Journal of Alzheimer's Disease - Volume 86, issue 2

Authors: Hsu, Yen-Hsuan | Huang, Sheng-Min | Lin, Shih-Yeh | Yang, Jir-Jei | Tu, Min-Chien | Kuo, Li-Wei

Article Type: Research Article

Abstract: Background: Prospective memory (PM), the ability to execute a previously formed intention given the proper circumstance, has been proven to be vulnerable to Alzheimer’s disease. Previous studies have indicated the involvement of the frontoparietal networks; however, it is proposed that PM may also be associated with other neural substrates that support stimulus-dependent spontaneous cognition. Objective: The present study aimed to examine the hypothesis that PM deficit in Alzheimer’s disease is related to altered functional connectivity (FC) within the default mode network (DMN). Methods: Thirty-four patients with very mild or mild dementia (17 with …Alzheimer’s disease and 17 with subcortical ischemic vascular disease) and 22 cognitively-normal participants aged above 60 received a computerized PM task and resting-state functional magnetic resonance imaging study. Seed-based functional connectivity analysis was performed at group level within the DMN. Results: We found that the dementia groups showed worse PM performance and altered FC within the DMN as compared to the normal aging individuals. The FC between the medial prefrontal cortices and precuneus/posterior cingulate cortex was significantly correlated with PM in normal aging, while the FC between the right precuneus and bilateral inferior parietal lobules was correlated with PM in patients with Alzheimer’s disease. Conclusion: These findings support a potential role for the DMN in PM, and corroborate that PM deficit in Alzheimer’s disease was associated with altered FC within the posterior hubs of the DMN, with spatial patterning different from normal aging. Show more

Keywords: Alzheimer’s disease, cerebral small vessel disease, default mode network, memory for intention, prospective memory

DOI: 10.3233/JAD-215293

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 753-762, 2022

Authors: Nowrangi, Milap A. | Outen, John D. | Naaz, Farah | Chen, Liuyi | Bakker, Arnold | Munro, Cynthia A. | Kamath, Vidyulata | Rebok, George W. | Rosenberg, Paul B.

Article Type: Research Article

Abstract: Background: Financial capacity (FC) is a complex ability commonly impaired in older individuals with cognitive impairment; however, the underlying neural mechanisms are not well understood. Objective: To assess resting state functional connectivity using functional magnetic resonance imaging (rs-fMRI) in individuals with mild cognitive impairment (MCI) and impaired FC compared to cognitively normal older adults. Methods: rs-fMRI scans were obtained from individuals with MCI (N  = 17) and normal older adults (N  = 15). All participants completed the Financial Capacity Instrument Short Form (FCI-SF) and neuropsychological assessments. Based on previous findings, the left angular gyrus (lAG) was used as …the seed region. Connectivity correlation coefficients were calculated for each seed-based connection that showed significantly altered connectivity. A Pearson’s correlation was calculated between the connectivity correlation values from relevant regions and FC and other cognitive measures. Results: A total of 26 brain regions showed significantly increased functional connectivity with the lAG. Of these regions, 14 were identified as relevant to higher-level cognitive function for analysis. Pearson’s correlations showed a significant negative correlation between the FCI-SF total score and increased connectivity between the IAG and the right temporal fusiform cortex (rTFC) (r  = –0.455, p  = 0.009). Conclusion: Results showed a significant correlation between FC and increased functional connectivity between the lAG and the rTFC in cognitively normal older adults compared to participants with MCI. These exploratory findings suggest that cognitive functions play important roles in FC as the functional connectivity between the lAG and rTFC was not associated with other tests of executive or visuospatial cognition. Show more

Keywords: Financial capacity, mild cognitive impairment, resting state functional connectivity

DOI: 10.3233/JAD-215148

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 763-771, 2022

Authors: Assogna, Martina | Motta, Caterina | Bonnì, Sonia | Borghi, Ilaria | Casula, Elias Paolo | Martorana, Alessandro | Koch, Giacomo

