Journal of Alzheimer's Disease - Volume 74, issue 1

Authors: Yang, Heyun | Wang, Wei | Jia, Longfei | Qin, Wei | Hou, Tingting | Wu, Qiaoqi | Li, Haitao | Tian, Yuanruhua | Jia, Jianping

Article Type: Research Article

Abstract: The blood-brain barrier (BBB) can restrict the therapeutic effects of Alzheimer’s disease (AD) medications. While a large number of AD drug treatment trials targeting BBB dynamics have emerged, most have failed due to insufficient permeability. Furthermore, a subset of AD cases, which also feature chronic hypoperfusion are complicated by BBB deficits. We used a mouse model of AD with chronic hypoperfusion—transgenic mice (PS1V97L) with right common carotid artery ligation. In this model, we assessed how chronic cerebral hypoperfusion changed the pathophysiological processes that increase BBB permeability. Compared with control mice, AD mice with chronic hypoperfusion revealed significantly upregulated expression of …the receptor for advanced glycation end products (RAGE) on the BBB. Upregulated RAGE caused increased accumulation of amyloid-β (Aβ) in the brain in these mice. Upregulation of RAGE (or binding to Aβ) can promote activation of the NF-κ B pathway and enhance oxidative stress and increase the release of pro-inflammatory factors. These factors promoted the reduction of tight junction proteins between the endothelial cells in the BBB and increased its permeability. These findings suggest that the transporter RAGE dysregulation on the BBB initiates a series of pathophysiological processes which lead to increased BBB permeability. Taken together, we have shown that chronic hypoperfusion can serve to enhance and aggravate the BBB impairment in AD. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, chronic cerebral hypoperfusion, NF-κB pathway, permeability, transgenic mice

DOI: 10.3233/JAD-191045

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 261-275, 2020

Authors: Jääskeläinen, Olli | Hall, Anette | Tiainen, Mika | van Gils, Mark | Lötjönen, Jyrki | Kangas, Antti J. | Helisalmi, Seppo | Pikkarainen, Maria | Hallikainen, Merja | Koivisto, Anne | Hartikainen, Päivi | Hiltunen, Mikko | Ala-Korpela, Mika | Soininen, Pasi | Soininen, Hilkka | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract: Accurate differentiation between neurodegenerative diseases is developing quickly and has reached an effective level in disease recognition. However, there has been less focus on effectively distinguishing the prodromal state from later dementia stages due to a lack of suitable biomarkers. We utilized the Disease State Index (DSI) machine learning classifier to see how well quantified metabolomics data compares to clinically used cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD). The metabolic profiles were quantified for 498 serum and CSF samples using proton nuclear magnetic resonance spectroscopy. The patient cohorts in this study were dementia (with a clinical AD diagnosis) (N = 359), …mild cognitive impairment (MCI) (N = 96), and control patients with subjective memory complaints (N = 43). DSI classification was conducted for MCI (N = 51) and dementia (N = 214) patients with low CSF amyloid-β levels indicating AD pathology and controls without such amyloid pathology (N = 36). We saw that the conventional CSF markers of AD were better at classifying controls from both dementia and MCI patients. However, quantified metabolic subclasses were more effective in classifying MCI from dementia. Our results show the consistent effectiveness of traditional CSF biomarkers in AD diagnostics. However, these markers are relatively ineffective in differentiating between MCI and the dementia stage, where the quantified metabolomics data provided significant benefit. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, machine learning, metabolomics

DOI: 10.3233/JAD-191226

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 277-286, 2020

Authors: Gezen-Ak, Duygu | Alaylıoğlu, Merve | Genç, Gençer | Şengül, Büşra | Keskin, Ebru | Sordu, Pelin | Güleç, Zeynep Ece Kaya | Apaydın, Hülya | Bayram-Gürel, Çiğdem | Ulutin, Turgut | Yılmazer, Selma | Ertan, Sibel | Dursun, Erdinç

Article Type: Research Article

Abstract: Mitochondrial dysfunctions are significant contributors to neurodegeneration. One result or a cause of mitochondrial dysfunction might be the disruption of mtDNA transcription. Limited data indicated an altered expression of mtDNA encoded transcripts in Alzheimer’s disease (AD) or Parkinson’s disease (PD). The number of mitochondria is high in cells with a high energy demand, such as muscle or nerve cells. AD or PD involves increased risk of cardiomyopathy, suggesting that mitochondrial dysfunction might be systemic. If it is systemic, we should observe it in different cell types. Given that, we wanted to investigate any disruption in the regulation of mtDNA encoded …gene expression in addition to PINK1, PARKIN, and ATP levels in peripheral blood samples of PD cases who are affected by a neurodegenerative disorder that is very well known by its mitochondrial aspects. Our results showed for the first time that: 1) age of onset > 50 PD sporadic (PDS) cases: mtDNA transcription and quality control genes were affected; 2) age of onset <50 PDS cases: only mtDNA transcription was affected; and 3) PD cases with familial background: only quality control genes were affected. mtDNA copy number was not a confounder. Intracellular ATP levels of PD case subgroups were significantly higher than those of healthy subjects. We suggest that a systemic dysregulation of transcription of mtDNA or mitochondrial quality control genes might result in the development of a sporadic form of the disease. Additionally, ATP elevation might be an independent compensatory and response mechanism. Hyperactive cells in AD and PD require further investigation. Show more

