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

Authors: Axelsson, Elin | Wallin, Anders | Svensson, Johan

Article Type: Research Article

Abstract: Background: Population-based studies have shown that cardiometabolic status is associated with the amount of white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI). However, little is known of cardiometabolic risk factors in the subcortical small vessel type of dementia (SSVD), in which WMHs are one of the most prominent manifestations. Objective: To determine whether the profile of cardiometabolic risk factors differed between SSVD, Alzheimer’s disease (AD), mixed dementia (combined AD and SSVD), and healthy controls. Methods: This was a mono-center, cross-sectional study of SSVD (n  = 40), AD (n  = 113), mixed dementia (n  = 62), and healthy controls …(n  = 94). In the statistical analyses, we adjusted for covariates using ANCOVA and binary logistic regression. Results: The prevalence of hypertension was increased in SSVD and mixed dementia (p  < 0.001 and p  < 0.05 versus controls, respectively). Diabetes was more prevalent in SSVD patients, and body mass index was lower in AD and mixed dementia, compared to the controls (all p  < 0.05). Serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) were reduced in the SSVD group (both p  < 0.05 versus control). These differences remained after adjustment for covariates. In the SSVD group, Trail Making Test A score correlated positively with systolic blood pressure, mean arterial pressure, and pulse pressure. Conclusion: All dementia groups had an altered cardiometabolic risk profile compared to the controls. The SSVD patients showed increased prevalence of hypertension and diabetes, and in line with previous population-based data, TC and LDL-C in serum were reduced. Show more

Keywords: Alzheimer’s disease, body mass index, diabetes, hypertension, lipid pattern, mixed dementia, subcortical small vessel type of dementia

DOI: 10.3233/JAD-191077

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1373-1383, 2020

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. 73, no. 4, pp. 1385-1405, 2020

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. 73, no. 4, pp. 1407-1419, 2020

Authors: Chintapaludi, Sumana R. | Uyar, Asli | Jackson, Harriet M. | Acklin, Casey J. | Wang, Xulong | Sasner, Michael | Carter, Gregory W. | Howell, Gareth R.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a common form of dementia characterized by amyloid plaque deposition, tau pathology, neuroinflammation, and neurodegeneration. Mouse models recapitulate some key features of AD. For instance, the B6.APP/PS1 model (carrying human transgenes for mutant forms of APP and PSEN1 ) shows plaque deposition and neuroinflammation involving both astrocytes and microglia beginning around 4–6 months of age. However, significant tau pathology and neurodegeneration are not apparent in this model even when assessed at old age. Therefore, this model is ideal for studying neuroinflammatory responses to amyloid deposition. Here, RNA sequencing of brain and retinal tissue, generalized …linear modeling (GLM), functional annotation followed by validation by immunofluorescence was performed in B6.APP/PS1 mice to determine the earliest molecular changes prior to and around the onset of plaque deposition (2–6 months of age). Multiple pathways were shown to be activated in response to amyloid deposition including the JAK/STAT and NALFD pathways. Putative, cell-specific targets of STAT3, a central component of the JAK/STAT pathway, were identified that we propose provide more precise options for assessing the potential for targeting activation of the JAK/STAT pathway as a treatment for human AD. In the retina, GLM predicted activation of vascular-related pathways. However, many of the gene expression changes comparing B6 with B6.APP/PS1 retina samples occurred prior to plaque onset (2 months of age). This suggests retinal changes in B6.APP/PS1 mice may be an artefact of overexpression of mutant forms of APP and PSEN1 providing limited translatability to human AD. Therefore, caution should be taken when using this mouse model to assess the potential of using the eye as a window to the brain for AD. Show more

Keywords: Alzheimer’s disease, amyloid, brain, generalized linear model, immunofluorescence, JAK/STAT, microhemorrhages, retina, RNA sequencing

DOI: 10.3233/JAD-190793

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1421-1434, 2020

Authors: Zhao, Tan | Quan, Meina | Jia, Jianping

Article Type: Research Article

Abstract: Background: The default mode network (DMN) could be divided into subsystems, the functional connectivity of which are different across the Alzheimer’s disease (AD) spectrum. However, the functional connectivity patterns within the subsystems are unknown in presymptomatic autosomal dominant AD (ADAD). Objective: To investigate functional connectivity patterns within the subsystems of the DMN in presymptomatic subjects carrying PSEN1 , PSEN2 , or APP gene mutations. Methods: Twenty-six presymptomatic mutation carriers (PMC) and twenty-nine cognitively normal non-carriers as normal controls (NC) from the same families underwent resting state functional MRI and structural MRI. Seed-based analyses were done …to obtain functional connectivity of posterior and anterior DMN. For the regions that showed significant connectivity difference between PMC and NC, volumes were extracted and compared between the two groups. Connectivity measures were then correlated with cognitive tests scores. Results: The posterior DMN showed connectivity decrease in the PMC group as compared with the NC group, which was primarily the connectivity of left precuneus with right precuneus and superior frontal gyrus; the anterior DMN showed significant connectivity decrease in the PMC group, which was the connectivity of medial frontal gyrus with middle frontal gyrus. In the brain regions showing connectivity changes in the PMC group, there was no group difference in volume. A positive correlation was observed between the precuneus connectivity value and Mini-Mental State Examination total score. Conclusion: Functional connectivity within both posterior and anterior DMN were disrupted in the presymptomatic stage of ADAD. Connectivity disruption within the posterior DMN may be useful for early identification of general cognitive decline and a potential imaging biomarker for early diagnosis. Show more

