Journal of Alzheimer's Disease - Volume 82, issue 3

Authors: Serra, Laura | D’Amelio, Marcello | Esposito, Sharon | Di Domenico, Carlotta | Koch, Giacomo | Marra, Camillo | Mercuri, Nicola Biagio | Caltagirone, Carlo | Artusi, Carlo Alberto | Lopiano, Leonardo | Cercignani, Mara | Bozzali, Marco

Article Type: Research Article

Abstract: Background: Recent cross-sectional studies highlighted the loss of dopaminergic neurons in the ventral tegmental area (VTA) as an early pathophysiological event in Alzheimer’s disease (AD). Objective: In this study, we longitudinally investigated by resting-state fMRI (rs-fMRI) a cohort of patients with mild cognitive impairment (MCI) due to AD to evaluate the impact of VTA disconnection in predicting the conversion to AD. Methods: A cohort of 35 patients with MCI due to AD were recruited and followed-up for 24 months. They underwent cognitive evaluation and rs-fMRI to assess VTA connectivity at baseline and at follow-up. …Results: At 24-month follow-up, 16 out of 35 patients converted to AD. Although converters and non-converters to AD did not differ in demographic and behavioral characteristics at baseline, the first group showed a significant reduction of VTA-driven connectivity in the posterior cingulate and precentral cortex. This pattern of additional disconnection in MCI-Converters compared to non-converters remained substantially unchanged at 24-month follow-up. Conclusion: This study reinforces the hypothesis of an early contribution of dopaminergic dysfunction to AD evolution by targeting the default-mode network. These results have potential implications for AD staging and prognosis and support new opportunities for therapeutic interventions to slow down disease progression. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, dopaminergic system, functional connectivity, restingstate MRI, ventral tegmental area

DOI: 10.3233/JAD-210171

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 985-1000, 2021

Authors: Tsoy, Elena | Sideman, Alissa Bernstein | Piña Escudero, Stefanie D. | Pintado-Caipa, Maritza | Kanjanapong, Suchanan | Al-Rousan, Tala | Mbakile-Mahlanza, Lingani | de Oliveira, Maira Okada | De la Cruz Puebla, Myriam | Zygouris, Stelios | Mohamed, Aya Ashour | Ibrahim, Hany | Goode, Collette A. | Miller, Bruce L. | Valcour, Victor | Possin, Katherine L.

Article Type: Research Article

Abstract: Background: Timely diagnosis of dementia is a global healthcare priority, particularly in low to middle income countries where rapid increases in older adult populations are expected. Objective: To investigate global perspectives on the role of brief cognitive assessments (BCAs) in dementia diagnosis, strengths and limitations of existing measures, and future directions and needs. Methods: This is a qualitative study of 18 dementia experts from different areas of the world. Participants were selected using purposeful sampling based on the following criteria: 1) practicing in countries with projected growth of older adult population of over 100%by 2050; 2) …expertise in dementia diagnosis and treatment; 3) involvement in clinical practice and training; and 4) recognition as a national dementia expert based on leadership positions within healthcare system, research, and/or policy work. Participants were individually interviewed in their language of choice over secure videoconference sessions. Interviews were analyzed by a multidisciplinary team using theme identification approach. Results: Four domains with subthemes emerged illustrating participants’ perspectives: 1) strengths of BCAs; 2) limitations of BCAs; 3) needs related to the use of BCAs; and 4) characteristics of an ideal BCA. While most experts agreed that BCAs were important and useful for dementia diagnosis, the themes emphasized the need for development and validation of novel measures that are sensitive, psychometrically sound, and culturally appropriate. Conclusion: BCAs are important for guiding diagnosis and care for dementia patients. Findings provide a roadmap for novel BCA development to assist in diagnostic decision making for clinicians serving a rapidly growing and diverse dementia population. Show more

Keywords: Alzheimer’s disease, cultural diversity, dementia, mental status and dementia tests, mild cognitive impairment

