Journal of Alzheimer's Disease - Volume 93, issue 2

Authors: Mao, Chenhui | You, Hui | Hou, Bo | Chu, Shanshan | Jin, Wei | Huang, Xinying | Shang, Li | Feng, Feng | Peng, Bin | Gao, Jing

Article Type: Research Article

Abstract: Background: Arterial spin labeling (ASL) is helpful in early diagnosis and differential diagnosis of Alzheimer’s disease (AD), with advantages including no exposure to radioactivity, no injection of a contrast agent, more accessible, and relatively less expensive. Objective: To establish the perfusion pattern of different dementia in Chinese population and evaluate the effectiveness of ASL in differentiating AD from cognitive unimpaired (CU), mild cognitive impairment (MCI), and frontotemporal dementia (FTD). Methods: Four groups of participants were enrolled, including AD, FTD, MCI, and CU based on clinical diagnosis from PUMCH dementia cohort. ASL image was collected using 3D …spiral fast spin echo–based pseudo-continuous ASL pulse sequence with background suppression and a high resolution T1-weighted scan covering the whole brain. Data processing was performed using Dr. Brain Platform to get cerebral blood flow (ml/100g/min) in every region of interest cortices. Results: Participants included 66 AD, 26 FTD, 21 MCI, and 21 CU. Statistically, widespread hypoperfusion neocortices, most significantly in temporal-parietal-occipital cortices, but not hippocampus and subcortical nucleus were found in AD. Hypoperfusion in parietal lobe was most significantly associated with cognitive decline in AD. Hypoperfusion in parietal lobe was found in MCI and extended to adjacent temporal, occipital and posterior cingulate cortices in AD. Significant reduced perfusion in frontal and temporal cortices, including subcortical nucleus and anterior cingulate cortex were found in FTD. Hypoperfusion regions were relatively symmetrical in AD and left predominant especially in FTD. Conclusion: Specific patterns of ASL hypoperfusion were helpful in differentiating AD from CU, MCI, and FTD. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, frontotemporal dementia, hypoperfusion, mild cognitive impairment

DOI: 10.3233/JAD-221023

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 509-519, 2023

Authors: Imai, Ayu | Matsuoka, Teruyuki | Narumoto, Jin

Article Type: Research Article

Abstract: Background: Mild behavioral impairment (MBI) has attracted attention as a possible precursor symptom of dementia, but its neural basis has not been fully investigated. Objective: We aimed to investigate the relationship between MBI and surface area, cortical thickness, and volume in the temporal and parietal lobes, which are strongly associated with dementia and emotional disorders. Methods: This retrospective study evaluated 123 participants: 90 with mild cognitive impairment (MCI), 13 with subjective cognitive decline (SCD), and 20 cognitively healthy (CH). Using analysis of covariance (ANCOVA) with sex, age, and MMSE score as covariates, cortical thickness, surface area, …and volume in 10 regions were compared between groups with and without MBI. Groups with MBI emotional dysregulation were also compared with groups without MBI. Results: ANCOVA revealed significantly smaller cortical thickness in the MBI group’s right parahippocampal (p  = 0.01) and supramarginal gyri (p  = 0.002). After multiple comparison correction, only the right supramarginal gyrus was significantly smaller (p  = 0.02). When considering only MBI emotional dysregulation, the right parahippocampal and supramarginal gyrus’ cortical thicknesses were significantly smaller in this MBI group (p  = 0.03, 0.01). However, multiple comparison correction identified no significant differences (p  = 0.14, 0.11). Conclusion: Overall MBI and the emotional dysregulation domains were associated with reduced cortical thickness in the right parahippocampal and supramarginal gyri. Since neurodegeneration in the medial temporal and parietal lobe precedes early Alzheimer’s disease (AD), MBI, particularly emotion dysregulation, may predict early AD below the diagnostic threshold. Show more

Keywords: Alzheimer’s disease, cortical thickness, emotional dysregulation, mild behavioral impairment, mild cognitive impairment, neural basis, surface area

DOI: 10.3233/JAD-220948

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 521-532, 2023

Authors: Sible, Isabel J. | Nation, Daniel A.

