Journal of Alzheimer's Disease - Volume 98, issue 1

Authors: Su, Wenlong | Li, Hui | Dang, Hui | Han, Kaiyue | Liu, Jiajie | Liu, Tianhao | Liu, Ying | Tang, Zhiqing | Lu, Haitao | Zhang, Hao

Article Type: Research Article

Abstract: Background: The mechanism(s) of cognitive impairment remains complex, making it difficult to confirm the factors influencing poststroke cognitive impairment (PSCI). Objective: This study quantitatively investigated the degree of influence and interactions of clinical indicators of PSCI. Methods: Information from 270 patients with PSCI and their Wechsler Adult Intelligence Scale (WAIS-RC) scores, totaling 18 indicators, were retrospectively collected. Correlations between the indicators and WAIS scores were calculated. Multiple linear regression model(MLR), genetic algorithm modified Back-Propagation neural network(GA-BP), logistic regression model (LR), XGBoost model (XGB), and structural equation model were used to analyze the degree of influence of …factors on the WAIS and their mediating effects. Results: Seven indicators were significantly correlated with the WAIS scores: education, lesion side, aphasia, frontal lobe, temporal lobe, diffuse lesions, and disease course. The MLR showed significant effect of education, lesion side, aphasia, diffuse lesions, and frontal lobe on the WAIS. The GA-BP included five factors: education, aphasia, frontal lobe, temporal lobe, and diffuse lesions. LR predicted that the lesion side contributed more to mild cognitive impairment, while education, lesion side, aphasia, and course of the disease contributed more to severe cognitive impairment. XGB showed that education, side of the lesion, aphasia, and diffuse lesions contributed the most to PSCI. Aphasia plays a significant mediating role in patients with severe PSCI. Conclusions: Education, lesion side, aphasia, frontal lobe, and diffuse lesions significantly affected PSCI. Aphasia is a mediating variable between clinical information and the WAIS in patients with severe PSCI. Show more

Keywords: Alzheimer’s disease, cognitive impairment, predictor, stroke, WAIS-R

DOI: 10.3233/JAD-230840

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 109-117, 2024

Authors: Ju, In Gyoung | Lee, Seungmin | Kim, Seong Hye | Im, Hyeri | Eo, Hyeyoon | Oh, Myung Sook

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), the most common form of dementia, is characterized by memory loss and the abnormal accumulation of senile plaques composed of amyloid-β (Aβ) protein. Trichosanthis Semen (TS) is a traditional herbal medicine used to treat phlegm-related conditions. While TS is recognized for various bioactivities, including anti-neuroinflammatory effects, its ability to attenuate AD remains unknown. Objective: To evaluate the effects of TS extract (TSE) on neuronal damage, Aβ accumulation, and neuroinflammation in AD models. Methods: Thioflavin T and western blot assays were used to assess effects on Aβ aggregation in vitro . TS was …treated to PC12 cells with Aβ to assess the neuroprotective effects. Memory functions and histological brain features were investigated in TSE-treated 5×FAD transgenic mice and mice with intracerebroventricularly injected Aβ. Results: TSE disrupted Aβ aggregation and increased the viability of cells and phosphorylation of both protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) in vitro . TSE treatment also suppressed the accumulation of Aβ plaques in the brain of 5×FAD mice, protected neuronal cells in both the subiculum and medial septum, and upregulated Akt/ERK phosphorylation in the hippocampus. Moreover, TSE ameliorated the memory decline and glial overactivation observed in 5×FAD mice. As assessing whether TS affect Aβ-induced neurotoxicity in the Aβ-injected mice, the effects of TS on memory improvement and neuroinflammatory inhibition were confirmed. Conclusions: TSE disrupted Aβ aggregation, protected neurons against Aβ-induced toxicity, and suppressed neuroinflammation, suggesting that it can suppress the development of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, neuroinflammation, neuroprotection, Trichosanthis semen