DOI: 10.3233/JAD-201403

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1001-1013, 2021

Authors: Won, Junyeon | Callow, Daniel D. | Pena, Gabriel S. | Jordan, Leslie S. | Arnold-Nedimala, Naomi A. | Nielson, Kristy A. | Smith, J. Carson

Article Type: Research Article

Abstract: Background: Exercise training (ET) has neuroprotective effects in the hippocampus, a key brain region for memory that is vulnerable to age-related dysfunction. Objective: We investigated the effects of ET on functional connectivity (FC) of the hippocampus in older adults with mild cognitive impairment (MCI) and a cognitively normal (CN) control group. We also assessed whether the ET-induced changes in hippocampal FC (Δhippocampal-FC) are associated with changes in memory task performance (Δmemory performance). Methods: 32 older adults (77.0±7.6 years; 16 MCI and 16 CN) participated in the present study. Cardiorespiratory fitness tests, memory tasks (Rey Auditory Verbal …Learning Test (RAVLT) and Logical Memory Test (LM)), and resting-state fMRI were administered before and after a 12-week walking ET intervention. We utilized a seed-based correlation analysis using the bilateral anterior and posterior hippocampi as priori seed regions of interest. The associations of residualized ET-induced Δhippocampal-FC and Δmemory performance were assessed using linear regression. Results: There were significant improvements in RAVLT Trial 1 and LM test performance after ET across participants. At baseline, MCI, compared to CN, demonstrated significantly lower posterior hippocampal FC. ET was associated with increased hippocampal FC across groups. Greater ET-related anterior and posterior hippocampal FC with right posterior cingulate were associated with improved LM recognition performance in MCI participants. Conclusion: Our findings indicate that hippocampal FC is significantly increased following 12-weeks of ET in older adults and, moreover, suggest that increased hippocampal FC may reflect neural network plasticity associated with ET-related improvements in memory performance in individuals diagnosed with MCI. Show more

Keywords: Exercise training, functional connectivity, hippocampus, memory, mild cognitive impairment, older adults

DOI: 10.3233/JAD-210051

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1015-1031, 2021

Authors: Fernández, Gerardo | Parra, Mario A.

Article Type: Research Article

Abstract: Background: Biological information drawn from eye-tracking metrics is providing evidence regarding drivers of cognitive decline in Alzheimer’s disease. In particular, pupil size has proved useful to investigate cognitive performance during online activities. Objective: To investigate the oculomotor correlates of impaired performance of patients with mild Alzheimer’s Clinical Syndrome (ACS) on a recently developed memory paradigm, namely the Short-Term Memory Binding Test (STMBT). Methods: We assessed a sample of eighteen healthy controls (HC) and eighteen patients with a diagnosis of mild ACS with the STMBT while we recorded their oculomotor behaviors using pupillometry and eye-tracking. …Results: As expected, a group (healthy controls versus ACS) by condition (Unbound Colours versus Bound Colours) interaction was found whereby behavioral group differences were paramount in the Bound Colours condition. Healthy controls’ pupils dilated significantly more in the Bound Colours than in the Unbound Colours condition, a discrepancy not observed in ACS patients. Furthermore, ROC analysis revealed the abnormal pupil behaviors distinguished ACS patients from healthy controls with values of sensitivity and specify of 100%, thus outperforming both recognition scores and gaze duration. Conclusion: The biological correlates of Short-Term Memory Binding impairments appear to involve a network much wider than we have thought to date, which expands across cortical and subcortical structures. We discuss these findings focusing on their implications for our understanding of neurocognitive phenotypes in the preclinical stages of Alzheimer’s disease and potential development of cognitive biomarkers that can support ongoing initiatives to prevent dementia. Show more

Keywords: Alzheimer’s disease, eye-tracking, gaze duration, pupil behavior, short-term memory binding test

