Journal of Alzheimer's Disease - Volume 69, issue 1

Authors: Bardach, Shoshana H. | Jicha, Gregory A. | Karanth, Shama | Zhang, Xuan | Abner, Erin L.

Article Type: Research Article

Abstract: Background: Genetic data help detect preclinical Alzheimer’s disease and target individuals for clinical trials, making genetic research engagement critical for continued advancement in dementia prevention and treatment. Objective: To understand what individual and institutional factors may relate to provision of genetic samples within the Alzheimer’s Disease Centers. Methods: Data from the National Alzheimer’s Coordinating Center Uniform Data Set (2009–2016) were obtained along with genetic sample availability. Logistic regression was used to assess independent contributions of demographic and clinical characteristics to the probability of sample provision. Sites contributing data completed a brief survey exploring regulatory and scientific …issues related to genetic research engagement. Results: Just over half (52.1%) of the 27,519 unique participants had genetic data available. Female sex, white race, non-Hispanic ethnicity, normal cognition, and greater than 5 years of follow-up were associated with greater probability of availability. Sites identified refusals as the most frequent barrier to sample provision, followed by staff availability. Conclusion: These results highlight the importance of strategies to promote minority engagement and encourage earlier genetic research participation. Show more

Keywords: Alzheimer’s disease, genetic research, patient participation, surveys and questionnaires

DOI: 10.3233/JAD-181159

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 123-133, 2019

Authors: Huang, Rong | Tian, Sai | Han, Jing | Lin, Hongyan | Guo, Dan | Wang, Jiaqi | An, Ke | Wang, Shaohua

Article Type: Research Article

Abstract: Background: Serum uric acid (SUA) is a natural antioxidant that may exert neuroprotective effects against neurodegenerative diseases. The relationship between uric acid and cognitive functions has been extensively studied, but results remain conflicting. Objective: To investigate potential associations between SUA level and mild cognitive impairment (MCI), and different domains of cognitive performances in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 352 T2DM subjects (208 males and 144 females) were enrolled. SUA level was determined by using the uricase method. Cognitive performances were assessed using a validated neuropsychological test battery. Generalized additive models …and binary logistic regression analysis were fitted to determine the association between SUA and cognitive functions. Results: A total of 157 T2DM patients had MCI, and 195 displayed normal cognition. Compared with the controls, MCI patients exhibited lower SUA level (p  = 0.009). Generalized additive models revealed a U-shaped curve relationship among SUA with Montreal Cognitive Assessment, Auditory Verbal Learning Test-immediate recall and Trail Making Test-B scores (all p  < 0.05). Further logistic regression analysis showed a significant trend toward decreased MCI risk with increased SUA level among the subjects whose SUA level was below the cut-point (388.63 μmol/L); each unit increment in SUA level reduced the MCI risk by 0.7% (p  = 0.003). Conclusion: A U-shaped association between SUA level and global cognitive function, especially executive and memory function, existed in T2DM patients. Our findings will provide additional suggestions that an increase of SUA to a certain level may be a novel method to reduce the burden of T2DM-associated cognitive impairment. Show more

Keywords: Executive function, memory function, mild cognitive impairment, type 2 diabetes mellitus, uric acid

