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

Show:

results per page

Mild Cognitive Impairment and Dementia Involving Multiple Cognitive Domains in Mexican Urbanites

Article Type: Research Article

Abstract: Exposures to fine particulate matter PM2.5 and ozone O3 are associated with Alzheimer’s disease (AD) risk. Mexico City residents have lifetime exposures to PM2.5 and O3 above annual USEPA standards and their brains contain high redox, combustion, and friction-derived magnetite nanoparticles. AD pathological changes with subcortical pre-tangle stages in infancy and cortical tau pre-tangles, NFT Stages I-II, and amyloid phases 1-2 are identified by the 2nd decade. Given their AD continuum, a reliable identification of cognitive impairment is of utmost importance. The Montreal Cognitive Assessment (MoCA) was administered to 517 urbanites, age 21.60±5.88 years, with 13.69±1.28 …formal education years, in Mexican PM2.5 polluted cities. MoCA score was 23.92±2.82, and 24.7% and 30.3% scored ≤24 and ≤22, respectively (MCI≤24, AD≤22). Cognitive deficits progressively targeted Visuospatial, Executive, Language, and Memory domains, body mass index (BMI) impacting total scores negatively (p = 0.0008), aging driving down Executive, Visuospatial, and Language index scores (p < 0.0001, 0.0037, and 0.0045), and males performing better in Executive tasks. Average age for AD MoCA scores was 22.38±7.7 years. Residency in polluted cities is associated with progression of multi-domain cognitive impairment affecting 55% of Mexican seemingly healthy youth. Normal BMI ought to be a neuroprotection goal. MoCA provides guidance for further mandatory neuropsychological testing in young populations. Identifying and lowering key neurotoxicants impacting neural risk trajectories in the developing brain and monitoring cognitive performance would greatly facilitate multidisciplinary early diagnosis and prevention of AD in high risk young populations. Cognitive deficits hinder development of those representing the force moving the country in future years. Show more

Keywords: Alzheimer’s disease, air pollution, attention, body mass index, cognition, combustion and friction-derived nanoparticles, dementia, females, food, gender, Mexico City, mild cognitive impairment, Montreal Cognitive Assessment, obesity, overweight, PM2.5 , tauopathies, young adults.

DOI: 10.3233/JAD-181208

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

Price: EUR 27.50

LY379268 Does Not Have Long-Term Procognitive Effects nor Attenuate Glutamatergic Signaling in A βPP/PS1 Mice

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

Price: EUR 27.50

Changes in Theta but not Alpha Modulation Are Associated with Impairment in Working Memory in Alzheimer’s Disease and Mild Cognitive Impairment

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

Price: EUR 27.50

Individual Prediction of Behavioral Variant Frontotemporal Dementia Development Using Multivariate Pattern Analysis of Magnetic Resonance Imaging Data

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

Price: EUR 27.50

Cognitive Performance in Parkinson’s Disease in the Brain Health Registry

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

Price: EUR 27.50

Metformin Therapy Aggravates Neurodegenerative Processes in ApoE– /– Mice

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

Price: EUR 27.50

Traditional Chinese Medicine as an Effective Complementary Non-Pharmacological Approach to Mild Cognitive Impairment: A Call for Collaboration

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

Price: EUR 27.50

Subjective Cognitive Decline May Be a Stronger Predictor of Incident Dementia in Women than in Men

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

Price: EUR 27.50

Calpastatin Mediates Development of Alzheimer’s Disease in Diabetes

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

Price: EUR 27.50

Gait Dysfunction in Motoric Cognitive Risk Syndrome

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

Price: EUR 27.50

Screening for Vision Impairments in Individuals with Dementia Living in Long-Term Care: A Scoping Review

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

Get PDF

Tumor Necrosis Factor-Alpha Alters Electrophysiological Properties of Rabbit Hippocampal Neurons

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

Price: EUR 27.50

The Healthy Brain Project: An Online Platform for the Recruitment, Assessment, and Monitoring of Middle-Aged Adults at Risk of Developing Alzheimer’s Disease

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

Price: EUR 27.50

Observational Study of Brain Atrophy and Cognitive Decline Comparing a Sample of Community-Dwelling People Taking Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Over Time

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

Price: EUR 27.50

The Digital Tree Drawing Test for Screening of Early Dementia: An Explorative Study Comparing Healthy Controls, Patients with Mild Cognitive Impairment, and Patients with Early Dementia of the Alzheim…

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

Price: EUR 27.50

Comparison between a Paper-Pencil Version and Computerized Version for the Realization of a Neuropsychological Test: The Example of the Trail Making Test

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

Price: EUR 27.50

Methylene Blue Inhibits Formation of Tau Fibrils but not of Granular Tau Oligomers: A Plausible Key to Understanding Failure of a Clinical Trial for Alzheimer’s Disease