DOI: 10.3233/JAD-201189

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1033-1044, 2021

Authors: Wang, Zuo-Teng | Li, Kun-Yan | Tan, Chen-Chen | Xu, Wei | Shen, Xue-Ning | Cao, Xi-Peng | Wang, Ping | Bi, Yan-Lin | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The relationship between alcohol consumption and Alzheimer’s disease (AD) pathology is unclear. Amyloid-β (Aβ) and tau biomarkers in cerebrospinal fluid (CSF) have been proven valuable in establishing prognosis in pre-clinical AD. Objective: We sought to examine the associations between alcohol consumption and CSF AD biomarkers in cognitive intact subjects. Methods: A total of 806 cognitively intact participants who had measurements of CSF Aβ, pTau, and total Tau proteins and drinking characteristics were included from the Chinese Alzheimer’s Biomarker and Lifestyle (CABLE) study. Linear and logistic regression analyses were utilized to explore the associations of alcohol …consumption with CSF AD biomarkers. We examined the interaction effects of age, gender, and apolipoprotein epsilon (APOE ) ɛ4 status on the relationships between the frequency of drinking and CSF biomarkers. Results: The multiple linear regression analyses revealed significant differences in CSF AD biomarkers between infrequent drinking (< 1 times/week) and frequent drinking groups (≥1 times/week). Participants in frequent drinking group had higher CSF p-tau/Aβ42 and tTau/Aβ42 . Frequent drinking was significantly associated with greater pTau and tTau abnormalities compared to the infrequent drinking group in older (> 65 years) participants. Conclusion: The present study showed significant associations between drinking frequency and CSF AD biomarkers in cognitively intact older adults. Alcohol consumption may have an influence on AD by modulating amyloid deposition and tau phosphorylation in the preclinical stage. Show more

Keywords: Alcohol consumption, Alzheimer’s disease, amyloid, cerebrospinal fluid, magnetic resonance imaging, tau proteins

DOI: 10.3233/JAD-210140

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1045-1054, 2021

Authors: Qu, Mingyue | Shi, Hanxu | Wang, Kai | Wang, Xinggang | Yu, Nan | Guo, Baoshi

Article Type: Research Article

Abstract: Background: Multiple lines of evidence indicate protective effects of carotenoids in Alzheimer’s disease (AD). However, previous epidemiological studies reported inconsistent results regarding the associations between carotenoids levels and the risk of AD. Objective: Our study aims to evaluate the associations of six major members of carotenoids with the occurrence of AD by conducting a systematic review and meta-analysis. Methods: Following PRISMA guidelines, a comprehensive literature search of PubMed, Web of Science, Ebsco, and PsycINFO databases was conducted, and the quality of each included studies was evaluated by a validated scoring systems. Standardized mean differences (SMD) with …95% confidence intervals (CI) were determined by using a random effects model. Heterogeneity was evaluated by I2 statistics. Publication bias was detected using funnel plots and Egger’s test. Results: Sixteen studies, with 10,633 participants were included. Pooled analysis showed significantly lower plasma/serum levels of lutein (SMD = –0.86, 95% CI: –1.67 to –0.05, p  = 0.04) and zeaxanthin (SMD = –0.59; 95% CI: –1.12 to –0.06, p  = 0.03) in patients with AD versus cognitively intact controls, while α-carotene (SMD = 0.21, 95% CI: –0.68 to 0.26, p  = 0.39), β-carotene (SMD = 0.04, 95% CI: –0.57 to 0.65, p  = 0.9), lycopene (SMD = –0.12, 95% CI: –0.96 to 0.72, p  = 0.78), and β-cryptoxanthin (SMD = –0.09, 95% CI: –0.83 to 0.65, p  = 0.81) did not achieve significant differences. Conclusion: Of six major members of carotenoids, only lutein and zeaxanthin concentrations in plasma/serum were inversely related to the risk of AD. More high-quality longitudinal studies are needed to verify these findings. Show more