Article Type: Research Article

Abstract: Background: Blood pressure variability (BPV) is associated with cognitive decline and Alzheimer’s disease (AD), but relationships with AD risk gene apolipoprotein (APOE ) ɛ4 remain understudied. Objective: Examined the longitudinal relationship between BPV and cognitive change in APOE ɛ4 carriers and APOE ɛ3 homozygotes. Methods: 1,194 Alzheimer’s Disease Neuroimaging Initiative participants (554 APOE ɛ4 carriers) underwent 3-4 blood pressure measurements between study baseline and 12-month follow-up. Visit-to-visit BPV was calculated as variability independent of mean over these 12 months. Participants subsequently underwent ≥1 neuropsychological exam at 12-month follow-up or later (up to 156 …months later). Composite scores for the domains of memory, language, executive function, and visuospatial abilities were determined. Linear mixed models examined the 3-way interaction of BPV×APOE ɛ4 carrier status x time predicting change in composite scores. Results: Higher systolic BPV predicted greater decline in memory (+1 SD increase of BPV: β = –0.001, p  < 0.001) and language (β = –0.002, p  < 0.0001) among APOE ɛ4 carriers, but not APOE ɛ3 homozygotes (memory: +1 SD increase of BPV: β = 0.0001, p  = 0.57; language: β = 0.0001, p  = 0.72). Systolic BPV was not significantly associated with change in executive function or visuospatial abilities in APOE ɛ4 carriers (p s = 0.08–0.16) or APOE ɛ3 homozygotes (p s = 0.48–0.12). Conclusion: Cognitive decline associated with high BPV may be specifically accelerated among APOE ɛ4 carriers. Show more

Keywords: Alzheimer’s disease, APOE, blood pressure, cognitive dysfunction, neuropsychology

DOI: 10.3233/JAD-221103

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 533-543, 2023

Authors: Zhang, Junyao | Zhang, Tong | Wang, Yinuo | Yao, Liangfang | Yao, Junyan

Article Type: Research Article

Abstract: Background: Our previous studies indicated that anesthesia and surgery could aggravate cognitive impairment of 5XFAD transgenic (Tg) mice, and this aggravation was associated with tau hyperphosphorylation. We previously identified that GNA13 (the gene encoding Gα13) was a hub gene with tau hyperphosphorylation. Objective: This study aims to further investigate the mechanism that whether the Gα13-mediated signaling pathway acts as an instigator to regulate cofilin activation and autophagy impairment in this process. Methods: 5XFAD Tg mice and their littermate (LM) mice were randomly allocated into four groups: LM Control group, LM Anesthesia/Surgery group, AD Control group, and …AD Anesthesia/Surgery group. For mice in the Anesthesia/Surgery groups, abdominal surgery was performed under 1.4% isoflurane anesthesia followed by sustaining anesthetic inhalation for up to 2 h. Results: Compared with the AD Control group, protein levels of Gα13, ROCK2, LPAR5, and p-tau/tau46 ratio were increased, while p-cofilin/cofilin protein expression ratio was decreased in the AD Anesthesia/Surgery group. However, the differences in these protein levels were not significant among LM groups. Conclusion: This study demonstrated that anesthesia and surgery might exacerbate p-tau accumulation in 5XFAD Tg mice but not in LM mice. And this might be closely related to cofilin activation via Gα13-mediated signaling cascade. Show more

Keywords: Alzheimer’s disease, anesthesia, autophagy, cofilin, cognitive dysfunction, Gα13, surgery, tau

DOI: 10.3233/JAD-221039

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 545-560, 2023

Authors: Biswas, Roshni | Kawas, Claudia | Montine, Thomas J. | Bukhari, Syed A. | Jiang, Luohua | Corrada, Maria M.

