Journal of Alzheimer's Disease - Volume 63, issue 4

Authors: Adams, Stephanie L. | Benayoun, Laurent | Tilton, Kathy | Mellott, Tiffany J. | Seshadri, Sudha | Blusztajn, Jan Krzysztof | Delalle, Ivana

Article Type: Research Article

Abstract: The pathophysiology of Alzheimer’s disease (AD) includes signaling defects mediated by the transforming growth factor β—bone morphogenetic protein—growth and differentiation factor (TGFβ-BMP-GDF) family of proteins. In animal models of AD, administration of BMP9/GDF2 improves memory and reduces amyloidosis. The best characterized type I receptor of BMP9 is ALK1. We characterized ALK1 expression in the hippocampus using immunohistochemistry. In the rat, ALK1 immunoreactivity was found in CA pyramidal neurons, most frequently and robustly in the CA2 and CA3 fields. In addition, there were sporadic ALK1-immunoreactive cells in the stratum oriens, mainly in CA1. The ALK1 expression pattern in human hippocampus was …similar to that of rat. Pyramidal neurons within the CA2, CA3, and CA4 were strongly ALK1-immunoreactive in hippocampi of cognitively intact subjects with no neurofibrillary tangles. ALK1 signal was found in the axons of alveus and fimbria, and in the neuropil across CA fields. Relatively strongest ALK1 neuropil signal was observed in CA1 where pyramidal neurons were occasionally ALK1-immunoractive. As in the rat, horizontally oriented neurons in the stratum oriens of CA1 were both ALK1- and GAD67-immunoreactive. Analysis of ALK1 immunoreactivity across stages of AD pathology revealed that disease progression was characterized by overall reduction of the ALK1 signal in CA3 in advanced, but not early, stages of AD. These data suggest that the CA3 pyramidal neurons may remain responsive to the ALK1 ligands, e.g., BMP9, during initial stages of AD and that ALK1 may constitute a therapeutic target in early and moderate AD. Show more

Keywords: ACVRL1, ALK1, CA1, CA3, GAD67, hippocampus, immunohistochemistry

DOI: 10.3233/JAD-171065

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1433-1443, 2018

Authors: Bourgin, Jessica | Guyader, Nathalie | Chauvin, Alan | Juphard, Alexandra | Sauvée, Mathilde | Moreaud, Olivier | Silvert, Laetitia | Hot, Pascal

Article Type: Research Article

Abstract: Emotional deficits have been repetitively reported in Alzheimer’s disease (AD) without clearly identifying how emotional processing is impaired in this pathology. This paper describes an investigation of early emotional processing, as measured by the effects of emotional visual stimuli on a saccadic task involving both pro (PS) and anti (AS) saccades. Sixteen patients with AD and 25 age-matched healthy controls were eye-tracked while they had to quickly move their gaze toward a positive, negative, or neutral image presented on a computer screen (in the PS condition) or away from the image (in the AS condition). The age-matched controls made more …AS mistakes for negative stimuli than for other stimuli, and triggered PSs toward negative stimuli more quickly than toward other stimuli. In contrast, patients with AD showed no difference with regard to the emotional category in any of the tasks. The present study is the first to highlight a lack of early emotional attention in patients with AD. These results should be taken into account in the care provided to patients with AD, since this early impairment might seriously degrade their overall emotional functioning. Show more

Keywords: Alzheimer’s disease, attention, emotion, eye movements, inhibition

DOI: 10.3233/JAD-180170

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1445-1458, 2018

Authors: Smith, Glenn E. | Chandler, Melanie | Fields, Julie A. | Aakre, Jeremiah | Locke, Dona E.C.

