Journal of Alzheimer's Disease - Volume 81, issue 3

Authors: Bernstein, John P.K. | Dorociak, Katherine E. | Mattek, Nora | Leese, Mira | Beattie, Zachary T. | Kaye, Jeffrey A. | Hughes, Adriana

Article Type: Research Article

Abstract: Background: Computer use is a cognitively complex instrumental activity of daily living (IADL) that has been linked to cognitive functioning in older adulthood, yet little work has explored its capacity to detect incident mild cognitive impairment (MCI). Objective: To examine whether routine home computer use (general computer use as well as use of specific applications) could effectively discriminate between older adults with and without MCI, as well as explore associations between use of common computer applications and cognitive domains known to be important for IADL performance. Methods: A total of 60 community-dwelling older adults (39 cognitively …healthy, 21 with MCI) completed a neuropsychological evaluation at study baseline and subsequently had their routine home computer use behaviors passively recorded for three months. Results: Compared to those with MCI, cognitively healthy participants spent more time using the computer, had a greater number of computer sessions, and had an earlier mean time of first daily computer session. They also spent more time using email and word processing applications, and used email, search, and word processing applications on a greater number of days. Better performance in several cognitive domains, but in particular memory and language, was associated with greater frequency of browser, word processing, search, and game application use. Conclusion: Computer and application use are useful in identifying older adults with MCI. Longitudinal studies are needed to determine whether decreases in overall computer use and specific computer application use are predictors of incident cognitive decline. Show more

Keywords: Aging, computer use, mild cognitive impairment, technology

DOI: 10.3233/JAD-210049

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1053-1064, 2021

Authors: Mizuno, Akiko | Karim, Helmet T. | Ly, Maria J. | Cohen, Ann D. | Lopresti, Brian J. | Mathis, Chester A. | Klunk, William E. | Aizenstein, Howard J. | Snitz, Beth E.

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) may be an early manifestation of pre-clinical Alzheimer’s disease. Elevated amyloid-β (Aβ) is a correlate of SCD symptoms in some individuals. The underlying neural correlates of SCD symptoms and their association with Aβ is unknown. SCD is a heterogeneous condition, and cognitive reserve may explain individual differences in its neural correlates. Objective: We investigated the association between brain activation during memory encoding and SCD symptoms, as well as with Aβ, among older individuals. We also tested the moderating role of education (an index of cognitive reserve) on the associations. Methods: We …measured brain activation during the “face-name” memory-encoding fMRI task and Aβ deposition with Pittsburgh Compound-B (PiB)-PET among cognitively normal older individuals (n = 63, mean age 73.1 ± 7.4 years). We tested associations between activation and SCD symptoms by self-report measures, Aβ, and interactions with education. Results: Activation was not directly associated with SCD symptoms or Aβ. However, education moderated the association between activation and SCD symptoms in the executive control network, salience network, and subcortical regions. Greater SCD symptoms were associated with greater activation in those with higher education, but with lower activation in those with lower education. Conclusion: SCD symptoms were associated with different patterns of brain activation in the extended memory system depending on level of cognitive reserve. Greater SCD symptoms may represent a saturation of neural compensation in individuals with greater cognitive reserve, while it may reflect diminishing neural resources in individuals with lower cognitive reserve. Show more

Keywords: Amyloid, cognitive reserve, functional MRI, PiB-PET, preclinical dementia, subjective cognitive decline

DOI: 10.3233/JAD-201087

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1065-1078, 2021

Authors: Michaelian, Johannes C. | Duffy, Shantel L. | Mowszowski, Loren | Guastella, Adam J. | McCade, Donna | McKinnon, Andrew C. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Older adults living with amnestic mild cognitive impairment (aMCI) not only demonstrate impairments in Theory of Mind (ToM), relative to adults with non-amnestic MCI (naMCI), but are also at a higher risk of developing dementia. Objective: Our primary objective was to ascertain whether default mode network (DMN) functional connectivity was differentially associated with ToM abilities between MCI subgroups. Methods: Using functional magnetic resonance imaging, we investigated alterations in resting-state functional connectivity within the brain’s DMN in a sample of 43 older adults with aMCI (n  = 19) and naMCI (n  = 24), previously reported to demonstrate poorer …ToM abilities. Results: Compared to naMCI, the aMCI subgroup revealed a significant association between poorer ToM performance and reduced functional connectivity between the bilateral temporal pole (TempP) and the left lateral temporal cortex (LTC) (LTC_L-TempP_L : b  = –0.06, t(33) = –3.53, p  = 0.02; LTC_L-TempP_R : b  = –0.07,t(33) = –3.20, p  = 0.03); between the right TempP and the dorsal medial prefrontal cortex (dMPFC) (b  = –0.04, t(33) = –3.02, p  = 0.03) and between the left and right TempP (b  = –0.05, t(33) = –3.26, p  = 0.03). In the naMCI subgroup, the opposite relationship was present between the bilateral TempP and the left LTC (Combined correlation: r  = –0.47, p  = 0.02), however, not between the right TempP and the dMPFC (r  = –0.14, p  = 0.51) or the left and right TempP (r  = –0.31, p  = 0.14). Conclusion: Our findings suggest that alterations in functional connectivity within the DMN involving temporal and frontal lobe regions are associated with ToM deficits in aMCI. Show more