DOI: 10.3233/JAD-231124

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 119-131, 2024

Authors: Altomare, Daniele | Rivolta, Jasmine | Libri, Ilenia | Mattioli, Irene | Cantoni, Valentina | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms cause significant suffering and poor quality of life for patients and their caregivers. They are not considered specific to frontotemporal dementia (FTD); therefore, their clinical role and impact might be underestimated. Objective: The aims of the present study are to: 1) describe the prevalence of neuropsychiatric symptoms in FTD starting from the prodromal stage, 2) define their association with disease severity, 3) identify symptoms which are unrelated to FTD-specific symptoms, and 4) assess their association with clinical features and outcomes. Results: In this retrospective study, we analyzed data of 461 FTD patients, including …behavioral variant of FTD (bvFTD, n  = 318) and primary progressive aphasia (PPA, n  = 143). Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory, and patients’ staging and global disease severity were estimated using the Clinical Dementia Rating plus NACC FTLD. Results: The most common neuropsychiatric symptoms in prodromal FTD were irritability (48%), depression (35%), and anxiety (34%); delusions were reported in 6%of prodromal bvFTD cases. The severity of most neuropsychiatric symptoms increased with global disease severity. Psychosis (delusions and hallucinations) and mood symptoms (depression and anxiety) were mostly independent from FTD-specific symptoms. Psychosis was associated with older age, higher disease severity, shorter survival rate, and was higher in bvFTD than in PPA. Conclusions: Neuropsychiatric symptoms are common in patients with FTD, also in the prodromal phase. Psychosis might be unrelated to FTD pathology, and be associated with worse clinical outcomes. The prompt detection and treatment of these symptoms might improve patient’s management and quality of life. Show more

Keywords: Clinical assessment, dementia, diagnosis, prodromal, psychogeriatrics

DOI: 10.3233/JAD-231256

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 133-144, 2024

Authors: Putignano, Salvatore | Forgione, Luigi | Fusco, Mariano | Giacummo, Attilio | Magli, Elisa | Marino, Saverio | Marzano, Raffaele | Putignano, Daria | Santamaria, Francesco | Spatarella, Micaela | Santagada, Vincenzo

Article Type: Research Article

Abstract: Background: Dementia is the fourth leading cause of death in people >  65 years old in western countries. Objective: This cross-sectional assisted survey aimed to evaluate a multidisciplinary team approach of specialists of the Associazione Geriatri Extraospedalieri a favore di Anziani Svantaggiati and pharmacists to facilitate progress in the early identification and management of cognitive decline in patients >  60 years. Methods: A multidisciplinary team conducted this cross-sectional assisted survey. Patients (>60 years) with independent and/or assisted walking, subjective memory impairment, mild cognitive impairment or mild Alzheimer’s disease (AD) who regularly attended pharmacies underwent the survey. An internal …medical examination, a cardiovascular visit, and a short neuropsychological evaluation were conducted for each patient. Demographic, anamnestic, and clinical data were collected anonymously. Results: 279 eligible patients underwent the screening phase. 44% were overweight, 23% obese and 29% hypertensive. 62% of cases showed alterations of supra-aortic trunk with different percentages of stenosis. The neuropsychological evaluation highlighted that 67% of cases were normal according to age and education level, while 18% were in a state condition of cognitive frailty. Mild/moderate cognitive decline, or probably AD, was identified in 14% of cases. Conclusions: A multidisciplinary collaboration between pharmacists and specialist medical doctors is essential in early identification of prodromal symptoms of cognitive impairment and AD. The Prompt detection of the condition in this group of patients allowed the specialists to recommend in-depth diagnostic tests and follow-up procedures to slow the course of the disease. This would give time to carry out adequate caregiver training. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, elderly, frail elderly, observational study

DOI: 10.3233/JAD-231295

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 145-150, 2024

Authors: Czuczwar, Stanisław J. | Kocki, Janusz | Miziak, Barbara | Bogucki, Jacek | Bogucka-Kocka, Anna | Pluta, Ryszard

Article Type: Research Article

Abstract: Background: Understanding the phenomena underlying the non-selective susceptibility to ischemia of pyramidal neurons in the CA3 is important from the point of view of elucidating the mechanisms of memory loss and the development of dementia. Objective: The aim of the study was to investigate changes in genes expression of amyloid precursor protein , its cleaving enzymes and tau protein in CA3 post-ischemia with survival of 12–24 months. Methods: We used an ischemic model of Alzheimer’s disease to study the above genes using an RT-PCR protocol. Results: The expression of the amyloid precursor protein …gene was above the control values at all times post-ischemia. The expression of the α-secretase gene also exceeded the control values post-ischemia. The expression of the β-secretase gene increased 12 and 24 months post-ischemia, and 18 months was below control values. Presenilin 1 and 2 genes expression was significantly elevated at all times post-ischemia. Also, tau protein gene expression was significantly elevated throughout the observation period, and peak gene expression was present 12 months post-ischemia. Conclusions: The study suggests that the genes studied are involved in the non-amyloidogenic processing of amyloid precursor protein. Additionally data indicate that brain ischemia with long-term survival causes damage and death of pyramidal neurons in the CA3 area of the hippocampus in a modified tau protein-dependent manner. Thus defining a new and important mechanism of pyramidal neuronal death in the CA3 area post-ischemia. In addition expression of tau protein gene modification after brain ischemia is useful in identifying ischemic mechanisms occurring in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid precursor protein, brainischemia, CA3 area, genes, presenilin 1 and 2, α-secretase, β-secretase, tau protein