Article Type: Research Article

Abstract: Background: Some oldest-old individuals can maintain superior cognition despite advanced age. Little is known about the neuropathological changes in the brains of oldest-old superior cognitive performers. Objective: Our objective was to examine the associations between Alzheimer’s disease (AD) and non-AD neuropathologic features in relation to superior cognitive performance in oldest-old individuals. Methods: We analyzed brain autopsy data from 102 participants with normal cognition from The 90+ Study . Superior global cognitive performers (SGCP) were defined as having Mini-Mental State Examination (MMSE) score ≥28 in the last visit 12 to 2 months before death. To examine the …associations between individual and multiple comorbid neuropathologic features with SGCP status we used multiple logistic regression models adjusting for age, sex, and education. Results: Alzheimer’s disease neuropathological change (ADNC) and low levels of vascular pathologic change were not associated with superior cognition. In contrast, participants with limbic (OR = 8.37; 95% CI: 1.48–47.44) and neocortical (OR = 10.80;95% CI: 1.03–113.82) Lewy body disease (LBD), or with hippocampal sclerosis (HS) (OR = 5.28; 95% CI: 1.10–25.47) were more likely to be non-SGCP. High total burden of multiple comorbid neuropathologic features was associated with a lower likelihood of being SGCP. Conclusion: Oldest-old superior cognitive performers were resilient to ADNC and low levels of vascular pathologic change and were resistant to non-AD neurodegenerative changes and multiple comorbid neuropathologic features. Understanding the factors underlying the ability of superior cognitive performers to resist these changes might provide useful insights on maintenance of superior cognition despite advanced age. Show more

Keywords: Alzheimer’s disease, cognitive aging, neurodegenerative disease, oldest-old, successful aging, vascular

DOI: 10.3233/JAD-221062

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 561-575, 2023

Authors: McIntyre, Clayton C. | Gaitán, Julian M. | Edmunds, Kyle J. | Lose, Sarah R. | Bendlin, Barbara B. | Sager, Mark | Asthana, Sanjay | Johnson, Sterling C. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: Background: Cardiorespiratory fitness (CRF) supports cognition, though it is unclear what mechanisms underly this relationship. Insulin resistance adversely affects cognition but can be reduced with habitual exercise. Objective: We investigated whether insulin resistance statistically mediates the relationship between CRF and cognition. Methods: In our observational study, we included n  = 1,131 cognitively unimpaired, nondiabetic older adults from a cohort characterized by elevated Alzheimer’s disease (AD) risk. We estimated CRF (eCRF) using a validated equation that takes age, sex, body mass index, resting heart rate, and habitual physical activity as inputs. The Homeostatic Model Assessment for Insulin Resistance …(HOMA-IR) quantified insulin resistance. Standardized cognitive factor scores for cognitive speed/flexibility, working memory, verbal learning/memory, and immediate memory were calculated from a battery of neuropsychological tests. Linear regression models and bootstrapped estimates of indirect effects were used to determine whether HOMA-IR mediated significant relationships between eCRF and cognition. Results: eCRF was positively associated with cognitive speed/flexibility (p  = 0.034). When controlling for HOMA-IR, eCRF was no longer associated with cognitive speed/flexibility (p  = 0.383). HOMA-IR had a significant indirect effect on the eCRF-cognition relationship (B  = 0.025, CI = [0.003,0.051]). eCRF was not associated with working memory (p  = 0.236), immediate memory (p  = 0.345), or verbal learning/memory (p  = 0.650). Conclusion: Among older adults at risk for AD, peripheral insulin resistance mediates the relationship between CRF and cognitive speed. Show more

Keywords: Alzheimer’s disease, cognition, cognitive decline, insulin, physical fitness

