Journal of Alzheimer's Disease - Volume 73, issue 4

Authors: Buciuc, Marina | Wennberg, Alexandra M. | Weigand, Stephen D. | Murray, Melissa E. | Senjem, Matthew L. | Spychalla, Anthony J. | Boeve, Bradley F. | Knopman, David S. | Jack Jr, Clifford R. | Kantarci, Kejal | Parisi, Joseph E. | Dickson, Dennis W. | Petersen, Ronald C. | Whitwell, Jennifer L. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Transactive response DNA-binding protein of 43 kDa (TDP-43) is associated with hippocampal atrophy in Alzheimer’s disease (AD), but whether the association is modified by other factors is unknown. Objective: To evaluate whether the associations between TDP-43 and hippocampal volume and atrophy rate are affected by age, gender, apolipoprotein E (APOE ) ɛ 4, Lewy bodies (LBs), amyloid-β (Aβ), or Braak neurofibrillary tangle (NFT) stage. Methods: In this longitudinal neuroimaging-clinicopathological study of 468 cases with AD neuropathological changes (Aβ-positive) that had completed antemortem head MRI, we investigated how age, gender, APOE ɛ 4, presence of LBs, …Aβ, TDP-43, and Braak NFT stages are associated with hippocampal volumes and rates of atrophy over time. We included field strength in the models since our cohort included 1.5T and 3T scans. We then determined whether the associations between hippocampal atrophy and TDP-43 are modified by these factors using mixed effects models. Results: Older age, female gender, APOE ɛ 4, higher field strength, higher TDP-43, and Braak NFT stages were associated with smaller hippocampi. Rate of atrophy was greater with higher TDP-43 and Braak NFT stage, but lower in older patients. The association of TDP-43 with greater rate of atrophy was enhanced in APOE ɛ 4 carriers (p  = 0.04). Conclusion: Neurodegenerative effects of TDP-43 seem to be independent of most factors except perhaps APOE in cases with AD neuropathological changes. TDP-43 and tau appear to behave independently of one another. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, atrophy, dementia, hippocampus, MRI, pathology, TDP-43

DOI: 10.3233/JAD-191040

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1511-1523, 2020

Authors: Hashiguchi, Debora | Campos, Henrique Correia | Wuo-Silva, Raphael | Faber, Jean | Gomes da Silva, Sérgio | Coppi, Antonio Augusto | Arida, Ricardo Mario | Longo, Beatriz Monteiro

Article Type: Research Article

Abstract: Neuroinflammation has been shown to play a crucial role in the development of Alzheimer’s disease (AD) and also has an association with amyloid-β (Aβ) plaques, a hallmark of this disease. Physical exercise has emerged as an alternative treatment for pathological impairment in AD. In light of this evidence, together with the fact that the hippocampus is one of the first structures to be affected in AD, we analyzed hippocampal changes in Aβ load, inflammatory responses, and locomotor activity in transgenic APP/PS1 mouse model for AD submitted to a resistance exercise (RE) program. One month after the start of the RE …program, the locomotor hyperactivity related to AD behavior was reduced and microglia recruitment was increased, which in turn may have contributed to the decrease in the volume of Aβ plaques. In addition, the RE program restored the levels of IL-1α , IL-4, and IL-6 cytokines to control levels. Our study indicates that RE has beneficial effects on the locomotor behavior, amyloid burden, and inflammation of AD pathology and can therefore be used as a therapy to improve the clinical symptoms and neurophysiological alterations in AD. To the best of our knowledge, this is the first study to use a resistance exercise program in transgenic AD model. Show more

Keywords: Alzheimer’s disease, amyloid-β , inflammation, resistance physical exercise

DOI: 10.3233/JAD-190729

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1525-1539, 2020

Authors: Prikhodko, Olga | Rynearson, Kevin D. | Sekhon, Travis | Mante, Mike M. | Nguyen, Phuong D. | Rissman, Robert A. | Tanzi, Rudolph E. | Wagner, Steven L.

