Journal of Alzheimer's Disease - Volume 60, issue 4

Authors: McLimans, Kelsey E. | Webb, Joseph L. | Anantharam, Vellareddy | Kanthasamy, Anumantha | Willette, Auriel A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background/Objective: Insulin-like growth factor binding protein 2 (IGFBP-2) regulates blood glucose levels, facilitates hippocampal synaptic plasticity and may have a predictive value for Alzheimer’s disease (AD) diagnosis. Methods: IGFBP-2 levels were studied in plasma in 566 subjects and in cerebrospinal fluid (CSF) in 245 subjects across the AD spectrum from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Variants in the IGFBP-2 gene were examined. Linear mixed modeling in SPSS tested main effects of IGFBP-2 and interactions with APOE4 on neurocognitive indices and biomarkers. Voxel-wise regression was used to gauge IGFBP-2 and regional grey matter and glucose metabolism associations. …Results: Each point increase in IGFBP-2 corresponded to a three times greater likelihood of having mild cognitive impairment (MCI) or AD. IGFBP-2 showed beneficial associations with respect to cognitive scores in individuals with two APOE4 alleles. Higher IGFBP-2 predicted higher insulin resistance, but not CSF amyloid or tau. Voxel-wise analyses showed that plasma IGFBP-2 predicted lower grey matter volume and FDG metabolism in a large area spanning the frontal, temporal, and occipital lobes. CSF IGFBP-2 levels showed similar voxel-wise analysis results, but were uniquely associated with CSF amyloid and tau. Analysis of single nucleotide polymorphisms (SNPs) in IGFBP-2 showed that subjects carrying risk alleles versus common alleles had increased risk of AD and lower memory scores. Voxel-wise analyses of these SNPs also implicated the hippocampus and prefrontal cortex. Conclusions: IGFBP-2 is associated with AD risk and outcomes; plasma IGFBP-2 provides stronger predictive power for brain outcomes, while CSF IGFBP-2 provides improved predictive accuracy for AD CSF biomarkers. Show more

Keywords: Biomarkers, diabetes mellitus, fluorodeoxyglucose F18, insulin resistance, magnetic resonance imaging, memory, neuroimaging, polymorphism, single nucleotide

DOI: 10.3233/JAD-170263

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1313-1324, 2017

Authors: Karve, Simantini J. | Jimenez, Elvira | Mendez, Mario F.

Article Type: Research Article

Abstract: Patients with Alzheimer’s disease (AD) often have generalized anxiety, particularly in early-onset AD (EOAD) or the first stages of their disease. This increased anxiety could be associated with decreased sensorimotor gating with increased attention to significant stimuli from AD pathology in the entorhinal cortex. We investigated whether widening initial attention to socioemotional stimuli was association with anxiety among 16 patients with first stage EOAD compared to 19 normal controls (NCs). The participants underwent assessment of their initial heart rate deceleration (“orienting response”; OR), a measure of attentional refocusing, to pictures (International Affective Picture Stimuli) varying in pleasant-unpleasant valence and social-nonsocial …content. The results showed group differences; the EOAD patients had significantly larger ORs than the NCs across conditions, with larger ORs in each valence and social condition. In addition, the EOAD patients, but not the NCs, showed ORs to normally less threatening stimuli, particularly pleasant, but also less significantly, social stimuli. On the Neuropsychiatric Inventory, the ORs among the EOAD patients significantly correlated with anxiety scores. Together, these findings suggest that anxiety in mild EOAD may be associated with widening attentional refocusing to socioemotional stimuli, possibly reflecting decreased sensorimotor gating in the entorhinal cortex. This finding could be a potential biomarker for the first stages of AD. Show more

Keywords: Alzheimer’s disease, anxiety, heart rate, orienting response

DOI: 10.3233/JAD-170319

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1325-1332, 2017

Authors: Broster, Lucas S. | Jenkins, Shonna L. | Holmes, Sarah D. | Jicha, Gregory A. | Jiang, Yang

