Journal of Alzheimer's Disease - Volume 68, issue 1

Authors: Taipale, Heidi | Lampela, Pasi | Koponen, Marjaana | Tanskanen, Antti | Tiihonen, Jari | Hartikainen, Sirpa | Tolppanen, Anna-Maija

Article Type: Research Article

Abstract: Background: Antiepileptic drugs (AEDs) have sedative properties which may lead to an increased risk of pneumonia. Objectives: To investigate whether incident AED use is associated with an increased risk of pneumonia among community-dwelling persons with Alzheimer’s disease (AD). In addition, we determined the risk according to duration of AED use and specific AEDs. Methods: Persons with AD were identified from the MEDALZ dataset which includes all community-dwelling persons who received a clinically verified diagnosis of AD during 2005-2011 in Finland (N=70,718). New AED users were identified with one-year washout period. A matched cohort (1 : 1, N=5,769, matching …criteria age, gender, and time since AD diagnoses) of nonusers was formed. Data from nationwide registers included dispensed medications which were modelled with PRE2DUP method, hospitalizations, and causes of death. The association between AED use and hospital admission or death due to pneumonia was analyzed with Cox proportional hazard models. Results: AED use was associated with an increased risk of pneumonia (adjusted HR 1.92, 95% CI 1.63-2.26; incidence rate per 100 person-years 12.58, 95% CI 12.49-12.66 during AED use and 6.41, 95% CI 6.37-6.45 during nonuse). The highest risk was observed during the first month of use (aHR 3.59, 95% CI 2.29-5.61) and the risk remained elevated until two years of use. Of specific drug substances, phenytoin, carbamazepine, valproic acid, and pregabalin were associated with an increased risk. Conclusion: Antiepileptic drug use may increase the risk of pneumonia which is concerning as persons with AD have elevated risk of pneumonia. Show more

Keywords: Alzheimer’s disease, anticonvulsant, antiepileptic, dementia, mood stabilizer, older person, pharmacoepidemiology, pneumonia

DOI: 10.3233/JAD-180912

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 127-136, 2019

Authors: Li, Li | Zhen, Eugene Y. | Decker, Rodney L. | Willis, Brian A. | Waters, David | Liu, Peng | Hake, Ann Marie | Demattos, Ronald Bradley | Ayan-Oshodi, Mosun

Article Type: Research Article

Abstract: LY2599666 is a humanized, affinity-optimized monoclonal antibody antigen-binding fragment linked to a PEG molecule and targets soluble amyloid-β (Aβ) monomers. This first-in-human dose ascending study assessed pharmacokinetics (PK) (measured as serum free LY2599666 concentration) and pharmacodynamic (PD) effects (measured as plasma total soluble Aβ40 and Aβ42 ) after a single subcutaneous (SC) dose of 10, 25, 100, and 200 mg LY2599666 in healthy subjects. As LY2599666 binds to multiple soluble Aβ monomers, a two-target mediated drug disposition model (TMDD) was developed to simultaneously fit serum LY2599666 concentration and Aβ monomer levels. Four Alzheimer’s disease patients completed 25 mg once-weekly dosing of …LY2599666 for 12 weeks. In addition, single cerebrospinal fluid samples were collected to assess penetration capability across the blood-brain barrier. PK and PD data collected from the multiple dose cohort aligned with model predictions, suggesting the established TMDD model predicted suppression of soluble Aβ40 and Aβ42 in plasma after SC dosing of LY2599666. Show more

Keywords: Aβ monomer, Alzheimer’s disease, pharmacokinetic/pharmacodynamic, target-mediated drug disposition

DOI: 10.3233/JAD-180925

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 137-144, 2019

Authors: Filshtein, Teresa Jenica | Dugger, Brittany N. | Jin, Lee-Way | Olichney, John M. | Farias, Sarah T. | Carvajal-Carmona, Luis | Lott, Paul | Mungas, Dan | Reed, Bruce | Beckett, Laurel A. | DeCarli, Charles