Article Type: Research Article

Abstract: Background: In the amyloid hypothesis of Alzheimer’s disease (AD), the dysregulation of amyloid-β protein (Aβ) production and clearance leads to amyloid deposits, tau tangles, neuronal loss, and cognitive dysfunction. Thus far, therapies targeting the enzymes responsible for Aβ production have been found ineffective or having significant side effects. Objective: To test whether a γ -secretase modulator, BPN-15606, is an effective disease-modifying or preventative treatment in the PSAPP mouse model of AD. Methods: We treated pre-plaque (3-month-old) and post-plaque (6-month-old) PSAPP AD transgenic mice for 3 months and examined behavioral, biochemical, and pathological end points. …Results: BPN-15606 attenuated cognitive impairment and reduced amyloid plaque load, microgliosis, and astrogliosis associated with the AD phenotype of PSAPP mice when administered to pre-plaque (3-month-old) but was ineffective when administered to post-plaque (6-month-old) mice. No treatment-related toxicity was observed. Conclusion: BPN-15606 appears efficacious when administered prior to significant pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β , BPN-15606, cognitive deficits, γ-secretase modulator, preventative therapy, PSAPP

DOI: 10.3233/JAD-190442

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1541-1554, 2020

Authors: Yu, Junhong | Feng, Qiushi | Yu, Jintai | Zeng, Yi | Feng, Lei

Article Type: Research Article

Abstract:  Significant variability exists in the trajectories of late-life cognitive decline; however, their associated lifestyle factors remain less studied. We examined these trajectories among elderly participants from the recent five waves (at three-year intervals) of the Chinese Longitudinal Healthy Longevity Study (CLHLS) from 2002 to 2014. Participants from this cohort were included if they completed at least four waves of measurements. Mini–Mental State Examination (MMSE) scores, demographics, medical diagnoses (e.g., hypertension, diabetes, and heart disease), and lifestyle-related information (e.g., smoking, drinking alcohol, and exercise) were collected from participants (N = 2,584; mean age at baseline = 73.3) at least four times across 12 years. MMSE …scores were entered into a latent class mixed model analysis. Subsequently, demographic, medical, and lifestyle predictors were entered into multinomial logistic regression models to predict the trajectories. One of the four emerged classes (no decline) was characterized by an absence of cognitive decline; the other three exhibited various degrees of cognitive decline. The inclusion of lifestyle factors significantly improved the prediction of the different trajectories, above and beyond demographics and medical variables; the ‘no decline’ class was significantly more likely to report exercising regularly. Changes in cognitive functioning across the late-life period are characterized by multiple trajectories. Cognitive decline is not inevitable across the late-life period; the absence of such cognitive decline is partly explained by certain lifestyle factors. Show more

Keywords: Cognitive aging, cognitive function, exercise, late-life, latent class mixed model, lifestyle

DOI: 10.3233/JAD-191058

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1555-1563, 2020

Authors: Xu, Ziyun | Wang, Jianjun | Lyu, Hanqing | Wang, Runshi | Hu, Yuanming | Guo, Zhouke | Xu, Jinping | Hu, Qingmao

Article Type: Research Article

Abstract: Background: Depressive symptoms were thought to increase the risk of vascular dementia. Previous studies reported widespread white matter damages in the subcortical vascular mild cognitive impairment (svMCI), but little is known about the mechanism of depressive symptoms in svMCI. Objective: In the current study, we aim to explore the white matter microstructural alterations in svMCI with depressive symptoms, and their associations with clinical measurements. Methods: Fifty-eight subjects including 18 svMCI with depression (svMCI+D), 17 svMCI without depression (svMCI-D), and 23 normal controls (NC) were included in the study. Voxel-based analyses were performed on fractional anisotropy (FA) …and mean diffusivity (MD). Results: Compared to NC, both svMCI groups showed decreased FA in the bilateral insula and the left precentral gyrus, and increased MD in the cerebellum. Compared to svMCI-D, svMCI+D showed increased FA in left precentral gyrus. Moreover, svMCI+D showed significant correlation between the increased MD in the cerebellum and the Hamilton Depression Rating Scale (HAMD) scores. Conclusion: Our findings of white matter alterations might be associated with executive function and memory performance in the svMCI patients. Moreover, the structural alterations in the cerebellum might underlie the mechanism of depressive symptoms in svMCI patients. Show more