Article Type: Research Article

Abstract: Emotional enhancement effects on memory have been reported to mitigate the pathophysiology of Alzheimer’s disease (AD). However, relative to their manifestation in persons without pathologic aging, these effects may be reduced in magnitude or even deleterious, especially in tasks that more closely model ecologic memory performance. Based upon a synthesis of such reports, we hypothesized that in persons with AD low arousal positive stimuli would evoke relatively intact emotional enhancement effects, but that high arousal negative stimuli would evoke disordered emotional enhancement effects. To assess this, participants with and without mild cognitive impairment (MCI) presumed to be due to AD …performed an emotionally-valenced short-term memory task while encephalography was recorded. Results indicated that for persons with MCI, high arousal negative stimuli led to working memory processing patterns previously associated with MCI presumed due to AD and dementia of the Alzheimer-type. In contrast, low arousal positive stimuli evoked a processing pattern similar to MCI participants’ unaffected spouses. Our current findings suggest that low arousal positive stimuli attenuate working memory deficits of MCI due to AD. Show more

Keywords: Affective cognition, Alzheimer’s disease, event-related potentials, mild cognitive impairment, emotional enhancement effects, working memory

DOI: 10.3233/JAD-170233

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1333-1349, 2017

Authors: Sheng, Min | Lu, Hanzhang | Liu, Peiying | Li, Yang | Ravi, Harshan | Peng, Shin-Lei | Diaz-Arrastia, Ramon | Devous, Michael D. | Womack, Kyle B.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the leading cause of degenerative dementia in the aging population. Patients with AD have alterations in cerebral hemodynamic function including reduced cerebral blood flow (CBF) and cerebral metabolic rate. Therefore, improved cerebrovascular function may be an attractive goal for pharmaceutical intervention in AD. Objective: We wished to observe the acute effects of sildenafil on cerebrovascular function and brain metabolism in patients with AD. Methods: We used several novel non-invasive MRI techniques to investigate the alterations of CBF, cerebral metabolic rate of oxygen (CMRO2 ), and cerebrovascular reactivity (CVR) after a single …dose of sildenafil administration in order to assess its physiological effects in patients with AD. CBF, CMRO2 , and CVR measurements using MRI were performed before and one hour after the oral administration of 50 mg sildenafil. Baseline Montreal Cognitive Assessment score was also obtained. Results: Complete CBF and CMRO2 data were obtained in twelve patients. Complete CVR data were obtained in eight patients. Global CBF and CMRO2 significantly increased (p  = 0.03, p  = 0.05, respectively) following sildenafil administration. Voxel-wise analyses of CBF maps showed that increased CBF was most pronounced in the bilateral medial temporal lobes. CVR significantly decreased after administration of sildenafil. Conclusion: Our data suggest that a single dose of sildenafil improves cerebral hemodynamic function and increases cerebral oxygen metabolism in patients with AD. Show more

Keywords: Cerebral blood flow, cerebral metabolic rate of oxygen, cerebrovascular reactivity, magnetic resonance imaging, Montreal Cognitive Assessment, sildenafil

DOI: 10.3233/JAD-161006

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1351-1364, 2017

Authors: Guo, Rui | Fan, Gang | Zhang, Jian | Wu, Chunxiao | Du, Yifeng | Ye, Hui | Li, Zhang | Wang, Lili | Zhang, Zhihui | Zhang, Lu | Zhao, Yueran | Lu, Zhiming

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common type of age-related neurodegenerative disorder; nevertheless, nowadays there are no reliable biomarkers or non-invasive techniques available for its early detection. Recent studies have indicated that the circulating level profiles of microRNAs (miRNAs) have the potential to be used as valuable biomarkers for diagnosis, staging, and progress monitoring of various diseases. Here we report a novel 9-miRNA signature (hsa-miR-26a-5p, hsa-miR-181c-3p, hsa-miR-126-5p, hsa-miR-22-3p, hsa-miR-148b-5p, hsa-miR-106b-3p, hsa-miR-6119-5p, hsa-miR-1246, and hsa-miR-660-5p) that can be utilized as biomarker for detecting AD. We respectively profiled the serum miRNAs from 19 AD patients and 9 healthy control (HC) participants using …the Next-Generation Sequencing (NGS). The NGS results were validated by quantitative real-time polymerase chain reaction (qRT-PCR) on a larger cohort of 121 AD and 86 HC cases. All the patients were divided into three groups (mild, moderate, and severe AD) based on the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating (CDR). Our research indicates that abnormal expression of distinct serum miRNAs occurs at different stages of AD. The difference of the area under the receiver operator characteristics curve (AUC) between the AD and the HC is between 70% and 85%. Among the 9 miRNAs, hsa-miR-22-3p has the best sensitivity (81.8%) and specificity (70.9%). The miRNA-panel is more valuable for AD diagnosis. The data suggest that the differentially expressed serum miRNAs could be used as biomarkers to improve the diagnosis of AD, particularly at the early stage, and to classify its clinical stages. Show more

