Journal of Alzheimer's Disease - Volume 101, issue 2 - Journals

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Slow Gait Speed Predicts Incident Dementia, Mortality, and Long-Term Functional Outcome in Cerebral Small-Vessel Disease

Authors: Hosoya, Megumi | Toi, Sono | Yoshizawa, Hiroshi | Kitagawa, Kazuo

Article Type: Research Article

Abstract: Background: Gait impairment is observed in patients with small vessel disease (SVD); however, the association between gait function and long-term outcome remains unclear. Objectives: This study aimed to clarify the predictive value of gait function on incident dementia, survival and functional outcome. Methods: Data were derived from a Japanese cohort of patients with SVD. This study included 522 participants who underwent 3-m timed up and go test (TUG), and gait speed, TUG time, was divided into tertiles. Magnetic resonance imaging was used to evaluate severity of white matter hyperintensities, lacunes, and medial temporal atrophy. Primary outcome …was dementia. All-cause death and functional outcome by modified Rankin scale at the last visit was also evaluated. Results: The median age was 71 years, and median TUG time was 9.91 s. During follow-up period of 4.8 years, 32 cases of dementia occurred. Cox proportional hazard analysis revealed that slow gait speed (TUG time > 10.88 s) was associated with a significantly higher risk of incident dementia than fast (TUG time < 9.03) and middle (TUG time, 9.04–10.87 s) speeds after adjusting risk factors, Mini-Mental State Examination, SVD severity and brain atrophy (adjusted hazard ratio, 2.73; 95% confidence interval, 1.16–6.42, p = 0.022). Slow speed was also associated with mortality and poor functional outcome compared with other speeds (adjusted odds ratio, 4.19; 95% confidence interval 1.92–9.18, p < 0.001). Conclusions: Gait function was associated with incident dementia, mortality and poor functional outcome independently of cognitive function, brain atrophy, and SVD severity. Show more

Keywords: Alzheimer’s disease, dementia, functional outcome, gait speed, small vessel disease

DOI: 10.3233/JAD-240304

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 499-508, 2024

Price: EUR 27.50

The Profile of the Italian Centers for Cognitive Disorders and Dementia in the Context of New Drugs in Alzheimer’s Disease

Article Type: Research Article

Abstract: Background: The wait for the upcoming disease-modifying therapies (DMT) for Alzheimer’s disease in Europe is raising questions about the preparedness of national healthcare systems to conduct accurate diagnoses and effective prescriptions. In this article, we focus on the current situation in Italy. Objective: The primary goal is to propose a profile of the Italian Centers for Cognitive Disorders and Dementias (CCDDs) that could be taken into consideration by regional and autonomous provincial authorities when deciding on the prescribing centers for DMT. Methods: Based on responses to a national survey on CCDDs in Italy, we identified the …CCDDs that meet the requirements for effective prescription: 1) Multidisciplinary team; 2) Minimum Core Test for the neuropsychological assessment; 3) PET, CSF, and Brain MRI assessments. Univariate and multivariate comparisons were conducted between CCDDs that met the criteria and the others. Results: Only 10.4% of CCDDs met the requirements for effective DMT prescription, mainly located in Northern Italy. They are also characterized by longer opening hours, a higher number of professionals, a university location, and a higher frequency of conducting genetic tests, and could potentially result in prescribing centers. Conclusions: The findings suggest that the Italian national healthcare system may benefit from further enhancements to facilitate the effective prescription of DMTs. This could involve initiatives to reduce fragmentation, ensure adequate resources and equipment, and secure sufficient funding to support this aspect of healthcare delivery. Show more

Keywords: Alzheimer’s disease, Centers for Cognitive Disorders and Dementias, cognitive assessment, disease-modifying therapy, memory clinic, public health

DOI: 10.3233/JAD-240594

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 509-524, 2024

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Degradation of Amyloid-β Species by Multi-Copper Oxidases