Keywords: Depressive symptoms, mild cognitive impairment, subcortical vascular dementia, white matter

DOI: 10.3233/JAD-190890

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1565-1573, 2020

Authors: Falgàs, Neus | Balasa, Mircea | Bargalló, Núria | Borrego-Écija, Sergi | Ramos-Campoy, Oscar | Fernández-Villullas, Guadalupe | Bosch, Beatriz | Olives, Jaume | Tort-Merino, Adrià | Antonell, Anna | Castellví, Magdalena | Allen, Isabel E. | Sánchez-Valle, Raquel | Lladó, Albert

Article Type: Research Article

Abstract: Background: The diagnosis of incipient symptomatic stages of early-onset dementia is challenging. The magnetic resonance imaging (MRI) is an easy-access biomarker. Objective: We aim to determine the distribution and diagnostic performance of the existing atrophy visual rating scales on MRI in initial stages of the most frequent neurodegenerative early onset dementias. Methods: We evaluated the visual atrophy scales usefulness in two hundred subjects: seventy sporadic early onset Alzheimer’s disease (AD) patients (48 amnestic and 22 non-amnestic), 14 patients with autosomal-dominant AD (ADAD), 25 sporadic frontotemporal dementia patients [11 with behavioral variant (bvFTD), nine with semantic variant …of primary progressive aphasia (svPPA), and 5 with non-fluent primary progressive aphasia (nfvPPA)], 7 with genetically determined FTD (genetic FTD), 25 mild cognitive impairment due to non-degenerative disorders, and 59 healthy controls. All had MMSE≥18, 3T-brain MRI, and biomarker-supported diagnosis. Two raters evaluated six frontal, temporal, and parietal scales. Inter-rater reliability and diagnostic performance in terms of area under the receiver-operator curves and balanced accuracy were analyzed. Results: Best scales to discriminate AD from controls were the anterior cingulate scale for amnestic and the posterior atrophy scale for sporadic non-amnestic AD and ADAD. The anterior temporal scale was the best for sporadic bvFTD and svPPA and the anterior cingulate scale was for nfvPPA. All scales performed well for the genetic FTD. However, no scale demonstrated good performance at discriminating AD from FTD or non-degenerative disorders. Conclusions: The clinicians should interpret with caution atrophy scale assessment in subjects with early-onset cognitive impairment given that none of the evaluated scales met the requirements for being a diagnostic biomarker. Show more

Keywords: Alzheimer’s disease, atrophy, frontotemporal dementia, magnetic resonance imaging

DOI: 10.3233/JAD-191167

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1575-1583, 2020

Authors: Faura, Júlia | Bustamante, Alejandro | Penalba, Anna | Giralt, Dolors | Simats, Alba | Martínez-Sáez, Elena | Alcolea, Daniel | Fortea, Juan | Lleó, Alberto | Teunissen, Charlotte E. | van der Flier, Wiesje M. | Ibañez, Laura | Harari, Oscar | Cruchaga, Carlos | Hernández-Guillamón, Mar | Delgado, Pilar | Montaner, Joan