DOI: 10.3233/JAD-221249

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 577-584, 2023

Authors: Zhao, Zixiao | Wang, Jie | Wang, Ying | Liu, Xia | He, Kun | Guo, Qihao | Xie, Fang | Huang, Qi | Li, Zijing

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is a self-perceived decline in cognitive ability, which exhibits no objective impairment but increased risk of conversion to mild cognitive impairment and Alzheimer’s disease (AD). Objective: To investigate how influencing factors (risk gene, age, sex, and education) affect amyloid-β (Aβ) deposition and gray matter (GM) atrophy in SCD population. Methods: 281 SCD subjects were included in this study, who underwent clinical evaluation, cognitive ability assessment, apolipoprotein E (APOE ) genotyping, 18 F-Florbetapir positron emission computed tomography, and magnetic resonance imaging screening. Two-sample t tests and analysis of variance were performed …based on voxel-wise outcome. Results: In 281 SCD subjects with an average age of 63.86, 194 subjects (69.04%) were females, and 56 subjects carried APOE ɛ4 genes. Statistical results revealed APOE ɛ4 gene, age, and sex influenced Aβ deposition in different brain regions; moreover, only the interaction exhibited between age and APOE ɛ4 genes. The GM atrophy of hippocampal, amygdala, precentral, and occipital lobes occurred in the group age over 60. The GM volume of the hippocampal, frontal, and occipital lobe in females was less than males. Education had an effect only on cognitive function. Conclusion: In SCD, APOE ɛ4 gene, age, and sex significantly influenced Aβ deposition and APOE ɛ4 gene can interact with age in impacting Aβ deposition. Both age and sex can affect GM atrophy. The results suggested that female SCD with APOE ɛ4 genes and aged more than 60 years old might exhibit advanced AD biomarkers. Show more

Keywords: Alzheimer’s disease, amyloid-β, atrophy, deposition, gray matter, subjective cognitive decline

DOI: 10.3233/JAD-221251

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 585-594, 2023

Authors: Zhang, Li-Ya | Wang, Duo-Zi | Wang, Jian | Guo, Lei | Li, Bing-Hu | Wang, Jian-Hong

Article Type: Research Article

Abstract: Background: A potential role of the antimicrobial peptide LL-37, which is upregulated after infection, in the pathogenesis of Alzheimer’s disease (AD) was identified. However, the clinical relevance of LL-37 in AD is not clear yet. Objective: This study aims to investigate the association of circulating LL-37 with longitudinal cognitive decline and neurodegeneration among older adults with memory complaints. Methods: This cohort study recruited 357 older adults with memory complaints. Participants were followed-up for two years and the cognitive functions were assessed using the Mini-Mental State Examination (MMSE). Serum LL-37, pTau181, and tTau levels were determined at …baseline. Associations of baseline LL-37 with longitudinal cognitive decline and change of neurodegenerative biomarkers were analyzed. Results: No difference was found in the slope of longitudinal cognitive decline during follow-up between the low and high LL-37 group, adjusting for age, sex, education, body mass index, APOE ɛ4 carrier status, comorbidities, and baseline MMSE scores (difference in slope: 0.226, 95% CI: –0.169 to 0.621). Higher LL-37 levels were associated with longitudinal cognitive decline, as indicated by a decrease of MMSE scores of 3 points or above during follow-up (OR = 2.11, 95% CI: 1.32 to 3.38). The high LL-37 group had larger slopes of the increase in neurofilament light (difference in slope: 3.759, 95% CI: 2.367 to 5.152) and pTau181 (difference in slope: 0.325, 95% CI: 0.151 to 0.499) than the low LL-37 group. Conclusion: These findings support an association of the antimicrobial peptide LL-37 with AD from a clinical perspective. Show more

Keywords: Alzheimer’s disease, Amyloid-β, antimicrobial peptide LL-37, cognitive decline, infection, neurodegeneration, neurofilament light, tau