Article Type: Research Article

Abstract: Background: The patient-centered movement in health care is increasing efforts to design studies and interventions that address the outcomes that matter most to patients and their families. Research has not adequately addressed Alzheimer’s disease patient and caregiver preferences. Objective: To survey the outcome and treatment preferences of patients and caregivers who had completed a multicomponent behavioral intervention for mild cognitive impairment (MCI). Methods: Extending prior work, we conducted an online survey regarding outcome and intervention preferences. Participants were patients with MCI and partners who completed the HABIT Healthy Action to Benefit Independence & Thinking ® program. …Results: Both patient and partner respondents ranked patient quality of life as the highest priority, followed by patient self-efficacy, functional status, patient mood, and patient memory performance. Distressing behaviors and caregiver outcomes (burden, mood, and self-efficacy) had low rankings. Regarding the importance of HABIT ® program components, memory compensation training was ranked highest and wellness education lowest by all groups. Conclusion: Additional research should compare patient preference for patient reported outcomes, traditional neuropsychological and clinician outcomes, and modern biomarker outcomes. Show more

Keywords: Behavioral intervention, caregiver, daily function, mild cognitive impairment, patient preference, quality of life

DOI: 10.3233/JAD-171161

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1459-1468, 2018

Authors: Falck, Ryan S. | Best, John R. | Davis, Jennifer C. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Current evidence suggests physical activity (PA) and sleep are important for cognitive health; however, few studies examining the role of PA and sleep for cognitive health have measured these behaviors objectively. Objective: We cross-sectionally examined whether 1) higher PA is associated with better cognitive performance independently of sleep quality; 2) higher sleep quality is associated with better cognitive performance independently of PA; and 3) whether higher PA is associated with better sleep quality. Methods: We measured PA, subjective sleep quality using the Pittsburgh Sleep Quality Index (PSQI), and objective sleep quality (i.e., fragmentation, efficiency, duration, …and latency) using the MotionWatch8© in community-dwelling adults (N = 137; aged 55+). Cognitive function was indexed using the Alzheimer’s Disease Assessment Scale-Plus. Correlation analyses were performed to determine relationships between PA, sleep quality, and cognitive function. We then used latent variable modelling to examine the relationships of PA with cognitive function independently of sleep quality, sleep quality with cognitive function independently of PA, and PA with sleep quality. Results: We found greater PA was associated with better cognitive performance independently of 1) PSQI (β = –0.03; p  < 0.01); 2) sleep fragmentation (β = –0.02; p  < 0.01); 3) sleep duration (β = –0.02; p  < 0.01); and 4) sleep latency (β = –0.02; p  < 0.01). In addition, better sleep efficiency was associated with better cognitive performance independently of PA (β = –0.01; p  = 0.04). We did not find any associations between PA and sleep quality. Conclusions: PA is associated with better cognitive performance independently of sleep quality, and sleep efficiency is associated with better cognitive performance independently of PA. However, PA is not associated with sleep quality and thus PA and sleep quality may be related to cognitive performance through independent mechanisms. Show more

Keywords: Cognitive function, older adults, physical activity, sleep

DOI: 10.3233/JAD-170936

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1469-1484, 2018

Authors: Banerjee, Gargi | Jang, Hyemin | Kim, Hee Jin | Kim, Sung Tae | Kim, Jae Seung | Lee, Jae Hong | Im, Kiho | Kwon, Hunki | Lee, Jong Min | Na, Duk L. | Seo, Sang Won | Werring, David John

Article Type: Research Article

Abstract: Background: Recent evidence suggests that combining individual imaging markers of cerebral small vessel disease (SVD) may more accurately reflect its overall burden and better correlate with clinical measures. Objective: We wished to establish the clinical relevance of the total SVD score in a memory clinic population by investigating the association with SVD score and cognitive performance, cortical atrophy, and structural network measures, after adjusting for amyloid-β burden. Methods: We included 243 patients with amnestic mild cognitive impairment (MCI), Alzheimer’s disease dementia, subcortical vascular MCI, or subcortical vascular dementia. All underwent MR and [11 C] PiB-PET scanning …and had standardized cognitive testing. Multiple linear regression was used to evaluate the relationships between SVD score and cognition, cortical thickness, and structural network measures. Path analyses were performed to evaluate whether network disruption mediates the effects of SVD score on cortical thickness and cognition. Results: Total SVD score was associated with the performance of frontal (β – 4.31, SE 2.09, p  = 0.040) and visuospatial (β – 0.95, SE 0.44, p  = 0.032) tasks, and with reduced cortical thickness in widespread brain regions. Total SVD score was negatively correlated with nodal efficiency, as well as changes in brain network organization, with evidence of reduced integration and increasing segregation. Path analyses showed that the associations between SVD score and frontal and visuospatial scores were partially mediated by decreases in their corresponding nodal efficiency and cortical thickness. Conclusion: Total SVD burden has clinical relevance in a memory clinic population and correlates with cognition, and cortical atrophy, as well as structural network disruption. Show more