DOI: 10.3233/JAD-181126

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 135-144, 2019

Authors: Li, Chunfei | Duara, Ranjan | Loewenstein, David A. | Izquierdo, Walter | Cabrerizo, Mercedes | Barker, Warren | Adjouadi, Malek | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Regional cortical thickness (rCTh) among cognitively normal (CN) adults (rCThCN ) varies greatly between brain regions, as does the vulnerability to neurodegeneration. Objective: The goal of this study was to: 1) rank order rCThCN for various brain regions, and 2) explore their vulnerability to neurodegeneration in Alzheimer’s disease (AD) within these brain regions. Methods: The relationship between rCTh among the CN group (rCThCN ) and the percent difference in CTh (% CThDiff ) in each region between the CN group and AD patients was examined. Pearson correlation analysis was performed accounting for amyloid-β (Aβ) …protein and APOE genotype using 210 age, gender, and APOE matched CN (n  = 105, age range: 56–90) and AD (n  = 105, age range: 56–90) ADNI participants. Results: Strong positive correlations were observed between rCThCN and % CThDiff accounting for Aβ deposition and APOE status. Regions, such as the entorhinal cortex, which had the greatest CTh in the CN state, were also the regions which had the greatest % CThDiff . Conclusions: Regions with the greatest CTh at the CN stage are found to aggregate in disease prone regions of AD, namely in the medial temporal lobe, including the temporal pole, ERC, parahippocampal gyrus, fusiform and the middle and inferior temporal gyrus. Although rCTh has been found to vary considerably across the different regions of the brain, our results indicate that regions with the greatest CTh at the CN stage are actually regions which have been found to be most vulnerable to neurodegeneration in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , APOE, cortical atrophy, neuroimaging

DOI: 10.3233/JAD-180231

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 145-156, 2019

Authors: Patrick, Sarah | Corrigan, Rachel | Grizzanti, John | Mey, Megan | Blair, Jeff | Pallas, Merce | Camins, Antonio | Lee, Hyoung-gon | Casadesus, Gemma

Article Type: Research Article

Abstract: Administration of the recombinant analog of the pancreatic amyloid amylin, Pramlintide, has shown therapeutic benefits in aging and Alzheimer’s disease (AD) models, both on cognition and amyloid-β (Aβ) pathology. However, the neuroprotective mechanisms underlying the benefits of Pramlintide remain unclear. Given the early and critical role of oxidative stress in AD pathogenesis and the known reactive oxygen species (ROS) modulating function of amyloids, we sought to determine whether Pramlintide’s neuroprotective effects involve regulation of oxidative stress mechanisms. To address this, we treated APP/PS1 transgenic mice with Pramlintide for 3 months, starting at 5.5 months prior to widespread AD pathology onset, …and measured cognition (Morris Water Maze), AD pathology, and oxidative stress-related markers and enzymes in vivo . In vitro , we determined the ability of Pramlintide to modulate H2 O2 -induced oxidative stress levels. Our data show that Pramlintide improved cognitive function, altered amyloid-processing enzymes, reduced plaque burden in the hippocampus, and regulated endogenous antioxidant enzymes (MnSOD and GPx1) and the stress marker HO-1 in a location specific manner. In vitro , Pramlintide treatment in neuronal models reduced H2 O2 -induced endogenous ROS production and lipid peroxidation in a dose-dependent manner. Together, these results indicate that Pramlintide’s benefits on cognitive function and pathology may involve antioxidant-like properties of this compound. Show more

Keywords: Alzheimer’s disease, amylin, metabolism, neuroprotection, oxidative stress, pramlintide

DOI: 10.3233/JAD-180421

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 157-168, 2019

Authors: Li, Wei-Wei | Shen, Ying-Ying | Tian, Ding-Yuan | Bu, Xian-Le | Zeng, Fan | Liu, Yu-Hui | Chen, Yang | Yao, Xiu-Qing | Li, Hui-Yun | Chen, Dong-Wan | Zhou, Fa-Ying | Yang, Heng | Li, Qi-Ming | Bao, Wei-Qi | Guan, Yi-Hui | Zhou, Hua-Dong | Jin, Rong-Bing | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Brain amyloid-β (Aβ) deposition is a hallmark to define Alzheimer’s disease (AD). We investigated the positive rate of brain amyloid deposition assessed with 11 C-Pittsburgh compound (PiB)-PET and blood Aβ levels in a cohort of probable AD patients who were diagnosed according to the 1984 NINCDS-ADRDA criteria. Eighty-four subjects with a clinical diagnosis of probable AD dementia, amnestic mild cognitive impairment (MCI), and cognitively normal (CN) status were subjected to PiB-PET and 18 F-fluorodeoxyglucose (FDG)-PET scans. Plasma biomarkers of Aβ42 , Aβ40 , and T-tau were measured using single molecule array technology. The positive rate of PiB-PET, the associations between …PiB-PET status and FDG-PET, plasma biomarkers, and clinical manifestations were analyzed. PiB-PET was positive in 77.36% of probable AD patients, 31.80% of MCI patients, and 0 of NC. Plasma Aβ42 /Aβ40 ratio was associated with PiB-PET, the ROC curve analysis revealing an AUC of 0.77 (95% CI: 0.66–0.87), with a sensitivity of 82% and specificity of 64%. Some clinical manifestations were associated with PiB-PET imaging. Our findings indicate that only three-fourths of patients diagnosed with probable AD fit the pathological criteria, suggesting that we should be cautious regarding the accuracy of AD diagnosis when no biomarker evidence is available in our clinical practice. Show more

