Alzheimer’s disease, diabetes, glucose, GLUT, hippocampus, insulin, metabolism

DOI: 10.3233/JAD-180707

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-29, 2019

Authors: Bocai, Nadia I. | Marcora, María S. | Belfiori-Carrasco, Lautaro F. | Morelli, Laura | Castaño, Eduardo M.

Article Type: Review Article

Abstract: The accumulation and spreading of protein tau in the human brain are major features of neurodegenerative disorders known as tauopathies. In addition to several subcellular abnormalities, tau aggregation within neurons seems capable of triggering endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). In metazoans, full activation of a complex ER-UPR network may restore proteostasis and ER function or, if stress cannot be solved, commit cells to apoptosis. Due to these alternative outcomes (survival or death), the pharmacological manipulation of ER-UPR has become the focus of potential therapies in many human diseases, including tauopathies. Here we update and …analyze the experimental data from human brain, cellular, and animal models linking tau accumulation and ER-UPR. We further discuss mechanistic aspects and put the ER-UPR into perspective as a possible therapeutic target in this group of diseases. Show more

Keywords: Dementia, endoplasmic reticulum stress, tau proteins, tauopathies, unfolded protein response

DOI: 10.3233/JAD-181021

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2019

Authors: Onojighofia Tobore, Tobore

Article Type: Research Article

Abstract: Alzheimers’ disease (AD) is the most common cause of dementia, with an estimated 5 million new cases occurring annually. Among the elderly, AD shortens life expectancy, results in disability, decreases quality of life, and ultimately, leads to institutionalization. Despite extensive research in the last few decades, its heterogeneous pathophysiology and etiopathogenesis have made it difficult to develop an effective treatment and prevention strategy. Aging is the biggest risk factor for AD and evidence suggest that the total number of older people in the population is going to increase astronomically in the next decades. Also, there is evidence that air pollution …may result in higher incidence and prevalence of AD. This makes the need for a comprehensive understanding of the etiopathogenesis and pathophysiology of the disease extremely critical. In this paper, a quintuple framework of thyroid dysfunction, vitamin D deficiency, sex hormones, and mitochondria dysfunction and oxidative stress are used to provide a comprehensive description of AD etiopathogenesis and pathophysiology. The individual role of each factor, their synergistic and genetic interactions, as well as the limitations of the framework are discussed. Show more

Keywords: Alzheimer’s disease, amyloid-β , dementia, hyperphosphorylated tau, melatonin, mitochondria dysfunction, oxidative stress, pathogenesis, sex hormones, thyroid hormone, vitamin D

DOI: 10.3233/JAD-181052

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

Authors: Dao, Elizabeth | Hsiung, Ging-Yuek Robin | Sossi, Vesna | Tam, Roger | Shahinfard, Elham | Nicklin, Eloise | Al Keridy, Walid | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Impaired physical function (i.e., slowing of gait, muscle weakness, and poor mobility) is common in older adults with cognitive impairment and dementia. Evidence suggests that cerebral small vessel disease, specifically white matter lesions (WMLs), is associated with impaired physical function, but little research has been conducted to understand the specific role of AD pathology in physical outcomes. Objective: The objective of this study was to examine the association between cerebral amyloid-β (Aβ ) deposition and physical function in people with cognitive impairment. Methods: Thirty participants completed an 11 C Pittsburgh compound B (PIB) position …emission tomography (PET) scan to quantify global Aβ deposition using standardized uptake value ratio (SUVR). We assessed usual gait speed, muscle strength of the lower extremities, balance, and functional mobility using the Short Physical Performance Battery (SPPB) and the Timed Up and Go Test (TUGT). Multiple linear regression analyses examined the association between Aβ and each measure of physical function, adjusting for age, body mass index, and WML load. Results: Global PIB SUVR was significantly associated with usual gait speed (β = –0.52, p  = 0.01) and SPPB performance (β = –0.47, p  = 0.02), such that increased Aβ deposition was associated with reduced performance on both measures. Global PIB SUVR was not significantly associated with TUGT performance (β = 0.32, p  = 0.08). Conclusions: Cerebral Aβ deposition is associated with reduced gait speed, muscle strength, and balance in older adults with cognitive impairment independent of WML load. However, Aβ deposition was not associated with functional mobility. Show more

Keywords: Alzheimer’s disease, amyloid-β , mild cognitive impairment, mobility, physical function

DOI: 10.3233/JAD-180848

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Takamatsu, Yoshiki | Ho, Gilbert | Waragai, Masaaki | Wada, Ryoko | Sugama, Shuei | Takenouchi, Takato | Masliah, Eliezer | Hashimoto, Makoto

