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

Authors: Li, Lexiao | Ismael, Saifudeen | Nasoohi, Sanaz | Sakata, Kazuko | Liao, Francesca-Fang | McDonald, Michael P. | Ishrat, Tauheed

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain-like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLRP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques in comparison …with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1β (IL-1β) were co-localized near Aβ plaques and p-tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1β, the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias. Show more

Keywords: Alzheimer’s disease, amyloid plaques, hyperphosphorylated tau, NLRP3 inflammasome interlukin-1, thioredoxin-interacting protein

DOI: 10.3233/JAD-180814

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 255-265, 2019

Authors: Manniche, Christina | Hejl, Anne-Mette | Hasselbalch, Steen Gregers | Simonsen, Anja Hviid

Article Type: Research Article

Abstract: Background: The diagnostic workup of idiopathic normal pressure hydrocephalus (iNPH) can be challenging due to an overlap in symptoms and neuroimaging features with other disorders. Despite a growing interest, a cerebrospinal fluid (CSF) biomarker profile in iNPH has not yet been identified. Objective: To determine the CSF biomarkers with the greatest evidence for differentiating iNPH from the most common differential diagnoses, Alzheimer’s disease (AD) and subcortical ischemic vascular disease (SIVD). Methods: A systematic literature search was conducted in PubMed to identify relevant articles up to July 2018 using the following MESH-terms: “Cerebrospinal fluid”, “diagnos*”, “hydrocephalus, normal …pressure”. Relevant data were extracted to assess the risk of bias in the included studies. Results: Twenty-five studies including 664 patients with iNPH, 502 with AD, 57 with SIVD, 81 with other disorders, and 338 healthy controls (HC) were included. They investigated the diagnostic value of 92 CSF biomarkers. Most evidence existed for amyloid-β 42 (Aβ 42 ), phosphorylated tau (p-tau), and total tau (t-tau) in iNPH versus AD and HC: Aβ 42 did not differ between iNPH and AD, but was lower than in HC subjects. T-tau and p-tau were lower in iNPH versus AD on a level comparable to HC subjects. There was moderate or limited evidence for 62 and 88 biomarkers, respectively. Several plausible biases characterize the literature including small sample sizes and inconsistent diagnostic criteria. Conclusion: T-tau and p-tau may differentiate iNPH from AD and Aβ 42 from HC. A combination of these biomarkers may improve the diagnostic accuracy in iNPH. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, normal pressure hydrocephalus, vascular dementia

DOI: 10.3233/JAD-180816

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 267-279, 2019

Authors: Depciuch, Joanna | Zawlik, Izabela | Skrzypa, Marzena | Pająk, Justyna | Potocka, Natalia | Łach, Kornelia | Bartosik-Psujek, Halina | Koziorowska, Anna | Kaznowska, Ewa | Cebulski, Józef

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a disease of advanced civilization and a common form of dementia in people over 65 years of age. We used Fourier transform infrared (FTIR) spectroscopy combined with principal component analysis (PCA) to determine changes in the quantity and quality of the cerebrospinal fluid from AD patients at three different stages of the disease (ADI, ADII, and ADIII), as well as from patients with mild cognitive impairment (MCI). Moreover, based on the FTIR spectra, we calculated the ratio of α -helix and β-sheet secondary protein structures as well as the lipid-protein balance as potential AD markers. The …FTIR spectra of cerebrospinal fluid obtained from MCI, ADI, ADII, and ADIII patients showed that peaks corresponding to protein and deoxyribonucleic acid (DNA), and phospholipid and lipid vibrations were shifted in comparison with those of control subjects. Furthermore, the levels of these chemical compounds were lower in the patients than in the control subjects. The β-sheet secondary protein structure levels were increased in the MCI and AD patients compared with the control subjects. In addition, significant changes in the lipid-protein balance were observed. Interestingly, as the disease progressed, the lipid-protein balance became further disrupted, that is, the lipid amount decreased with disease progression. PCA analysis of lipid-protein FTIR regions revealed that the spectra could be used to distinguish between controls and patients with MCI, ADI, ADII, and ADIII. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, Fourier transform infrared spectroscopy, lipid-protein balance, PCA-LDA

DOI: 10.3233/JAD-181008

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 281-293, 2019

Authors: Cedres, Nira | Machado, Alejandra | Molina, Yaiza | Diaz-Galvan, Patricia | Hernández-Cabrera, Juan Andres | Barroso, Jose | Westman, Eric | Ferreira, Daniel