Article Type: Research Article

Abstract: CCL23 is a chemokine implicated in inflammation and host defense responses. It has been recently associated with acquired brain damage and stroke outcomes. In this study, we reported the role of CCL23 in Alzheimer’s disease (AD). We evaluated the levels of CCL23 in 659 individuals: cognitively normal, mild cognitive impaired (MCI), and AD patients. Two cross-sectional (study 1, n  = 53; study 2, n  = 200) and two longitudinal (study 3, n  = 74; study 4, n  = 332) studies were analyzed separately. CCL23 levels in the blood and/or cerebrospinal fluid (CSF) of each study were measured by immunoassays. Globally, our results suggest a …predictive role of CCL23 protein levels both in the plasma in study 3 (hazard ratio (HR) = 2.5 (confidence interval (CI) 95% : 1.2–5.3), p  = 0.02) and in the CSF in study 4 (HR = 3.05 (CI 95% : 1.02–5), p  = 0.04) in cases of MCI that progress to AD. Moreover, we observed that the APOE ɛ 4 allele was associated with higher levels of CCL23 in study 2 (470.33 pg/mL (interquartile range (IQR): 303.33–597.76) versus 377.94 pg/mL (IQR: 267.16–529.19), p  = 0.01) (APOE genotypes were available in studies 2 and 4). Together, these findings support the role of CCL23 in neuroinflammation in the early stages of AD, suggesting that CCL23 might be a candidate blood biomarker for MCI to AD progression. Show more

Keywords: Alzheimer’s disease, biomarkers, chemokines, cognitive dysfunction, early diagnosis

DOI: 10.3233/JAD-190753

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1585-1595, 2020

Authors: Ono, Kenjiro | Zhao, Daisy | Wu, Qingli | Simon, James | Wang, Jun | Radu, Aurelian | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Plant-derived polyphenolic compounds possess diverse biological activities, including strong anti-oxidant, anti-inflammatory, anti-microbial, and anti-tumorigenic activities. There is a growing interest in the development of polyphenolic compounds for preventing and treating chronic and degenerative diseases, such as cardiovascular disorders, cancer, and neurological diseases including Alzheimer’s disease (AD). Two neuropathological changes of AD are the appearance of neurofibrillary tangles containing tau and extracellular amyloid deposits containing amyloid-β protein (Aβ). Our laboratory and others have found that polyphenolic preparations rich in proanthocyanidins, such as grape seed extract, are capable of attenuating cognitive deterioration and reducing brain neuropathology in animal models of AD. Oligopin …is a pine bark extract composed of low molecular weight proanthocyanidins oligomers (LMW-PAOs), including flavan-3-ol units such as catechin (C) and epicatechin (EC). Based on the ability of its various components to confer resilience to the onset of AD, we tested whether oligopin can specifically prevent or attenuate the progression of AD dementia preclinically. We also explored the underlying mechanism(s) through which oligopin may exert its biological activities. Oligopin inhibited oligomer formation of not only Aβ1-40 and Aβ1-42 , but also tau in vitro . Our pharmacokinetics analysis of metabolite accumulation in vivo resulted in the identification of Me-EC-O -β-Glucuronide, Me-(±)-C-O -β-glucuronide, EC-O -β-glucuronide, and (±)-C-O -β-glucuronide in the plasma of mice. These metabolites are primarily methylated and glucuronidated C and EC conjugates. The studies conducted provide the necessary impetus to design future clinical trials with bioactive oligopin to prevent both prodromal and residual forms of AD. Show more

Keywords: Alzheimer’s disease, amyloid β-peptide, polyphenols, tau

DOI: 10.3233/JAD-190543

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1597-1606, 2020

Authors: Planton, Mélanie | Saint-Aubert, Laure | Raposo, Nicolas | Payoux, Pierre | Salabert, Anne-Sophie | Albucher, Jean-François | Olivot, Jean-Marc | Péran, Patrice | Pariente, Jérémie