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), the most common neurodegenerative dementia, leads to memory dysfunction due to widespread neuronal loss associated with aggregation of amyloidogenic proteins (APs), while schizophrenia (SCZ) represents a major psychiatric disorder characterized by delusions, hallucinations, and other cognitive abnormalities, the underlying mechanisms of which remain obscure. Although AD and SCZ partially overlap in terms of psychiatric symptoms and some aspects of cognitive impairment, the causal relationship between AD and SCZ is unclear. Based on the similarity of APs with yeast prion in terms of stress-induced protein aggregation, we recently proposed that evolvability of APs might be an epigenetic phenomenon …to transmit stress information of parental brain to cope with the stressors in offspring. Although amyloid evolvability may be beneficial in evolution, AD might be manifested during parental aging as the mechanism of antagonistic pleiotropy phenomenon. Provided that accumulating evidence implicates stress as an important factor in SCZ, the main objective of this paper is to better understand the possible connection of AD and SCZ through amyloid evolvability. Hypothetically, the delivery of information of stress by APs may be less efficient under the decreased evolvability conditions such as disease-modifying treatment, leading to SCZ in offspring. Conversely, the increased evolvability conditions including gene mutations of APs are supposed to be beneficial for offspring, but might lead to AD in parents. Collectively, AD and SCZ might transgenerationally interfere with each other through amyloid evolvability, and this could explain why both AD and SCZ have not been selected out through evolution. Show more

Keywords: Alzheimer’s disease, amyloid-β , antagonistic pleiotropy, disease-modifying therapy, evolvability, natural selection, schizophrenia, transgenerational

DOI: 10.3233/JAD-180986

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2018

Authors: Cherbuin, Nicolas | Walsh, Erin I. | Prina, A. Matthew

Article Type: Research Article

Abstract: Background: Chronic obstructive pulmonary disease (COPD) is a major disease burden which accounts for 5% of all deaths globally, with most of those (>90%) occurring in lower to middle income countries (LMIC). It is also emerging as an important modifiable dementia risk factor. Objective: To address the knowledge gap surrounding the nature of the associations between COPD, dementia, and mortality, and the geographical variation of those associations in LMIC. Methods: Data from the 10/66 study surveying 15,394 participants (mean age 74 years, 62% female) across 8 countries was used to estimate the prevalence of self-reported COPD …and its association with incident dementia and premature death. Proportional sub-hazards models using a cumulative incidence function were applied to identify the probability of incident dementia onset given the risk of premature death, with estimates pooled across countries via random effect meta-analysis. Results: Over the 3-year follow-up, almost 10% of participants developed dementia and 14% were deceased. COPD was not significantly associated with dementia incidence except in Cuba. However, fully adjusted models indicated that individuals with COPD were at a 28% increased risk of premature death, a trend present across most countries when analyzed individually. Conclusion: The link between COPD and dementia is currently somewhat different and weaker in LMIC than in developed countries. This may be because premature death in the populations studied mask the development of clinical dementia. Given the global trend toward increased life expectancy, it is critical that the disease burden associated with COPD be addressed without delay if a further rise in dementia prevalence associated with COPD is to be avoided in LMIC. Show more

Keywords: Chronic obstructive pulmonary disease, lower to middle income countries, mild cognitive impairment, premature death, prevalence

DOI: 10.3233/JAD-180562

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

Authors: Danat, Isaac M. | Clifford, Angela | Partridge, Martin | Zhou, Weiju | Bakre, Aishat T. | Chen, Anthony | McFeeters, Danielle | Smith, Tina | Wan, Yuhui | Copeland, John | Anstey, Kaarin J. | Chen, Ruoling

Article Type: Research Article

Abstract: Background: It is unclear whether overweight and obesity in older age reduces or increases the risk of incident dementia. Objective: To assess the impacts of overweight and obesity in older age on incident dementia. Methods: We searched cohort studies reporting body weight measured in older age and dementia through PubMed, Embase, Medline, PyschInfo, and Cochrane library until July 2016. Sixteen articles were identified for the review. We pooled data from them and a new unpublished study from China, to calculate relative risk (RR) of incident dementia in relation to body mass index (BMI) and waist circumference …(WC). Results: All 16 cohort studies were undertaken in high income countries, with follow-up periods ranging between 3 to 18 years. Thirteen studies showed an inverse association between BMI and dementia, and three studies demonstrated a positive association. Pooled RR of dementia in relation to continuous BMI from 14 studied populations, including the new Chinese data was 0.97 (95% CI 0.95–1.00); in those with followed up <9 years was 0.95 (0.93–0.96) while in ≥9 years follow-up was 1.03 (0.96–1.11). In five studied populations examining categorical BMI, RR of dementia in older people classified as overweight and obese was 0.98 (0.54–1.77) and 1.17 (0.65–2.10) respectively, in comparison with other weights. The pooled WC data showed no association between increased WC and reduced risk of dementia. Conclusion: The current evidence did not support a paradox on beneficial impacts of overweight and obesity in older age on incident dementia. More studies with long term follow up are needed to clarify the association of body weight in older age with dementia risk. Show more