Article Type: Research Article

Abstract: Background: Reduction of the production of amyloid-β (Aβ) species has been intensively investigated as potential therapeutic approaches for Alzheimer’s disease (AD). However, the degradation of Aβ species, another potential beneficial approach, has been far less explored. Objective: To investigate the potential of multi-copper oxidases (MCOs) in degrading Aβ peptides and their potential benefits for AD treatment. Methods: We investigated the degradation efficiency of MCOs by using electrophoresis and validated the ceruloplasmin (CP)-Aβ interaction using total internal reflection fluorescence microscopy, fluorescence photometer, and fluorescence polarization measurement. We also investigated the therapeutic effect of ascorbate oxidase (AO) by …using induced pluripotent stem (iPS) neuron cells and electrophysiological analysis with brain slices. Results: We discovered that CP, an important MCO in human blood, could degrade Aβ peptides. We also found that other MCOs could induce Aβ degradation as well. Remarkably, we revealed that AO had the strongest degrading effect among the tested MCOs. Using iPS neuron cells, we observed that AO could rescue neuron toxicity which induced by Aβ oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Aβ-induced deficit in synaptic transmission in the hippocampus. Conclusions: To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β degradation, ascorbate oxidase, ceruloplasmin

DOI: 10.3233/JAD-240625

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 525-539, 2024

Price: EUR 27.50

Unique Pathology in the Locus Coeruleus of Individuals with Down Syndrome

Article Type: Research Article

Abstract: Background: Down syndrome (DS) is one of the most commonly occurring chromosomal conditions. Most individuals with DS develop Alzheimer’s disease (AD) by 50 years of age. Recent evidence suggests that AD pathology in the locus coeruleus (LC) is an early event in sporadic AD. It is likely that the widespread axonal network of LC neurons contributes to the spread of tau pathology in the AD brain, although this has not been investigated in DS-AD. Objective: The main purpose of this study was to profile AD pathology and neuroinflammation in the LC, comparing AD and DS-AD in postmortem human …tissues. Methods: We utilized immunofluorescence and semi-quantitative analyses of pTau (4 different forms), amyloid-β (Aβ), glial, and neuronal markers in the LC across 36 cases (control, DS-AD, and AD) to compare the different pathological profiles. Results: Oligomeric tau was highly elevated in DS-AD cases compared to LOAD or EOAD cases. The distribution of staining for pT231 was elevated in DS-AD and EOAD compared to the LOAD group. The DS-AD group exhibited increased Aβ immunostaining compared to AD cases. The number of tau-bearing neurons was also significantly different between the EOAD and DS-AD cases compared to the LOAD cases. Conclusions: While inflammation, pTau, and Aβ are all involved in AD pathology, their contribution to disease progression may differ depending on the diagnosis. Our results suggest that DS-AD and EOAD may be more similar in pathology than LOAD. Our study highlights unique avenues to further our understanding of the mechanisms governing AD neuropathology. Show more

Keywords: Alzheimer’s disease, amyloid-beta, astrocyte, Down syndrome, locus coeruleus, microglia, tau

DOI: 10.3233/JAD-240043

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 541-561, 2024

Price: EUR 27.50

Impact of Preanalytical Procedures on Complement Biomarkers in Cerebrospinal Fluid and Plasma from Controls and Alzheimer’s Disease Patients

Article Type: Research Article

Abstract: Background: Studies comparing cerebrospinal fluid (CSF) and plasma complement proteins in Alzheimer’s disease (AD) patients versus healthy controls (HC) have yielded inconsistent results. Discrepancies in the preanalytical sample handling could contribute to the heterogeneity in the reported findings. Objective: Using qualified immunoassays, we aimed at assessing the impact of preanalytical procedures on complement proteins in blood and CSF from AD patients and HCs. Methods: We supplemented HC and AD CSF/plasma with complement stabilizers and measured the complement proteins C4a, C4, C3a, C3, Factor Bb and Factor B by immunoassay. We tested the impact of freeze-thaw (FT) …cycles on fluid complement proteins. Results: Most complement proteins were mildly impacted by FT cycles in plasma but not CSF, except for C3a which displayed greater sensitivity to FTs in CSF than in plasma. In CSF, the effect of FTs on C3a was reduced but not prevented by the supplementation with EDTA (±Futhan). Conclusions: Our findings provide recommendations for CSF/plasma sample handling to ensure robust and reproducible complement biomarker analyses in AD. Show more

