Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

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. Pre-press, no. Pre-press, pp. 1-9, 2019

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 in 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. Pre-press, no. Pre-press, pp. 1-13, 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. Pre-press, no. Pre-press, pp. 1-13, 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, 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 tented to be higher in CAA patients in region-based analysis but was no 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. Pre-press, no. Pre-press, pp. 1-8, 2019

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. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Wong, Dickson | Atiya, Samir | Fogarty, Jennifer | Montero-Odasso, Manuel | Pasternak, Stephen H. | Brymer, Chris | Borrie, Michael J. | Bartha, Robert

Article Type: Research Article

Abstract: Identification of biological changes underlying the early symptoms of Alzheimer’s disease (AD) will help to identify and stage individuals prior to symptom onset. The limbic system, which supports episodic memory and is impaired early in AD, is a primary target. In this study, brain metabolism and microstructure evaluated by high field (7 Tesla) proton magnetic resonance spectroscopy (1 H-MRS) and diffusion tensor imaging (DTI) were evaluated in the limbic system of eight individuals with mild cognitive impairment (MCI), nine with AD, and sixteen normal elderly controls (NEC). Left hippocampal glutamate and posterior cingulate N -acetyl aspartate concentrations were reduced in …MCI and AD compared to NEC. Differences in DTI metrics indicated volume and white matter loss along the cingulum in AD compared to NEC. Metabolic and microstructural changes were associated with episodic memory performance assessed using Craft Story 21 Recall and Benson Complex Figure Copy. The current study suggests that metabolite concentrations measured using 1 H-MRS may provide insight into the underlying metabolic and microstructural processes of episodic memory impairment. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, diffusion tractography, episodic memory, glutamate, hippocampus, magnetic resonance imaging, magnetic resonance spectroscopy, posterior cingulate cortex

DOI: 10.3233/JAD-190773

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 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. Pre-press, no. Pre-press, pp. 1-9, 2019

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. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Coebergh, Jan A.F. | McDowell, Steven | van Woerkom, Theodorus C.A.M. | Koopman, Jan P. | Mulder, Jacqueline | Bruijn, Sebastiaan F.T.M.

Article Type: Research Article

Abstract: Auditory agnosia for environmental sounds (AES) is an example of central auditory dysfunction. It is presumed to be independent of language deficits and in presence of normal hearing. We undertook a detailed neuropsychological assessment including environmental sound naming and recognition in 34 clinically mild Alzheimer’s disease (AD) patients and 29 age-matched healthy control subjects. In patients with AD, audiometry was performed to assess the impact on test performance, and in normal controls the Hearing Handicap Inventory for the Elderly – Screening Version to exclude more than mild hearing loss. We adapted a validated environmental sound battery and found near perfect …scores in controls. We found that environmental sound agnosia is common in mild AD. We found a statistically significant difference in mean pure tone audiometry in the best ear between patients with and those patients without naming deficits of 11.3 dB (p  = 0.010) and of 14.7 dB (p  = 0.000) between those with and without recognition deficits. Statistical significance remained after correcting for age, aphasia, Mini-Mental State Examination score, and working memory. Slight and moderate peripheral hearing loss increases the odds ratio of recognition deficits by 13.75 (confidence interval 2.3–81.5) compared to normal hearing patients. We did not find evidence for different forms of AES. This work suggests that an interaction between peripheral hearing loss and AD pathology produces problems with environmental sound recognition. It confirms that the relationship between hearing and dementia is complex but also suggests that interventions to prevent and treat hearing loss could have an effect on AD in its clinical expression. Show more

Keywords: Alzheimer’s disease, central auditory dysfunction, environmental sound agnosia, hearing loss

DOI: 10.3233/JAD-190431

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 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. Pre-press, no. Pre-press, pp. 1-9, 2020