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

Authors: Nallapu, Bhargav T. | Petersen, Kellen K. | Lipton, Richard B. | Davatzikos, Christos | Ezzati, Ali

Article Type: Research Article

Abstract: Background: Blood-based biomarkers (BBMs) are of growing interest in the field of Alzheimer’s disease (AD) and related dementias. Objective: This study aimed to assess the ability of plasma biomarkers to 1) predict disease progression from mild cognitive impairment (MCI) to dementia and 2) improve the predictive ability of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) measures when combined. Methods: We used data from the Alzheimer’s Disease Neuroimaging Initiative. Machine learning models were trained using the data from participants who remained cognitively stable (CN-s) and with Dementia diagnosis at 2-year follow-up visit. The models were used …to predict progression to dementia in MCI individuals. We assessed the performance of models with plasma biomarkers against those with CSF and MRI measures, and also in combination with them. Results: Our models with plasma biomarkers classified CN-s individuals from AD with an AUC of 0.75±0.03 and could predict conversion to dementia in MCI individuals with an AUC of 0.64±0.03 (17.1% BP, base prevalence). Models with plasma biomarkers performed better when combined with CSF and MRI measures (CN versus AD: AUC of 0.89±0.02; MCI-to-AD: AUC of 0.76±0.03, 21.5% BP). Conclusions: Our results highlight the potential of plasma biomarkers in predicting conversion to dementia in MCI individuals. While plasma biomarkers could improve the predictive ability of CSF and MRI measures when combined, they also show the potential to predict non-progression to AD when considered alone. The predictive ability of plasma biomarkers is crucially linked to reducing the costly and effortful collection of CSF and MRI measures. Show more

Keywords: Alzheimer’s disease, dementia, disease progression, feature engineering, plasma biomarkers, predictive models

DOI: 10.3233/JAD-230620

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 231-246, 2024

Authors: Sabbir, Mohammad Golam

Article Type: Research Article

Abstract: Background: Loss of Cholinergic Receptor Muscarinic 1 (CHRM1) has been linked to the pathogenesis of Alzheimer’s disease (AD). Our recent study found significantly lower CHRM1 protein levels in AD patient cortices, linked to reduced survival. Furthermore, using knockout mice (Chrm1−/− ) we demonstrated that deletion of Chrm1 alters cortical mitochondrial structure and function, directly establishing a connection between its loss and mitochondrial dysfunction in the context of AD. While CHRM1’s role in the brain has been extensively investigated, its impact on peripheral neurons in AD remains a crucial area of research, especially considering reported declines in peripheral nerve conduction among …AD patients. Objective: The objective was to characterize Chrm1 localization and mitochondrial deficits in Chrm1−/− dorsal root ganglion (DRG) neurons. Methods: Recombinant proteins tagged with Green or Red Fluorescent Protein (GFP/RFP) were transiently expressed to investigate the localization of Chrm1 and mitochondria, as well as mitochondrial movement in the neurites of cultured primary mouse DRG neurons, using confocal time-lapse live cell imaging. Transmission electron microscopy was performed to examine the ultrastructure of mitochondria in both wild-type and Chrm1−/− DRGs. Results: Fluorescence imaging revealed colocalization and comigration of N-terminal GFP-tagged Chrm1 and mitochondrial localization signal peptide-tagged RFP-labelled mitochondria in the DRGs neurons. A spectrum of mitochondrial structural abnormalities, including disruption and loss of cristae was observed in 87% neurons in Chrm1−/− DRGs. Conclusions: This study suggests that Chrm1 may be localized in the neuronal mitochondria and loss of Chrm1 in peripheral neurons causes sever mitochondrial structural aberrations resembling AD pathology. Show more

Keywords: Alzheimer’s disease, Cholinergic Receptor Muscarinic 1, cristae, dorsal root ganglion neuron, endoplasmic reticulum, mitochondria, sensory neuron, transmission electron microscopy

DOI: 10.3233/JAD-230883

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 247-264, 2024

Authors: Alva, Gus | Cubała, Wiesław J. | Berrio, Ana | Coate, Bruce | Abler, Victor | Pathak, Sanjeev

Article Type: Research Article

Abstract: Background: Pimavanserin, a 5-HT2A receptor inverse agonist/antagonist, is the only medication approved by the FDA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Further expanding knowledge of the safety profile of pimavanserin in PDP and neurodegenerative diseases (NDD) such as Alzheimer’s disease is of great interest for informing its use in patients with PDP (with or without dementia), given this population is highly sensitive to adverse effects following antipsychotic use. Objective: This trial evaluated the effects of pimavanserin compared to placebo in frail older adults and elderly patients with neuropsychiatric symptoms related …to NDD, such as hallucinations and delusions, to better understand the safety of pimavanserin in this population. Methods: This was a phase 3b, 8-week treatment (study duration of up to 16 weeks), multicenter, randomized, double-blind, placebo-controlled, two-arm parallel-group trial (NCT03575052). The primary endpoint was safety and tolerability, measured by treatment-emergent adverse events (TEAEs). Secondary safety endpoints were change from baseline in motor and cognitive function; exploratory endpoints included suicidality, sleep quality, and neuropsychiatric symptoms. Results: Incidences of TEAEs were similar between treatment groups; 29.8% reported ≥1 TEAE (pimavanserin: 30.4%; placebo: 29.3%), and 1.8% reported serious TEAEs (pimavanserin: 2.0%; placebo: 1.5%). Pimavanserin did not impact motor- or cognitive-related function. Conclusions: Pimavanserin was well tolerated and not associated with motor or cognitive impairment. Together, these findings highlight the manageable and generally favorable safety profile of pimavanserin in patients with NDD, contributing to our knowledge on the safety of pimavanserin as it generalizes to patients with PDP. Show more