Keywords: Autosomal dominant Alzheimer’s disease, default mode network, functional connectivity, structural imaging

DOI: 10.3233/JAD-191065

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1435-1444, 2020

Authors: Meléndez, Juan C. | Satorres, Encarnación | Oliva, Itxasne

Article Type: Research Article

Abstract: Background: Impairments in the ability to recognize facial affective expressions may lead to social dysfunction and difficulties with interpersonal communication. Objective: The objective was to compare the attentional responses on a Stroop emotional task using words and faces by testing whether the two stimuli differ in the degree of interference they produce in patients with Alzheimer’s disease (AD). Methods: There were 75 participants: 25 healthy older adults, 25 with mild AD, and 25 with moderate AD. A variation of the classic emotional Stroop test was administered. This task combined emotional words (happy or sad) superimposed on …facial expressions (happy or sad), where the words were either incongruent or congruent with the emotion expressed by the face stimuli. Results: Facilitation was shown on negative words in healthy older adults, and significant effects were obtained for condition, valence, group, and the condition x group interaction. Although less interference was observed on negative stimuli, the fastest reaction times were found for congruent positive stimuli. The effect of interference in healthy older adults is similar in both conditions. However, in the AD groups, there is less interference on the words task than on the faces task. Conclusion: The more complex nature of faces, as opposed to the over-learning and automaticity of words, may explain the higher interference in AD patients in the faces condition. In patients with AD, words can be a better method for recognizing emotions than affective facial expressions. Show more

Keywords: Alzheimer’s disease, emotional Stroop, interference

DOI: 10.3233/JAD-190989

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1445-1453, 2020

Authors: Liu, Yongqiang | Kong, Cheng | Gong, Li | Zhang, Xiaohui | Zhu, Yuefei | Wang, Haichao | Qu, Xiao | Gao, Renyuan | Yin, Fang | Liu, Xueyuan | Qin, Huanlong

Article Type: Research Article

Abstract: Background: Post-stroke cognitive impairment (PSCI) is an important factor causing disabilities after acute ischemic stroke (AIS). Emerging evidence suggested that gut microbiota play an important role in cognitive impairment. Objective: This study aimed to explore the association between PSCI and gut microbiota. Method: 65 patients with newly diagnostic AIS finished the fecal collection on admission and cognitive assessment 3 months later in the clinic. Fecal samples were subjected to 16SrRNA gene sequencing and gas chromatography-mass spectrometry analysis. Additionally, we enrolled new 18 AIS patients, whose treatment was supplemented by probiotics, to assess the potential of microbial …treatment in PSCI. Results: PSCI patients were characterized by the significantly decreased alpha-diversity, disturbed microbial composition, and corresponding metabolites compared with non-PSCI patients. Increased Fusobacterium and deficiency of microbial metabolized short-chain fatty acids (SCFAs) were significantly associated with PSCI. A model based on gut microbiota and SCFAs could predict 3 months or longer PSCI early and accurately after stroke onset. While traditional probiotic administration had little effect on PSCI, it could ameliorate patients’ mood, including depression and anxiety in the 3 months after stroke. Conclusion: Our study revealed the association between PSCI and gut microbiota and its corresponding metabolites for the first time, suggesting the potential for applying microbiota and its corresponding metabolites to early clinical diagnosis and treatment of PSCI. Show more

Keywords: Cognitive dysfunction, microbiota, predictors, probiotics, stroke

DOI: 10.3233/JAD-191066

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1455-1466, 2020

Authors: Mendes, Aline | Herrmann, François R. | Scheffler, Max | Gabriel, Gemma | Sveikata, Lukas | Rakotomiaramanana, Barinjaka | Frisoni, Giovanni B. | Zekry, Dina | Gold, Gabriel