Keywords: Alzheimer’s disease, amyloid-beta, amyloid PET, blood biomarkers, diagnosis, mild cognitive impairment, probable AD dementia, tau

DOI: 10.3233/JAD-190056

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 169-178, 2019

Authors: Costa, Andrea Saul | Guerini, Franca Rosa | Arosio, Beatrice | Galimberti, Daniela | Zanzottera, Milena | Bianchi, Anna | Nemni, Raffaello | Clerici, Mario

Article Type: Research Article

Abstract: The SNARE complex plays a crucial role in the synaptic exocytosis of neurotransmitters, a process involved in the Alzheimer’s disease (AD), the most common form of dementia. SNAP-25, STX1a, and VAMP2 are the core proteins of the SNARE complex, and changes in protein level are suggested to contribute to cognitive impairment and neuropsychiatric disorders. Single nucleotide polymorphisms (SNPs) in SNARE complex genes were shown to be associated with different diseases and different cognitive impairments. Chi-square analysis was used to compare case-control difference of ApoE4, SNAP-25 rs363039, rs363043, rs363950, STX1a rs4717806, rs2293489, and VAMP2 26bp Ins/Del genotype distribution …in 192 AD, 187 mild cognitive impairment (MCI), and 200 healthy controls (HC). Results of genotype and allelic distribution of SNAP-25 rs363050 showed that AA genotype (AD versus HC: p  = 1.5×10–4 ; MCI versus HC: p  = 8.7×10–3 ) as well as A allele (AD versus HC: p  = 6.0×10–4 ; MCI versus HC: p  = 5.7×10–3 ) are significantly more frequent in AD and MCI compared to HC. Genotype distribution of STX1a rs4717806 and rs2293489 resulted significantly different in AD compared to HC (p  = 0.032 and p  = 0.047, respectively). Moreover, distribution of the STX1a rs4717806 allele in SNAP-25 rs363050 AA carriers was significantly different between MCI and HC (p  = 0.018). Notably, in MCI, visual selective attention impairment was associated with the STX1a rs4717806 AA (pc  = 0.027) genotype as well as the SNAP-25/STX1a rs363050/rs4717806 AA/A (pc  = 0.022) combination. These data suggest that SNPs in SNARE complex genes may interfere and/or modulate the activity of the SNARE complex resulting in impairments of neurotransmission that involve attention brain areas. Show more

Keywords: Alzheimer’s disease, cognitive impairment, gene polymorphisms, mild cognitive impairment, SNAP-25, SNARE, SNPs, STX1a, VAMP2

DOI: 10.3233/JAD-190147

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 179-188, 2019

Authors: Jernerén, Fredrik | Cederholm, Tommy | Refsum, Helga | Smith, A. David | Turner, Cheryl | Palmblad, Jan | Eriksdotter, Maria | Hjorth, Erik | Faxen-Irving, Gerd | Wahlund, Lars-Olof | Schultzberg, Marianne | Basun, Hans | Freund-Levi, Yvonne