Keywords: Body weight, dementia, meta-analysis, older people

DOI: 10.3233/JAD-180763

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

Authors: Oliveira, Deborah | Jun Otuyama, Leonardo | Mabunda, Dirceu | Mandlate, Flavio | Gonçalves-Pereira, Manuel | Xavier, Miguel | Laks, Jerson | Ferri, Cleusa P.

Article Type: Research Article

Abstract: Background: Most people with dementia live in low- and middle-income countries and little is known about the potential for reducing these numbers by reducing key risk factors. Objective: To investigate the potential for dementia incidence reduction in Brazil, Mozambique, and Portugal (a culturally related, high-income country). Methods: We replicated previously published methods and based on the relative risks from previous studies, we estimated the population-attributable risk (PAR) of dementia in Mozambique, Brazil, and Portugal for seven modifiable risk factors associated with dementia (low educational attainment, physical inactivity, midlife hypertension, midlife obesity, depression, smoking, …and diabetes mellitus). The combined PAR was calculated and adjusted for associations between risk factors. The potential for risk factor reduction was assessed by examining the effect of relative reductions of 10% and 20% per decade for each of the risk factors on projections for dementia cases for each decade until 2050. Results: After adjusting for non-independence of risk factors, 24.4%, 32.3%, and 40.1% of dementia cases could be related to seven potentially modifiable risk factors in Mozambique, Brazil, and Portugal, respectively. Reducing the prevalence of each risk factor by 20% per decade could, by 2050, potentially reduce the prevalence of dementia in Mozambique, Brazil, and Portugal by 12.9%, 16.2%, and 19.5%, respectively. Conclusion: There is a substantial difference between the countries on in the percentage of dementia cases that could be attributable to the seven potentially modifiable risk factors. The proportion of cases that could be prevented by 2050 if measures were taken to address these main risk factors was higher in Portugal than in Brazil and Mozambique. Each country or region should consider their unique risk factor profile when developing dementia risk reduction programs. Show more

Keywords: Alzheimer’s disease, dementia, low- and middle-income countries, prevention, risk reduction

DOI: 10.3233/JAD-180636

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2018

Authors: Abu Bakar, Zulzikry Hafiz | Damanhuri, Hanafi Ahmad | Makpol, Suzana | Wan Kamaruddin, Wan Mohd Aizat | Abdul Sani, Nur Fathiah | Amir Hamzah, Ahmad Imran Zaydi | Nor Aripin, Khairun Nain | Rani, Mohd Dzulkhairi Mohd | Azila Noh, Nor | Razali, Rosdinom | Mazlan, Musalmah | Abdul Hamid, Hamzaini | Mohamad, Mazlyfarina | Wan Ngah, Wan Zurinah

Article Type: Research Article

Abstract: Background: Many studies on biochemical and psychological variables have aimed to elucidate the association between aging and cognitive function. Demographic differences and protein expression have been reported to play a role in determining the cognitive capability of a population. Objective: This study aimed to determine the effect of age on the protein profile of Malay individuals and its association with cognitive competency. Methods: A total of 160 individuals were recruited and grouped accordingly. Cognitive competency of each subject was assessed with several neuropsychological tests. Plasma samples were collected and analyzed with Q Exactive HF Orbitrap. Proteins …were identified and quantitated with MaxQuant and further analyzed with Perseus to determine differentially expressed proteins. PANTHER, Reactome, and STRING were applied for bioinformatics output. Results: Our data showed that the Malay individuals are vulnerable to the deterioration of cognitive function with aging, and most of the proteins were differentially expressed in concordance. Several physiological components and pathways were shown to be involved, giving a hint of a promising interpretation on the induction of aging toward the state of the Malays’ cognitive function. Nevertheless, some proteins have shown a considerable interaction with the generated protein network, which provides a direction of focus for further investigation. Conclusion: This study demonstrated notable changes in the expression of several proteins as age increased. These changes provide a promising platform for understanding the biochemical factors affecting cognitive function in the Malay population. The exhibited network of protein-protein interaction suggests the possibility of implementing regulatory intervention in ameliorating Malay cognitive function. Show more

