Journal of Alzheimer's Disease - Volume 62, issue 2

Authors: van Middelaar, Tessa | van Dalen, Jan W. | van Gool, Willem A. | van den Born, Bert-Jan H. | van Vught, Lonneke A. | Moll van Charante, Eric P. | Richard, Edo

Article Type: Research Article

Abstract: Background: High visit-to-visit variability (VVV) in blood pressure (BP) is associated with cerebrovascular lesions on neuroimaging. Objective: Our primary objective was to investigate whether VVV is associated with incident all-cause dementia. As a secondary objective, we studied the association of VVV with cognitive decline and cardiovascular disease (CVD). Methods: We included community-dwelling people (age 70–78 year) from the ‘Prevention of Dementia by Intensive Vascular Care’ (preDIVA) trial with three to five 2-yearly BP measurements during 6–8 years follow-up. VVV was defined using coefficient of variation (CV; SD/mean×100). Cognitive decline was assessed using the Mini-Mental State Examination …(MMSE). Incident CVD was defined as myocardial infarction or stroke. We used a Cox proportional hazard regression and mixed-effects model adjusted for sociodemographic factors and cardiovascular risk factors. Results: In 2,305 participants (aged 74.2±2.5), mean systolic BP over all available visits was 150.1 mmHg (SD 13.6), yielding a CV of 9.0. After 6.4 years (SD 0.8) follow-up, 110 (4.8%) participants developed dementia and 140 (6.1%) CVD. Higher VVV was not associated with increased risk of dementia (hazard ratio [HR] 1.00 per point CV increase; 95% confidence interval [CI] 0.96–1.05), although the highest quartile of VVV was associated with stronger decline in MMSE (β –0.09, 95% CI –0.17 to –0.01). Higher VVV was associated with incident CVD (HR 1.07; 95% CI 1.04–1.11). Conclusion: In our study among older people, high VVV is not associated with incident all-cause dementia. It is associated with decline in MMSE and incident CVD. Show more

Keywords: Blood pressure, blood pressure variability, cognition, cardiovascular disease, dementia

DOI: 10.3233/JAD-170757

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 727-735, 2018

Authors: Liu, Ziyi | Kameshima, Naoko | Nanjo, Toshifumi | Shiino, Akihiko | Kato, Tomoko | Shimizu, Shino | Shimizu, Takeshi | Tanaka, Sachiko | Miura, Katsuyuki | Tooyama, Ikuo

Article Type: Research Article

Abstract: Cost-effective and feasible methods for early diagnosis of Alzheimer’s disease (AD) are needed. We present two methods to measure AD-related biomarkers simultaneously from one nasal smear for the purpose of diagnosing AD. Japanese men and women aged 63–85 years old were recruited in 2015–2016 for this case–control study. A total of 25 AD cases and 25 controls (22 men and 28 women) participated in this research. Nasal smears were collected from the common nasal meatus, inferior concha, middle nasal meatus, and olfactory cleft, and the proteins in the samples were analyzed by two methods, which we named PGD (Pre-treatment with …guanidine- n-Dodecyl-beta-D-maltoside solution) method 1 (PGD-I) and 2 (PGD-II). The PGD-I method measured total tau and amyloid-β (Aβ)42 , but no differences in median levels of total tau and Aβ42 between AD cases and controls were found in any of the nasal locations. The PGD-II method measured Aβ42 , total tau, and phosphorylated tau, but levels of Aβ40 in all nasal locations of both groups were near zero. Median levels of phosphorylated tau to total tau (p-tau/t-tau) ratios in the middle nasal meatus and in the olfactory cleft were significantly higher in AD cases than in controls, and could significantly predict AD. To assess diagnostic reliability, areas under the ROC curve were 0.74 (95% CL = 0.52–0.95, p  = 0.030) for the middle nasal meatus and 0.72 (95% CL = 0.52–0.92, p  = 0.029) for the olfactory cleft. Thus, PGD-I and PGD-II can detect AD-related biomarkers in nasal smears and PGD-II may be a useful tool for diagnosing AD. Show more