Article Type: Research Article

Abstract: Background: Long-term potentiation (LTP) like-cortical plasticity impairment and cholinergic neurotransmission deficits have been widely demonstrated in Alzheimer’s disease (AD) patients. Objective: In this study we aim to investigate the neurophysiological features underlying cognitive decline in AD patients according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) classification and APOE genotype. Methods: 65 newly diagnosed AD patients were enrolled. APOE genotype and lumbar puncture for the analysis of cerebrospinal fluid biomarkers were performed for diagnostic purposes. Patients were subdivided upon NIA-AA criteria, according to the presence of biomarkers of amyloid-β (Aβ) deposition (A) and fibrillar …tau (T), in four groups: A+/T–E4 (n  = 9), A+/T–E3 (n  = 18), A+/T+ E4 (n  = 21), and A+/T+ E3 (n  = 17). We applied intermittent theta burst stimulation protocol over the primary motor cortex to assess LTP-like cortical plasticity and short latency afferent inhibition (SAI) protocol to investigate central cholinergic activity. Patients were followed over 24 months. Cognitive decline was evaluated considering changes in Mini-Mental State Examination (MMSE) scores respect to the baseline. Results: A+/T–E4 patients showed preserved LTP-like cortical plasticity as compared to A+/T–E3 and to A+/T+ patients independently from genotype (p  < 0.001). In addition, A+/T–E4 patients showed a slower cognitive decline with respect to A+/T+ E4 (delta MMSE –0.5±2.12 versus –6.05±4.95; post-hoc p  = 0.004) and to A+/T+ E3 patients (–4.12±4.14; post-hoc p  = 0.028). No differences were found for SAI protocol (p  > 0.05). Conclusion: Our results suggest that APOE4 in patients with isolated Aβ pathology could exert positive effects on LTP-like cortical plasticity with a consequent slower cognitive decline. Show more

Keywords: Alzheimer’s disease, APOE4, dementia, isolated Aβ pathology, long-term potentiation, tau pathology, transcranial magnetic stimulation

DOI: 10.3233/JAD-215218

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 773-778, 2022

Authors: Dou, Yuchao | Liu, Shuai | Li, Yuqing | Wu, Hao | Chen, Hui | Ji, Yong

Article Type: Research Article

Abstract: Background: The relationship between cholesterol level and the risk of developing Alzheimer’s disease has been well established, but the relationship between cholesterol level and Lewy body dementia (LBD) is still not well known. Objective: The aim of this case-control study was to explore the association between blood cholesterol levels and LBD in Chinese older adults. Methods: A total of 65 patients with LBD and 110 older adult controls were enrolled during the study period. The levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and fasting glucose were measured …separately. The associations between LBD, blood cholesterol levels, and fasting glucose levels were assessed using multiple binary logistic regression analyses adjusted for multiple covariates. Results: Increased plasma LDL-C levels and lower HDL-C levels were independently associated with the risk of LBD in models adjusted for age, sex, education, alcohol use status, smoking status, and vascular disorders. Higher fasting glucose levels may be associated with the risk of LBD. Conclusion: The results of this study suggest that elevated levels of LDL-C and reduced levels of HDL-C were associated with LBD development and therefore are potential nutritional risk factors for LBD. Adjusting diet and individualized and effective cholesterol-lowering therapy in high-risk adults may aid in the prevention or management of LBD. Show more

Keywords: Cholesterol, fasting glucose, high-density lipoprotein cholesterol, Lewy body dementia, low-density lipoprotein cholesterol

DOI: 10.3233/JAD-215295

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 779-786, 2022

Authors: Shafir, Adi | Ritchie, Christine S. | Garrett, Sarah B. | Bernstein Sideman, Alissa | Naasan, Georges | Merrilees, Jennifer | Widera, Eric | Flint, Lynn | Harrison, Krista L.