Keywords: Aging, cognitive function, Malay population, protein profiling

DOI: 10.3233/JAD-180511

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2018

Authors: Marino Gammazza, Antonella | Restivo, Vincenzo | Baschi, Roberta | Caruso Bavisotto, Celeste | Cefalù, Angelo B. | Accardi, Giulia | Conway de Macario, Everly | Macario, Alberto J.L. | Cappello, Francesco | Monastero, Roberto

Article Type: Research Article

Abstract: Molecular chaperones play essential roles in many processes such as cell differentiation, tissue homeostasis, and organ remodeling. Recent data indicate that chaperones can act as cytoprotectants for brain cells during the progression of neurodegenerative diseases, including Alzheimer’s disease (AD). However, very few data on the levels of chaperones in dementia, including its prodromal phases, have been reported. In this study, we used biological samples and epidemiological data collected during the Zabùt Aging Project (a prospective, community-based, cohort study of normal/pathological aging conducted in Sicily, Italy, with a follow-up of ten years) to determine if there is an association between plasma …levels of the chaperones Hsp60, Hsp70, and Hsp90 with amnestic mild cognitive impairment (aMCI) and AD. Twenty-six aMCI individuals, 26 AD and 26 controls, matched for age and sex, were enrolled. After adjustment for education subjects with AD showed significantly higher levels of Hsp60 than aMCI (OR = 1.16, 95% CI 1.04–1.30) and controls (OR = 1.12, 95% CI 1.03–1.22), while Hsp70 was significantly higher only in AD (OR = 1.84, 95% CI 1.09–3.10) than controls. In contrast, circulating levels of Hsp90 were significantly diminished in aMCI (OR = 0.69, 95% CI 0.52–0.91) and AD (OR = 0.51, 95% CI 0.35–0.75) compared to controls. However, these results were no longer significant after adjustment for multiple comparisons. Although the results lost significance after adjustment for multiple comparisons, they are encouraging despite the smallness of the sample and new studies should be carried out with larger populations to determine to what extent sequential measurement of serum chaperones in aMCI and AD can be trusted as indicators of disease status and progression. Show more

Keywords: Alzheimer’s disease, cognitive impairment, Hsp60, Hsp70, Hsp90, molecular chaperones, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-180825

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

Authors: Wan Nasri, Wan Nurzulaikha | Makpol, Suzana | Mazlan, Musalmah | Tooyama, Ikuo | Wan Zurinah Wan Ngah, Wan Zurinah | Damanhuri, Hanafi Ahmad

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive abilities. AD is associated with aggregation of amyloid-β (Aβ ) deposited in the hippocampal brain region. Our previous work has shown that tocotrienol rich fraction (TRF) supplementation was able to attenuate the blood oxidative status, improve behavior, and reduce fibrillary-type Aβ deposition in the hippocampus of an AD mouse model. In the present study, we investigate the effect of 6 months of TRF supplementation on transcriptome profile in the hippocampus of APPswe/PS1dE9 double transgenic mice. TRF supplementation can alleviate AD conditions by …modulating several important genes in AD. Moreover, TRF supplementation attenuated the affected biological process and pathways that were upregulated in the AD mouse model. Our findings indicate that TRF supplementation can modulate hippocampal gene expression as well as biological processes that can potentially delay the progression of AD. Show more

Keywords: Alzheimer’s disease, hippocampus, microarray analysis, tocotrienol-rich fraction, transgenic mouse

DOI: 10.3233/JAD-180496

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

Authors: Collins, Rachel | Silarova, Barbora | Clare, Linda

Article Type: Research Article

Abstract: Background: Understanding policy context and how policy is implemented at the local and clinical level is an important precursor to developing preventive strategies focusing on dementia risk reduction in primary healthcare settings. Objective: Using England as a case study, we review policies and strategies relevant to dementia prevention from the national to local level and how these are translated into primary healthcare services. Methods: We conducted a scoping review covering: 1) identification of national, regional, and local policies and strategies that include dementia prevention; 2) identification of national guidelines for implementing dementia prevention at the clinical …level; and 3) evaluation of the implementation of these at the clinical level. Results: Dementia prevention is addressed in national policy, and this filters through to regional and local levels. Focus on dementia prevention is limited and variable. Reference to modifiable risk factors is associated with other non-communicable diseases, placing less emphasis on factors more dementia specific. Evidence of implementation of dementia prevention policies at the clinical level is limited and inconsistent. Available evidence suggests messages about dementia prevention may best be delivered through primary healthcare services such as the National Health Service (NHS) Health Check. Conclusion: The limitations identified in this review could be addressed through development of a national policy focused specifically on dementia prevention. This could provide a platform for increasing knowledge and understanding among the general population and healthcare professionals. It would be important for such a policy to cover the full range of modifiable risk factors relevant to dementia. Show more