Keywords: Amnestic mild cognitive impairment, default mode network, functional connectivity, functional magnetic resonance imaging, theory of mind

DOI: 10.3233/JAD-201284

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1079-1091, 2021

Authors: Sakurai, Keita | Kaneda, Daita | Inui, Shohei | Uchida, Yuto | Morimoto, Satoru | Nihashi, Takashi | Kato, Takashi | Ito, Kengo | Hashizume, Yoshio

Article Type: Research Article

Abstract: Background: The differentiation of Alzheimer’s disease (AD) from age-related limbic tauopathies (LT), including argyrophilic grain disease (AGD) and senile dementia of the neurofibrillary tangle type (SD-NFT), is often challenging because specific clinical diagnostic criteria have not yet been established. Despite the utility of specific biomarkers evaluating amyloid and tau to detect the AD-related pathophysiological changes, the expense and associated invasiveness preclude their use as first-line diagnostic tools for all demented patients. Therefore, less invasive and costly biomarkers would be valuable in routine clinical practice for the differentiation of AD and LT. Objective: The purpose of this study is …to develop a simple reproducible method on magnetic resonance imaging (MRI) that could be adopted in daily clinical practice for the differentiation of AD and other forms of LT. Methods: Our newly proposed three quantitative indices and well-known medial temporal atrophy (MTA) score were evaluated using MRI of pathologically-proven advanced-stage 21 AD, 10 AGD, and 2 SD-NFT patients. Results: Contrary to MTA score, hippocampal angle (HPA), inferior horn area (IHA), and ratio between HPA and IHA (i.e., IHPA index) demonstrated higher diagnostic performance and reproducibility, especially to differentiate advanced-stage AD patients with Braak neurofibrillary tangle stage V/VI from LT patients (the area under the receiver-operating-characteristic curve of 0.83, 089, and 0.91; intraclass correlation coefficients of 0.930, 0.998, and 0.995, respectively). Conclusion: Quantitative indices reflecting hippocampal deformation with ventricular enlargement are useful to differentiate advanced-stage AD from LT. This simple and convenient method could be useful in daily clinical practice. Show more

Keywords: Alzheimer’s disease, argyrophilic grain disease, hippocampal angle, limbic tauopathy, magnetic resonance imaging, senile dementia of the neurofibrillary tangle type, ventricular enlargement

DOI: 10.3233/JAD-210043

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1093-1102, 2021

Authors: Halminen, Olli | Vesikansa, Aino | Mehtälä, Juha | Hörhammer, Iiris | Mikkola, Teija | Virta, Lauri J. | Ylisaukko-oja, Tero | Linna, Miika

Article Type: Research Article

Abstract: Background: Dementia is one of the strongest predictors of admission to a 24-hour care facility among older people, and 24-hour care is the major cost of Alzheimer’s disease (AD). Objective: The aim of this study was to evaluate the association of early start of anti-dementia medication and other predisposing factors with 2-year risk of transition to 24-hour care in the nationwide cohort of Finnish AD patients. Methods: This was a retrospective, non-interventional study based on individual-level data from Finnish national health and social care registers. The incident cohort included 7,454 AD patients (ICD-10, G30) comprised of …two subgroups: those living unassisted at home (n  = 5,002), and those receiving professional home care (n  = 2,452). The primary outcome was admission to a 24-hour care facility. Exploratory variables were early versus late anti-dementia medication start, sociodemographic variables, care intensity level, and comorbidities. Results: Early anti-dementia medication reduced the risk of admission to 24-hour care both in patients living unassisted at home, with a hazard ratio (HR) of 0.58 (p  < 0.001), and those receiving professional home care (HR, 0.84; p  = 0.039). Being unmarried (HR, 1.69; p  < 0.001), having an informal caregiver (HR, 1.69; p  = 0.003), or having a diagnosis of additional neurological disorder (HR, 1.68; p  = 0.006) or hip fracture (HR, 1.61; p  = 0.004) were associated with higher risk of admission to 24-hour care in patients living unassisted at home. Conclusion: To support living at home, early start of anti-dementia medication should be a high priority in newly diagnosed AD patients. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, dementia, Finland, healthcare, institutionalization, memantine, nursing homes, register

