Journal of Alzheimer's Disease - Volume 91, issue 1

Authors: Carlew, Anne R. | Kaser, Alyssa | Schaffert, Jeff | Goette, William | Lacritz, Laura | Rossetti, Heidi

Article Type: Systematic Review

Abstract: Background: The concept of mild cognitive impairment (MCI) has evolved since its original conception. So, too, have MCI diagnostic methods, all of which have varying degrees of success in identifying individuals at risk of conversion to dementia. The neuropsychological actuarial method is a straightforward diagnostic approach that has shown promise in large datasets in identifying individuals with MCI who are likely to have progressive courses. This method has been increasingly applied in various iterations and samples, raising questions of how best to apply this method and when caution should be used. Objective: Our objective was to review the …literature investigating use of the neuropsychological actuarial method to diagnose MCI to identify strengths and weaknesses of this approach, as well as highlight areas for further research. Methods: Databases PubMed and PsychInfo were systematically searched for studies that compared the neuropsychological actuarial method to some other diagnostic method. Results: We identified 13 articles and extracted relevant study characteristics and findings. Existing literature was reviewed and integrated, with focus on the neuropsychological actuarial method’s performance relative to existing diagnostic methods/criteria as well as associations with longitudinal outcomes and biomarkers. Tables with pertinent methodological information and general findings are also provided. Conclusion: The neuropsychological actuarial method to diagnose MCI has shown utility some in large-scale homogenous databases compared to research criteria. However, its standing relative to consensus diagnostic methods is unclear, and emerging evidence suggests the neuropsychological actuarial method may be more prone to diagnostic errors in more demographically diverse populations. Show more

Keywords: Alzheimer’s disease, clinical decision-making, cognition disorders, neuropsychology, review

DOI: 10.3233/JAD-220805

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 169-182, 2023

Authors: Johnson, Adrienne L. | Seep, Elaina | Norton, Derek L. | Mundt, Marlon P. | Wyman, Mary F. | James, Taryn T. | Zuelsdorff, Megan | Lambrou, Nickolas H. | McLester-Davis, Lauren W.Y. | Umucu, Emre | Gleason, Carey E.

Article Type: Short Communication

Abstract: Individuals with Alzheimer’s disease and related dementias (ADRD) accrue higher healthcare utilization costs than peers without ADRD, but incremental costs of ADRD among American Indians/Alaska Natives (AI/AN) is unknown. State-wide paid electronic health record data were retrospectively analyzed using percentile-based bootstrapped 95% confidence intervals of the weighted mean difference of total 5-year billed costs to compare total accrued for non-Tribal and Indian Health Service utilization costs among Medicaid and state program eligible AI/AN, ≥40 years, based on the presence/absence of ADRD (matching by demographic and medical factors). AI/AN individuals with ADRD accrued double the costs compared to those without ADRD, …costing an additional $880.45 million to $1.91 billion/year. Show more

Keywords: Alaska Native, Alzheimer’s disease, American Indian, cost, dementia, healthcare utilization, incremental cost, Medicaid, Native American

DOI: 10.3233/JAD-220393

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 183-189, 2023

Authors: Chen, Liang | Xue, Jun | Zhao, Qianhua | Liang, Xiaoniu | Zheng, Li | Fan, Zhen | Souare, Ibrahima Sory Jnr | Suo, Yuanzhen | Wei, Xunbin | Ding, Ding | Mao, Ying

Article Type: Research Article

Abstract: Background: Laboratory investigations have demonstrated that near-infrared (NIR) light treatment can reduce amyloid-β burden in models of Alzheimer’s disease (AD). However, previous clinical studies are rather insufficient. Objective: Before starting a large-scale clinical trial, we performed a pilot study to characterize the efficacy of NIR light for AD patients. Methods: Twenty participants with mild to moderate AD were assigned randomly to the intervention (1060-1080 nm and 800-820 nm NIR light treatment for 12 weeks) or control group (without sham treatment). Safety and efficacy were evaluated at baseline, week 4, 8, and 12, and 4 weeks after treatment. …Results: In the intervention and control groups at week 12, mean changes from baseline on the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog) were -3.1 and -1.3 (p  = 0.5689). Mean changes from baseline on the Activities of Daily Living (ADL) were -3.6 versus 3.1 (p  = 0.0437). Mean changes from baseline on the Mini-Mental State Examination (MMSE) were 4.4 versus 1.0 (p  = 0.0253). The percentage of participants who exhibited a change larger than 4 points from baseline to week 12 was determined for the intervention and control groups on the ADAS-Cog (57% versus 29%), ADL (29% versus 0%), and MMSE (57% versus 14%). Treatment with NIR light did not increase the incidence of adverse events in participants. Conclusion: NIR light treatment appears to be safe and potentially beneficial for AD patients. It improved cognitive function and activities of daily living. The preliminary data encouraged us to launch a large-sample, multicenter, double-blind clinical trial. Show more

Keywords: Alzheimer’s disease, clinical study, cognition, pilot project, physical therapy

DOI: 10.3233/JAD-220866

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 191-201, 2023

Authors: Cowley, Alison | Booth, Vicky | Di Lorito, Claudio | Chandria, Pooja | Chadwick, Olivia | Stanislas, Catherine | Dunlop, Marianne | Howe, Louise | Harwood, Rowan H. | Logan, Pip A.