Article Type: Research Article

Abstract: Background: Trials of supplementation with omega-3 fatty acids (ω 3-FAs) in patients with mild cognitive impairment or Alzheimer’s disease (AD) have produced inconsistent effects on cognitive decline. There is evidence of an interaction between B vitamin status and ω 3-FAs in relation to brain atrophy and cognitive decline. Objective: We investigated whether baseline levels of plasma total homocysteine (tHcy), a marker of B vitamin status, modify the effects of ω 3-FAs supplementation on cognitive performance in moderate AD. Methods: This post hoc analysis of the OmegAD trial included 171 community-based patients with AD (MMSE≥15): 88 …patients received daily doses of 1.7 g docosahexaenoic acid and 0.6 g eicosapentaenoic acid for 6 months. Treatment outcome on cognition was analyzed according to baseline levels of tHcy using a general linear model and ANCOVA. Results: We found significant interactions between ω 3-FA supplementation and tHcy on cognition and clinical stage assessed by MMSE (p  = 0.040), global CDR (p  = 0.059), and CDRsob (p  = 0.023), but not on ADAS-cog (p  = 0.649). In patients with tHcy levels <11.7μ mol/L, ω 3-FA supplementation improved cognitive performance as measured by MMSE (+7.1%, 95% CI: 0.59 to 13.7%, p  = 0.033) and clinical status as measured by CDRsob (–22.3%, 95% CI: –5.8 to –38.7%, p  = 0.009) compared with placebo. Conclusion: The effect of ω 3-FA supplementation on MMSE and CDR appears to be influenced by baseline tHcy, suggesting that adequate B vitamin status is required to obtain beneficial effects of ω 3-FA on cognition. Show more

Keywords: Alzheimer’s disease, B vitamins, cognition, dementia, homocysteine, omega-3 fatty acids

DOI: 10.3233/JAD-181148

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 189-197, 2019

Authors: Qiu, Qiongqiong | Shen, Luxi | Jia, Longfei | Wang, Qi | Li, Fangyu | Li, Ying | Jia, Jianping

Article Type: Research Article

Abstract: Background: Presenilin1 (PSEN1 ) is the most common gene related to familial Alzheimer’s disease (AD). Only several mutation types from Chinese have been reported, with less biological function research conducted. Objectives: We explore the pathological function of PSEN1 M139L, a mutation located at α -helix of PSEN1 transmembrane 2, using predictive programs and in vitro study and compare its effects on Aβ production to those of an artificial PSEN1 S141G located at non α -helix mutation face. Methods: APP , PSEN1, and PSEN2 genes were screened for mutations using Sanger sequencing in the …DNA samples of the proband and additional available family members. Disease-mutation cosegregation analysis and three software programs were performed to predict the mutation’s pathogenicity. In vitro , we investigated the impact of these mutations on Aβ production in HEK293-APPswe cells using lentiviral vectors harboring PSEN1 WT, PSEN1 M139L, the positive control (PSEN1 M139V) and the non α -helical mutation (PSEN1 S141G). In addition, we co-transfected PSEN1 and tau into cells to determine the mutations’ impact on tau phosphorylation. Results: PSEN1 M139L mutation was discovered in the index patient and four affected siblings. Cosegregation analysis and silicon prediction suggested the mutation was probably disease causing. In vitro studies demonstrated that both PSEN1 M139L and PSEN1 S141G caused elevated ratios of Aβ42 /Aβ40 , but changes of tau phosphorylation were not detected. Conclusion: The novel PSEN1 M139L mutation found in familial AD increases the Aβ42 /Aβ40 ratio significantly. Mutations at non α -helical mutation face of PSEN1 TM2 can affect Aβ production and the region may play a key role in PSEN1 function. Show more

Keywords: α-helix, Alzheimer’s disease, amyloid-β , mutation, presenilin

DOI: 10.3233/JAD-181291

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 199-212, 2019

Authors: Kim, Seung Joo | Jung, Na-Yeon | Kim, Young Ju | Park, Seong Beom | Kim, KoWoon | Kim, Yeshin | Jang, Hyemin | Kim, Si Eun | Cho, Soo Hyun | Kim, Jun Pyo | Jung, Young Hee | Woo, Sook-Young | Kim, Seon Woo | Lockhart, Samuel N. | Kim, Eun-Joo | Kim, Hee Jin | Lee, Jong-Min | Chin, Juhee | Na, Duk L. | Seo, Sang Won