Keywords: Amyloid-β, biomarker, nasal smear, phosphorylated tau, tau

DOI: 10.3233/JAD-170962

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 737-744, 2018

Authors: Del-Aguila, Jorge L. | Fernández, Maria Victoria | Schindler, Suzanne | Ibanez, Laura | Deming, Yuetiva | Ma, Shengmei | Saef, Ben | Black, Kathleen | Budde, John | Norton, Joanne | Chasse, Rachel | Alzheimer’s Disease Neuroimaging Initiative (ADNI) | Harari, Oscar | Goate, Alison | Xiong, Chengjie | Morris, John C. | Cruchaga, Carlos

Article Type: Research Article

Abstract: Many genetic studies for Alzheimer’s disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University, and we calculated PRS (polygenic risk score) based on the IGAP study to …compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β = 0.146, p  = 0.03). In the case of rare variants, TREM2 (β = 0.309, p  = 0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients. Show more

Keywords: Alzheimer’s disease risk, Clinical Dementia Rating sum of boxes, International Genomics of Alzheimer’s Project (IGAP), polygenic risk score, progression

DOI: 10.3233/JAD-170834

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 745-756, 2018

Authors: Squarzoni, Paula | Duran, Fabio Luis Souza | Busatto, Geraldo F. | Alves, Tania Correa Toledo de Ferraz

Article Type: Research Article

Abstract: Background: Many cross-sectional voxel-based morphometry (VBM) investigations have shown significant inverse correlations between chronological age and gray matter (GM) volume in several brain regions in healthy humans. However, few VBM studies have documented GM decrements in the healthy elderly with repeated MRI measurements obtained in the same subjects. Also, the extent to which the APOE ɛ 4 allele influences longitudinal findings of GM reduction in the healthy elderly is unclear. Objective: Verify whether regional GM changes are associated with significant decrements in cognitive performance taking in account the presence of the APOE ɛ 4 allele. Methods: …Using structural MRI datasets acquired in 55 cognitively intact elderly subjects at two time-points separated by approximately three years, we searched for voxels showing significant GM reductions taking into account differences in APOE genotype. Results: We found global GM reductions as well as regional GM decrements in the right thalamus and left parahippocampal gyrus (p  < 0.05, family-wise error corrected for multiple comparisons over the whole brain). These findings were not affected by APOE ɛ 4. Conclusions: Irrespective of APOE ɛ 4, longitudinal VBM analyses show that the hippocampal region and thalamus are critical sites where GM shrinkage is greater than the degree of global volume reduction in healthy elderly subjects. Show more

Keywords: Aging, APOE4, cardiovascular risk, cognition, longitudinal study, magnetic resonance imaging

DOI: 10.3233/JAD-161036

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 757-771, 2018

Authors: D’Iorio, Alfonsina | Garramone, Federica | Piscopo, Fausta | Baiano, Chiara | Raimo, Simona | Santangelo, Gabriella

Article Type: Research Article

Abstract: Background: The role of specific personality traits as factor risks of Alzheimer’s disease (AD) has been consistently found, whereas personality traits specifically related to AD (after the diagnosis) have not been outlined yet. Objective: A meta-analysis of published studies was performed to determine whether AD patients have a distinctive personality trait profile compared to healthy subjects (HC), similar to or different from a premorbid personality profile consistently reported in previous studies. Methods: A systematic literature search was performed using PsycInfo (PROQUEST), PubMed, and Scopus. The meta-analysis pooled results from primary studies using Hedges’ g unbiased approach. …Results: The meta-analysis included 10 primary studies and revealed that, when the personality was evaluated by informant-rated measures, AD patients had significantly higher levels of Neuroticism, lower levels of Openness, Agreeableness, Conscientiousness, and Extraversion than HCs. When the personality was evaluated by self-rated measures, the results obtained from informants were confirmed for Neuroticism, Openness, and Extraversion but not for Agreeableness and Conscientiousness where AD patients and HCs achieved similar scores. Conclusions: The meta-analysis revealed that high Neuroticism and low Openness and Extraversion are distinctive personality traits significantly associated with a diagnosis of AD when evaluated both self-rated and informant-rated measures. This personality trait profile is similar to premorbid one, which contributes to development of AD over time. Therefore, our findings indirectly support the idea of specific premorbid personality traits as harbingers of AD. Show more