DOI: 10.3233/JAD-230007

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 595-603, 2023

Authors: Tian, Jing | Stucky, Chase Samuel | Wang, Tienju | Muma, Nancy A. | Johnson, Michael | Du, Heng

Article Type: Research Article

Abstract: Background: Deprivation of extracellular serotonin has been linked to cognitive decline and neuropsychiatric disturbances in Alzheimer’s disease (AD). However, despite degeneration of serotonin-producing neurons, whether serotonin release is affected in AD-sensitive brain regions is unknown. Objective: This study investigated the impact of mitochondrial dysfunction in decreased hippocampal serotonin release in AD amyloidosis mouse model 5xFAD mice. Methods: Electrochemical assays were applied to examine hippocampal serotonin release. We also employed multidisciplinary techniques to determine the role of oligomeric amyloid-β (Aβ) in hippocampal mitochondrial deficits and serotonin release deficiency. Results: 5xFAD mice exhibited serotonin release decrease …and relatively moderate downregulation of serotonergic fiber density as well as serotonin content in the hippocampal region. Further experiments showed an inhibitory effect of oligomeric amyloid-β (Aβ) on hippocampal serotonin release without affecting the density of serotonergic fibers. Pharmaceutical uncoupling of mitochondrial oxidative phosphorylation (OXPHOS) disrupted hippocampal serotonin release in an ex vivo setting. This echoes the mitochondrial defects in serotonergic fibers in 5xFAD mice and oligomeric Aβ-challenged primary serotonergic neuron cultures and implicates a link between mitochondrial dysfunction and serotonin transmission defects in AD-relevant pathological settings. Conclusion: The most parsimonious interpretation of our findings is that mitochondrial dysfunction is a phenotypic change of serotonergic neurons, which potentially plays a role in the development of serotonergic failure in AD-related conditions. Show more

Keywords: Alzheimer’s disease, amyloid-β, hippocampus, mitochondria, serotonin

DOI: 10.3233/JAD-230072

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 605-619, 2023

Authors: Aguilar-Barberà, Miquel | Soler-Girabau, Paquita | Tabuenca-Martín, Ana Isabel | Prieto-del Val, Laura

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) manifest in the early stages of the disease and impair patients’ and caregivers’ quality of life. Objective: To assess the effectiveness of the nutritional supplement Fortasyn Connect on BPSD for 12 months in people with mild cognitive impairment (MCI) and dementia in clinical practice. Methods: Retrospective, national, single-center study of 236 patients (158 MCI and 78 dementia; 55.1% of AD etiology). BPSD were assessed with the Neuropsychiatric Inventory (NPI) at month 3, 6, and 12. Cognition (Mini-Mental State Examination, MMSE), depression (Geriatric Depression Scale, GDS), and everyday functioning …(Blessed Dementia Scale, BLS-D; Rapid Disability Rating Scale 2, RDRS2) were also evaluated. Results: Total NPI score, caregiver impact, and symptoms of depression, anxiety, apathy, and irritability improved after 3, 6, and 12 months from Fortasyn Connect initiation (p  < 0.001). NPI decreases were more pronounced when baseline NPI score was higher than > 20 points (p  < 0.001). The benefit was independent of gender, age, diagnosis, etiology, or concomitant treatment (p  < 0.0001), although larger decreases in NPI total score were observed in MCI patients (p  < 0.0001). After 12 months, GDS scores decreased (p  = 0.042), and MMSE, BLS-D, and RDRS 2 scores remained stable. Conclusion: Fortasyn Connect improved BPSD over at least a year in patients with MCI and dementia. Depression, anxiety, apathy, and irritability were the symptoms that improved the most. The benefit was independent of patients’ characteristics and treatment but was greater if prescribed early and when baseline NPI scores were higher. Show more

Keywords: Alzheimer’s disease, anxiety, apathy, dementia, depression, mild cognitive impartment, neuropsychiatric symptoms

DOI: 10.3233/JAD-221122

Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 621-631, 2023