DOI: 10.3233/JAD-231333

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 151-161, 2024

Authors: Acharya, Nimish K. | Grossman, Henya C. | Clifford, Peter M. | Levin, Eli C. | Light, Kenneth R. | Choi, Hana | Swanson II, Randel L. | Kosciuk, Mary C. | Venkataraman, Venkat | Libon, David J. | Matzel, Louis D. | Nagele, Robert G.

Article Type: Research Article

Abstract: Background: Increased blood-brain barrier (BBB) permeability and amyloid-β (Aβ) peptides (especially Aβ1–42 ) (Aβ42 ) have been linked to Alzheimer’s disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood. Objective: To test the hypothesis that chronic extravasation of bloodborne Aβ42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model. Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble …monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled Aβ42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes. Results: Mice injected with both PT and Aβ42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aβ42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aβ42 in animals injected with both PT and Aβ42 compared to controls. Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aβ42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD. Show more

Keywords: Aβ42, Alzheimer’s disease, amyloid-beta peptides, amyloid plaques, autoantibodies, blood-brain barrier, dementia, immunoglobulin G

DOI: 10.3233/JAD-231028

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 163-186, 2024

Authors: Vaishnav, Neil | Gonzalez, Rosa | Karunungan, Krystal | Tyler, Ana | Zheng, William | Arias, Jalayne J.

Article Type: Research Article

Abstract: Background: Documentation of preclinical biomarker tests for Alzheimer’s disease (AD) in the medical record may expose patients to employment and insurance discrimination risks. There is a gap in research describing clinicians’ approaches to documenting biomarker results. Objective: To evaluate discrimination risks faced by patients undergoing biomarker testing for AD through a qualitative analysis of clinician documentation practices. Methods: Semi-structured interviews using hypothetical patient scenarios. The qualitative analysis focused on interviewees’ responses related to documentation and disclosure of results. Results: We collected and analyzed 17 interviews with dementia experts; and identified three approaches to documenting …biomarkers as: an association with active AD, noninformative, and an increased susceptibility for AD. Those who associated biomarkers with active disease were more likely to favor disclosure to employers and insurers, which could increase discrimination risks. Conclusions: This study demonstrates the variety of documentation and disclosure practices likely to emerge for preclinical AD biomarker tests and highlights a need for guidelines in this area. Show more

Keywords: Alzheimer’s disease, biomarkers, legal liability, patient data privacy

DOI: 10.3233/JAD-230067

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 187-195, 2024

Authors: Kim, Sung-a | Maeda, Megumi | Murata, Fumiko | Fujii, Takayuki | Ueda, Emi | Ono, Rei | Fukuda, Haruhisa

Article Type: Research Article

Abstract: Background: The prevalence of Alzheimer’s disease (AD) is increasing in Japan due to population aging. The association between sensory impairment and incident AD remains unclear. Objective: This study aimed to investigate the impact of sensory impairment on incident AD. Methods: We analyzed residents of five municipalities participating in the Longevity Improvement & Fair Evidence (LIFE) Study. The participants comprised individuals who had newly applied for long-term care needs certification between 2017 and 2022 and had no cognitive impairment upon application or AD diagnosis within the preceding six months. Participants were classified according to sensory impairment status: …visual impairment (VI), hearing impairment (HI), neither sensory impairment (NSI), and dual sensory impairment (DSI). The month succeeding the certification application was set as the index month, and the interval from that month until AD onset was assessed. Multivariable Cox proportional hazards analysis was performed to calculate the risk of AD onset according to sensory impairment status while adjusting for sex, age, dependence level, self-reliance level, and comorbidities. Results: Among 14,186 participants, we identified 1,194 (8.4%) who developed AD over a median follow-up period of 22.6 months. VI and HI only were not associated with incident AD. However, DSI conferred a significantly higher risk (HR: 1.6, CI: 1.1–2.2, p  = 0.008) of AD onset than NSI. Conclusions: Individuals with concurrent DSI have a higher risk of developing AD than those with single or NSI. Preventing and treating sensory impairment may not only improve functional outcomes, but could also help to reduce the future risk of AD. Show more