Article Type: Research Article

Abstract: Background: After a diagnosis of Alzheimer’s disease and related disorders, people living with dementia (PWD) and caregivers wonder what disease trajectory to expect and how to plan for functional and cognitive decline. This qualitative study aimed to identify patient and caregiver experiences receiving anticipatory guidance about dementia from a specialty dementia clinic. Objective: To examine PWD and caregiver perspectives on receiving anticipatory guidance from a specialty dementia clinic. Methods: We conducted semi-structured interviews with PWD, and active and bereaved family caregivers, recruited from a specialty dementia clinic. Interviews were recorded, transcribed, and systematically summarized. Thematic analysis …identified anticipatory guidance received from clinical or non-clinical sources and areas where respondents wanted additional guidance. Results: Of 40 participants, 9 were PWD, 16 were active caregivers, and 15 were bereaved caregivers. PWD had a mean age of 75 and were primarily male (n  = 6/9); caregivers had a mean age of 67 and were primarily female (n  = 21/31). Participants felt they received incomplete or “hesitant” guidance on prognosis and expected disease course via their clinicians and filled the gap with information they found via the internet, books, and support groups. They appreciated guidance on behavioral, safety, and communication issues from clinicians, but found more timely and advance guidance from other non-clinical sources. Guidance on legal and financial planning was primarily identified through non-clinical sources. Conclusion: PWD and caregivers want more information about expected disease course, prognosis, and help planning after diagnosis. Clinicians have an opportunity to improve anticipatory guidance communication and subsequent care provision. Show more

Keywords: Caregiver, communication, dementia, patients, prognosis

DOI: 10.3233/JAD-215203

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 787-800, 2022

Authors: Gao, Ling | Dang, Liangjun | Wei, Shan | Hu, Ningwei | Gao, Fan | Peng, Wei | Shang, Suhang | Zhao, Yi | Chen, Chen | Guo, Xiaojuan | Huo, Kang | Wang, Jingyi | Wang, Jin | Qu, Qiumin

Article Type: Research Article

Abstract: Background: Soluble low-density lipoprotein receptor-related protein-1 (sLRP1) and soluble receptor of advanced glycation end products (sRAGE) play major roles in peripheral clearance of amyloid-β (Aβ). Objective: To determine the relationship between baseline sLRP1/sRAGE and early cognitive decline in a longitudinal study and explore the possible effect of apolipoprotein E (APOE ) on their association. Methods: Cognitively normal subjects were followed-up for 4 years. The baseline plasma levels of sLRP1 and sRAGE were measured using commercial ELISA kits. Global cognition was evaluated by Mini-Mental State Examination (MMSE), and cognitive decline was defined as a …≥2-point decrease of MMSE after 4 years. The association between baseline sLRP1/sRAGE and 4-year cognitive decline were analyzed using logistic regression analysis. Interaction analysis was performed to discover the potential effect of APOE genotype on the relationship. Results: 769 participants were included in the final analysis, with 122 subjects (15.86%) were cognitive decline. Baseline sLRP1/sRAGE levels were not associated with 4-year cognitive decline after multivariable adjustments in the total cohort. However, there was significant interaction effect between sRAGE and APOE genotype on cognitive decline (adjusted odds ratio [OR] = 2.09, 95% confidence interval [CI]: 1.13–3.86, p  = 0.019). Lower levels of sRAGE were associated with increased risk of cognitive decline among APOE ɛ4 non-carriers (adjusted OR = 1.60, 95% CI: 1.04–2.48, p  = 0.034). Conclusion: Individuals with lower levels of sRAGE had an increased risk of 4-year cognitive decline in APOE ɛ4 non-carriers, indicating that the association between sRAGE and cognitive decline might depend on the APOE genotype. However, the specific mechanisms need to be further elucidated. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, cognitive impairment, longitudinal study, plasma amyloid-β transporters