Article Type: Research Article

Abstract: Background: The Promoting Activity, Independence and Stability in Early Dementia (PrAISED) intervention is a programme of physical activity and exercise designed to maintain participation in activities of daily living, mobility, and quality of life for people living with dementia. During the COVID-19 pandemic first national lockdown in England, the PrAISED physiotherapists, occupational therapists, and rehabilitation support workers adapted to delivering the intervention remotely via telephone or video conferencing. Objective: The aim of this study was to explore therapists’ experience of delivering the PrAISED intervention during the COVID-19 pandemic and derive implications for clinical practice. Methods: Qualitative …semi-structured interviews were conducted with 16 therapists using purposive sampling. Thematic analysis was used to analyze the transcripts. Results: Therapists reported a change in the relationship between themselves, the person with dementia and the caregiver, with an increased reliance on the caregiver and a loss of autonomy for the person living with dementia. There was concern that this would increase the burden on the caregiver. The therapists reported using creativity to adapt to different modes of delivery. They felt their sessions were mostly focused on providing social and emotional support, and that assessing, progressing, and tailoring the intervention was difficult. Conclusion: It is possible to deliver some elements of a physical intervention using remote delivery, but a dual modal approach including remote and face-to-face delivery would optimize treatment efficacy. Educational support would be required to enable people living with dementia and their caregivers to overcome barriers relating to digital literacy. Show more

Keywords: COVID-19, dementia, exercise, physical activity, rehabilitation, telerehabilitation

DOI: 10.3233/JAD-220424

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 203-214, 2023

Authors: Rajczyk, Jenna I. | Ferketich, Amy | Wing, Jeffrey J.

Article Type: Research Article

Abstract: Background: Smoking status may influence subjective cognitive decline (SCD); however, few studies have evaluated this association. Objective: To assess whether smoking status is associated with SCD among middle age and older adults, and to determine if this association is modified by sex at birth. Methods: A cross-sectional analysis was conducted using data from the 2019 Behavioral Risk Factor Surveillance System (BRFSS) survey to analyze the relationship between SCD and smoking status (current, recent former, and remote former). Eligible respondents included participants 45 years of age or older who responded to the SCD and tobacco questions of …interest. Survey-weighted Poisson regression models were employed to estimate the crude and adjusted prevalence ratios (cPR/aPR) and corresponding 95% confidence intervals (CI) of the association between smoking status and SCD. A Wald test was computed to determine the significance of the interaction term between smoking status and sex (α = 0.05). Results: There were 136,018 eligible respondents, of which approximately 10% had SCD. There was a graded association between smoking and SCD, with the greatest prevalence of SCD among current smokers (aPR = 1.87; CI: 1.54, 2.28), followed by recent former smokers (aPR = 1.47; 95% CI: 1.02, 2.12), and remote former smokers (aPR = 1.11; 95% CI: 0.93, 1.33) each compared to never smokers. There was no evidence of effect modification by sex (p interaction = 0.73). Conclusion: The consistency of smoking as a risk factor for objective and subjective cognitive decline supports the need for future studies to further the evidence on whether changes to smoking status impacts cognition in middle age. Show more

Keywords: Alzheimer’s disease, cigarette smoking, cognition, cognitive aging, dementia

DOI: 10.3233/JAD-220501

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 215-223, 2023

Authors: Soppela, Helmi | Krüger, Johanna | Hartikainen, Päivi | Koivisto, Anne | Haapasalo, Annakaisa | Borroni, Barbara | Remes, Anne M. | Katisko, Kasper | Solje, Eino