Keywords: Alzheimer’s disease, complement, neuroinflammation biomarkers, preanalytical handling

DOI: 10.3233/JAD-240287

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 563-576, 2024

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Correlation Between the Fractional Amplitude of Low-Frequency Fluctuation and Cognitive Defects in Alzheimer’s Disease

Article Type: Research Article

Abstract: Background: The fractional amplitude of low-frequency fluctuations (fALFFs) can detect spontaneous brain activity. However, the association between abnormal brain activity and cognitive function, amyloid protein (Aβ), and emotion in Alzheimer’s disease (AD) patients remains unclear. Objective: This study aimed to survey alterations in fALFF in different frequency bands and the relationship between abnormal brain activity, depressive mood, and cognitive function to determine the potential mechanism of AD. Methods: We enrolled 34 AD patients and 32 healthy controls (HC). All the participants underwent resting-state magnetic resonance imaging, and slow-4 and slow-5 fALFF values were measured. Subsequently, the …study determined the correlation of abnormal brain activity with mood and cognitive function scores. Results: AD patients revealed altered mfALFF values in the slow-5 and slow-4 bands. In the slow-4 band, the altered mfALFF regions were the right cerebellar crus I, right inferior frontal orbital gyrus (IFOG), right supramarginal gyrus, right precuneus, angular gyrus, and left middle cingulate gyrus. Elevated mfALFF values in the right IFOG were negatively associated with Montreal Cognitive Assessment scores, Boston Naming Test, and Aβ1–42 levels. The mfALFF value of the AD group was lower than the HC group in the slow-5 band, primarily within the right inferior parietal lobule and right precuneus. Conclusions: Altered mfALFF values in AD patients are linked with cognitive dysfunction. Compared with HCs, Aβ1–42 levels in AD patients are related to abnormal IFOG activity. Therefore, mfALFF could be a potential biomarker of AD. Show more

Keywords: Alzheimer’s disease, cerebellum, cognitive function, resting-state functional MRI

DOI: 10.3233/JAD-231040

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 577-587, 2024

Price: EUR 27.50

Convergent Multimodal Imaging Abnormalities in the Dorsal Precuneus in Subjective Cognitive Decline

Article Type: Research Article

Abstract: Background: A range of imaging modalities have reported Alzheimer’s disease-related abnormalities in individuals experiencing subjective cognitive decline (SCD). However, there has been no consistent local abnormality identified across multiple neuroimaging modalities for SCD. Objective: We aimed to investigate the convergent local alterations in amyloid-β (Aβ) deposition, glucose metabolism, and resting-state functional MRI (RS-fMRI) metrics in SCD. Methods: Fifty SCD patients (66.4±5.7 years old, 19 men [38%]) and 15 normal controls (NC) (66.3±4.4 years old, 5 men [33.3%]) were scanned with both [18 F]-florbetapir PET and [18 F]-fluorodeoxyglucose PET, as well as simultaneous RS-fMRI from February 2018 …to November 2018. Voxel-wise metrics were retrospectively analyzed, including Aβ deposition, glucose metabolism, amplitude of low frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality(DC). Results: The SCD group showed increased Aβ deposition and glucose metabolism (p < 0.05, corrected), as well as decreased ALFF, ReHo, and DC (p < 0.05, uncorrected) in the left dorsal precuneus (dPCu). Furthermore, the dPCu illustrated negative resting-state functional connectivity with the default mode network. Regarding global Aβ deposition positivity, the Aβ deposition in the left dPCu showed a gradient change, i.e., Aβ positive SCD > Aβ negative SCD > Aβ negative NC. Additionally, both Aβ positive SCD and Aβ negative SCD showed increased glucose metabolism and decreased RS-fMRI metrics in the dPCu. Conclusions: The dorsal precuneus, an area implicated in early AD, shows convergent neuroimaging alterations in SCD, and might be more related to other cognitive functions (e.g., unfocused attention) than episodic memory. Show more