Keywords: Alzheimer’s disease, carotenes, carotenoids, xanthophylls

DOI: 10.3233/JAD-210384

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1055-1066, 2021

Authors: Lourenco, Mychael V. | Ribeiro, Felipe C. | Santos, Luis E. | Beckman, Danielle | Melo, Helen M. | Sudo, Felipe K. | Drummond, Cláudia | Assunção, Naima | Vanderborght, Bart | Tovar-Moll, Fernanda | De Felice, Fernanda G. | Mattos, Paulo | Ferreira, Sergio T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and Lewy body disease (LBD) are complex neurodegenerative disorders that have been associated with brain inflammation and impaired neurotransmission. Objective: We aimed to determine concentrations of multiple cytokines, chemokines, and neurotransmitters previously associated with brain inflammation and synapse function in cerebrospinal fluid (CSF) from AD and LBD patients. Methods: We examined a panel of 50 analytes comprising neurotransmitters, cytokines, chemokines, and hormones in CSF in a cohort of patients diagnosed with mild cognitive impairment (MCI), AD, LBD, or non-demented controls (NDC). Results: Among neurotransmitters, noradrenaline (NA) was increased in AD …CSF, while homovanillic acid (HVA), a dopamine metabolite, was reduced in both AD and LBD CSF relative to NDC. Six cytokines/chemokines out of 30 investigated were reliably detected in CSF. CSF vascular endothelial growth factor (VEGF) was significantly reduced in LBD patients relative to NDC. Conclusions: CSF alterations in NA, HVA, and VEGF in AD and LBD may reflect pathogenic features of these disorders and provide tools for improved diagnosis. Future studies are warranted to replicate current findings in larger, multicenter cohorts. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cytokines, homovanillic acid, inflammation, Lewy body disease, neurotransmitters, noradrenaline, vascular endothelial growth factor.

DOI: 10.3233/JAD-210147

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1067-1074, 2021

Authors: Samara, Myrto | Levine, Stephen Z. | Yoshida, Kazufumi | Goldberg, Yair | Cipriani, Andrea | Efthimiou, Orestis | Iwatsubo, Takeshi | Leucht, Stefan | Furakawa, Toshiaki A.

Article Type: Research Article

Abstract: Background: In patients with Alzheimer’s disease, global assessment scales, such as the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Clinician’s Interview-Based Impression Plus Caregiver Input (CIBI plus), and the Clinical Global Impression (CGI) are commonly used. Objective: To clinically understand and interpret the associations between these scales, we examined the linkages for the total and change scores of CDR-SB, CIBI plus, and CGI. Methods: Individual participant data (N = 2,198) from five pivotal randomized placebo-controlled trials of donepezil were included. Data were collected at baseline and scheduled visits for up to 6 months. Spearman’s correlation coefficients ρ …were examined between corresponding total and change scores of simultaneous CDR-SB, CIBI plus, and CGI ratings. To link between the simultaneous ratings, equipercentile linking was used. Results: We found strong evidence that the Spearman’s correlation coefficients between the CDR-SB and CGI, and CDR-SB and CIBI plus total scores were at least adequately correlated (ρ = 0.50 to 0.71, with p  < 0.01). The correlation coefficients between the change scores of CDR-SB and CGI were deemed adequate for weeks 6 to 24 (ρ = 0.44 to 0.65); the remaining correlations were smaller in magnitude (ρ = 0.09 to 0.35). Overall, the linkages were in-line with expectations, e.g., CDR-SB range score of 3-4 (= very mild dementia) was linked to a CGI score of 3 (= mildly ill), and an increase of CDR-SB of 1 was linked to a change of 5 (= minimal worsening) in both CGI and CIBI plus. Conclusion: The study findings can be useful for clinicians wishing to compare scores of different scales across patients. They can also help researchers understand results of studies using different scales and can facilitate meta-analyses, to increase statistical power. Show more

Keywords: Alzheimer’s disease, clinical dementia rating-sum of boxes, clinical global impression, clinician’s interview-based impression of change, clinician’s interview-based impression of severity, global ratings, minimal clinically important difference

DOI: 10.3233/JAD-201541

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1075-1084, 2021

Authors: Babiloni, Claudio | Ferri, Raffaele | Noce, Giuseppe | Lizio, Roberta | Lopez, Susanna | Lorenzo, Ivan | Tucci, Federico | Soricelli, Andrea | Nobili, Flavio | Arnaldi, Dario | Famà, Francesco | Orzi, Francesco | Buttinelli, Carla | Giubilei, Franco | Cipollini, Virginia | Marizzoni, Moira | Güntekin, Bahar | Aktürk, Tuba | Hanoğlu, Lutfu | Yener, Görsev | Özbek, Yağmur | Stocchi, Fabrizio | Vacca, Laura | Frisoni, Giovanni B. | Del Percio, Claudio