Keywords: Alzheimer’s disease, biomarker, microRNAs, next-generation sequencing, quantitative Real-Time PCR, serum

DOI: 10.3233/JAD-170343

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1365-1377, 2017

Authors: Paterson, Euan N. | Williams, Michael A. | Passmore, Peter | Silvestri, Giuliana | MacGillivray, Tom J. | Maxwell, Alexander P. | McKay, Gareth J.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) prevalence is increasing globally and typically progresses for several years prior to clinical presentation of dementia. Renal dysfunction and vascular disease have been reported in association with dementia in several cross-sectional and longitudinal studies, and may contribute to AD risk. Experimental and observational studies suggest amyloid-β (Aβ) clearance may be impaired in chronic kidney disease (CKD) indicating a mechanism for increased AD risk. Objective: The objective of this study was to compare estimated glomerular filtration rate (eGFR) between individuals with AD and cognitively intact controls, controlling for potential confounding factors. Methods: A …cross-sectional, case-control study was carried out in 317 cognitively normal participants and 253 cases with a clinical diagnosis of AD in a UK tertiary care dementia clinic. Associations were considered using logistic regression adjusting for confounding variables (age, APOE ɛ 4 genotype, systolic blood pressure, education (left school at 14), and smoking status). Results: AD cases were older than cognitively intact controls, had lower MMSE scores, were more likely to have at least one APOE ɛ 4 allele, had higher rates of smoking, were more likely to be taking aspirin and/or clopidogrel, and had lower blood pressure. We found no significant association between eGFR and AD both before and following adjustment for appropriate confounders. Conclusion: This study failed to find an association between eGFR and AD in a cross-sectional sample study of elderly white individuals. Show more

Keywords: Alzheimer’s disease, chronic kidney diseases, chronic renal insufficiency, dementia, glomerular filtration rate, kidney

DOI: 10.3233/JAD-170480

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1379-1385, 2017

Authors: Reijs, Babette L.R. | Vos, Stephanie J.B. | Soininen, Hilkka | Lötjonen, Jyrki | Koikkalainen, Juha | Pikkarainen, Maria | Hall, Anette | Vanninen, Ritva | Liu, Yawu | Herukka, Sanna-Kaisa | Freund-Levi, Yvonne | Frisoni, Giovanni B. | Frölich, Lutz | Nobili, Flavio | Rikkert, Marcel Olde | Spiru, Luiza | Tsolaki, Magda | Wallin, Åsa K. | Scheltens, Philip | Verhey, Frans | Visser, Pieter Jelle

Article Type: Research Article

Abstract: Background: Lifestyle factors have been associated with the risk of dementia, but the association with Alzheimer’s disease (AD) remains unclear. Objective: To examine the association between later life lifestyle factors and AD biomarkers (i.e., amyloid-β 1–42 (Aβ42 ) and tau in cerebrospinal fluid (CSF), and hippocampal volume) in individuals with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). In addition, to examine the effect of later life lifestyle factors on developing AD-type dementia in individuals with MCI. Methods: We selected individuals with SCD (n  = 111) and MCI (n  = 353) from the DESCRIPA and Kuopio Longitudinal …MCI studies. CSF Aβ42 and tau concentrations were assessed with ELISA assay and hippocampal volume with multi-atlas segmentation. Lifestyle was assessed by clinical interview at baseline for: social activity, physical activity, cognitive activity, smoking, alcohol consumption, and sleep. We performed logistic and Cox regression analyses adjusted for study site, age, gender, education, and diagnosis. Prediction for AD-type dementia was performed in individuals with MCI only. Results: Later life lifestyle factors were not associated with AD biomarkers or with conversion to AD-type dementia. AD biomarkers were strongly associated with conversion to AD-type dementia, but these relations were not modulated by lifestyle factors. Apolipoprotein E (APOE) genotype did not influence the results. Conclusions: Later life lifestyle factors had no impact on key AD biomarkers in individuals with SCD and MCI or on conversion to AD-type dementia in MCI. Show more