Article Type: Research Article

Abstract: Background: Sporadic cerebral amyloid angiopathy shows progressive amyloid-β deposition in the wall of small arterioles and capillaries of the leptomeninges and cerebral cortex. Objective: To investigate whether amyloid load and distribution, assessed by florbetapir positron emission tomography (PET), differs between patients with probable CAA-related intracerebral hemorrhage (CAA-ICH) and mild cognitive impairment due to Alzheimer’s disease (MCI-AD). Methods: We assessed [18 F]florbetapir uptake in 15 patients with probable CAA-ICH and 20 patients with MCI-AD patients. Global and regional florbetapir retention were assessed using standard uptake values ratio (SUVr) in region-based and voxel-wise approaches. Visual reading of florbetapir …scans was performed for all participants. Group comparisons were performed using univariate and multivariate analysis. Results: Global florbetapir retention was lower in patients with CAA-ICH than MCI-AD (median SUVr, 1.33 [1.21–1.41] versus 1.44 [1.35–1.66]; p  = 0.032). In the region-based analysis, regional florbetapir distribution was similar between the two groups. There was a trend for an increased occipital/global ratio in CAA-ICH patients compared to MCI-AD (p  = 0.060). In the voxel-wise approach, two clusters, one in parietal regions and the other in temporal regions, had higher uptake in MCI-AD relative to CAA patients. Conclusions: Patients with CAA-ICH had a lower global florbetapir PET burden than patients with MCI-AD. Relative florbetapir retention in the posterior regions tended to be higher in CAA patients in region-based analysis but was not statistically different between groups. Investigation on differences in amyloid deposits distribution between groups required a fine-grained voxel-wise analysis. In future studies, selective amyloid tracers are needed to differentiate vascular from parenchymal amyloid. Show more

Keywords: Alzheimer’s disease, amyloid PET imaging, cerebral amyloid angiopathy, intracerebral hemorrhage, voxel-wise analysis

DOI: 10.3233/JAD-190625

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1607-1614, 2020

Authors: Rauchmann, Boris-Stephan | Sadlon, Angélique | Perneczky, Robert | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The present study explores the associations of soluble TREM2, an important regulator of microglial activity linked to Alzheimer’s disease (AD), with other known inflammatory proteins in cerebrospinal fluid (CSF). We studied 303 participants, including 89 controls, 135 mild cognitive impairment, and 79 AD dementia patients. Using established CSF biomarkers, subjects were classified according to the National Institute on Aging-Alzheimer’s Association research framework, which groups markers into those of amyloid-β deposition (A), tau pathology (T), and neurodegeneration (N). TNFR1, TNFR2, TGF-β1, TGFβ2, IL-9, TNF-α , ICAM1, and VCAM1 showed significant concentration differences between the ATN groups, with higher concentrations in more …advanced disease categories. sTREM2 was positively associated with the pro-inflammatory proteins TNF-α , TNFR1, TNFR2, ICAM1, VCAM1, and IP-10 and negatively with IL-21; also, positive associations with the anti-inflammatory proteins TGFβ1, IL-10, and IL-9 were found. Pathway enrichment analysis highlighted the involvement of sTREM2 in key functional clusters including immunoglobulin and cytokine production and cellular response to lipopolysaccharides, cytokines, and steroid hormones. Our work provides further evidence in support of TREM2 as amarker of neuroinflammatory response in AD. Show more

Keywords: Alzheimer’s disease, biomarker, functional annotation, interactions network, neurodegeneration, neuroinflammation

DOI: 10.3233/JAD-191120

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1615-1626, 2020

Authors: Mold, Matthew | Linhart, Caroline | Gómez-Ramírez, Johana | Villegas-Lanau, Andrés | Exley, Christopher

Article Type: Research Article

Abstract: Genetic predispositions associated with metabolism of the amyloid-β protein precursor underlie familial Alzheimer’s disease; a form of dementia characterized by early disease onset and elevated levels of cortical amyloid-β. Human exposure to aluminum is linked to the etiology of Alzheimer’s disease and recent research measured a high content of aluminum in brain tissue in familial Alzheimer’s disease. To elaborate upon this finding, we have obtained brain tissues from a Colombian cohort of donors with familial Alzheimer’s disease. We have used established methods to measure the aluminum content of these tissues and we have compared the data with a recently measured …dataset for control brain tissues. We report significantly higher levels of aluminum in brain tissues in donors with familial Alzheimer’s disease than in control tissues from donors without neurological impairment or neurodegeneration. We have used aluminum-specific fluorescence microscopy along with complementary imaging for amyloid-β to demonstrate a very high degree of co-localization of these two risk factors in brain tissue in familial Alzheimer’s disease. Aluminum and amyloid-β were co-located in senile plaques as well as vasculature, the latter resembling cerebral amyloid angiopathy. Aluminum was also found separately from amyloid-β in intracellular compartments including glia and neuronal axons. The research has identified an arguably unique association between high brain aluminum content and amyloid-β and allows postulation that genetic predispositions defining familial Alzheimer’s disease underlie this relationship. Show more