DOI: 10.3233/JAD-215228

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 801-812, 2022

Authors: Jansson, Deidre | Wang, Marie | Thomas, Ronald G. | Erickson, Michelle A. | Peskind, Elaine R. | Li, Ge | Iliff, Jeffrey

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multifactorial process that takes years to manifest clinically. We propose that brain-derived indicators of cerebrovascular dysfunction and inflammation would inform on AD-related pathological processes early in, and perhaps prior to neurodegenerative disease development. Objective: Define the relationship between cerebrospinal fluid (CSF) markers of cerebrovascular dysfunction and neuroinflammation with AD CSF biomarkers in cognitively normal individuals. Methods: Analytes were measured from CSF and plasma collected at baseline from two randomized control trials. We performed Pearson correlation analysis (adjusting for age, sex, APOE haplotype, and education) between markers of central nervous …system (CNS) barrier disruption, cerebrovascular dysfunction, CSF inflammatory cytokines and chemokines, and plasma lipid levels. We then developed a statistical prediction model using machine learning to test the ability of measured CSF analytes and blood lipid profiles to predict CSF AD biomarkers (total tau, phospho-tau (181), Aβ42 ) in this clinical population. Results: Our analysis revealed a significant association between markers of CNS barrier dysfunction and markers of cerebrovascular dysfunction, acute inflammatory responses, and CSF inflammatory cytokines. There was a significant association of blood lipid profiles with cerebrovascular injury markers, and CSF inflammatory cytokine levels. Using machine learning, we show that combinations of blood lipid profiles, CSF markers of CNS barrier disruption, cerebrovascular dysfunction and CSF inflammatory cytokines predict CSF total tau, p-tau, and, to a lesser extent, Aβ42 in cognitively normal subjects. Conclusion: This suggests that these parallel pathological processes may contribute to the development of AD-related neuropathology in the absence of clinical manifestations. Show more

Keywords: Biomarkers, blood-brain barrier, cerebrospinal fluid, HDL, LDL, ptau, tau

DOI: 10.3233/JAD-215400

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 813-826, 2022

Authors: Zarei, Shadi | Colman, Sarah | Rostas, Aviva | Burhan, Amer M. | Chu, Li | Davies, Simon JC | Derkach, Peter | Elmi, Sarah | Hussain, Maria | Gerretsen, Philip | Graff-Guerrero, Ariel | Ismail, Zahinoor | Kim, Donna | Krisman, Linda | Moghabghab, Rola | Mulsant, Benoit H. | Nair, Vasavan | Pollock, Bruce G. | Rej, Soham | Simmons, Jyll | Van Bussel, Lisa | Rajji, Tarek K. | Kumar, Sanjeev | on behalf of the StaN Study Group

Article Type: Research Article

Abstract: Background: Agitation and aggression are common in patients with Alzheimer’s disease and related dementias and pose a significant burden on patients, caregivers, and the healthcare systems. Guidelines recommend personalized behavioral interventions as the first-line treatment; however, these interventions are often underutilized. The Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov Identifier # NCT0367220) is a multisite randomized controlled trial comparing an Integrated Care Pathway, that includes a sequential pharmacological algorithm and structured behavioral interventions, with treatment-as-usual to treat agitation in dementia in long-term care and inpatient settings. Objective: To describe the rationale …and design of structured behavioral interventions in the StaN study. Methods: Structured behavioral interventions are designed and implemented based on the following considerations: 1) personalization, 2) evidence base, 3) dose and duration, 4) measurement-based care, and 5) environmental factors and feasibility. Results: The process to design behavioral interventions for each individual starts with a comprehensive assessment, followed by personalized, evidence-based interventions delivered in a standardized manner with ongoing monitoring of global clinical status. Measurement-based care is used to tailor the interventions and integrate them with pharmacotherapy. Conclusion: Individualized behavioral interventions in patients with dementia may be challenging to design and implement. Here we describe a process to design and implement individualized and structured behavioral interventions in the context of a multisite trial in long-term care and inpatient settings. This process can inform the design of behavioral interventions in future trials and in clinical settings for the treatment of agitation in dementia. Show more

Keywords: Agitation, behavioral interventions, dementia, randomized controlled trial

DOI: 10.3233/JAD-215261

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 827-840, 2022

Authors: Xu, Amy | Kouznetsova, Valentina L. | Tsigelny, Igor F.