Article Type: Research Article

Abstract: Background: Currently, there are few studies considering possible modifiable risk factors of frontotemporal dementia (FTD). Objective: In this retrospective case-control study, we evaluated whether a history of traumatic brain injury (TBI) associates with a diagnosis of FTD or modulates the clinical phenotype or onset age in FTD patients. Methods: We compared the prevalence of prior TBI between individuals with FTD (N = 218) and age and sex-matched AD patients (N = 214) or healthy controls (HC; N = 100). Based on the patient records, an individual was categorized to the TBI+ group if they were reported to have suffered from TBI during …lifetime. The possible associations of TBI with age of onset and disease duration were also evaluated in the whole FTD patient group or separately in the sporadic and genetic FTD groups. Results: The prevalence of previous TBI was the highest in the FTD group (19.3%) when compared to the AD group (13.1%, p  = 0.050) or HC group (12%, p  = 0.108, not significant). Preceding TBI was more often associated with the sporadic FTD cases than the C9orf72 repeat expansion-carrying FTD cases (p  = 0.003). Furthermore, comparison of the TBI+ and TBI- FTD groups indicated that previous TBI was associated with an earlier onset age in the FTD patients (B = 3.066, p  = 0.010). Conclusion: A preceding TBI associates especially with sporadic FTD and with earlier onset of symptoms. The results of this study suggest that TBI may be a triggering factor for the neurodegenerative processes in FTD. However, understanding the precise underlying mechanisms still needs further studies. Show more

Keywords: Comorbidity, dementia, frontotemporal dementia, head trauma, risk factors, traumatic brain injury

DOI: 10.3233/JAD-220545

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 225-232, 2023

Authors: Katabathula, Sreevani | Davis, Pamela B. | Xu, Rong

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI), a prodromal phase of Alzheimer’s disease (AD), is heterogeneous with different rates and risks of progression to AD. There are significant gender disparities in the susceptibility, prognosis, and outcomes in patients with MCI, with female being disproportionately negatively impacted. Objective: The aim of this study was to identify sex-specific heterogeneity of MCI using multi-modality data and examine the differences in the respective MCI subtypes with different prognostic outcomes or different risks for MCI to AD conversion. Methods: A total of 325 MCI subjects (146 women, 179 men) and 30 relevant features …were considered. Mixed-data clustering was applied to women and men separately to discover gender-specific MCI subtypes. Gender differences were compared in the respective subtypes of MCI by examining their MCI to AD disease prognosis, descriptive statistics, and conversion rates. Results: We identified three MCI subtypes: poor-, good-, and best-prognosis for women and for men, separately. The subtype-wise comparison (for example, poor-prognosis subtype in women versus poor-prognosis subtype in men) showed significantly different means for brain volumetric, cognitive test-related, also for the proportion of comorbidities. Also, there were substantial gender differences in the proportions of participants who reverted to normal function, remained stable, or converted to AD. Conclusion: Analyzing sex-specific heterogeneity of MCI offers the opportunity to advance the understanding of the pathophysiology of both MCI and AD, allows stratification of risk in clinical trials of interventions, and suggests gender-based early intervention with targeted treatment for patients at risk of developing AD. Show more

Keywords: Alzheimer’s disease, comorbidity, gender differences, heterogeneity, mild cognitive impairment, subtypes

DOI: 10.3233/JAD-220600

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 233-243, 2023

Authors: Dover, Mary | Moseley, Taylor | Biskaduros, Adrienne | Paulchakrabarti, Mousumi | Hwang, Sung Hee | Hammock, Bruce | Choudhury, Biswa | Kaczor-Urbanowicz, Karolina Elżbieta | Urbanowicz, Andrzej | Morselli, Marco | Dang, Johnny | Pellegrini, Matteo | Paul, Ketema | Bentolila, Laurent A. | Fiala, Milan

Article Type: Research Article

Abstract: Background: Macrophages of healthy subjects have a pro-resolution phenotype, upload amyloid-β (Aβ) into endosomes, and degrade Aβ, whereas macrophages of patients with Alzheimer’s disease (AD) generally have a pro-inflammatory phenotype and lack energy for brain clearance of Aβ. Objective: To clarify the pathogenesis of sporadic AD and therapeutic effects of polyunsaturated fatty acids (PUFA) with vitamins B and D and antioxidants on monocyte/macrophage (MM) migration in the AD brain, MM transcripts in energy and Aβ degradation, MM glycome, and macrophage clearance of Aβ. Methods: We followed for 31.3 months (mean) ten PUFA-supplemented neurodegenerative patients: 3 with …subjective cognitive impairment (SCI), 2 with mild cognitive impairment (MCI), 3 MCI/vascular cognitive impairment, 2 with dementia with Lewy bodies, and 7 non-supplemented caregivers. We examined: monocyte migration in the brain and a blood-brain barrier model by immunochemistry and electron microscopy; macrophage transcriptome by RNAseq; macrophage glycome by N-glycan profiling and LTQ-Orbitrap mass spectrometry; and macrophage phenotype and phagocytosis by immunofluorescence. Results: MM invade Aβ plaques, upload but do not degrade Aβ, and release Aβ into vessels, which develop cerebrovascular amyloid angiopathy (CAA); PUFA upregulate energy and Aβ degradation enzyme transcripts in macrophages; PUFA enhance sialylated N-glycans in macrophages; PUFA reduce oxidative stress and increase pro-resolution MM phenotype, mitochondrial membrane potential, and Aβ phagocytosis (p  < 0.001). Conclusion: Macrophages of SCI, MCI, and AD patients have interrelated defects in the transcriptome, glycome, Aβ phagocytosis, and Aβ degradation. PUFA mend macrophage transcriptome, enrich glycome, enhance Aβ clearance, and benefit the cognition of early-stage AD patients. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebrovascular amyloid angiopathy, coenzyme Q2, glycome, macrophage, mitochondrial membrane potential, phagocytosis, polyunsaturated fatty acids, transcriptome