Article Type: Research Article

Abstract: Our nation is becoming increasingly diverse; however, few autopsy studies examine multiple ethnoracial groups, especially Hispanics. We examined differences in neuropathological diagnoses of 423 deceased participants with dementia from three ethnoracial groups (35 Black, 28 Hispanic, and 360 non-Hispanic White) evaluated at the University of California Davis Alzheimer’s Disease Center. We used novel applications of bootstrap resampling and logistic regression standardization to project neuropathological diagnostic rates for non-Hispanic Whites to minority sample characteristics to improve inference of findings. Alzheimer’s disease (AD) without significant cerebrovascular disease (CVD) or other dementia-related pathologies (AD (non-mixed)) was present in 15 Black (43%), 4 Hispanic …(14%), and 156 (43%) non-Hispanic Whites. CVD sufficient to contribute to dementia was confirmed in 14 Black (40%), 15 Hispanic (54%), and 101 (28%) non-Hispanic White decedents. The observed CVD prevalence of 40% in Blacks exceeded the predicted 29% [95% CI: 22%-36%]. Despite being outside the 95% confidence interval, the difference between observed and predicted was not statistically significant after bootstrap testing. Conversely, for Hispanics, the observed proportion at 54% exceeded significantly the predicted prevalence of 24% from non-Hispanic Whites [95% CI: 16%-34%], avg. p = 0.008). An identical analysis using AD (non-mixed) as the outcome predicted AD (non-mixed) in Blacks averaging 41% [95% CI: 34%-48%], nearly equal to observed prevalence. For Hispanics, however, the observed proportion at 14%, was well below predictions (mean = 42%, 95% CI: 32%-53%], avg. p = 0.008). We conclude mixed diagnoses and CVD are more common in Hispanic and Black decedents than Non-Hispanic Whites with dementia in our cohort. The increased prevalence of vascular co-morbidity may be a potential opportunity to intervene more effectively in dementia treatment of those individuals. Show more

Keywords: Alzheimer’s disease, autopsy, brain, cognitive aging, cohort studies, dementia, minority groups, neuropathology, vascular

DOI: 10.3233/JAD-180992

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 145-158, 2019

Authors: Fung, Yi Leng | Ng, Kelly E.T. | Vogrin, Simon J. | Meade, Catherine | Ngo, Michael | Collins, Steven J. | Bowden, Stephen C.

Article Type: Research Article

Abstract: Structural neuroimaging is a useful non-invasive biomarker commonly employed to evaluate the integrity of mesial temporal lobe structures that are typically compromised in Alzheimer’s disease. Advances in quantitative neuroimaging have permitted the development of automated segmentation protocols (e.g., FreeSurfer) with significantly increased efficiency compared to earlier manual techniques. While these protocols have been found to be suitable for large-scale, multi-site research studies, we were interested in assessing the practical utility and reliability of automated FreeSurfer protocols compared to manual volumetry on routinely acquired clinical scans. Independent validation studies with newer automated segmentation protocols are scarce. Two FreeSurfer protocols for each …of two regions of interest—the hippocampus and entorhinal cortex—were compared against manual volumetry. High reliability and agreement was found between FreeSurfer and manual hippocampal protocols, however, there was lower reliability and agreement between FreeSurfer and manual entorhinal protocols. Although based on a the relatively small sample of subjects drawn from a memory clinic (n = 27), our study findings suggest further refinements to improve measurement error and most accurately depict true regional brain volumes using automated segmentation protocols are required, especially for non-hippocampal mesial temporal structures, to achieve maximal utility for routine clinical evaluations. Show more

Keywords: Alzheimer’s disease, biomarker, entorhinal cortex, hippocampus, neuroimaging, reproducibility of results, temporal lobe

DOI: 10.3233/JAD-181172

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 159-171, 2019

Authors: Li, Hong | Leurgans, Sue | Elm, Jordan | Gebregziabher, Mulugeta

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a common, devastating disease which carries a heavy economic burden. Accelerated efforts to identify presymptomatic stages of AD and biomarkers to classify the disease are urgent needs. Currently, no biomarkers can perfectly discriminate individuals into multiple disease categories of AD (no cognitive impairment, mild cognitive impairment, and dementia). Although many biomarkers for diagnosis and their various features are being studied, we lack advanced statistical methods which can fully utilize biomarkers to classify AD accurately, thereby facilitating evaluation of putative markers both alone and in combination. In this paper, we propose two approaches: 1) a forward addition …procedure in which we adapt an additive logistic regression model to the setting for disease with ordered multiple categories. Using this approach, we select and combine multiple cross-sectional biomarkers to improve diagnostic accuracy, and 2) a method by extending the Neyman-Pearson Lemma to the ordered three disease categories to construct optimal cutoff points to distinguish multiple disease categories. We evaluate the robustness of the proposed model using a simulation study. Then we apply these two methods to data from the Religious Orders Study to examine the feasibility of combining biomarkers, and compare the diagnostic accuracy between the proposed methods and existing methods including model-based methods (ordinal logistic regression and quadratic discriminant analysis), a tree-based method CART, and the Youden index method. The two proposed methods facilitate evaluations of biomarkers for conditions with graded, rather than binary, classifications. The evaluation of the performance of different approaches provides guidance of how to choose approaches to address research questions. Show more

Keywords: Alzheimer’s disease, diagnostic accuracy, generalized additive model, multiclass classification, optimal cutoff point, volume under the surface