Keywords: Alcohol consumption, Alzheimer’s disease, amyloid-β (1–42), cerebrospinal fluid, cognitive reserve, exercise, hippocampus, lifestyle, mild cognitive impairment

DOI: 10.3233/JAD-170039

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1387-1395, 2017

Authors: Barha, Cindy K. | Hsiung, Ging-Yuek R. | Best, John R. | Davis, Jennifer C. | Eng, Janice J. | Jacova, Claudia | Lee, Philip E. | Munkacsy, Michelle | Cheung, Winnie | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Aerobic training (AT) is a promising, non-pharmacological intervention to mitigate the deleterious effects of aging and disease on brain health. However, a large amount of variation exists in its efficacy. This is a secondary analysis of a randomized controlled trial of AT in 71 older adults with subcortical ischemic vascular cognitive impairment (NCT01027858). Specifically, we investigated: 1) whether sex moderates the relationship between AT and executive functions, and 2) the role of brain derived neurotrophic factor (BDNF) and gains in functional fitness capacity. Older adults were randomly assigned to either 6-month, thrice-weekly AT or to usual care plus education (CON). …At baseline, trial completion, and 6-month follow-up, executive functions were assessed with the Trail Making Test (A & B), verbal digits forward and backward test, and the Stroop Test. Functional fitness capacity was assessed with the 6-Minute Walk Test. Compared with CON, AT significantly improved Trail Making Test performance in females but not males, an effect that was retained at follow-up. AT significantly increased BDNF levels in females but decreased levels in males. On the other hand, AT led to significant gains in functional fitness capacity in males only. This study provides evidence that sex differences exist in AT efficacy on brain health as well as in the biological mechanisms subserving AT. Show more

Keywords: Aerobic exercise, brain derived neurotrophic factor, executive function, randomized controlled trial, sex differences, vascular cognitive impairment

DOI: 10.3233/JAD-170221

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1397-1410, 2017

Authors: Waragai, Masaaki | Moriya, Masaru | Nojo, Takeshi

Article Type: Research Article

Abstract: Although molecular positron emission tomography imaging of amyloid and tau proteins can facilitate the detection of preclinical Alzheimer’s disease (AD) pathology, it is not useful in clinical practice. More practical surrogate markers for preclinical AD would provide valuable tools. Thus, we sought to validate the utility of conventional magnetic resonance spectroscopy (MRS) as a screening method for preclinical AD. A total of 289 older participants who were cognitively normal at baseline were clinically followed up for analysis of MRS metabolites, including N-acetyl aspartate (NAA) and myo-inositol (MI) in the posterior cingulate cortex (PCC) for 7 years. The 289 participants were …retrospectively divided into five groups 7 years after baseline: 200 (69%) remained cognitively normal; 53 (18%) developed mild cognitive impairment (MCI); 21 (7%) developed AD; eight (2%) developed Parkinson’s disease with normal cognition, and seven (2%) developed dementia with Lewy bodies (DLB). The NAA/MI ratios of the PCC in the AD, MCI, and DLB groups were significantly decreased compared with participants who maintained normal cognition from baseline to 7 years after baseline. MMSE scores 7 years after baseline were significantly correlated with MI/Cr and NAA/MI ratios in the PCC. These results suggest that cognitively normal elderly subjects with low NAA/MI ratios in the PCC might be at risk of progression to clinical AD. Thus, the NAA/MI ratio in the PCC measured with conventional 1 H MRS should be reconsidered as a possible adjunctive screening marker of preclinical AD in clinical practice. Show more

Keywords: Magnetic resonance spectroscopy, myo-inositol, N-acetyl aspartate, posterior cingulate cortex, preclinical Alzheimer’s disease, screening marker

DOI: 10.3233/JAD-170450

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1411-1427, 2017

Authors: Sundaram, Jeyapriya Raja | Poore, Charlene Priscilla | Sulaimee, Noor Hazim Bin | Pareek, Tej | Cheong, Wei Fun | Wenk, Markus R. | Pant, Harish C. | Frautschy, Sally A. | Low, Chian-Ming | Kesavapany, Sashi

Article Type: Research Article

Abstract: Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer’s disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and …neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases. Show more

Keywords: Amyloid, Cdk5, curcumin, neurodegeneration, neuroinflammation, p25, tau

DOI: 10.3233/JAD-170093

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1429-1442, 2017