Keywords: Alzheimer’s disease, ATP, mitochondrial DNA, OXPHOS, PARKIN, Parkinson’s disease, PINK1

DOI: 10.3233/JAD-191164

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 287-307, 2020

Authors: Sinha, Neha | Berg, Chelsie N. | Shaw, Ashlee | Gluck, Mark A.

Article Type: Research Article

Abstract: African Americans are at elevated risk for age-related cognitive decline, with double the prevalence of Alzheimer’s disease (AD) compared to Caucasians Americans. Various behavioral, biological, and lifestyle factors may underlie this health disparity, but little is known about the relative importance and interactions among these different risk factors in African Americans. While the neuroprotective effects of aerobic exercise on biomarkers are well established, few studies have examined the differential benefits of exercise based on genetic risk for AD. Furthermore, evidence is limited regarding the potential moderating effects of ABCA7 , a gene known to confer significantly greater AD risk in …African Americans. In a case-control matched sample of 56 healthy older African Americans, we investigated the effect of an aerobic exercise intervention on a hippocampus-related assessment of generalization following rule learning, in individuals who were carriers of the ABCA7 rs3764650 non-risk (TT) or high-risk (GG) genotype. Following the exercise-intervention, the non-risk group made significantly fewer generalization errors, while there was no improvement in generalization for the high-risk group. For the controls, no changes in generalization scores were observed regardless of genotype status. Our results indicate that the ongoing adverse effects of ABCA7 high-risk genotype may diminish the benefits associated with aerobic exercise. As such, the potential disease-modifying effects of aerobic exercise on AD-related neuropathology may be limited to carriers of the ABCA7 rs3764650 non-risk genotype. Show more

Keywords: ABCA7, aerobic exercise, African American, Alzheimer’s disease

DOI: 10.3233/JAD-190723

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 309-318, 2020

Authors: Talaei, Mohammad | Feng, Lei | Barrenetxea, Jon | Yuan, Jian-Min | Pan, An | Koh, Woon-Puay

Article Type: Research Article

Abstract: Background: Few prospective studies with long duration of follow-up have assessed the relations of body mass index (BMI) and weight change with cognitive function, especially in Asian populations. Objective: To investigate whether BMI and weight change in midlife are associated with cognitive impairment in old age. Methods: We used data from 14,691 participants in the Singapore Chinese Health Study and computed weight change as the difference between weight reported at baseline (1993–1998) at mean age of 53.0 years and follow-up 1 (1999–2004) at mean age of 58.6 years. Cognitive impairment was determined using education-specific cut-offs of …the Singapore Modified Mini-Mental State Examination at follow-up 3 (2014–2016) at mean age of 72.9 years. We used multivariable logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations. Results: Obesity (as defined BMI ≥27.5 kg/m2 ) was associated with a higher risk of cognitive impairment at baseline (OR 1.33, 95% CI 1.12–1.58) and follow-up 1 (OR 1.30, 95% CI 1.10–1.54) compared to BMI of 18.5–22.9 kg/m2 . Underweight (BMI <18.5 kg/m2 ) was not associated with a significant risk either at baseline (OR 0.91, 95% CI 0.73–1.13) or follow-up 1 (OR 1.05, 95% CI 0.85–1.28). Compared to participants with <5% weight change, the ORs (95% CIs) of cognitive impairment were 1.20 (1.03–1.41) for those with 5–9.9% weight loss, 1.53 (1.29–1.81) for ≥10% weight loss, 1.00 (0.85–1.17) for 5–9.9% weight gain, and 1.50 (1.28–1.75) for ≥10% weight gain. Conclusion: Obesity, weight loss, and excessive weight gain at midlife were associated with an increased risk of cognitive impairment at old age. Show more

Keywords: Body mass index, Chinese, cognitive impairment, cohort study, weight change

DOI: 10.3233/JAD-191052

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 319-329, 2020

Authors: Benvenutto, Agnès | Guedj, Eric | Felician, Olivier | Eusebio, Alexandre | Azulay, Jean-Philippe | Ceccaldi, Mathieu | Koric, Lejla