Keywords: Commissioner, government, modifiable risk, primary healthcare, policymaker

DOI: 10.3233/JAD-180608

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

Authors: Radford, Kylie | Lavrencic, Louise M. | Delbaere, Kim | Draper, Brian | Cumming, Robert | Daylight, Gail | Mack, Holly A. | Chalkley, Simon | Bennett, Hayley | Garvey, Gail | Hill, Thi Yen | Lasschuit, Danielle | Broe, Gerald A.

Article Type: Research Article

Abstract: Dementia prevalence in Aboriginal and Torres Strait Islander Australians is three to five times higher than the general Australian population. A better understanding of the underlying biomedical and social risk factors is needed to guide dementia prevention in Aboriginal Australians. The current study is the first to examine potential risk factors for dementia in the majority urban and regional population, with a representative sample of 336 Aboriginal Australians aged 60 years and older. Participants included 45 people with a dementia diagnosis (n  = 27 probable/possible Alzheimer’s disease); and 286 people without dementia. Univariate logistic regression analyses (controlling for age) identified childhood …trauma, mid-life factors (history of unskilled work, past high-risk alcohol use), and medical factors (history of stroke, head injury with loss of consciousness, epilepsy) as risk factors for dementia. Multivariable analysis revealed age, childhood trauma, unskilled work, stroke, and head injury as independent predictors of all-cause dementia. A range of comorbid factors related to dementia was also identified (i.e., functional impairment, incontinence, recent hospital admission, low body mass index, living in residential care, depression, current high-risk alcohol use, social isolation, low physical activity levels). These findings extend previous outcomes in a remote Aboriginal population by highlighting that life-course social determinants of health, in addition to neurological disorders, likely play an important role in elevating dementia risk. Certain psychosocial and medical exposures are highly prevalent in Aboriginal Australians, similar to other indigenous populations, and should be considered when designing targeted and culturally appropriate prevention initiatives to reduce the burden of dementia. Show more

Keywords: Aged, Alzheimer’s disease, indigenous population, neurocognitive disorders, social determinants of health

DOI: 10.3233/JAD-180573

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

Authors: Yaffe, Kristine | Barnes, Deborah E. | Rosenberg, Dori | Dublin, Sascha | Kaup, Allison R. | Ludman, Evette J. | Vittinghoff, Eric | Peltz, Carrie B. | Renz, Anne D. | Adams, Kristin J. | Larson, Eric B.

Article Type: Research Article

Abstract: This article describes the protocol for the Systematic Multi-domain Alzheimer’s Risk Reduction Trial (SMARRT), a single-blind randomized pilot trial to test a personalized, pragmatic, multi-domain Alzheimer’s disease (AD) risk reduction intervention in a US integrated healthcare delivery system. Study participants will be 200 higher-risk older adults (age 70–89 years with subjective cognitive complaints, low normal performance on cognitive screen, and ≥ two modifiable risk factors targeted by our intervention) who will be recruited from selected primary care clinics of Kaiser Permanente Washington, oversampling people with non-white race or Hispanic ethnicity. Study participants will be randomly assigned to a two-year Alzheimer’s …risk reduction intervention (SMARRT) or a Health Education (HE) control. Randomization will be stratified by clinic, race/ethnicity (non-Hispanic white versus non-white or Hispanic), and age (70–79, 80–89). Participants randomized to the SMARRT group will work with a behavioral coach and nurse to develop a personalized plan related to their risk factors (poorly controlled hypertension, diabetes with evidence of hyper or hypoglycemia, depressive symptoms, poor sleep quality, contraindicated medications, physical inactivity, low cognitive stimulation, social isolation, poor diet, smoking). Participants in the HE control group will be mailed general health education information about these risk factors for AD. The primary outcome is two-year cognitive change on a cognitive test composite score. Secondary outcomes include: 1) improvement in targeted risk factors, 2) individual cognitive domain composite scores, 3) physical performance, 4) functional ability, 5) quality of life, and 6) incidence of mild cognitive impairment, AD, and dementia. Primary and secondary outcomes will be assessed in both groups at baseline and 6, 12, 18, and 24 months. Show more

Keywords: Alzheimer’s disease, dementia, health promotion, integrated delivery of health care, risk reduction behavior

DOI: 10.3233/JAD-180634

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