Keywords: Alzheimer’s disease, functional magnetic resonance imaging, positron emission tomography, precuneus, subjective cognitive decline

DOI: 10.3233/JAD-231360

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 589-601, 2024

Price: EUR 27.50

Association of Young-Onset Dementia with Pre-Existing Peripheral Vestibular Disorders

Authors: Hung, Shih-Han | Chang, Alison H. | Cheng, Yen-Fu | Lin, Herng-Ching | Chen, Chin-Shyan

Article Type: Research Article

Abstract: Background: The relationship between young-onset dementia and peripheral vestibular disorders remained largely unknown although this association was observed in the older population. Objective: This case-control study aims to investigate the association of young-onset dementia with a pre-existing diagnosis of peripheral vestibular disorders using a population-based data from Taiwan’s Longitudinal Health Insurance Database 2010. Methods: This study included 989 patients with young-onset dementia and 2967 propensity-score-matching controls. Differences in baseline characteristic between patients with young-onset dementia and controls were investigated using chi-square tests or t-tests. Multiple logistic regression models were employed to assess the association of young-onset …dementia (outcome) with pre-existing peripheral vestibular disorders (predictor). Results: Compared to patients without young-onset dementia, those affected by this condition exhibited a statistically significantly higher rate of peripheral vestibular disorders (18.3% versus 8.2%, p < 0.001). Furthermore, our analysis found notable between-group disparities in the rates of Meniere’s Disease (3.5% versus 2.0%, p = 0.015), benign paroxysmal positional vertigo (2.4% versus 1.1%, p = 0.006), and vestibular neuritis (2.4% versus 1.1%, p = 0.003). Multiple logistic regression analysis showed that the presence of prior peripheral vestibular disorders increased the odds of young-onset dementia [2.603 (95% CI = 2.105∼3.220)] after adjusting for age, sex, monthly income, geographic location, urbanization level, hyperlipidemia, diabetes, coronary heart disease, hearing loss, and hypertension. Conclusions: The study findings demonstrate a notable association between young-onset dementia and pre-existing peripheral vestibular disorders, suggesting that vestibular malfunction could play a role in the development of young-onset dementia. Show more

Keywords: Alzheimer’s disease, dementia, peripheral vestibular disorders, young-onset dementia

DOI: 10.3233/JAD-240309

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 603-610, 2024

Price: EUR 27.50

Identification of the Shared Gene Signatures Between Alzheimer’s Disease and Diabetes-Associated Cognitive Dysfunction by Bioinformatics Analysis Combined with Biological Experiment

Authors: Chen, Yixin | Ji, Xueying | Bao, Zhijun

Article Type: Research Article

Abstract: Background: The connection between diabetes-associated cognitive dysfunction (DACD) and Alzheimer’s disease (AD) has been shown in several observational studies. However, it remains controversial as to how the two related. Objective: To explore shared genes and pathways between DACD and AD using bioinformatics analysis combined with biological experiment. Methods: We analyzed GEO microarray data to identify DEGs in AD and type 2 diabetes mellitus (T2DM) induced-DACD datasets. Weighted gene co-expression network analysis was used to find modules, while R packages identified overlapping genes. A robust protein-protein interaction network was constructed, and hub genes were identified with Gene …ontology enrichment and Kyoto Encyclopedia of Genome and Genome pathway analyses. HT22 cells were cultured under high glucose and amyloid-β 25–35 (Aβ25-35 ) conditions to establish DACD and AD models. Quantitative polymerase chain reaction with reverse transcription verification analysis was then performed on intersection genes. Results: Three modules each in AD and T2DM induced-DACD were identified as the most relevant and 10 hub genes were screened, with analysis revealing enrichment in pathways such as synaptic vesicle cycle and GABAergic synapse. Through biological experimentation verification, 6 key genes were identified. Conclusions: This study is the first to use bioinformatics tools to uncover the genetic link between AD and DACD. GAD1, UCHL1, GAP43, CARNS1, TAGLN3, and SH3GL2 were identified as key genes connecting AD and DACD. These findings offer new insights into the diseases’ pathogenesis and potential diagnostic and therapeutic targets. Show more