Article Type: Research Article

Abstract: Corticobasal syndrome (CBS) is a neuropathologically heterogeneous entity. The use of cerebrospinal fluid and amyloid biomarkers enables detection of underlying Alzheimer’s disease (AD) pathology. We thus compared clinical, eye movement, and 18 FDG-PET imaging characteristics in CBS in two groups of patients divided according to their amyloid biomarkers profile. Fourteen patients presenting with CBS and amyloidosis (CBS-A+ ) were compared with 16 CBS patients without amyloidosis (CBS-A- ). The two groups showed similar motor abnormalities (parkinsonism, dystonia) and global cognitive functions. Unlike CBS-A+ patients who displayed more posterior cortical abnormalities, CBS-A- patients demonstrated more anterior cortical and brain …stem dysfunctions on the basis of neuropsychological testing, study of saccade velocities and brain hypometabolism areas on 18 FDG-PET. Interestingly, Dopamine Transporter SPECT imaging showed similar levels of dopaminergic degeneration in both groups. These findings confirm common and distinct brain abnormalities between the different neurodegenerative diseases that result in CBS. We demonstrate the importance of a multidisciplinary approach to improve diagnosis in vivo in particular on oculomotor examination. Show more

Keywords: Alzheimer’s disease, corticobasal syndrome, DaTSCAN© , eye movements, 18FDG-PET, video-oculography

DOI: 10.3233/JAD-190961

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 331-343, 2020

Authors: Goldwaser, Eric L. | Acharya, Nimish K. | Wu, Hao | Godsey, George A. | Sarkar, Abhirup | DeMarshall, Cassandra A. | Kosciuk, Mary C. | Nagele, Robert G.

Article Type: Research Article

Abstract: Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer’s disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro . Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-β1-42 (Aβ42 ), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (α 7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of Aβ42, IgG, GluR2/3, and α 7nAChR as …well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble Aβ42 peptide and serum from AD and control subjects. The rate and extent of Aβ42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for α 7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM Aβ42 . Initial co-localization of IgG, α 7nAChR, and Aβ42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). Aβ42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then rescued by coupling F(ab) fragments with divalent human anti-Fab. Overall, results suggest that cross-linking of neuron-binding autoantibodies targeting cell surface proteins can accelerate intraneuronal Aβ42 deposition in AD. Show more

Keywords: Aβ1-42 , Alzheimer’s disease, autoantibodies, blood-brain barrier, brain-reactive autoantibodies, cerebrovasculature

DOI: 10.3233/JAD-190962

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 345-361, 2020

Authors: Casaletto, Kaitlin B. | Rentería, Miguel Arce | Pa, Judy | Tom, Sarah E. | Harrati, Amal | Armstrong, Nicole M. | Rajan, K. Bharat | Mungas, Dan | Walters, Samantha | Kramer, Joel | Zahodne, Laura B.

Article Type: Research Article

Abstract: Background: Active lifestyles are related to better cognitive aging outcomes, yet the unique role of different types of activity are unknown. Objective: To examine the independent contributions of physical (PA) versus cognitive (CA) leisure activities to brain and cognitive aging. Methods: Independent samples of non-demented older adults from University of California, San Francisco Hillblom Aging Network (UCSF; n  = 344 typically aging) and University of California, Davis Diversity cohort (UCD; n  = 485 normal to MCI) completed: 1) self-reported engagement in current PA and CA (UCSF: Physical Activity Scale for the Elderly and Cognitive Activity Scale; UCD: Life …Experiences Assessment Form); 2) neuropsychological batteries; and 3) neuroimaging total gray matter volume, white matter hyperintensities, and/or global fractional anisotropy. PA and CA were simultaneously entered into multivariable linear regression models, adjusting for demographic characteristics and functional impairment severity. Results: Brain outcomes : In UCSF, only PA was positively associated with gray matter volume and attenuated the relationship between age and fractional anisotropy. In UCD, only CA was associated with less white matter hyperintensities and attenuated the relationship between age and gray matter volume. Cognitive outcomes : In both cohorts, greater CA, but not PA, related to better cognition, independent of age and brain structure. In UCSF, CA attenuated the relationship between fractional anisotropy and cognition. In UCD, PA attenuated the association between white matter hyperintensities and cognition. Conclusions: Although their specificity was not easily teased apart, both PA and CA are clearly related to better brain and cognitive resilience markers across cohorts with differing educational, racial, and disease statuses. PA and CA may independently contribute to converging neuroprotective pathways for brain and cognitive aging. Show more