DOI: 10.3233/JAD-220764

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 245-261, 2023

Authors: Kong, Yu | Chen, Zhongyun | Shi, Qi | Zuo, Ya | Zhang, Jing

Article Type: Research Article

Abstract: Background: The 14-3-3 protein in cerebrospinal fluid (CSF) is a suitable biomarker for the diagnosis of Creutzfeldt-Jakob disease (CJD). However, it has also been detected in various non-prion-related rapidly progressive dementia (RPD), which affected its diagnostic performance and clinical utilization. Objective: To investigate the general disease distribution with positive 14-3-3 result and to evaluate the association between CSF 14-3-3 protein and the clinical features in patients with non-prion RPD. Methods: A total of 150 patients with non-prion RPD were enrolled. The clinical data were collected and CSF 14-3-3 test was performed for all patients. The distribution …of various diseases with a positive 14-3-3 result was analyzed and the association of CSF 14-3-3 with clinical features was tested. Results: The CSF 14-3-3 protein was detected in 23.3% of non-prion RPD patients, and the most frequent diagnoses were autoimmune encephalitis (22.9%) and neurodegenerative disease (22.9%). CSF 14-3-3 protein was more common in older patients (p  = 0.028) and those presenting myoclonus (p  = 0.008). In subgroup analysis, the positive 14-3-3 test was more common in neurodegenerative disease with a long time from the symptom onset to CSF 14-3-3 test (p  = 0.014). Conclusion: CSF 14-3-3 protein could be detected in a broad spectrum of non-prion RPD. In particular, patients with autoimmune encephalitis and rapidly progressive neurodegenerative diseases and those with myoclonus have a greater likelihood of a positive 14-3-3 result. These results could help clinicians interpret the results of CSF 14-3-3 protein more reasonably. Show more

Keywords: 14-3-3 protein, biomarker, cerebrospinal fluid, rapidly progressive dementia

DOI: 10.3233/JAD-220718

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 263-272, 2023

Authors: Wiseman, Alyssa L. | Briggs, Clark A. | Peritt, Ariel | Kapecki, Nicolas | Peterson, Daniel A. | Shim, Seong S. | Stutzmann, Grace E.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder with a progressive loss of cognitive function. Currently, no effective treatment regimen is available. Lithium, a mood stabilizer for bipolar disorder, exerts broad neuroprotective and neurotrophic actions and improves cognitive function. Objective: The study investigated if lithium stabilizes Ca2+ signaling abnormalities in hippocampal neurons and subsequently normalize downstream effects on AD neuropathology and synaptic plasticity in young AD mice. Methods: Four-month-old 3xTg-AD mice were treated with a LiCl diet chow for 30 days. At the end of the lithium treatment, a combination of two-photon Ca2+ …imaging, electrophysiology, and immunohistochemistry assays were used to assess the effects of the LiCl treatment on inositol trisphosphate receptor (IP3 R)-dependent endoplasmic reticulum (ER) Ca2+ and voltage-gated Ca2+ channel (VGCC)-mediated Ca2+ signaling in CA1 neurons, neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels and synaptic plasticity in the hippocampus and overlying cortex from 3xTg-ADmice. Results: Thirty-day LiCl treatment reduced aberrant IP3 R-dependent ER Ca2+ and VGCC-mediated Ca2+ signaling in CA1 pyramidal neurons from 3xTg-AD mice and restored neuronal nitric oxide synthase (nNOS) and hyperphosphorylated tau (p-tau) levels to control levels in the hippocampal subfields and overlying cortex. The LiCl treatment enhanced post-tetanic potentiation (PTP), a form of short-term plasticity in the hippocampus. Conclusion: The study found that lithium exerts therapeutic effects across several AD-associated early neuronal signaling abnormalities including aberrant Ca2+ signaling, nNOS, and p-tau formation and enhances short-term synaptic plasticity. Lithium could serve as an effective treatment or co-therapeutic for AD. Show more

Keywords: Alzheimer’s disease, Ca2+signaling, lithium, neuronal nitric oxide synthase, phosphorylated tau, synaptic plasticity

DOI: 10.3233/JAD-220758

Citation: Journal of Alzheimer's Disease, vol. 91, no. 1, pp. 273-290, 2023