DOI: 10.3233/JAD-201502

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1103-1115, 2021

Authors: Nerg, Ossi | Junkkari, Antti | Hallikainen, Ilona | Rauramaa, Tuomas | Luikku, Antti | Hiltunen, Mikko | Jääskeläinen, Juha E. | Leinonen, Ville | Hänninen, Tuomo | Koivisto, Anne

Article Type: Research Article

Abstract: Background: The usefulness of CERAD Neuropsychological Battery for describing the cognitive impairment in idiopathic normal pressure hydrocephalus (iNPH) is unknown. Objective: To compare the cognitive profile of patients with iNPH to patients with mild Alzheimer’s disease (AD) and age-matched cognitively healthy individuals by using the CERAD-NB. Methods: We studied CERAD-NB subtest results, including the Mini-Mental State Examination (MMSE), between 199 patients with probable iNPH, 236 patients with mild AD, and 309 people with normal cognition, using age, education, and gender adjusted multivariate linear regression model. In addition, the effects of AD-related brain pathology detected in frontal …cortical brain biopsies in iNPH patients’ cognitive profiles were examined. Results: The iNPH patients performed worse than cognitively healthy people in all CERAD-NB subtests. Despite similar performances in the MMSE, AD patients outperformed iNPH patients in Verbal Fluency (p  = 0.016) and Clock Drawing (p  < 0.001) tests. However, iNPH patients outperformed AD patients in the Boston Naming Test and Word List Recall and Recognition (p  < 0.001). AD-related pathology in brain biopsies did not correlate with the CERAD-NB results. Conclusion: At the time of the iNPH diagnosis, cognitive performances differed from cognitively healthy people in all CERAD-NB subtests. When the iNPH and AD patients’ results were compared, the iNPH patients performed worse in Verbal Fluency and Clock Drawing tests while the AD group had more pronounced episodic memory dysfunctions. This study demonstrates significant differences in the CERAD-NB subtests between cognitive profiles of iNPH and AD patients. These differences are not captured by the MMSE alone. Show more

Keywords: Alzheimer’s disease, CERAD-NB, Mini-Mental Status Examination, neuropsychological test, normal pressure hydrocephalus

DOI: 10.3233/JAD-201363

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1117-1130, 2021

Authors: Gottesman, Reena T. | Kociolek, Anton | Fernandez, Kayri | Cosentino, Stephanie | Devanand, D.P. | Stern, Yaakov | Gu, Yian

Article Type: Research Article

Abstract: Background: Psychotic symptoms are an important and increasingly recognized aspect of Alzheimer’s disease (AD). They have been shown to contribute to faster disease progression in clinic-based, demographically homogenous samples with high educational attainment. Objective: We studied the association between baseline psychotic symptoms and disease progression among individuals with incident AD or ‘at risk’ of developing AD, from a demographically heterogenous, community-based cohort with minimal educational attainment. Methods: 212 participants received the Columbia University Scale of Psychopathology in Alzheimer’s Disease scale. Participants had psychotic symptoms with any of: visual illusions, delusions, hallucinations, or agitation/aggression. Disease progression was …measured yearly and defined by meeting cognitive (≤10 on the Folstein MMSE) or functional endpoints (≥10 on the Blessed Dementia Rating Scale or ≥4 on the Dependence Scale). Results: The mean age was 85 years old. The cohort was 78.3% female, 75.9% Hispanic, and had a mean 6.96 years of education. Within the follow-up period (mean: 3.69 years), 24 met the cognitive endpoint, 59 met the functional endpoint, and 132 met the cutoff for dependence. The presence of at least one psychotic symptom was initially associated with an increased risk of reaching the functional endpoint (HR 3.12, 95% CI 1.67–5.86, p  < 0.001) and the endpoint of dependence (HR = 1.498, 95% CI 1.05–2.13, p  = 0.03). However, these associations were attenuated and non-significant when adjusted for baseline functional status. Psychotic symptoms were not associated with the cognitive endpoint. Conclusion: Psychotic symptoms may predict functional decline in patients of non-Caucasian ethnicity and with lower educational attainment. Show more

Keywords: Alzheimer’s disease, ethnic groups, neurobehavioral manifestations, prognosis