Article Type: Research Article

Abstract: Background: Frontal behavioral impairment (FrBI) is commonly observed in various degenerative diseases and refers to various behavioral symptoms. Objective: We investigated the effects of the presence of FrBI on cortical thickness, and the longitudinal neuropsychological changes in people in the predementia stage. Methods: A total of 794 individuals completed neuropsychological tests and the Frontal Behavioral Inventory (FBI) Questionnaire, and underwent magnetic resonance (MR) scanning. Participants were analyzed and grouped into non-FrBI (FBI = 0) or FrBI (FBI≥1). Cortical thickness was measured on MR images using a surface-based method. Results: In total, 281 people with subjective cognitive …decline (SCD) and 513 with amnestic mild cognitive impairment (aMCI) were assessed for FrBI. Relative to people without FrBI, those with FrBI presented reduced cortical thickness in the frontal, anterior temporal and lateral parietal regions (p  < 0.05, FDR corrected). People with FrBI developed Alzheimer’s disease, rather than behavioral variant frontotemporal dementia, as observed over seven years. Mixed effects models reported that people with FrBI have greater cognitive decline than those with non-FrBI in multiple domains, including language, memory, and executive functions (p  < 0.05, FDR corrected). Furthermore, while negative FrBI symptoms (e.g., deficit behaviors) were associated with greater declines in multiple domains, positive FrBI symptoms (e.g., disinhibition symptoms) were related to declines in visuospatial function and verbal memory. Finally, the occurrence of both types of symptoms correlated with multi-domain cognitive decline. Conclusions: FrBI predicted worse clinical outcomes, including reduced cortical thickness and cognitive decline, which are not necessarily specific to frontal dysfunction. Show more

Keywords: Cognitive decline, cortical thickness, frontotemporal dementia, neuropsychiatric symptoms, neuropsychological tests

DOI: 10.3233/JAD-190007

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 213-225, 2019

Authors: Wilfling, Denise | Dichter, Martin N. | Trutschel, Diana | Köpke, Sascha

Article Type: Research Article

Abstract: Background: Sleep disturbances and insomnia occur frequently in people with dementia and are associated with a number of problems for affected persons, relatives, and carers. Objective: Considering the lack of high-quality data especially from Germany, this study aimed to determine the prevalence of sleep disturbances and possible associated factors with in German nursing home residents. Methods: Multicenter cross-sectional study. Nursing homes in Northern Germany were randomly selected from nursing home registers and contacted consecutively. All residents with cognitive impairment living in the nursing homes were included. Data collection took place between June and December 2017. In …addition to the characteristics of nursing homes, nurses, and residents, sleep disturbances of residents with dementia were assessed using the Sleep Disorder Inventory (SDI). Descriptive statistics were applied for prevalence assessment. A generalized linear mixed model was used to investigate associated factors. Results: 38 nursing homes and 1,187 residents with cognitive impairment were included in the study. Sleep disturbances were reported for 23% of residents with pronounced differences between centers, ranging from 0-85%. The prescription of psychotropic drugs (OR 4.47; 95% CI 3.06-6.43; p  < 0.01), residence at a specialized dementia care unit (OR 2.43; 95% CI 1.30–4.53; p  < 0.01), and male sex (OR 1.56, 95% CI 1.08-2.25, p  < 0.02) were significantly associated with sleep problems. Conclusions: In Germany, prevalence of sleep disturbances in people with dementia is comparable to reports from other countries. Therefore, the development and rigorous evaluation of preferably non-pharmacological interventions is strongly warranted. Show more

Keywords: Dementia, Germany, nursing homes, sleep wake disorders, survey

DOI: 10.3233/JAD-180784

Citation: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 227-236, 2019