Article Type: Research Article

Abstract: Subjective cognitive complaints in cognitively normal individuals are a relevant predictor of Alzheimer’s disease (AD), cerebrovascular disease, and age-related tauopathy. Complaints starting after the age of 60 increase the likelihood of preclinical AD. However, this criterion is arbitrary and current data show that neurodegenerative disorders likely start before that age. Further, data on the role of subjective complaints below the age of 60 in individuals qualifying for subjective cognitive decline (SCD) are lacking. We investigated the association of subjective cognitive complaints with an extensive number of neuroimaging, demographic, clinical, and cognitive measures in individuals fulfilling criteria for SCD below and …above the age of 60. Nine complaints were scored in 416 individuals. Complaints were related to a higher load of white matter signal abnormalities, and this association was stronger the more subclinical changes in personality, interest, and drive were reported. In individuals <60 years, complaints were associated with lower global cognitive performance. In individuals ≥60 years, complaints were related to greater global brain atrophy and smaller total intracranial volume, and this association was stronger the more subclinical difficulties in activities of daily living were reported. Also, complaints were associated with increased depressive symptomatology irrespective of age. We conclude that complaints below the age of 60 may be associated with subtle signs of brain pathology. In the community, screening for risk of future cognitive decline should include subjective cognitive complaints, depressive symptomatology, and subclinical reduced cognition (<60 years)/activities of daily living (≥60 years), supported by basic neuroimaging examinations. Show more

Keywords: Brain atrophy, depressive symptomatology, middle-age, multivariateanalysis, subjective cognitive decline, white matter signal abnormalities

DOI: 10.3233/JAD-180720

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 295-309, 2019

Authors: Groeneveld, Onno N. | Moneti, Costanza | Heinen, Rutger | de Bresser, Jeroen | Kuijf, Hugo J. | Exalto, Lieza G. | Boomsma, Jooske M.F. | Kappelle, L.Jaap | Barkhof, Frederik | Prins, Niels D. | Scheltens, Philip | van der Flier, Wiesje M. | Biessels, Geert Jan | and on behalf of the TRACE-VCI study group

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer’s disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis. Objective: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM. Methods: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n  = 147, 68.4±7.9 years, 63% men; …no T2DM: n  = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer’s disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death. Results: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p  < 0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: – 0.17, p  = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.∥ Show more

Keywords: Cerebrospinal fluid, magnetic resonance imaging, prognosis, type 2 diabetes mellitus, vascular brain injury

DOI: 10.3233/JAD-180914

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 311-322, 2019

Authors: Fujikura, Mai | Iwahara, Naotoshi | Hisahara, Shin | Kawamata, Jun | Matsumura, Akihiro | Yokokawa, Kazuki | Saito, Taro | Manabe, Tatsuo | Matsushita, Takashi | Suzuki, Syuuichirou | Shimohama, Shun

Article Type: Research Article

Abstract: We previously demonstrated that microglia play an essential role in clearance of amyloid-β (Aβ) in Alzheimer’s disease (AD)-like pathology. Our prior work also showed that several receptors expressed on microglia participated in Aβ phagocytosis. However, clathrin-mediated endocytosis (CME), which is associated with production and release of Aβ in neurons, has received much less attention in the context of microglial Aβ uptake. To elucidate the detailed mechanisms of microglial Aβ uptake pathways, we focused on CD14 and Toll-like receptor 4 (TLR4), which have been shown to mediate fibrillar Aβ1 - 42 (fAβ42 ) phagocytosis in microglia. CD14 has also been known to …control lipopolysaccharide-induced internalization of TLR4 in a clathrin-dependent manner. However, it remains unclear whether CD14 and TLR4 engage in CME in microglial fAβ42 uptake, including whether CD14 interacts with TLR4 in the process. In the present study, we found that CD14-positive microglia increased in an age-dependent manner in the cortex of AD model mice. Immunostaining showed that CD14 interacted with TLR4 to internalize fAβ42 in the mouse microglial cell line MG6. Knock-down of CD14 and TLR4 in MG6 cells significantly reduced intracellular fAβ42 , showing their involvement in fAβ42 uptake. We also found that clathrin participated in fAβ42 uptake by MG6 cells. Furthermore, CD14 and TLR4 mediated fAβ42 uptake via clathrin-dependent mechanisms. These results indicate that CD14 and TLR4 participate not only in phagocytosis but also in clathrin-dependent fAβ42 internalization in microglia. These findings provide novel molecular understanding of microglial fAβ42 uptake, which could be of therapeutic relevance for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , CD14, clathrin, microglia, Toll-like receptor 4