DOI: 10.3233/JAD-200729

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1131-1139, 2021

Authors: Xu, Lujie | Li, Tao | Xiong, Lingchuan | Wang, Xiao | Ismail, Zahinoor | Fukuda, Masami | Sun, Zhiyu | Wang, Jing | Gauthier, Serge | Yu, Xin | Wang, Huali

Article Type: Research Article

Abstract: Background: Mild behavioral impairment (MBI) has been proposed as an early manifestation of dementia. The Mild Behavioral Impairment Checklist (MBI-C) may help identify MBI in prodromal and preclinical dementia. Objective: The study aimed to evaluate the reliability and validity of the Chinese version of MBI-C in mild cognitive impairment (MCI) and mild Alzheimer’s disease (AD), and to explore the structure of the five factors of the MBI-C in Chinese culture. Methods: Sixty dyads of MCI and mild AD (MCI, n  = 33; mild AD, n  = 35) were recruited. The informants completed the MBI-C and Neuropsychiatric Inventory Questionnaire …(NPI-Q) and were interviewed for clinician rating of the NPI. The Cronbach’s coefficient was used to measure the structural reliability of the MBI-C. The criterion-validity was evaluated with the correlation coefficient between the MBI-C and the total scores of NPI-Q and NPI. Exploratory factor analysis was conducted to investigate the structure of the MBI-C. Results: The Cronbach’s α coefficient was 0.895. The MBI-C total score was positively correlated with all five domains (r  = 0.577∼0.840). The total score of MBI-C was significantly correlated with the total scores of NPI-Q (r  = 0.714) and NPI (r  = 0.749). Similarly, the five domain scores of MBI-C were significantly correlated with the factor and total scores of NPI-Q (r  = 0.312∼0.673) and NPI (r  = 0.389∼0.673). The components of each factor in Chinese version of MBI-C were slightly different from those of the a priori defined domains (χ 2  = 1818.202, df = 496, p  < 0.001). Conclusion: The Chinese version of MBI-C has good reliability and validity, and can be used to evaluate the psychological and behavioral changes in MCI and mild AD. Show more

Keywords: Mild behavioral impairment, Mild Behavioral Impairment Checklist (MBI-C), mild cognitive impairment, reliability, validity

DOI: 10.3233/JAD-210098

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1141-1149, 2021

Authors: Beuckmann, Carsten T. | Suzuki, Hiroyuki | Musiek, Erik S. | Ueno, Takashi | Sato, Toshitaka | Bando, Masahiro | Osada, Yoshihide | Moline, Margaret

Article Type: Research Article

Abstract: Background: Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia. Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running …wheel activity were evaluated. Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances. Show more

Keywords: Alzheimer’s disease, animal models, dual orexin receptor antagonist, E2006, in vivo , irregular sleep-wake rhythm disorder, lemborexant, mouse, orexin, running wheel, sleep

DOI: 10.3233/JAD-201054

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1151-1167, 2021

Authors: Feldman, Robin

Article Type: Research Article

Abstract: Background: US direct-to-consumer advertising spending for medicine has soared in recent decades. Advertising has been shown to impact drug utilization. Most Alzheimer’s disease patients are above age 65 and may take a range of prescription medications for various disease states. Objective: To investigate how direct-to-consumer advertising is associated with the drug utilization of patients ≥65 years old. Methods: Using advertising expenditure data and Medicare Part D drug purchase claims, we performed regression analyses for each of the highest-spending drugs and age group, with cumulative monthly spending as the predictor variable and drug utilization as the response …variable. For each drug, we ran a second set of regression analyses to determine if the spending-utilization correlation showed a significant difference between the two patient age groups (older than 65, younger than 65). Results: For all 14 drugs in our study, advertising spending is positively correlated with utilization (p  < 0.01) in both age groups. For seven of the 14 drugs studied, the difference in the utilization of patients older than 65 and the utilization of patients younger than 65 is statistically significant at a p  < 0.01 level. The 65-and-older age bracket exhibits significantly greater utilization for all seven of these drugs. Conclusion: We find televised advertising for certain drugs to be associated with significantly stronger drug utilization among seniors, as compared to younger patients. Alzheimer’s disease physicians should be aware of this result, in light of the medications that patients may take for other disease states, particularly mood and mental health medications. Show more

Keywords: Aged, direct-to-consumer advertising, drug utilization, health services for the aged, prescription drugs, public health, television

DOI: 10.3233/JAD-210294

Citation: Journal of Alzheimer's Disease, vol. 81, no. 3, pp. 1169-1179, 2021