Journal of Alzheimer's Disease - Volume 95, issue 1

Authors: Li, Jixuan | Zeng, Qingze | Luo, Xiao | Li, Kaicheng | Liu, Xiaocao | Hong, Luwei | Zhang, Xinyi | Zhong, Siyan | Qiu, Tiantian | Liu, Zhirong | Chen, Yanxing | Huang, Peiyu | Zhang, Minming

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is accompanied with impaired neurovascular coupling. However, its early alteration remains elusive along the AD continuum. Objective: This study aimed to investigate the early disruption of neurovascular coupling in cognitively normal (CN) and mild cognitive impairment (MCI) elderly and its association with cognition and AD pathologies. Methods: We included 43 amyloid-β-negative CN participants and 38 amyloid-β-positive individuals (18 CN and 20 MCI) from the Alzheimer’s Disease Neuroimaging Initiative dataset. Regional homogeneity (ReHo) map was used to represent neuronal activity and cerebral blood flow (CBF) map was used to represent cerebral blood perfusion. …Neurovascular coupling was assessed by CBF/ReHo ratio at the voxel level. Analyses of covariance to detect the between-group differences and to further investigate the relations between CBF/ReHo ratio and AD biomarkers or cognition. In addition, the correlation of cerebral small vessel disease (SVD) burden and neurovascular coupling was assessed as well. Results: Related to amyloid-β-negative CN group, amyloid-β-positive groups showed decreased CBF/ReHo ratio mainly in the left medial and inferior temporal gyrus. Furthermore, lower CBF/ReHo ratio was associated with a lower Mini-Mental State Examination score as well as higher AD pathological burden. No association between CBF/ReHo ratio and SVD burden was observed. Conclusion: AD pathology is a major correlate of the disturbed neurovascular coupling along the AD continuum, independent of SVD pathology. The CBF/ReHo ratio may be an index for detecting neurovascular coupling abnormalities, which could be used for early diagnosis in the future. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, functional magnetic resonance imaging, neurovascular coupling, positron emission tomography

DOI: 10.3233/JAD-230503

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 287-298, 2023

Authors: Yabuuchi, Kenichi | Kimura, Noriyuki | Masuda, Teruaki | Matsubara, Etsuro

Article Type: Research Article

Abstract: Background: The differences in positron emission tomography (PET) imaging among older adults with mild cognitive impairment (MCI), according to the recruitment source, remain unclear. Objective: To investigate the differences in brain amyloid deposition and cortical glucose metabolism according to recruitment source among older adults with MCI. Methods: Participants in the clinic-based MCI cohort, who were referred to Oita University Hospital for cognitive decline, consisted of 90 adults with MCI. The community-based MCI cohort, which participated in a prospective cohort study, consisted of 118 adults with MCI. Participants underwent cognitive function evaluation, 11 C-Pittsburgh compound B (PiB)-PET, …and 18 F-fluorodeoxyglucose (FDG)-PET. The prevalence of amyloid positivity and mean PiB and FDG uptake values were compared between the cohorts. Moreover, a voxel-by-voxel group study was performed to determine the areas with significant differences between the clinic- and community-based MCI cohorts. Results: The prevalence of amyloid positivity and mean PiB uptake value in the clinic-based MCI cohort were significantly higher than those in the community-based MCI cohort (p  < 0.001 and p  < 0.001, respectively). The mean FDG uptake value in the clinic-based MCI cohort was significantly lower than that in the community-based MCI cohort (p  < 0.001). SPM 8 analysis showed significantly increased PiB uptake in the precuneus and parietotemporal lobe and significantly decreased FDG uptake in the posterior cingulate in the clinic-based MCI cohort compared to the community-based MCI cohort. Conclusion: The prevalence and severity of amyloid pathology in older adults with MCI varied depending on the recruitment source. Show more

Keywords: Alzheimer’s disease, brain amyloid deposition, clinic-based cohort, community-based cohort, cortical glucose metabolism, mild cognitive impairment

DOI: 10.3233/JAD-230550

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 299-306, 2023

Authors: White, Lon R. | Corrada, Maria M. | Kawas, Claudia H. | Cholerton, Brenna A. | Edland, Steve E. | Flanagan, Margaret E. | Montine, Thomas J.

Article Type: Research Article

Abstract: Background: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer’s disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia. Objective: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC. Methods: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were …examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC). Results: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels. Conclusion: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease and related dementias, autopsy, co-morbidity, dementia, neuropathology, polymorbidity, prevention

DOI: 10.3233/JAD-230331

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 307-316, 2023

Authors: Vicente, Mariane C. | Paneghini, Julia L. | Stabile, Angelita M. | Amorim, Mateus | Anibal Silva, Conceição E. | Patrone, Luis Gustavo A. | Cunha, Thiago M. | Bícego, Kênia C. | Almeida, Maria C. | Carrettiero, Daniel C. | Gargaglioni, Luciane H.