Keywords: Alzheimer’s disease, cerebral small vessel diseases, cognitive dysfunction, magnetic resonance imaging, positron-emission tomography, vascular dementia

DOI: 10.3233/JAD-170943

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1485-1497, 2018

Authors: Paire-Ficout, Laurence | Lafont, Sylviane | Conte, Fanny | Coquillat, Amandine | Fabrigoule, Colette | Ankri, Joël | Blanc, Frédéric | Gabel, Cécilia | Novella, Jean-Luc | Morrone, Isabella | Mahmoudi, Rachid

Article Type: Research Article

Abstract: Background: Because cognitive processes decline in the earliest stages of Alzheimer’s disease (AD), the driving abilities are often affected. The naturalistic driving approach is relevant to study the driving habits and behaviors in normal or critical situations in a familiar environment of participants. Objective: This pilot study analyzed in-car video recordings of naturalistic driving in patients with early-stage AD and in healthy controls, with a special focus on tactical self-regulation behavior. Methods: Twenty patients with early-stage AD (Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria), and 21 healthy older adults were included in …the study. Data collection equipment was installed in their personal vehicles. Two expert psychologists assessed driving performance using a specially designed Naturalistic Driving Assessment Scale (NaDAS), paying particular attention to tactical self-regulation behavior, and they recorded all critical safety events. Results: Poorer driving performance was observed among AD drivers: their tactical self-regulation behavior was of lower quality. AD patients had also twice as many critical events as healthy drivers and three times more “unaware” critical events. Conclusion: This pilot study used a naturalistic approach to accurately show that AD drivers have poorer tactical self-regulation behavior than healthy older drivers. Future deployment of assistance systems in vehicles should specifically target tactical self-regulation components. Show more

Keywords: Alzheimer’s disease, critical events, dementia, naturalistic driving, self-awareness

DOI: 10.3233/JAD-171031

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1499-1508, 2018

Authors: Niemantsverdriet, Ellis | Ribbens, Annemie | Bastin, Christine | Benoit, Florence | Bergmans, Bruno | Bier, Jean-Christophe | Bladt, Roxanne | Claes, Lene | De Deyn, Peter Paul | Deryck, Olivier | Hanseeuw, Bernard | Ivanoiu, Adrian | Lemper, Jean-Claude | Mormont, Eric | Picard, Gaëtane | Salmon, Eric | Segers, Kurt | Sieben, Anne | Smeets, Dirk | Struyfs, Hanne | Thiery, Evert | Tournoy, Jos | Triau, Eric | Vanbinst, Anne-Marie | Versijpt, Jan | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer’s disease (AD). Objective: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. Methods: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n  = 887) and follow-up (FU, n  = 95) T1-weighted …brain MRIs and time-linked neuropsychological data were available. Results: The cohort consisted of cognitively healthy controls (HC, n  = 93), subjective cognitive decline (n  = 102), mild cognitive impairment (MCI, n  = 379), and AD dementia (n  = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n  = 95) compared to HC (FU>24months, p  = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment. Conclusion: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials. Show more

Keywords: Alzheimer’s disease, biomarkers, magnetic resonance image, MSmetrix, volumetry

DOI: 10.3233/JAD-171140

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1509-1522, 2018

Authors: Bessi, Valentina | Mazzeo, Salvatore | Padiglioni, Sonia | Piccini, Carolina | Nacmias, Benedetta | Sorbi, Sandro | Bracco, Laura