Keywords: Alzheimer’s disease, elderly patients, neurodegenerative diseases, neuropsychiatric symptoms, pimavanserin, safety

DOI: 10.3233/JAD-231167

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 265-274, 2024

Authors: Matsuzono, Kosuke | Mashiko, Takafumi | Koide, Reiji | Yoshizumi, Hiroaki | Fujimoto, Shigeru

Article Type: Research Article

Abstract: Background: While many studies focus on the prognosis of individual neurological diseases, very few comprehensively compare and analyze real-world data of these diseases. Objective: To address this gap in knowledge, in this study, we comprehensively analyzed the real-life data of patients with neurological diseases. Methods: We prospectively enrolled patients with neurological diseases at three hospitals from December 1, 2016 to September 30, 2020. Neurological diseases were classified into nine groups: Dementia, Cerebrovascular disease, Parkinson’s and related, Functional, Spinocerebellar degeneration, Neuroimmune, Epilepsy, Muscle dystrophy disease, and Hypertension. Patients were followed up for three years, and their prognosis …and evaluation of their cognitive function served as the endpoint. Results: A total of 426 patients were finally enrolled. Both mortality and cognitive function differed among the neurological disease categories. After 3 years, mortality was highest in the Dementia (25.5%), Parkinson’s and related (21.6%), and Spinocerebellar degeneration (35.3%) groups while the cognitive function of patients in these three groups was significantly lowest. Conclusions: When the neurological diseases were holistically observed, both mortality and cognitive function of the Dementia, Parkinson’s and related, and Spinocerebellar degeneration groups were significantly worse than the remaining diseases. Show more

Keywords: Aging society, Alzheimer’s disease, dementia, geriatric medicine, relentless neurological disease, prognosis

DOI: 10.3233/JAD-231390

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 275-285, 2024

Authors: Torres-Atencio, Ivonne | Carreira, Maria B. | Méndez, Alondra | Quintero, Maryonelly | Broce, Adriana | Oviedo, Diana C. | Rangel, Giselle | Villarreal, Alcibiades E. | Tratner, Adam E. | Rodríguez-Araña, Sofía | Britton, Gabrielle B.

Article Type: Research Article

Abstract: Background: A growing body of evidence points to potential risks associated with polypharmacy (using ≥5 medications) in older adults, but most evidence is derived from studies where racial and ethnic minorities remain underrepresented among research participants. Objective: Investigate the association between polypharmacy and cognitive function, subjective health state, frailty, and falls in Hispanic older adults. Methods: Panama Aging Research Initiative–Health Disparities (PARI-HD) is a community-based cohort study of older adults free of dementia at baseline. Cognitive function was measured with a neuropsychological test battery. Frailty assessment was based on the Fried criteria. Subjective health state and …falls were self-reported. Linear and multinomial logistic regression analyses were used to examine association. Results: Baseline evaluations of 468 individuals with a mean age of 69.9 years (SD = 6.8) were included. The median number of medications was 2 (IQR: 1–4); the rate of polypharmacy was 19.7% (95% confidence interval [CI] = 16.1–23.3). Polypharmacy was inversely associated with self-rated overall health (b  =−5.89, p  < 0.01). Polypharmacy users had 2.3 times higher odds of reporting two or more falls in the previous 12 months (odds ratio [OR] = 2.31, 95% CI = 1.06–5.04). Polypharmacy was independently associated with Fried’s criteria for pre-frailty (OR = 2.90, 95% CI = 1.36–5.96) and frailty (OR = 5.14, 95% CI = 1.83–14.42). Polypharmacy was not associated with cognitive impairment. Conclusions: These findings illustrate the potential risks associated with polypharmacy among older adults in Panama and may inform interventions to improve health outcomes in this population. Show more

Keywords: Aging, Alzheimer’s disease, Central America, cognitive impairment, dementia, falls, frailty, Latin America, polypharmacy

