Journal of Alzheimer's Disease - Volume 68, issue 4

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-181029

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1561-1574, 2019

Authors: Black, Christopher M. | 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, healthcare costs, time-to-treatment

DOI: 10.3233/JAD-180983

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1575-1585, 2019

Authors: D’Onofrio, Grazia | Sancarlo, Daniele | Raciti, Massimiliano | Burke, Megan | Teare, Aimee | Kovacic, Tanja | Cortis, Keith | Murphy, Kathy | Barrett, Eva | Whelan, Sally | Dolan, Aisling | Russo, Alessandro | Ricciardi, Francesco | Pegman, Geoff | Presutti, Valentina | Messervey, Thomas | Cavallo, Filippo | Giuliani, Francesco | Bleaden, Andy | Casey, Dympna | Greco, Antonio

Article Type: Research Article

Abstract: Background: In the EU funded MARIO project, specific technological tools are adopted for the people living with dementia (PLWD). In the final stage of the project, a validation of the MARIO companion robot was performed from August to October 2017. Objective: The aims of the present study are: 1) to illustrate the key results and evidence obtained in the final evaluation phase of the project across the three different pilot sites; 2) to assess the engagement dimensions of the PLWD who interacted with the MARIO robot; and 3) to assess the acceptability and efficacy of the MARIO companion …robot on clinical, cognitive, neuropsychiatric, affective and social aspects, resilience, quality of life in PLWD, and burden level of the caregivers. Methods: 38 people (M = 14; F = 24) with Alzheimer’s disease were screened for eligibility and all were included. The following tests were administered Pre and Post interactions with MARIO: Observational Measurement of Engagement (OME), Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), Frontal Assessment Battery (FAB), Neuropsychiatric Inventory (NPI), Cornell Scale for Depression in Dementia (CSDD), Multidimensional Scale of Perceived Social Support (MSPSS), 14-item Resilience Scale (RS-14), Quality of Life in Alzheimer’s Disease (QOL-AD), Caregiver Burden Inventory (CBI), Tinetti Balance Assessment (TBA), and Comprehensive Geriatric Assessment (CGA) was carried out. Results: In Post-MARIO interactions, significant improvements were observed in RS-14 (p  = 0.020).Considering the age of the people, PLWD with 68–76 years perceived that they had major social support (MSPSS Total: p  = 0.016) and friends to support them (MSPSS Fri: p  = 0.014). Indeed, the younger people (55–67 years) were less depressed (CSDD: p  = 0.033), and more resilient (RS-14: p  = 0.003). The people aged 77–85 years perceived they had major family support (MSPSS Fam: p  = 0.018). The participants were gender and education matched without any statistically significant difference. Conclusion: MARIO may be a useful tool in mitigating depression and loneliness, while enhancing social connectedness, resilience, and overall quality of life for people with dementia. Show more

Keywords: Acceptability, comprehensive geriatric assessment, dementia, loneliness, resilience, robots, quality of care, quality of life, safety

DOI: 10.3233/JAD-181165

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1587-1601, 2019

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

Article Type: Research Article

Abstract: Neuropsychiatric symptoms (NPS) have been frequently described in Parkinson’s disease (PD), even in the earliest stages of the disease. Recently the construct of mild behavioral impairment (MBI) has been proposed as an at-risk state for incident cognitive decline and dementia. The aim of the present study is to evaluate the prevalence and associated factors of MBI in PD. Cross-sectional data from 429 consecutive PD patients enrolled in the PArkinson’s disease COgnitive impairment Study (PACOS) were included in the study. All subjects underwent neuropsychological assessment, according to the MDS Level II criteria. NPS were evaluated with the Neuropsychiatric Inventory. Multivariate logistic …regression models were used to evaluate clinical and behavioral characteristics, which are associated with PD-MBI. The latter 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 marginally with 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. 68, no. 4, pp. 1603-1610, 2019

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-180975

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1611-1624, 2019

Authors: Roe, Catherine M. | Stout, Sarah H. | Rajasekar, Ganesh | Ances, Beau M. | Jones, Jessica M. | Head, Denise | Benzinger, Tammie L.S. | Williams, Monique M. | Davis, Jennifer Duncan | Ott, Brian R. | Warren, David K. | Babulal, Ganesh M.

Article Type: Research Article

Abstract: Background: Emerging evidence shows that cognitively normal older adults with preclinical Alzheimer’s disease (AD) make more errors and are more likely to receive a marginal/fail rating on a standardized road test compared to older adults without preclinical AD, but the extent to which preclinical AD impacts everyday driving behavior is unknown. Objective: To examine self-reported and naturalistic longitudinal driving behavior among persons with and without preclinical AD. Method: We prospectively followed cognitively normal drivers (aged 65 + years) with (n  = 10) and without preclinical AD (n  = 10) for 2.5 years. Preclinical AD was assessed using amyloid positron emission …tomography (PET) with Pittsburgh Compound B. The Driving Habits Questionnaire assessed self-reported driving outcomes. Naturalistic driving was captured using a commercial GPS data logger plugged into the on-board diagnostics II port of each participant’s vehicle. Data were sampled every 30 seconds and all instances of speeding, hard braking, and sudden acceleration were recorded. Results: Preclinical AD participants went to fewer places/unique destinations, traveled fewer days, and took fewer trips than participants without preclinical AD. The preclinical AD group reported a smaller driving space, greater dependence on other drivers, and more difficulty driving due to vision difficulties. Persons with preclinical AD had fewer trips with any aggression and showed a greater decline across the 2.5-year follow-up period in the number of days driving per month and the number of trips between 1–5 miles. Conclusion: Changes in driving occur even during the preclinical stage of AD. Show more