DOI: 10.3233/JAD-180580

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 173-186, 2019

Authors: DeCarli, Charles | Villeneuve, Sylvia | Maillard, Pauline | Harvey, Danielle | Singh, Baljeet | Carmichael, Owen | Fletcher, Evan | Olichney, John | Farias, Sarah | Jagust, William | Reed, Bruce | Mungas, Dan

Article Type: Research Article

Abstract: Background/Objective: To determine the impact of vascular burden on rates of decline in episodic memory and executive function. We hypothesize that greater vascular burden will have an additive negative impact on cognition after accounting for baseline cognitive impairment, positron emission tomography (PET) amyloid burden, and magnetic resonance imaging (MRI) measures. Methods: Individuals were followed an average of 5 years with serial cognitive assessments. Predictor variables include vascular burden score (VBS), quantitative brain MRI assessment, and amyloid imaging. Subjects consisted of 65 individuals, 53% of whom were male, aged 73.2±7.2 years on average with an average of 15.5±3.3 years …of educational achievement. Results: Baseline cognitive impairment was significantly associated poorer episodic memory (p  < 0.0001), smaller hippocampal volume (p  < 0.0001), smaller brain volume (p  = 0.0026), and greater global Pittsburg Imaging Compound B (PiB) index (p  = 0.0008). Greater amyloid burden was associated with greater decline in episodic memory over time (β= –0.20±0.07, p  < 0.005). VBS was significantly associated with the level of executive function performance (β= –0.14±0.05, p  < 0.005) and there was a significant negative interaction between VBS, cognitive impairment, and PiB index (β= –0.065±0.03, p  = 0.03). Conclusions: Our results find a significant influence of VBS independent of standard MRI measures and cerebral amyloid burden on executive function. In addition, VBS reduced the amount of cerebral amyloid burden needed to result in cognitive impairment. We conclude that the systemic effects of vascular disease as reflected by the VBS independently influence cognitive ability. Show more

Keywords: Alzheimer’s disease, cerebrovascular disorders, cognition, neuroimaging

DOI: 10.3233/JAD-180965

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 187-196, 2019

Authors: Feng, Lei | Cheah, Irwin Kee-Mun | Ng, Maisie Mei-Xi | Li, Jialiang | Chan, Sue Mei | Lim, Su Lin | Mahendran, Rathi | Kua, Ee-Heok | Halliwell, Barry

Article Type: Research Article

Abstract: We examined the cross-sectional association between mushroom intake and mild cognitive impairment (MCI) using data from 663 participants aged 60 and above from the Diet and Healthy Aging (DaHA) study in Singapore. Compared with participants who consumed mushrooms less than once per week, participants who consumed mushrooms >2 portions per week had reduced odds of having MCI (odds ratio = 0.43, 95% CI 0.23–0.78, p  = 0.006) and this association was independent of age, gender, education, cigarette smoking, alcohol consumption, hypertension, diabetes, heart disease, stroke, physical activities, and social activities. Our cross-sectional data support the potential role of mushrooms and their bioactive compounds …in delaying neurodegeneration. Show more

Keywords: Aging, Asians, cross-sectional analysis, mild cognitive impairment, mushrooms

DOI: 10.3233/JAD-180959

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 197-203, 2019

Authors: Byman, Elin | Schultz, Nina | the Netherlands Brain Bank | Blom, Anna M. | Wennström, Malin

Article Type: Research Article

Abstract: Background: Astrocytes produce and store the energy reserve glycogen. However, abnormal large glycogen units accumulate if the production or degradation of glycogen is disturbed, a finding often seen in patients with Alzheimer’s disease (AD). We have shown increased activity of glycogen degrading α -amylase in AD patients and α -amylase positive glial cells adjacent to AD characteristic amyloid-β (Aβ) plaques. Objectives: Investigate the role of α -amylase in astrocytic glycogenolysis in presence of Aβ. Methods: Presence of α -amylase and large glycogen units in postmortem entorhinal cortex from AD patients and non-demented controls were analyzed by …immunohistological stainings. Impact of different Aβ42 aggregation forms on enzymatic activity (α -amylase, pyruvate kinase, and lactate dehydrogenase), lactate secretion, and accumulation of large glycogen units in cultured astrocytes were analyzed by activity assays, ELISA, and immunocytochemistry, respectively. Results: AD patients showed increased number of α -amylase positive glial cells. The glial cells co-expressed the astrocytic marker glial fibrillary acidic protein, displayed hypertrophic features, and increased amount of large glycogen units. We further found increased load of large glycogen units, α -amylase immunoreactivity and α -amylase activity in cultured astrocytes stimulated with fibril Aβ42 , with increased pyruvate kinase activity, but unaltered lactate release as downstream events. The fibril Aβ42 -induced α -amylase activity was attenuated by β-adrenergic receptor antagonist propranolol. Discussion: We hypothesize that astrocytes respond to fibril Aβ42 in Aβ plaques by increasing their α -amylase production to either liberate energy or regulate functions needed in reactive processes. These findings indicate α -amylase as an important actor involved in AD associated neuroinflammation. Show more