Article Type: Research Article

Abstract: Background: The current standard for Alzheimer’s disease (AD) diagnosis is often imprecise, as with memory tests, and invasive or expensive, as with brain scans. However, the dysregulation patterns of miRNA in blood hold potential as useful biomarkers for the non-invasive diagnosis and even treatment of AD. Objective: The goal of this research is to elucidate new miRNA biomarkers and create a machine-learning (ML) model for the diagnosis of AD. Methods: We utilized pathways and target gene networks related to confirmed miRNA biomarkers in AD diagnosis and created multiple models to use for diagnostics based on the …significant differences among miRNA expression between blood profiles (serum and plasma). Results: The best performing serum-based ML model, trained on filtered disease-specific miRNA datasets, was able to identify miRNA biomarkers with 92.0% accuracy and the best performing plasma-based ML model, trained on filtered disease-specific miRNA datasets, was able to identify miRNA biomarkers with 90.9% accuracy. Through analysis of AD implicated miRNA, thousands of descriptors reliant on target gene and pathways were created which can then be used to identify novel biomarkers and strengthen disease diagnosis. Conclusion: Development of a ML model including miRNA and their genomic and pathway descriptors made it possible to achieve considerable accuracy for the prediction of AD. Show more

Keywords: Alzheimer’s disease, machine learning, miRNA

DOI: 10.3233/JAD-215502

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 841-859, 2022

Authors: Castillo-García, Isabel M. | López-Álvarez, Jorge | Osorio, Ricardo | Olazarán, Javier | Ramos García, Maria I. | Agüera-Ortiz, Luis

Article Type: Research Article

Abstract: Background: There is high prevalence of neuropsychiatric symptoms (NPS) among dementia patients. NPS are correlated with dementia progression, functional decline, early institutionalization, and death. There is scarce evidence on the progression of NPS in the latest stages of dementia. Objective: To describe the prevalence of NPS in mild-moderate to severe dementia and to reveal the progression of each NPS over time. Methods: We studied 317 patients (77.3% female, average age: 81.5 years) with a DSM-IV-TR diagnosis of dementia. This is a cross-sectional, and a prospective longitudinal study with 78-month follow-up. We assessed cognitive status (Mini-Mental State …Examination and Severe Mini-Mental State Examination), dementia severity (Global Deterioration Scale and Clinical Dementia Rating), and psychopathological measures (Neuropsychiatric Inventory, APADEM-Nursing Home, Apathy Inventory, Cornell Scale for Depression in Dementia, and Cohen-Mansfield Agitation Inventory). Results: Overall prevalence of NPS was 94.6%, being apathy the most prevalent (66.7%) and the one whose severity increased the most with progression of dementia. Agitation/aggression, irritability, and sleeping and eating disorders also increased over time. Delusions and depressive symptoms decreased in severity with disease progression. In severe dementia, female displayed more depressive symptoms and eating disorders, while male displayed more agitation/aggression and sleep disturbances. Conclusion: NPS in dementia follow a heterogeneous course. Apathy is the most prevalent NPS and the one that worsens most significantly over time. The course of some NPS differs between sexes. Further research is required to understand the evolution of NPS at advanced stages of dementia. Show more

Keywords: Advanced dementia, behavioral symptoms, moderate dementia, neurocognitive disorders

DOI: 10.3233/JAD-215133

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 861-875, 2022