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

Price: EUR 27.50

Vascular Mild Cognitive Impairment: Identifying Disease in Community- Dwelling Older Adults, Reducing Risk Factors, and Providing Support. The Osaki-Tajiri and Kurihara Projects

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

Get PDF

A Meta-Analysis of Alzheimer’s Disease Brain Transcriptomic Data

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

Get PDF

Dyadic Wind of Change: New Approaches to Improve Biopsychological Stress Regulation in Patients with Dementia and Their Spousal Caregivers

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

Price: EUR 27.50

The Role of Word Properties in Performance on Fluency Tasks in People with Primary Progressive Aphasia

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

Price: EUR 27.50

Using Varying Diagnostic Criteria to Examine Mild Cognitive Impairment Prevalence and Predict Dementia Incidence in a Community-Based Sample

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

Price: EUR 27.50

Multivariate Prediction of Hippocampal Atrophy in Alzheimer’s Disease

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

Price: EUR 27.50

Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer’s Disease

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

Price: EUR 27.50

Mild Behavioral Impairment in Parkinson’s Disease: Data from the PArkinson’s Disease COgnitive Impairment Study

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

Price: EUR 27.50

Plasma Levels of Soluble AβPPβ as a Biomarker for Alzheimer’s Disease with Dementia

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

Price: EUR 27.50

Self-Efficacy Mediates the Association Between Physical Function and Perceived Quality of Life in Individuals with Mild Cognitive Impairment

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

Price: EUR 27.50

Effect of Visit-to-Visit Blood Pressure Variability on Cognitive and Functional Decline in Mild to Moderate Alzheimer’s Disease

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

Price: EUR 27.50

Cognitive Resilience to Alzheimer’s Disease Pathology in the Human Brain

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

Price: EUR 27.50

Relationship Between Treatment Initiation and Healthcare Costs in Alzheimer’s Disease

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

Price: EUR 27.50

Heterogeneity of Informant-Reported Functional Performance in Mild Cognitive Impairment: A Latent Profile Analysis of the Functional Activities Questionnaire

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

Price: EUR 27.50

Correlation of Lobar Cerebral Microbleeds with Amyloid, Perfusion, and Metabolism in Alzheimer’s Disease

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

Price: EUR 27.50

Traumatic Brain Injury and Suicidal Behavior: A Review

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

Price: EUR 27.50

How Do Different Forms of Vascular Brain Injury Relate to Cognition in a Memory Clinic Population: The TRACE-VCI Study

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

Price: EUR 27.50

The Epistasis Project: A Multi-Cohort Study of the Effects of BDNF, DBH, and SORT1 Epistasis on Alzheimer’s Disease Risk

Article Type: Research Article

Abstract: Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer’s disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF , DBH , and SORT1 loci comprising 5,682 controls and 2,454 …AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1–1.2, p = 0.005–0.3), an effect size that was consistent in the Northern European (OR = 1.1–1.2, p = 0.002–0.8) but not the smaller Spanish (OR = 0.8–1.6, p = 0.4–1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3–1.5 p = 0.002–0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2–1.3, p = 0.007–0.00008) than men (OR = 0.9–1.0, p = 0.3–0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, dopamine beta-hydroxylase, epistasis, genetics, neurotrophins, Sortilin

DOI: 10.3233/JAD-181116

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

Price: EUR 27.50

Combined Transcriptomics and Proteomics in Frontal Cortex Area 8 in Frontotemporal Lobar Degeneration Linked to C9ORF72 Expansion

Article Type: Research Article

Abstract: Background: Frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) may appear as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD). Objective: Analysis of differential mRNA and protein expression in the frontal cortex in c9FLTD and evaluation with previous observations in frontal cortex in sFTLD-TDP and amyotrophic lateral sclerosis with TDP-43 inclusions. Methods: Microarray hybridization and mass spectrometry-based quantitative proteomics followed by RT-qPCR, gel electrophoresis, and western blotting in frontal cortex area 8 in 19 c9FTLD cases and 14 age- and gender-matched controls. Results: …Microarray hybridization distinguish altered gene transcription related to DNA recombination, RNA splicing regulation, RNA polymerase transcription, myelin synthesis, calcium regulation, and ubiquitin-proteasome system in c9FTLD; proteomics performed in the same tissue samples pinpoints abnormal protein expression involving apoptosis, inflammation, metabolism of amino acids, metabolism of carbohydrates, metabolism of membrane lipid derivatives, microtubule dynamics, morphology of mitochondria, neuritogenesis, neurotransmission, phagocytosis, receptor-mediated endocytosis, synthesis of reactive oxygen species, and calcium signaling in c9FTLD. Conclusion: Transcriptomics and proteomics, as well as bioinformatics processing of derived data, reveal similarly altered pathways in the frontal cortex in c9FTLD, but different RNAs and proteins are identified by these methods. Combined non-targeted ‘-omics’ is a valuable approach to deciphering altered molecular pathways in FTLD provided that observations are approached with caution when assessing human postmortem brain samples. Show more