Keywords: Alzheimer’s disease,, automobile driving,, biomarkers, motor vehicles

DOI: 10.3233/JAD-181242

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1625-1633, 2019

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-181085

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1635-1656, 2019

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-180396

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1657-1666, 2019

Authors: Shi, Xiaowen | Ohta, Yasuyuki | Liu, Xia | Shang, Jingwei | Morihara, Ryuta | Nakano, Yumiko | Feng, Tian | Huang, Yong | Sato, Kota | Takemoto, Mami | Hishikawa, Nozomi | Yamashita, Toru | Abe, Koji

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common dementia and a progressive neurodegenerative disorder aggravated by chronic hypoperfusion (HP). Since numerous evidence suggests that inflammation is related with AD pathology, we investigated the expression change of two anti-inflammatory markers, inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and alpha-2-HS-glycoprotein (AHSG), in a novel AD model (APP23) with HP at 12 month of age. As compared with wild type (WT, n  = 10), immunohistochemical analysis showed a higher ITIH4 and a lower AHSG expressions in the cerebral cortex, hippocampus, and thalamus of the APP23 + HP group (n  = 12) than the simple APP23 (n  = 10) group (* …p  < 0.05 and ** p  < 0.01 versus WT; # p  < 0.05 and # # p  < 0.01 versus APP23). The present study provides an upregulation of anti-inflammatory ITIH4 and a downregulation of pro-inflammatory TNFα -dependent AHSG in a novel AD plus HP mice model. Show more

Keywords: AHSG, alzheimer’s disease, APP23 mice, hypoperfusion, inflammation, ITIH4

DOI: 10.3233/JAD-181218

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1667-1675, 2019

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-181001

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1677-1686, 2019

Authors: Ju, Shiming | Xu, Chen | Wang, Gan | Zhang, Lin

Article Type: Research Article

Abstract: Traumatic brain injury (TBI), a brain disorder that causes death and long-term disability in humans, is increasing in prevalence, though there is a lack of protective or therapeutic strategies for mitigating the damage after TBI and for preserving neurological functionality. Microglia cells play a key role in neuroinflammation following TBI, but their regulation and polarization by a member of the vascular endothelial growth factor (VEGF) family, VEGF-C, is unknown. Here, we show that VEGF-C induced M2 polarization in a murine microglia cell line, BV-2, in vitro , by a mechanism that required signaling from its unique receptor, VEGF receptor 3 …(VEGFR3). Moreover, in a TBI model in rats, VEGF-C administration induced M2 polarization of microglia cells, significantly improved motor deficits after experimental TBI, and significantly improved neurological function following TBI, likely through a reduction in cell apoptosis. Together, our data reveal a previously unknown role of VEGF-C/VEGFR3 signaling in the regulation of post-TBI microglia cell polarization, which appears to be crucial for recovery from TBI. Show more

Keywords: Microglia, polarization, traumatic brain injury, VEGF-C, VEGFR3

DOI: 10.3233/JAD-190063

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1687-1697, 2019

Authors: Farr, Susan A. | Roesler, Elizabeth | Niehoff, Michael L. | Roby, Deborah A. | McKee, Alexis | Morley, John E.

Article Type: Research Article

Abstract: Metformin is used for the treatment of insulin resistant diabetes. Diabetics are at an increased risk of developing dementia. Recent epidemiological studies suggest that metformin treatment prevents cognitive decline in diabetics. A pilot clinical study found cognitive improvement with metformin in patients with mild cognitive impairment (MCI). Preclinical studies suggest metformin reduces Alzheimer-like pathology in mouse models of Alzheimer’s disease (AD). In the current study, we used 11-month-old SAMP8 mice. Mice were given daily injections of metformin at 20 mg/kg/sc or 200 mg/kg/sc for eight weeks. After four weeks, mice were tested in T-maze footshock avoidance, object recognition, and Barnes maze. At …the end of the study, brain tissue was collected for analysis of PKC (PKCζ , PKCι , PKCα , PKCγ , PKCɛ ), GSK-3β , pGSK-3β ser9, pGSK-3β tyr216, pTau404, and APP. Metformin improved both acquisition and retention in SAMP8 mice in T-maze footshock avoidance, retention in novel object recognition, and acquisition in the Barnes maze. Biochemical analysis indicated that metformin increased both atypical and conventional forms of PKC; PKCζ , and PKCα at 20 mg/kg. Metformin significantly increased pGSK-3β ser9 at 200 mg/kg, and decreased Aβ at 20 mg/kg and pTau404 and APPc99 at both 20 mg/kg and 200 mg/kg. There were no differences in blood glucose levels between the aged vehicle and metformin treated mice. Metformin improved learning and memory in the SAMP8 mouse model of spontaneous onset AD. Biochemical analysis indicates that metformin improved memory by decreasing APPc99 and p Tau. The current study lends support to the therapeutic potential of metformin for AD. Show more

Keywords: Learning, memory, metformin, PKC, SAMP8, tau

DOI: 10.3233/JAD-181240

Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1699-1710, 2019