Article Type: Research Article

Abstract: Background: Cortical superficial siderosis (cSS) is a hemorrhagic marker of blood-brain barrier disruption detected in brain MRI. Together with cerebral microbleeds (CMB), they are recognized as a small vessel disease marker associated with cerebral amyloid angiopathy. Objective: This study aims to determine the prevalence and the characteristics of cSS in a memory clinic population. Methods: Cross-sectional retrospective analysis of 613 patients from Geneva University Hospitals memory clinic. All patients underwent standardized brain MRI and neuropsychological assessment with diagnosis confirmed by an expert. The presence of cSS was visually assessed and classified as focal (restricted to 3 …sulci) or disseminated within the correspondent topography. CMB were classified according to the Microbleed Anatomical Rating Scale. Results: cSS was detected in 26/613 patients (4.2%), classified as disseminated in 5/26 cases (19%). Alzheimer’s disease (AD) and AD associated with a significant vascular component were the diagnoses more frequently related to cSS (18/26; 69%). Patients with cSS had an increased prevalence of both hypertension (81% versus 57%; p  = 0.015) and WMH burden (p  = 0.012). The overall prevalence of cerebral microbleeds (69% versus 32%; p  < 0.01), as well as their mean number (0.69±0.47 versus 0.32±0.46; p  < 0.01) were both increased in patients with cSS. In the logistic regression model, the presence of 5 or more CMB (OR 11.35; 95% CI 4.68–27.55; p  < 0.01) and hypertension (OR 3.31; 95% CI 1.19–9.15; p  = 0.021) were significantly associated with cSS. Conclusions: cSS is observed in patients diagnosed with AD and AD with a vascular component, being independently associated with multiple CMB and hypertension. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, cerebral microbleeds, cerebral small vessel disease, cortical superficial siderosis, vascular dementia, white matter hyperintensities

DOI: 10.3233/JAD-190619

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1467-1479, 2020

Authors: Tuzzi, Elisa | Balla, David Z. | Loureiro, Joana R.A. | Neumann, Manuela | Laske, Christoph | Pohmann, Rolf | Preische, Oliver | Scheffler, Klaus | Hagberg, Gisela E.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia worldwide. So far, diagnosis of AD is only unequivocally defined through postmortem histology. Amyloid plaques are a classical hallmark of AD and amyloid load is currently quantified by Positron Emission tomography (PET) in vivo . Ultra-high field magnetic resonance imaging (UHF-MRI) can potentially provide a non-invasive biomarker for AD by allowing imaging of pathological processes at a very-high spatial resolution. The first aim of this work was to reproduce the characteristic cortical pattern previously observed in vivo in AD patients using weighted-imaging at 7T. We extended these findings using …quantitative susceptibility mapping (QSM) and quantification of the effective transverse relaxation rate (R2 *) at 9.4T. The second aim was to investigate the origin of the contrast patterns observed in vivo in the cortex of AD patients at 9.4T by comparing quantitative UHF-MRI (9.4T and 14.1T) of postmortem samples with histology. We observed a distinctive cortical pattern in vivo in patients compared to healthy controls (HC), and these findings were confirmed ex vivo . Specifically, we found a close link between the signal changes detected by QSM in the AD sample at 14.1T and the distribution pattern of amyloid plaques in the histological sections of the same specimen. Our findings showed that QSM and R2 * maps can distinguish AD from HC at UHF by detecting cortical alterations directly related to amyloid plaques in AD patients. Furthermore, we provided a method to quantify amyloid plaque load in AD patients at UHF non-invasively. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid plaque load, biomarkers, effective transverse relaxation rate, histology, quantitative susceptibility mapping, ultra-high field

DOI: 10.3233/JAD-190424

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1481-1499, 2020

Authors: Tan, Chin Hong | Hilal, Saima | Xu, Xin | Vrooman, Henri | Cheng, Ching-Yu | Wong, Tien Yin | Venketasubramanian, Narayanaswamy | Chen, Christopher

Article Type: Research Article

Abstract: There is a need to elucidate the combined influence of neurodegeneration and cerebrovascular disease (CeVD) on cognitive impairment, especially in diverse populations. Here, we evaluated 840 multiethnic individuals (mean age = 70.18) across the disease spectrum from the Epidemiology of Dementia in Singapore study. First, we determined whether a validated quantitative MRI score of mixed pathology is associated with clinical diagnosis and whether the score differed between ethnicities (Chinese, Malays, and Indians). We then evaluated whether the score was associated with multidomain cognitive impairment and if additional measures of CeVD were further associated with cognitive impairment. We found that lower quantitative MRI …scores were associated with severity of clinical diagnosis and Chinese individuals had the highest quantitative MRI scores, followed by Indians and Malays. Lower quantitative MRI scores were also associated with lower performance in attention, language, visuoconstruction, visuomotor, visual, and verbal memory domains. Lastly, the presence of intracranial stenosis and cortical cerebral microinfarcts, but not cerebral microbleeds, were associated with memory performance beyond quantitative MRI scores. Taken together, our results demonstrate the utility of using multiple MRI markers of neurodegeneration and CeVD for identifying multiethnic Asians with the greatest cognitive impairment due to mixed pathology. Show more

Keywords: Alzheimer’s disease, cerebrovascular diseases, cognition, cortical cerebral microinfarcts, ethnicity, intracranial stenosis, magnetic resonance imaging, mixed dementia

DOI: 10.3233/JAD-190866

Citation: Journal of Alzheimer's Disease, vol. 73, no. 4, pp. 1501-1509, 2020