Article Type: Research Article

Abstract: Background: In relaxed adults, staying in quiet wakefulness at eyes closed is related to the so-called resting state electroencephalographic (rsEEG) rhythms, showing the highest amplitude in posterior areas at alpha frequencies (8–13 Hz). Objective: Here we tested the hypothesis that age may affect rsEEG alpha (8–12 Hz) rhythms recorded in normal elderly (Nold) seniors and patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI). Methods: Clinical and rsEEG datasets in 63 ADMCI and 60 Nold individuals (matched for demography, education, and gender) were taken from an international archive. The rsEEG rhythms were investigated at individual delta, theta, …and alpha frequency bands, as well as fixed beta (14–30 Hz) and gamma (30–40 Hz) bands. Each group was stratified into three subgroups based on age ranges (i.e., tertiles). Results: As compared to the younger Nold subgroups, the older one showed greater reductions in the rsEEG alpha rhythms with major topographical effects in posterior regions. On the contrary, in relation to the younger ADMCI subgroups, the older one displayed a lesser reduction in those rhythms. Notably, the ADMCI subgroups pointed to similar cerebrospinal fluid AD diagnostic biomarkers, gray and white matter brain lesions revealed by neuroimaging, and clinical and neuropsychological scores. Conclusion: The present results suggest that age may represent a deranging factor for dominant rsEEG alpha rhythms in Nold seniors, while rsEEG alpha rhythms in ADMCI patients may be more affected by the disease variants related to earlier versus later onset of the AD. Show more

Keywords: Aging, exact Low-resolution brain electromagnetic source tomography, mild cognitive impairment due to Alzheimer’s disease, resting state electroencephalographic rhythms

DOI: 10.3233/JAD-201271

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1085-1114, 2021

Authors: Watanabe, Kazuhisa | Umegaki, Hiroyuki | Sugimoto, Taiki | Fujisawa, Chisato | Komiya, Hitoshi | Nagae, Masaaki | Yamada, Yosuke | Kuzuya, Masafumi | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Polypharmacy, usually defined as the use of 5 or more drugs, is associated with reduced quality of life, adverse events, and frailty. Slow gait speed is a component of physical frailty, and some studies have suggested an association between polypharmacy and slow gait speed. Objective: We aimed to determine the effects of polypharmacy on the gait difference according to stages of cognitive decline in a cross-sectional study of memory clinic patients. Methods: Participants were 431 outpatients aged 65 year or older who were cognitively normal (CN) or had mild cognitive impairment (MCI) or dementia due …to Alzheimer’s disease. Participants were divided into a polypharmacy group and a non-polypharmacy group in each group. Multiple regression analysis and logistic analysis were used for data analysis. Results: There were 182 patients in the polypharmacy group and 249 patients in the non-polypharmacy group. Multiple regression analysis revealed that gait speed had significant negative associations with number of medications and polypharmacy status in the CN group (β: –0.026 [–0.041 to –0.0018] and –0.128 [–0.022 to –0.0033], respectively) and MCI group (–0.018 [–0.028 to –0.0009] and –0.100 [–0.166 to –0.0034]). Logistic regression analysis also showed that number of medications was associated with slow gait status (< 1 m/s) in the CN group (OR: 1.336 [1.115 to 1.601]) and MCI group (1.128 [1.022 to 1.244]). Conclusion: CN and MCI patients with polypharmacy have slower gait speed. Attention should be paid to decreased gait speed in older adults with polypharmacy even when their cognitive function is relatively preserved. Show more

Keywords: Alzheimer’s disease, cross-sectional study, gait speed, older adults, outpatient clinic, polypharmacy

DOI: 10.3233/JAD-201601

Citation: Journal of Alzheimer's Disease, vol. 82, no. 3, pp. 1115-1122, 2021