Article Type: Research Article

Abstract: The aim of this study was to evaluate the accuracy of neuropsychological assessment in predicting conversion from subjective cognitive decline (SCD) and mild cognitive impairment (MCI) to Alzheimer’s disease (AD) and the effect of personality traits and cognitive reserve in progression from SCD to MCI. As part of a longitudinal, clinical-neuropsychological-genetic survey on SCD and MCI, 284 patients referred to our hospital between 1990 and 2017 were included. All patients underwent clinical-extensive neuropsychological evaluation and Apolipoprotein E genotyping; personality traits were assessed in a subgroup. Each patient underwent clinical-neuropsychological follow-up. Subjects with a follow-up shorter than two years were excluded. …A total of 212 subjects were, after exclusions, considered: 26 out of 109 SCD subjects progressed to MCI (SCD-p), 15 converted to AD (SCD-c), and 68 remained stable (SCD-s). Of 103 MCI subjects, 39 converted to AD (MCI-c) and 64 remained stable (MCI-s). At baseline, SCD-c performed significantly worse than SCD-s in tests assessing long-term verbal memory. MCI-c showed worse performance on neuropsychological tests for short- and long-term verbal memory and for ecological evaluation of memory (RBMT). These tests provided good accuracy in distinguishing MCI-c and MCI-s. Emotional stability was significantly lower in SCD-s than in SCD-p while higher intellectual activities were associated with a lower risk of conversion to MCI. Our results suggest that memory neuropsychological tests may represent a reliable tool to estimate the risk of progression to AD. Personality and lifestyle factors could provide useful information to identify SCD subjects who may develop an objective cognitive impairment. Show more

Keywords: Alzheimer’s disease, APOE, cognitive reserve, dementia, mild cognitive impairment, neuropsychology, personality traits, prediction, subjective cognitive decline

DOI: 10.3233/JAD-171180

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1523-1535, 2018

Authors: Chai, Gao-Shang | Feng, Qiong | Ma, Rong-Hong | Qian, Xiao-Hang | Luo, Dan-Ju | Wang, Zhi-Hao | Hu, Yu | Sun, Dong-Sheng | Zhang, Jun-Fei | Li, Xiao | Li, Xiao-Guang | Ke, Dan | Wang, Jian-Zhi | Yang, Xi-Fei | Liu, Gong-Ping

Article Type: Research Article

Abstract: There is accumulating evidence that decreased histone acetylation is involved in normal aging and neurodegenerative diseases. Recently, we found that ANP32A, a key component of INHAT (inhibitor of acetyltransferases) that suppresses histone acetylation, increased in aged and cognitively impaired C57 mice and expressing wild-type human full length tau (htau) transgenic mice. Downregulating ANP32A restored cognitive function and synaptic plasticity through upregulation of the expressions of synaptic-related proteins via increasing histone acetylation. However, there is no direct evidence that ANP32A can induce neurodegeneration and memory deficits. In the present study, we overexpressed ANP32A in the hippocampal CA3 region of C57 mice …and found that ANP32A overexpression induced cognitive abilities and synaptic plasticity deficits, with decreased synaptic-related protein expression and histone acetylation. Combined with our recent studies, our findings reveal that upregulated ANP32A induced-suppressing histone acetylation may underlie the cognitive decline in neurodegenerative disease, and suppression of ANP32A may represent a promising therapeutic approach for neurodegenerative diseases including Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, ANP32A, cognition, histone acetylation, synaptic-related protein

DOI: 10.3233/JAD-180090

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1537-1546, 2018

Authors: Miron, Justin | Picard, Cynthia | Frappier, Josée | Dea, Doris | Théroux, Louise | Poirier, Judes

Article Type: Research Article

Abstract: One important aspect in Alzheimer’s disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer’s disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF …genes (p  = 0.001 and p  = 0.025, respectively), as well as a trend for higher IL6 gene expression in the frontal cortex of AD subjects when compared to age-matched controls. Similarly, using a mouse model of hippocampal deafferentation without amyloidosis, (i.e., the entorhinal cortex lesioned mouse), we observed significant increases in the expression of both the Tlr4 (p  = 0.0367 and p  = 0.0193 compared to sham-lesioned mice or to the contralateral side, respectively) and Il1b (p  = 0.0055 and p  = 0.0066 compared to sham-lesioned mice or to the contralateral side, respectively) genes in the deafferentation phase, but not during the ensuing reinnervation process. In conclusion, we suggest that the modulation of cytokines by TLR4 is differentially regulated whether by the presence of amyloid plaques or by the ongoing deafferentation process. Show more

Keywords: Alzheimer’s disease, cytokines, inflammation, TLR4

DOI: 10.3233/JAD-171160

Citation: Journal of Alzheimer's Disease, vol. 63, no. 4, pp. 1547-1556, 2018