DOI: 10.3233/JAD-180904

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 323-337, 2019

Authors: Han, Zhijie | Xue, Weiwei | Tao, Lin | Zhu, Feng

Article Type: Research Article

Abstract: The pathogenesis of Alzheimer’s disease (AD) is identified to be significantly regulated by long non-coding RNA (lncRNA) based on in vivo and clinical experiments. Single nucleotide polymorphisms (SNPs) can strongly impact expression and function of lncRNA in AD, and previous genome-wide associations studies (GWAS) have discovered substantial amount of risk SNPs associated with AD. However, current studies omit the important information about SNPs when identifying potential AD-related lncRNAs. In addition to single discovery approach and small-scale samples in these studies, the number of lncRNAs discovered as keys in AD is limited. Here, multiple computational methods were integrated to discover …novel and key lncRNA of the pathology of AD. First, large-scale GWAS data involved in three ethnicities were collected from two authoritative sources, and meta-analyses were conducted to find SNPs significantly associated with AD (tag SNPs). Second, these tag SNPs together with their linkage disequilibrium information were used to discover potential lncRNAs related to AD. Third, after validation by microarray probe re-annotation of 1,282 samples and RNA-seq data analysis of 117 samples, respectively, a total of five key lncRNAs of AD were identified. Finally, possible function of these lncRNAs was predicted by genome mapping, expression quantitative trait loci, differential co-expression, and gene set enrichment analysis. Based on function prediction, four of the five key lncRNAs were identified to affect the risk of AD by regulating corresponding pathogenic genes and pathways, which are involved in regulation of amyloid-β peptide and the immune system. In summary, these findings can facilitate the discovery of potential disease-related lncRNAs and enhance understanding of the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, differential co-expression, genome-wide association study, long non-coding RNA, microarray probe re-annotation

DOI: 10.3233/JAD-181051

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 339-355, 2019

Authors: Conner, Sarah C. | Benayoun, Laurent | Himali, Jayandra J. | Adams, Stephanie L. | Yang, Qiong | DeCarli, Charles | Blusztajn, Jan K. | Beiser, Alexa | Seshadri, Sudha | Delalle, Ivana

Article Type: Research Article

Abstract: Genome-wide association studies identified a single nucleotide polymorphism (SNP) in the MSRB3 gene encoding Methionine Sulfoxide Reductase-B3 (MsrB3) to be associated with the risk for low hippocampal volume and late onset Alzheimer’s disease (AD). Subsequently, we identified AD-associated abnormal patterns of neuronal and vascular MsrB3 expression in postmortem hippocampi. The present study investigated the relationship between the MSRB3 SNP rs61921502 , G (minor/risk allele) and MRI measures of brain injury including total brain volume, hippocampal volume, and white matter hyperintensities using linear regression models; the presence of brain infarcts using logistic regression models; and the incidence of stroke, …dementia, and AD using Cox proportional hazards models in 2,038 Framingham Heart Study Offspring participants with MRI administered close to examination cycle 7 (1998–2001). Participants with neurological conditions that impede evaluation of vascular pathology by MRI, i.e., brain tumors, multiple sclerosis, and major head trauma, were excluded from the study. When adjusted for age and age squared at MRI exam, sex, and presence of Apolipoprotein ɛ 4 allele (APOE4 ), individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele. However, in stratified analyses, MSRB3 rs61921502 minor allele was significantly associated with increased odds for MRI brain infarcts only in the absence of APOE4 . Show more