Keywords: C9ORF72, frontotemporal lobar degeneration, FTLD-TDP, gene expression, proteomics

DOI: 10.3233/JAD-181123

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

Price: EUR 27.50

Choroid Plexus Acts as Gatekeeper for TREM2, Abnormal Accumulation of ApoE, and Fibrillary Tau in Alzheimer’s Disease and in Down Syndrome Dementia

Article Type: Research Article

Abstract: Background: Genetic factors that influence Alzheimer’s disease (AD) risk include mutations in TREM2 and allelic variants of Apolipoprotein E , influencing AD pathology in the general population and in Down syndrome (DS). Evidence shows that dysfunction of the choroid plexus may compromise the blood-cerebrospinal fluid (CSF) barrier, altering secretary, transport and immune function that can affect AD pathology. Objective: To investigate the genotype and phenotype of DS individuals in relation to choroid plexus damage and blood-CSF barrier leakage to identify markers that could facilitate early diagnosis of AD in DS. Methods: To assess allele frequency …and haplotype associations ApoE, Tau, TREM2 , and HLA-DR were analyzed by SNP analysis in DS participants (n = 47) and controls (n = 50). The corresponding plasma protein levels were measured by ELISA. Postmortem brains from DS, AD, and age-matched controls were analyzed by immunohistochemistry. Results: Haplotype analysis showed that individuals with Tau H1/H1 and ApoE ɛ 4 genotypes were more prevalent among DS participants with an earlier diagnosis of dementia (17%) compared to H1/H2 haplotypes (6%). Plasma TREM2 levels decreased whereas phospho-tau levels increased with age in DS. In AD and DS brain, insoluble tau and ApoE were found to accumulate in the choroid plexus. Conclusion: Accumulation of tau and ApoE in the choroid plexus may increase the oligomerization rate of Aβ42 and impair tau trafficking, leading to AD pathology. We have identified a high-risk haplotype: ApoE ɛ 4, Tau/H1 , and TREM2/T, that manifests age-related changes potentially opening a window for treatment many years prior to the manifestation of the AD dementia. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, blood-CSF barrier, choroid plexus, Down syndrome, high-risk haplotype, neuroinflammation, tau trafficking, TREM2, white matter tract

DOI: 10.3233/JAD-181179

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

Get PDF

Switching Ability Mediates the Age-Related Difference in Timed Up and Go Performance

Article Type: Research Article

Abstract: Age-related mobility and cognitive declines are closely linked, but their relationship is complex and needs to be further investigated. The study aimed to test if cognition (processing speed, inhibition and switching performances) mediate the age-related difference in mobility. Mediation analyses were used to test whether processing speed, inhibition and switching performances on the Stroop test mediate the relationship between age and performances at the Timed Up and Go (TUG). Only switching performances mediated the age-related difference in TUG (65.1% of the total effect) supporting the notion that executive control plays a critical role in older adults’ mobility.

Keywords: Aging, cognition, gait, inhibition, locomotion, mediation

DOI: 10.3233/JAD-181176

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

Price: EUR 27.50

Diagnostic Behavior for Mild Cognitive Impairment in General and Neuropsychiatric Practices in Germany

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

Price: EUR 27.50

Cyclooxygenase-2 is Essential for Mediating the Effects of Calcium Ions on Stimulating Phosphorylation of Tau at the Sites of Ser 396 and Ser 404

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

Price: EUR 27.50

Are Disease Modifying Treatments Enough? Improving Quality of Life in Late-Stage Patients

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

Price: EUR 27.50

Modulation of SPARC/Hevin Proteins in Alzheimer’s Disease Brain Injury

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

Get PDF

TREM2 Variants and Neurodegenerative Diseases: A Systematic Review and Meta-Analysis

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

Price: EUR 27.50

Low-Density Lipoprotein Particle Size Subfractions and Cerebral Amyloidosis

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

Price: EUR 27.50

Effects of CD33 Variants on Neuroimaging Biomarkers in Non-Demented Elders

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

Price: EUR 27.50

The NAAG’ing Concerns of Modeling Human Alzheimer’s Disease in Mice

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

Price: EUR 27.50

Altered Low-Frequency EEG Connectivity in Mild Cognitive Impairment as a Sign of Clinical Progression

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

Price: EUR 27.50

Rationale and Design of a Clinical Trial of Adapted Tango to Improve Negative Health Impacts in Middle Aged African-American Female Caregivers of Persons with Alzheimer’s Disease (ACT Trial)

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

Price: EUR 27.50

Intake of Meat, Fish, Fruits, and Vegetables and Long-Term Risk of Dementia and Alzheimer’s Disease

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

Price: EUR 27.50

Revisiting the Cerebrospinal Fluid Biomarker Profile in Idiopathic Normal Pressure Hydrocephalus: The Bologna Pro-Hydro Study

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

Price: EUR 27.50

Display: 10 | 50 | 100 items per page

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

North America

Europe

Asia