Keywords: Alzheimer’s disease, dementia, factor risk, neuroticism, personality

DOI: 10.3233/JAD-170901

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 773-787, 2018

Authors: Katisko, Kasper | Haapasalo, Annakaisa | Koivisto, Anne | Krüger, Johanna | Hartikainen, Päivi | Korhonen, Ville | Helisalmi, Seppo | Herukka, Sanna-Kaisa | Remes, Anne M. | Solje, Eino

Article Type: Research Article

Abstract:  Several studies have reported reduced risk of cancer in patients with Alzheimer’s disease (AD) or Parkinson’s disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p  = 0.012, FTLD versus NCI p  = 0.029) groups. …No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study. Show more

Keywords: C9ORF72, cancer, comorbidity, frontotemporal dementia, frontotemporal lobar degeneration

DOI: 10.3233/JAD-170854

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 789-794, 2018

Authors: McEwen, Sarah C. | Siddarth, Prabha | Abedelsater, Berna | Kim, Yena | Mui, Wenli | Wu, Pauline | Emerson, Natacha D. | Lee, Jacob | Greenberg, Shayna | Shelton, Tiffany | Kaiser, Scott | Small, Gary W. | Merrill, David A.

Article Type: Research Article

Abstract: Background: Several modifiable lifestyle factors have been shown to have potential beneficial effects in slowing cognitive decline. Two such factors that may affect cognitive performance and slow the progression of memory loss into dementia in older adults are cognitive training and physical activity. There are currently no effective treatments for dementia; therefore, preventative strategies to delay or prevent the onset of dementia are of critical importance. Objective: The aim of this study was to determine the relative effectiveness of simultaneous performance of memory training and aerobic exercise to a sequential performance intervention on memory functioning in older adults. …Methods: 55 older adults (aged 60– 75) with subjective memory impairments (non-demented and non-MCI) completed the intervention that consisted of 90-minute small group classes held twice weekly. Participants were randomized to either 4-weeks of supervised strategy-based memory training done simultaneously while stationary cycling (SIM) or sequentially after the stationary cycling (SEQ). Standardized neurocognitive measures of memory, executive functioning, speed of processing, attention, and cognitive flexibility were assessed at baseline and post-intervention. Results: The SIM group, but not the SEQ group, had a significant improvement on composite memory following the intervention (t(51) = 2.7, p  = 0.01, effect size (ES) = 0.42) and transfer to non-trained reasoning abilities (t(51) = 6.0, ES = 0.49) and complex attention (t(51) = 3.1, p  = 0.003, ES = 0.70). Conversely, the SEQ group, but not the SIM, showed significant improvement in executive functioning (t(51) = 5.0, p  = 0.0001, ES = 0.96). Conclusion: These findings indicate that a 4-week simultaneous memory training and aerobic exercise program is sufficient to improve memory, attention, and reasoning abilities in older adults. Show more

Keywords: Aerobic exercise, Alzheimer’s disease, cognitive decline, cognitive training, dementia, memory training, physical activity, subjective memory complaints

DOI: 10.3233/JAD-170846

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 795-806, 2018

Authors: Zhang, Wei | Guo, Yi | Li, Bo | Zhang, Qi | Liu, Jian-hui | Gu, Guo-jun | Wang, Jin-hong | Bao, Rui-kang | Chen, Yu-jie | Xu, Jian-rong