Keywords: Framingham Heart Study, hippocampus, MSRB3 , vascular pathology

DOI: 10.3233/JAD-180977

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 357-365, 2019

Authors: Guo, Jing | Xu, Cheng | Ni, Shaozhou | Zhang, Shujuan | Li, Qihang | Zeng, Peng | Pi, Guilin | Liu, Enjie | Sun, Dong-Sheng | Liu, Yanchao | Wang, Zhouyi | Chen, Haote | Yang, Ying | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Hyperhomocysteinemia is an independent risk factor of Alzheimer’s disease (AD), which is not diagnosed for many years before onset due to lack of peripherally detectable early biomarkers. Visual dysfunction is prevalent in AD patients and correlates with the severity of cognitive defects. Importantly, alterations in eyes can be non-invasively detected. To search for early biomarkers in eyes from high risk factors of AD, we injected homocysteine (Hcy) into the rats via vena caudalis for 3, 7, and 14 days, respectively, and characterized the chronological order of the AD-like pathologies appearing in retina and the hippocampus during the progression of …hyperhomocysteinemia, and their correlations with cognitive impairment. We found that administration of Hcy for 14 days, but not 3 or 7 days, induced hyperhomocysteinemia, although a gradually increased blood Hcy level was detected. In retina and/or the hippocampus, significant loss of retinal ganglion cells and stenosis of retinal arteries with the AD-like tau and amyloid-β (Aβ) pathologies and memory deficit were shown only in the 14-day Hcy group. Interestingly, accumulation of Ser262 hyperphosphorylated tau (pS262-tau) but not Aβ with decreased methylation of protein phosphatase-2A catalytic subunit (M-PP2Ac) and increased de-methylated PP2Ac (DM-PP2Ac) was detected in retina of the 3-day Hcy group, in which the retinal pathologies were preceded by those of the hippocampus. These findings suggest that elevated pS262-tau and DM-PP2Ac and reduced M-PP2Ac in retina may serve as surveillance biomarkers for diagnosis of the hyperhomocysteinemia-induced AD in the early stage. Show more

Keywords: Alzheimer’s disease, hyperhomocysteinemia, methylated/de-methylated protein phosphatase-2A, phosphorylated tau, retina

DOI: 10.3233/JAD-180978

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 367-381, 2019

Authors: Brugnolo, Andrea | De Carli, Fabrizio | Pagani, Marco | Morbelli, Slivia | Jonsson, Cathrine | Chincarini, Andrea | Frisoni, Giovanni B. | Galluzzi, Samantha | Perneczky, Robert | Drzezga, Alexander | van Berckel, Bart N.M. | Ossenkoppele, Rik | Didic, Mira | Guedj, Eric | Arnaldi, Dario | Massa, Federico | Grazzini, Matteo | Pardini, Matteo | Mecocci, Patrizia | Dottorini, Massimo E. | Bauckneht, Matteo | Sambuceti, Gianmario | Nobili, Flavio

Article Type: Research Article

Abstract: Background: Several automatic tools have been implemented for semi-quantitative assessment of brain [18 ]F-FDG-PET. Objective: We aimed to head-to-head compare the diagnostic performance among three statistical parametric mapping (SPM)-based approaches, another voxel-based tool (i.e., PALZ), and a volumetric region of interest (VROI-SVM)-based approach, in distinguishing patients with prodromal Alzheimer’s disease (pAD) from controls. Methods: Sixty-two pAD patients (MMSE score = 27.0±1.6) and one hundred-nine healthy subjects (CTR) (MMSE score = 29.2±1.2) were enrolled in five centers of the European Alzheimer’s Disease Consortium. The three SPM-based methods, based on different rationales, included 1) a cluster identified through the correlation analysis between …[18 ]F-FDG-PET and a verbal memory test (VROI-1), 2) a VROI derived from the comparison between pAD and CTR (VROI-2), and 3) visual analysis of individual maps obtained by the comparison between each subject and CTR (SPM-Maps). The VROI-SVM approach was based on 6 VROI plus 6 VROI asymmetry values derived from the pAD versus CTR comparison thanks to support vector machine (SVM). Results: The areas under the ROC curves between pAD and CTR were 0.84 for VROI-1, 0.83 for VROI-2, 0.79 for SPM maps, 0.87 for PALZ, and 0.95 for VROI-SVM. Pairwise comparisons of Youden index did not show statistically significant differences in diagnostic performance between VROI-1, VROI-2, SPM-Maps, and PALZ score whereas VROI-SVM performed significantly (p  < 0.005) better than any of the other methods. Conclusion: The study confirms the good accuracy of [18 ]F-FDG-PET in discriminating healthy subjects from pAD and highlights that a non-linear, automatic VROI classifier based on SVM performs better than the voxel-based methods. Show more

Keywords: European Alzheimer Disease Consortium, FDG-PET, head-to-head comparison, prodromal Alzheimer’s disease, statistical parametric mapping, volumetric region of interest

DOI: 10.3233/JAD-181022

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 383-394, 2019

Authors: Seino, Yusuke | Nakamura, Takumi | Kawarabayashi, Takeshi | Hirohata, Mie | Narita, Sakiko | Wakasaya, Yasuhito | Kaito, Kozue | Ueda, Tetsuya | Harigaya, Yasuo | Shoji, Mikio