Article Type: Research Article

Abstract: Background: Neuroinflammation in Alzheimer’s disease (AD) can occur due to excessive activation of microglia in response to the accumulation of amyloid-β peptide (Aβ). Previously, we demonstrated an increased expression of this peptide in the locus coeruleus (LC) in a sporadic model for AD (streptozotocin, STZ; 2 mg/kg, ICV). We hypothesized that the STZ-AD model exhibits neuroinflammation, and treatment with an inhibitor of microglia (minocycline) can reverse the cognitive, respiratory, sleep, and molecular disorders of this model. Objective: To evaluate the effect of minocycline treatment in STZ model disorders. Methods: We treated control and STZ-treated …rats for five days with minocycline (30 mg/kg, IP) and evaluated cognitive performance, chemoreflex response to hypercapnia and hypoxia, and total sleep time. Additionally, quantification of Aβ, microglia analyses, and relative expression of cytokines in the LC were performed. Results: Minocycline treatment improved learning and memory, which was concomitant with a decrease in microglial cell density and re-establishment of morphological changes induced by STZ in the LC region. Minocycline did not reverse the STZ-induced increase in CO2 sensitivity during wakefulness. However, it restored the daytime sleep-wake cycle in STZ-treated animals to the same levels as those observed in control animals. In the LC, levels of A and expression of Il10 , Il1b , and Mcp1 mRNA remained unaffected by minocycline, but we found a strong trend of minocycline effect on Tnf- α. Conclusion: Our findings suggest that minocycline effectively reduces microglial recruitment and the inflammatory morphological profile in the LC, while it recovers cognitive performance and restores the sleep-wake pattern impaired by STZ. Show more

Keywords: Alzheimer’s disease, locus coeruleus, microglia, minocycline, streptozotocin

DOI: 10.3233/JAD-230151

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 317-337, 2023

Authors: Lin, Yijia | Hu, Tingjun | Cheng, Lizhen | Chen, Yixin | Li, Wei | Guo, Qihao | Miao, Ya

Article Type: Research Article

Abstract: Background: A connection between plasma levels of haptoglobin (Hp) and Alzheimer’s disease (AD) has been shown in several observational studies. It is debatable, nonetheless, how the two are related causally. Objective: To establish the causal relationship between Hp and AD using a two-sample Mendelian randomization (MR) study. Methods: From the extensive genome-wide association studies and FinnGen dataset, summaries and statistics pertaining to AD were gathered. We investigated the possibility of a causal link between Hp and AD using a two-sample MR study. Inverse variance weighting was used as the primary analytical technique, and it was supported …by the joint application of complementary analyses and fixed effects meta-analysis to combine results from various sources. Results: Genetically determined Hp was causally associated with AD [odds ratio (OR), 1.05; 95% confidence interval (CI), 1.02 to 1.09; p  = 8.96×10–4 ]; Inverse variance-weighted estimates coming from different data sources were combined in a meta-analysis with consistent findings (OR, 1.03; 95% CI, 1.01 to 1.05; p  = 2.00×10–3 ). The outcomes of the inverse MR analysis showed that AD had no appreciable causal impact on Hp. Conclusion: The present MR analysis shows that higher plasma Hp leads to an increased risk of AD. Strategies for plasma Hp testing may open up new doors for the early diagnosis and prevention of AD. Show more

Keywords: Alzheimer’s disease, causality, haptoglobins, Mendelian randomization analysis

DOI: 10.3233/JAD-230159

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 339-348, 2023

Authors: Leitão, André D.G. | Spencer, Brian | Sarsoza, Floyd | Ngolab, Jennifer | Amalraj, Jessica | Masliah, Eliezer | Wu, Chengbiao | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) cases are often characterized by the pathological accumulation of α-synuclein (α-syn) in addition to amyloid-β (Aβ) and tau hallmarks. The role of α-syn has been extensively studied in synucleinopathy disorders, but less so in AD. Recent studies have shown that α-syn may also play a role in AD and its downregulation may be protective against the toxic effects of Aβ accumulation. Objective: We hypothesized that selectively knocking down α-syn via RNA interference improves the neuropathological and biochemical findings in AD mice. Methods: Here we used amyloid precursor protein transgenic …(APP-Tg) mice to model AD and explore pathologic and behavioral phenotypes with knockdown of α-syn using RNA interference. We selectively reduced α-syn levels by stereotaxic bilateral injection of either LV-shRNA α-syn or LV-shRNA-luc (control) into the hippocampus of AD mice. Results: We found that downregulation of α-syn results in significant reduction in the number of Aβ plaques. In addition, mice treated with LV-shRNA α-syn had amelioration of abnormal microglial activation (Iba1) and astrocytosis (GFAP) phenotypes in AD mice. Conclusion: Our data suggests a novel link between Aβ and α-syn pathology as well as a new therapeutic angle for targeting AD. Show more

Keywords: Alzheimer’s disease, alpha-synuclein, amyloid-β , biomarkers, lentivirus

DOI: 10.3233/JAD-230232

Citation: Journal of Alzheimer's Disease, vol. 95, no. 1, pp. 349-361, 2023