DOI: 10.3233/JAD-231001

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 287-300, 2024

Authors: Culibrk, Robert A. | Ebbert, Katherine A. | Yeisley, Daniel J. | Chen, Rui | Qureshi, Fatir A. | Hahn, Juergen | Hahn, Mariah S.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by disrupted proteostasis and macroautophagy (hereafter “autophagy”). The pharmacological agent suramin has known autophagy modulation properties with potential efficacy in mitigating AD neuronal pathology. Objective: In the present work, we investigate the impact of forebrain neuron exposure to suramin on the Akt/mTOR signaling pathway, a major regulator of autophagy, in comparison with rapamycin and chloroquine. We further investigate the effect of suramin on several AD-related biomarkers in sporadic AD (sAD)-derived forebrain neurons. Methods: Neurons differentiated from ReNcell neural progenitors were used to assess the impact of suramin on the Akt/mTOR …signaling pathway relative to the autophagy inducer rapamycin and autophagy inhibitor chloroquine. Mature forebrain neurons were differentiated from induced pluripotent stem cells (iPSCs) sourced from a late-onset sAD patient and treated with 100μM suramin for 72 h, followed by assessments for amyloid-β, phosphorylated tau, oxidative/nitrosative stress, and synaptic puncta density. Results: Suramin treatment of sAD-derived neurons partially ameliorated the increased p-Tau(S199)/Tau ratio, and fully remediated the increased glutathione to oxidized nitric oxide ratio, observed in untreated sAD-derived neurons relative to healthy controls. These positive results may be due in part to the distinct increases in Akt/mTOR pathway mediator p-p70S6K noted with suramin treatment of both ReNcell-derived and iPSC-derived neurons. Longer term neuronal markers, such as synaptic puncta density, were unaffected by suramin treatment. Conclusions: These findings provide initial evidence supporting the potential of suramin to reduce the degree of dysregulation in sAD-derived forebrain neurons in part via the modulation of autophagy. Show more

Keywords: Alzheimer’s disease, autophagy, induced pluripotent stem cells, neurons, suramin

DOI: 10.3233/JAD-230600

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 301-318, 2024

Authors: Nester, Caroline O. | Gao, Qi | Katz, Mindy J. | Mogle, Jacqueline A. | Wang, Cuiling | Derby, Carol A. | Lipton, Richard B. | Saykin, Andrew J. | Rabin, Laura A.

Article Type: Research Article

Abstract: Background: The Cognitive Change Index (CCI) is a widely-used measure of self-perceived cognitive ability and change. Unfortunately, it is unclear if the CCI predicts future cognitive and clinical decline. Objective: We evaluated baseline CCI to predict transition from normal cognition to cognitive impairment in nondemented older adults and in predementia groups including, subjective cognitive decline, motoric cognitive risk syndrome, and mild cognitive impairment. Different versions of the CCI were assessed to uncover any differential risk sensitivity. We also examined the effect of ethnicity/race on CCI. Methods: Einstein Aging Study participants (N  = 322, Mage  = 77.57±4.96, % female=67.1, …Meducation  = 15.06±3.54, % non-Hispanic white = 46.3) completed an expanded 40-item CCI version (CCI-40) and neuropsychological evaluation (including Clinical Dementia Rating Scale [CDR], Montreal Cognitive Assessment, and Craft Story) at baseline and annual follow-up (Mfollow - up =3.4 years). CCI-40 includes the original 20 items (CCI-20) and the first 12 memory items (CCI-12). Linear mixed effects models (LME) and generalized LME assessed the association of CCI total scores at baseline with rate of decline in neuropsychological tests and CDR. Results: In the overall sample and across predementia groups, the CCI was associated with rate of change in log odds on CDR, with higher CCI at baseline predicting faster increase in the odds of being impaired on CDR. The predictive validity of the CCI broadly held across versions (CCI-12, 20, 40) and ethnic/racial groups (non-Hispanic black and white). Conclusions: Self-perception of cognitive change on the CCI is a useful marker of dementia risk in demographically/clinically diverse nondemented samples. All CCI versions successfully predicted decline. Show more

Keywords: Alzheimer’s disease, cognitive change index, ethnic/racial minoritized groups, mild cognitive impairment, motoric cognitive risk syndrome, non-Hispanic Black older adults, normal aging, subjective cognitive decline

DOI: 10.3233/JAD-230752

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 319-332, 2024

Authors: Cogram, Patricia | Garduño, B. Maximiliano | Ren, Bing | Xu, Xiangmin

Article Type: Meeting Report

Abstract: The first International Conference on Unconventional Animal Models of Alzheimer’s Disease and Aging (UAMAA) took place on December 13–16, 2023, in Santiago, Chile. The Alzheimer’s disease (AD) research field is currently in search for new and unconventional models that could hold greater translational potential than transgenic mouse models. Thus this UAMAA conference is timely and significant. The event consisted of 6 sessions with talks from 28 world-class scientists from all over the world. These animal models of interest include the degu (Octodon degu ), the dog (Canis familiaris ), and certain species of nonhuman primates that may better recapitulate neuropathology …and cognitive impairments in human AD. Our conference has provided a formal forum to discuss and highlight new research directions, alternative animal models, and innovative approaches for the AD and aging research field. Show more

Keywords: Aging, Alzheimer’s disease, animal model, Chile, conference, degu, dog, marmoset, meeting report

DOI: 10.3233/JAD-249004

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 333-336, 2024

Authors: Perry, George

Article Type: Book Review

DOI: 10.3233/JAD-249002

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 337-337, 2024

Article Type: Retraction

DOI: 10.3233/JAD-239015

Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 339-339, 2024