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and tau are biomarkers for Alzheimer’s disease (AD); however, the effects of other neurodegenerative processes on these biomarkers remain unclear. We measured Aβ40 , Aβ42 , total tau, phosphorylated-tau, and α -synuclein in CSF and plasma using matched samples from various neurodegenerative diseases to expand our basic knowledge on these biomarkers and their practical applications. A total of 213 CSF and 183 plasma samples were analyzed from cognitively unimpaired subjects, and patients with Alzheimer’s disease dementia (ADD), mild cognitive impairment (MCI), non-AD dementias, and other neurological diseases. The CSF/plasma ratios of Aβ40 and …Aβ42 were approximately 25:1. Aβ40/42 ratios in CSF and plasma were both 10:1. The CSF total tau/P181tau ratio was 6:1. The CSF/plasma α -synuclein ratio was 1:65. Significantly decreased Aβ42 levels and an increased Aβ40/42 ratio in CSF in ADD/MCI suggested that these relationships were specifically altered in AD. Increased total tau levels in ADD/MCI, encephalopathy, and multiple system atrophy, and increased P181tau in ADD/MCI indicated that these biomarkers corresponded to neurodegeneration and tauopathy, respectively. Although CSF α -synuclein levels were increased in ADD/MCI, there was no merit in measuring α -synuclein in CSF or plasma as a biomarker. The combination of biomarkers by the Aβ40/42 ratio×p181tau reflected specific changes due to the AD pathology in ADD/MCI. Thus, CSF Aβ40 , Aβ42 , p181tau, and tau were identified as biomarkers for aggregated Aβ associated state (A), aggregated tau associated state (T), and neurodegeneration state (N) pathologies in AD based on the NIA-AA criteria. Overlaps in these biomarkers need to be considered in clinical practice for differential diagnoses of neurodegenerative diseases. Show more

Keywords: Aβ40, Aβ42, α-synuclein, cerebrospinal fluid, neurodegenerative diseases, phosphorylated-tau, plasma, total-tau

DOI: 10.3233/JAD-181152

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 395-404, 2019

Authors: Xia, Hui | Wang, Min | Li, Jie-Qiong | Tan, Chen-Chen | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The brain-derived neurotrophic factor (BDNF ) Val66Met polymorphism emerged as a risk factor for Alzheimer’s disease (AD). However, little was known about its effects on the process of potential AD. Objective: To explore the effects of the Val66Met polymorphism on cognition, cerebrospinal fluid (CSF), and neuroimaging markers in non-demented elderly individuals. Methods: A total of 1,081 adults without dementia (375 healthy subjects and 706 individuals with mild cognitive impairment) were recruited from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to test the influence of BDNF Val66Met polymorphism on cognitive impairment, brain structure atrophy, and change …in the levels of CSF biomarkers. Moreover, we also conducted our study in abnormal amyloid-β (A +) subgroup and normal amyloid-β (A–) subgroup, as well as in APOE ɛ 4 carriers and non-carriers. Results: The BDNF Val66Met polymorphism had significant association with atrophy of the entorhinal cortex and Mini-Mental State Examination (MMSE) scores in the non-demented elderly and A  + subgroup, while no association was found in A–subgroup. What is more, there was a significant effect of interaction between BDNF Val66Met and amyloid-β load in MMSE. In addition, significant associations of BDNF Val66Met with the entorhinal cortex and ventricular volumes were found among APOE ɛ 4 non-carriers, but not APOE ɛ 4 carriers. Conclusions: The BDNF Val66Met polymorphism is associated with cognitive impairment and brain atrophy among the non-demented elderly, APOE ɛ 4 non-carriers and A  + subgroup, implying the potential of the Val66Met polymorphism as an important genetic factor for AD-related neurodegeneration. Show more

Keywords: Alzheimer’s disease, amyloid-β, brain-derived neurotrophic factor, polymorphism

DOI: 10.3233/JAD-180971

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 405-414, 2019

Authors: Gulisano, Walter | Maugeri, Daniele | Baltrons, Marian A. | Fà, Mauro | Amato, Arianna | Palmeri, Agostino | D’Adamio, Luciano | Grassi, Claudio | Devanand, D.P. | Honig, Lawrence S. | Puzzo, Daniela | Arancio, Ottavio

Article Type: Correction

DOI: 10.3233/JAD-189015

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 415-415, 2019