Article Type: Research Article

Abstract: Cerebral amyloid angiopathy (CAA) is present in up to 90% of patients with Alzheimer's disease (AD), and may interact with classical neuropathology to exacerbate cognitive decline. Since growth differentiation factor 11 (GDF11) can activate vascular remodeling, we tested its effects on cognitive function and neuroinflammatory changes of AD model mice. We intravenously administered GDF11 or vehicle daily to 12-month-old transgenic mice overexpressing the amyloid-β protein precursor (AβPP)/PS1). Cognitive function was monitored using the Morris water maze, and after conclusion of the treatment, we assessed the morphology and presence of inflammatory markers in the cerebral vasculature. Subchronic treatment of adult AβPP/PS1 …mice with GDF11 rescued cognitive function and ameliorated cerebrovascular function. In particular, the de novo genesis of small blood vessels and the expression of vascular-related proteins were significantly higher than in the vehicle-treated AβPP/PS1 mice, whereas the expressions of the inflammatory markers Iba-1 and GFAP significantly decreased in proportion to the lower ratio of two forms of amyloid-β (Aβ40/42 ). Daily intravenous treatment with GDF11-injection can rejuvenate respects of cognition and cerebrovascular changes in AD mice. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, cerebral blood flow, growth differentiation factor 11, neuroinflammation

DOI: 10.3233/JAD-170474

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 807-819, 2018

Authors: Le Guennec, Kilan | Tubeuf, Hélène | Hannequin, Didier | Wallon, David | Quenez, Olivier | Rousseau, Stéphane | Richard, Anne-Claire | Deleuze, Jean-François | Boland, Anne | Frebourg, Thierry | Gaildrat, Pascaline | Campion, Dominique | Martins, Alexandra | Nicolas, Gaël

Article Type: Research Article

Abstract: Heterozygous SORL1 protein truncating variants (PTV) are a strong risk factor for early-onset Alzheimer’s disease (EOAD). In case control studies performed at the genome-wide level, PTV definition is usually straightforward. Regarding splice site variants, only those affecting canonical sites are typically included. Some other variants, not annotated as PTV, could, however, affect splicing and hence result in a loss of SORL1 function. We took advantage of the whole exome sequencing data from the 9/484 patients with a previously reported SORL1 PTV in the French EOAD series and searched for a second variant which may affect splicing and eventually …result in more than 50% loss of function overall. We found that one patient, known to carry a variant predicted to disrupt the canonical 5’ splice site of exon 8, also carried a second novel intronic variant predicted to affect SORL1 splicing of exon 29. Segregation analysis showed that the second variant was located in trans from the known PTV. We performed ex vivo minigene splicing assays and showed that both variants led to the generation of transcripts containing a premature stop codon. This is therefore the first evidence of a human carrying biallelic SORL1 PTV. This patient had a family history of dementia in both maternal and paternal lineages with later ages of onset than the proband himself. However, his 55 years age at onset was in the same ranges as previously published SORL1 heterozygous PTV carriers. This suggests that biallelic loss of SORL1 function is an extremely rare event that was not associated with a dramatically earlier age at onset than heterozygous SORL1 loss-of-function variant carriers, in this single patient. Show more

Keywords: Compound heterozygous, early-onset Alzheimer’s disease, haploinsufficiency, knockout, recessive, SORL1

DOI: 10.3233/JAD-170981

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 821-831, 2018

Authors: Burns, Christine M. | Kaszniak, Alfred W. | Chen, Kewei | Lee, Wendy | Bandy, Daniel J. | Caselli, Richard J. | Reiman, Eric M.

Article Type: Research Article

Abstract: Background: The association between longitudinal changes in serum glucose level and longitudinal changes in [18 F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer’s disease (AD) risk are unknown. Objective: To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer’s disease (AD). Methods: Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) ɛ 4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4±1.0-years. …An automated brain-mapping algorithm was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl. Results: This study included 80 adults aged 61.5±5 years, including 38 carriers and 42 non-carriers of the APOE ɛ 4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p  < 0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE ɛ 4 status and baseline and advancing age. Conclusions: Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD. Show more

Keywords: Alzheimer’s disease, blood glucose, longitudinal studies, positron emission tomography

DOI: 10.3233/JAD-170767

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 833-840, 2018