Keywords: Alzheimer’s disease, cognition, cohort study, dementia, sensory impairment

DOI: 10.3233/JAD-230806

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 197-207, 2024

Authors: Sun, Haoqi | Li, Peng | Gao, Lei | Yang, Jingyun | Yu, Lei | Buchman, Aron S. | Bennett, David A. | Westover, M. Brandon | Hu, Kun

Article Type: Research Article

Abstract: Background: Fractal motor activity regulation (FMAR), characterized by self-similar temporal patterns in motor activity across timescales, is robust in healthy young humans but degrades with aging and in Alzheimer’s disease (AD). Objective: To determine the timescales where alterations of FMAR can best predict the clinical onset of AD. Methods: FMAR was assessed from actigraphy at baseline in 1,077 participants who had annual follow-up clinical assessments for up to 15 years. Survival analysis combined with deep learning (DeepSurv) was used to examine how baseline FMAR at different timescales from 3 minutes up to 6 hours contributed differently to the …risk for incident clinical AD. Results: Clinical AD occurred in 270 participants during the follow-up. DeepSurv identified three potential regions of timescales in which FMAR alterations were significantly linked to the risk for clinical AD: <10, 20–40, and 100–200 minutes. Confirmed by the Cox and random survival forest models, the effect of FMAR alterations in the timescale of <10 minutes was the strongest, after adjusting for covariates. Conclusions: Subtle changes in motor activity fluctuations predicted the clinical onset of AD, with the strongest association observed in activity fluctuations at timescales <10 minutes. These findings suggest that short actigraphy recordings may be used to assess the risk of AD. Show more

Keywords: Actigraphy, Alzheimer’s disease, deep learning, motor activity

DOI: 10.3233/JAD-230928

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 209-220, 2024

Authors: Rajabli, Farid | Seixas, Azizi A. | Akgun, Bilcag | Adams, Larry D. | Inciute, Jovita | Hamilton, Kara L. | Whithead, Patrice G. | Konidari, Ioanna | Gu, Tianjie | Arvizu, Jamie | Golightly, Charles G. | Starks, Takiyah D. | Laux, Renee | Byrd, Goldie S. | Haines, Jonathan L. | Beecham, Gary W. | Griswold, Anthony J. | Vance, Jeffery M. | Cuccaro, Michael L. | Pericak-Vance, Margaret A.

Article Type: Research Article

Abstract: Background: Cognitive and functional abilities in individuals with Alzheimer’s disease (AD) pathology (ADP) are highly variable. Factors contributing to this variability are not well understood. Previous research indicates that higher educational attainment (EA) correlates with reduced cognitive impairments among those with ADP. While cognitive and functional impairments are correlated, they are distinguishable in their manifestations. Objective: To investigate whether levels of education are associated with functional impairments among those with ADP. Methods: This research involved 410 African American (AA) individuals (Institutional Review Boards 20070307, 01/27/2023) to ascertain whether EA correlates with functional resilience and if this …effect varies between APOE ɛ4 carriers and non-carriers. Utilizing EA as a cognitive reserve proxy, CDR-FUNC as a functional difficulties measure, and blood pTau181 as an ADP proxy, the non-parametric Mann-Whitney U test assessed the relationship between EA and CDR-FUNC in individuals with advanced pTau181 levels. Results: The results showed that EA correlated with functional difficulties in AA individuals with high levels of pTau181, such that individuals with high EA are more likely to have better functional ability compared to those with lower EA (W  = 730.5, p  = 0.0007). Additionally, we found that the effect of high EA on functional resilience was stronger in ɛ4 non-carriers compared to ɛ4 carriers (W  = 555.5, p  = 0.022). Conclusion: This study extends the role of cognitive reserve and EA to functional performance showing that cognitive reserve influences the association between ADP burden and functional difficulties. Interestingly, this protective effect seems less pronounced in carriers of the strong genetic risk allele ɛ4. Show more

Keywords: Alzheimer’s disease, APOE, biomarker, education

DOI: 10.3233/JAD-231116

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 221-229, 2024