Keywords: Aluminum in human brain tissue, amyloid-β, familial Alzheimer’s disease, human exposure to aluminum

DOI: 10.3233/JAD-191140

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1627-1635, 2020

Authors: Furman, Ran | Ng, Sharon C.W. | Komatsu, Hiroaki | Axelsen, Paul H.

Article Type: Research Article

Abstract: Various amyloid-β (Aβ) peptides accumulate in brain in Alzheimer’s disease, and the amounts of specific peptide variants may have pathological significance. The quantitative determination of these variants is challenging because losses inevitably occur during tissue processing and analysis. This report describes the use of stable-isotope-labeled Aβ peptides as internal standards for quantitative mass spectrometric assays, and the use of cyanogen bromide (CNBr) to remove C-terminal residues beyond Met35. The removal of residues beyond Met35 reduces losses due to aggregation, and facilitates the detection of post-translationally modified Aβ peptides. Results from 8 human brain samples suggest that the tissue concentrations of …the 42-residue Aβ peptide tend to be similar in different patients. Concentrations of the 40-residue Aβ peptide are more variable, and may be greater or lesser than the 42-residue peptide. The concentration of the CNBr cleavage product closely matches the sum of the 40-residue and 42-residue peptide concentrations, indicating that these two Aβ peptides account for most of the C-terminal variants in these patients. CNBr treatment facilitated the detection of post-translational modifications such as pyroglutamyl and hexose-modified Aβ peptides. Show more

Keywords: Immunoprecipitation, internal standards, isotope labeling, post-translational modification

DOI: 10.3233/JAD-190647

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1637-1645, 2020

Authors: Spallazzi, Marco | Michelini, Giovanni | Barocco, Federica | Dieci, Francesca | Copelli, Sandra | Messa, Giovanni | Scarlattei, Maura | Pavesi, Giovanni | Ruffini, Livia | Caffarra, Paolo

Article Type: Research Article

Abstract: Background: Free and Cued Selective Reminding Test (FCSRT) is a reliable cognitive marker for Alzheimer’s disease (AD), and the identification of neuropsychological tests sensitive to the early signs of AD pathology is crucial both in research and clinical practice. Objective: The study aimed to ascertain the ability of FCSRT in predicting the amyloid load as determined from amyloid PET imaging (Amy-PET) in patients with cognitive disorders. Methods: For our purpose, 79 patients (71 MCI, 8 mild dementia) underwent a complete workup for dementia, including the FCSRT assessment and a [18 F]florbetaben PET scan. FCSRT subitem scores …were used as predictors in different binomial regression models. Results: Immediate free recall and delayed free recall were the best predictors overall in the whole sample; whereas in patients <76 years, all models further improved with immediate total recall (ITR) and Index of Sensitivity of Cueing (ISC) resulting the most accurate in anticipating Amy-PET results, with a likelihood of being Amy-PET positive greater than 85% for ITR and ISC scores of less than 25 and 0.5, respectively. Conclusion: FCSRT proved itself to be a valid tool in dementia diagnosis, also being able to correlate with amyloid pathology. The possibility to predict Amy-PET results through a simple and reliable neuropsychological test might be helpful for clinicians in the dementia field, adding value to a paper and pencil tool compared to most costly biomarkers. Show more

Keywords: Alzheimer’s disease, amyloid PET, biomarkers, Free and Cued Selective Reminding Test, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-190950

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1647-1659, 2020