Keywords: α-amylase, Alzheimer’s disease, amyloid-β, astrocytes, glycogenolysis

DOI: 10.3233/JAD-180997

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 205-217, 2019

Authors: Marwarha, Gurdeep | Claycombe-Larson, Kate | Lund, Jonah | Schommer, Jared | Ghribi, Othman

Article Type: Research Article

Abstract: Epidemiological studies have suggested a positive correlation between saturated fat intake and the risk for developing Alzheimer’s disease (AD). While diets-enriched in the saturated free fatty acid (sFFA) palmitate has been shown to induce cognitive dysfunction and AD-like pathology, polyunsaturated fatty acids (PUFA) such as linoleate have been suggested to protect against AD in mouse models. However, the underlying cellular and molecular mechanisms that mediate the deleterious effects of palmitate or the protective effects of linoleate remain to be characterized. We fed 9-month-old cohorts of triple transgenic AD mice (3xTg-AD) and their-matched controls with a palmitate-enriched/linoleate-deficient diet for three months …and determined the impact of the diet on oxidative stress, Bace1 promoter transactivation status, and amyloid-β (Aβ) burden. The palmitate-enriched/linoleate-deficient diet causes a profound increase in oxidative stress burden characterized by significant oxidative damage to lipids, proteins, and nucleic acids concomitant with deficits in the endogenous antioxidant defense capacity in the hippocampi of 3xTg-AD mice. These effects were also associated with increased NF-κ B transcriptional activity resulting in NF-κ B-mediated transactivation of the Bace1 promoter that culminated in higher BACE1 expression and activity, and Aβ production. Our study unveils a novel mechanism by which a diet enriched in the sFFA palmitate and deficient in the PUFA linoleate exacerbates AD-like pathology involving signaling cross-talk between oxidative stress and NF-κ B activation as a critical underlying factor in upregulating BACE1 activity and increasing Aβ burden. Show more

Keywords: Alzheimer’s disease, amyloid-β, BACE1, linoleate, NF-κB, oxidative stress, palmitate

DOI: 10.3233/JAD-180835

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 219-237, 2019

Authors: Giil, Lasse Melvaer | Solvang, Stein-Erik Hafstad | Giil, Malin Melvaer | Hellton, Kristoffer H. | Skogseth, Ragnhild Eide | Vik-Mo, Audun Osland | Hortobágyi, Tibor | Aarsland, Dag | Nordrehaug, Jan Erik

Article Type: Research Article

Abstract: Background: Epidemiological studies link serum potassium (K+ ) to cognitive performance, but whether cognitive prognosis in dementia is related to K+ levels is unknown. Objective: To determine if K+ levels predict cognitive prognosis in dementia and if this varies according to diagnosis or neuropathological findings. Methods: This longitudinal cohort study recruited 183 patients with mild Alzheimer’s disease or Lewy body dementia (LBD). Serum K+ and eGFR were measured at baseline and medications which could affect K+ registered. The Mini-Mental State Examination (MMSE) was measured annually over 5 years, and mortality registered. Association …between K+ and √(30 -MMSE) was estimated overall, and according to diagnosis (joint model). Associations between MMSE-decline and K+ were assessed in two subgroups with neuropathological examination (linear regression) or repeated measurements of K+ over 3 years (mixed model). Results: Serum K+ at baseline was associated with more errors on MMSE over time (Estimate 0.18, p  = 0.003), more so in LBD (p  = 0.048). The overall association and LBD interaction were only significant in the 122 patients not using K+ relevant medication. Repeated K+ measures indicated that the association with MMSE errors over time was due to a between-person effect (p  < 0.05, n  = 57). The association between the annual MMSE decline was stronger in patients with autopsy confirmed LBD and more α -synuclein pathology (all: p  < 0.05, n  = 41). Conclusion: Higher serum K+ predicts poorer cognitive prognosis in demented patients not using medications which affect K+ , likely a between-person effect seen mainly in LBD. Show more

Keywords: α-synuclein, Alzheimer’s disease, cognitive decline, kalium, Lewy body dementia, Mini-Mental State Examination, MMSE-decline, potassium, prognosis

DOI: 10.3233/JAD-181131

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 239-253, 2019