Keywords: Alzheimer’s disease, diabetes-associated cognitive dysfunction, diabetes mellitus, hub genes, protein-protein interaction network, weighted gene co-expression network analysis

DOI: 10.3233/JAD-240353

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 611-625, 2024

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Enlarged Perivascular Spaces Are Independently Associated with High Pulse Wave Velocity: A Cross-Sectional Study

Article Type: Research Article

Abstract: Background: Recent studies have demonstrated an association between pulse wave velocity (PWV), cerebral small vessel disease (SVD), and cognitive impairment such as Alzheimer’s disease. However, the association between brachial-ankle PWV and enlarged perivascular spaces (EPVS), one component of cerebral SVD remains controversial. Objective: To investigate the relationship between brachial-ankle PWV and EPVS severity in participants without dementia. Methods: We performed a cross-sectional study of data of 74 participants from sub-analysis of ongoing research. We assessed cognitive function, brachial-ankle PWV, and brain magnetic resonance imaging (MRI) features. Using brain MRI, EPVS were separately assessed as basal ganglia …(BG)-EPVS or centrum semiovale (CSO)-EPVS on the basis of their location. The relationship between EPVS severity and brachial-ankle PWV was evaluated using multivariable ordinal logistic regression analyses. Results: We analyzed 74 participants (women: 47%, mean age: 73 years, mild cognitive impairment [MCI]: 74%). Compared with participants with normal cognition, those with MCI were more likely to have both severe BG-EPVS and severe CSO-EPVS. In multivariable analyses, high brachial-ankle PWV and age were independently associated with BG-EPVS severity (odds ratio [95% confidence interval]: 1.19 [1.02–1.38], 1.09 [1.01–1.17], respectively), whereas only age was independently associated with CSO-EPVS severity. A causal mediation analysis under a counterfactual approach revealed a significant pure natural indirect effect of brachial-ankle PWV on MCI that was mediated by BG-EPVS (estimate: 1.04, 95% CI: 1.01–1.12, p = 0.006). Conclusions: Brachial-ankle PWV was associated with BG-EPVS severity. High PWV may cause cerebrovascular pulsatility, which accelerates BG-EPVS and may worsen cognitive impairment. Show more

Keywords: Alzheimer’s disease, cerebral small vessel disease, cognitive decline, enlarged perivascular spaces, pulsatility, pulse wave velocity

DOI: 10.3233/JAD-240589

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 627-636, 2024

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Journal of Alzheimer's Disease - Volume 101, issue 2

Slow Gait Speed Predicts Incident Dementia, Mortality, and Long-Term Functional Outcome in Cerebral Small-Vessel Disease

The Profile of the Italian Centers for Cognitive Disorders and Dementia in the Context of New Drugs in Alzheimer’s Disease

Degradation of Amyloid-β Species by Multi-Copper Oxidases

Unique Pathology in the Locus Coeruleus of Individuals with Down Syndrome

Impact of Preanalytical Procedures on Complement Biomarkers in Cerebrospinal Fluid and Plasma from Controls and Alzheimer’s Disease Patients

Correlation Between the Fractional Amplitude of Low-Frequency Fluctuation and Cognitive Defects in Alzheimer’s Disease

Convergent Multimodal Imaging Abnormalities in the Dorsal Precuneus in Subjective Cognitive Decline

Association of Young-Onset Dementia with Pre-Existing Peripheral Vestibular Disorders

Identification of the Shared Gene Signatures Between Alzheimer’s Disease and Diabetes-Associated Cognitive Dysfunction by Bioinformatics Analysis Combined with Biological Experiment

Enlarged Perivascular Spaces Are Independently Associated with High Pulse Wave Velocity: A Cross-Sectional Study

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