Keywords: Brain aging, cognitive aging, exercise, mental stimulation, reserve

DOI: 10.3233/JAD-191114

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 363-376, 2020

Authors: Whitwell, Jennifer L. | Tosakulwong, Nirubol | Weigand, Stephen D. | Graff-Radford, Jonathan | Duffy, Joseph R. | Clark, Heather M. | Machulda, Mary M. | Botha, Hugo | Utianski, Rene L. | Schwarz, Christopher G. | Senjem, Matthew L. | Strand, Edythe A. | Ertekin-Taner, Nilufer | Jack Jr , Clifford R. | Lowe, Val J. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Rates of amyloid-β (Aβ) accumulation have been characterized across the cognitively normal to typical Alzheimer’s dementia spectrum, but little is known about Aβ accumulation in atypical Alzheimer’s disease (AD) and other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD). Objective: We aimed tocharacterize longitudinal Aβ accumulation anddetermine the influence of age, apolipoprotein E (APOE) genotype, disease duration, and sexin atypical AD and FTLD. Methods: 322 patients (138 atypical AD, 184 FTLD) underwent Pittsburgh compound B PET scanning, with 73 having serialPiB-PET scans (42 atypical AD, 31 FTLD). Global Aβ standard uptake value ratios were calculated …for every scan. Mixed effects models were used to assess the effect of age, APOE genotype, disease duration, and sex on baseline and change measures of Aβ. Results: Atypical AD showed higher baseline Aβ than FTLD. Rate of Aβ accumulation was not associated with baseline Aβ in either group. Older age was associated with greater baseline Aβ and faster rates of accumulation in FTLD. In patients under age 70, atypical AD showed faster rates of accumulation than FTLD. APOE ɛ 4 genotype was associated with greater baseline Aβ in FTLD but did not influence rates of accumulation. Rates of Aβ accumulation were faster in FTLD patents with time from onset-to-PET≤4 years. Female sex was associated with faster rates of accumulation in atypical AD. Conclusion: Accumulation of Aβ is observed in atypical AD and FTLD, although different demographic factors influence accumulation in these diseases providing insight into potentially different biological mechanisms of Aβ deposition. Show more

Keywords: Alzheimer’s disease, amyloid plaques, frontotemporal lobar degeneration, positron emission tomography

DOI: 10.3233/JAD-190699

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 377-389, 2020

Authors: Soares Martins, Tânia | Magalhães, Sandra | Rosa, Ilka Martins | Vogelgsang, Jonathan | Wiltfang, Jens | Delgadillo, Ivonne | Catita, José | da Cruz e Silva, Odete A.B. | Nunes, Alexandra | Henriques, Ana Gabriela

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) diagnosis is based on psychological and imaging tests but can also include monitoring cerebrospinal fluid (CSF) biomarkers. However, CSF based-neurochemical approaches are expensive and invasive, limiting their use to well-equipped settings. In contrast, blood-based biomarkers are minimally invasive, cost-effective, and a widely accessible alternative. Blood-derived exosomes have recently emerged as a reliable AD biomarker source, carrying disease-specific cargo. Fourier-transformed infrared (FTIR) spectroscopy meets the criteria for an ideal diagnostic methodology since it is rapid, easy to implement, and has high reproducibility. This metabolome-based technique is useful for diagnosing a broad range of diseases, although to our knowledge, …no reports for FTIR spectroscopy applied to exosomes in AD exist. In this ground-breaking pilot study, FTIR spectra of serum and serum-derived exosomes from two independent cohorts were acquired and analyzed using multivariate analysis. The regional UA-cohort includes 9 individuals, clinically diagnosed with AD, mean age of 78.7 years old; and the UMG-cohort comprises 12 individuals, clinically diagnosed with AD (based on molecular and/or imaging data), mean age of 73.2 years old. Unsupervised principal component analysis of FTIR spectra of serum-derived exosomes revealed higher discriminatory value for AD cases when compared to serum as a whole. Consistently, the partial least-squares analysis revealed that serum-derived exosomes present higher correlations than serum. In addition, the second derivative peak area calculation also revealed significant differences among Controls and AD cases. The results obtained suggest that this methodology can discriminate cases from Controls and thus be potential useful to assist in AD clinical diagnosis. Show more

Keywords: Alzheimer’s disease, biomarker, blood, diagnosis, exosomes, serum, spectroscopy

DOI: 10.3233/JAD-191034

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 391-405, 2020

Article Type: Correction

DOI: 10.3233/JAD-209001

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 407-407, 2020

Article Type: Correction

DOI: 10.3233/JAD-199670

Citation: Journal of Alzheimer's Disease, vol. 74, no. 1, pp. 409-409, 2020