Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Won, Junyeon | Callow, Daniel D. | S. Pena, Gabriel | 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. Pre-press, no. Pre-press, pp. 1-17, 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 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. Pre-press, no. Pre-press, pp. 1-8, 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. Pre-press, no. Pre-press, pp. 1-13, 2021

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

Article Type: Research Article

Abstract: Background: Homocysteine is a common risk factor for cognitive impairment and sarcopenia. However, very few studies have shown an association between sarcopenia and serum homocysteine levels after adjustment for cognitive function. Objective: The purpose of this study was to investigate the relationship between homocysteine and sarcopenia in memory clinic patients. Methods: This cross-sectional study investigated outpatients in a memory clinic. We enrolled 1,774 participants (≥65 years old) with measured skeletal muscle mass index (SMI), hand grip strength (HGS), and homocysteine. All participants had undergone cognitive assessments and were diagnosed with dementia, mild cognitive impairment, or normal …cognition. Patient characteristics were compared according to sarcopenia presence, SMI level, or HGS. Multivariate logistic regression analysis was performed to determine the association of homocysteine with sarcopenia, low SMI, or low HGS. Next, linear regression analysis was performed using HGS as a continuous variable. Results: Logistic regression analysis showed that low HGS was significantly associated with homocysteine levels (p  = 0.002), but sarcopenia and low SMI were not. In linear regression analysis, HGS was negatively associated with homocysteine levels after adjustment for Mini-Mental State Examination score (β= –2.790, p  <  0.001) or clinical diagnosis of dementia (β= –3.145, p  <  0.001). These results were similar for men and women. Conclusion: Our results showed a negative association between homocysteine and HGS after adjustment for cognitive function. Our findings strengthen the assumed association between homocysteine and HGS. Further research is needed to determine whether lower homocysteine levels lead to prevent muscle weakness. Show more

Keywords: Cognitive impairment, hand grip strength, homocysteine, sarcopenia

DOI: 10.3233/JAD-210083

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 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. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Darmanthé, Nicolas | Tabatabaei-Jafari, Hossein | Cherbuin, Nicolas | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Individuals with mild cognitive impairment (MCI) are at high risk of progression to Alzheimer’s disease (AD) dementia, but some remain stable. There is a need to identify those at higher risk of progression to improve patient management and outcomes. Objective: To evaluate the trajectory of plasma neurofilament light chain (pNFL) prior to progression from MCI to AD dementia, the performance of pNFL, in combination with the Mini-Mental State Examination (MMSE), as a predictor of progression from MCI to AD dementia and to inform clinicians on the use of pNFL as a predictive biomarker. Methods: Participants …(n  = 440) with MCI and longitudinal follow-up (mean = 4.2 years) from the AD Neuroimaging Initiative dataset were included. pNFL as a marker for neurodegeneration and the MMSE as a cognitive measure were investigated as simple/practical predictors of progression. The risk of progressing from MCI to AD dementia associated with pNFL and MMSE scores was assessed using Cox and logistic regression models. Results: The current risk of progression to AD dementia was 37%higher in individuals with high pNFL (>  56 ng/L) compared to those with average pNFL (≤40 ng/L). A combination of baseline pNFL and MMSE could differentiate those who progressed within 5 years (AUC = 0.75) from stable individuals. Including change in MMSE over 6-12 months further improved the model (AUC = 0.84). Conclusion: Our findings reveal that combining pNFL with a simple dementia screener (MMSE) can reliably predict whether a person with MCI is likely to progress to AD dementia within 5 years. Show more

Keywords: Alzheimer’s disease, clinical progression, mild cognitive impairment, neurofilament, plasma biomarkers

DOI: 10.3233/JAD-210092

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Kvello-Alme, Marte | Bråthen, Geir | White, Linda R. | Sando, Sigrid Botne

Article Type: Research Article

Abstract: Background: Young onset dementia is associated with a longer time to diagnosis compared to late onset dementia. Earlier publications have indicated that atypical presentation is a key contributing factor to the diagnostic delay. Our hypothesis was that even the most common presentation of Alzheimer’s disease is associated with a substantial diagnostic delay in patients <  65 years. Objective: To determine the time to diagnosis, and time lags in the diagnostic pathway in typical young onset Alzheimer’s disease in central Norway. Methods: The main sources of patients were the databases at the Department of Neurology, University Hospital of …Trondheim (St. Olav’s Hospital), and Department of Psychiatry, Levanger Hospital. Other sources included key persons in the communities, collaborating hospital departments examining patients with suspected cognitive impairment, and review of hospital records of all three hospitals in the area. Information on the time lags, and the clinical assessment, including the use of biomarkers, was collected from hospital notes. Caregivers were interviewed by telephone. Results: Time from first symptom to diagnosis in typical young onset Alzheimer’s disease was 5.5 years (n  = 223, SD 2.8). Time from onset to contact with healthcare services (usually a general practitioner) was 3.4 years (SD 2.3). Time from contact with healthcare services to the first visit at a hospital was 10.3 months (SD 15.5). Time from first visit at a hospital to diagnosis was 14.8 months (SD 22.6). The analysis of cerebrospinal fluid core biomarkers was performed after 8.3 months (SD 20.9). Conclusion: Typical Alzheimer’s disease is associated with a substantial diagnostic delay in younger patients. Raising public awareness, and education of healthcare professionals on the aspects of young onset Alzheimer’s disease is warranted. CSF core biomarkers should be performed earlier in the hospital evaluation process. Show more

Keywords: Clinical characteristics, delayed diagnosis, diagnosis, early onset Alzheimer’s disease, early onset dementia, young onset dementia

DOI: 10.3233/JAD-210090

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Serra, Laura | D’Amelio, Marcello | Esposito, Sharon | Domenico, Carlotta Di | 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. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Stoiljkovic, Milan | Gutierrez, Karel Otero | Kelley, Craig | Horvath, Tamas L. | Hajós, Mihály

Article Type: Research Article

Abstract: Background: Genetic mutations in triggering receptor expressed on myeloid cells-2 (TREM2) have been strongly associated with increased risk of developing Alzheimer’s disease (AD) and other progressive dementias. In the brain, TREM2 protein is specifically expressed on microglia suggesting their active involvement in driving disease pathology. Using various transgenic AD models to interfere with microglial function through TREM2, several recent studies provided important data indicating a causal link between TREM2 and underlying amyloid-β (Aβ) and tau pathology. However, mechanisms by which TREM2 contributes to increased predisposition to clinical AD and influences its progression still remain largely unknown. Objective: Our …aim was to elucidate the potential contribution of TREM2 on specific oscillatory dynamic changes associated with AD pathophysiology. Methods: Spontaneous and brainstem nucleus pontis oralis stimulation-induced hippocampal oscillation paradigm was used to investigate the impact of TREM2 haploinsufficiency TREM2(Het) or total deficiency TREM2(Hom) on hippocampal network function in wild-type and Aβ overproducing Tg2576 mice under urethane anesthesia. Results: Partial (TREM2(Het)) or total (TREM2(Hom)) deletion of TREM2 led to increased incidence of spontaneous epileptiform seizures in both wild-type and Tg2576 mice. Importantly, deficiency of TREM2 in Tg2576 mice significantly diminished power of theta oscillation in the hippocampus elicited by brainstem-stimulation compared to wild-type mice. However, it did not affect hippocampal theta-phase gamma-amplitude coupling significantly, since over a 60%reduction was found in coupling in Tg2576 mice regardless of TREM2 function. Conclusion: Our findings indicate a role for TREM2-dependent microglial function in the hippocampal neuronal excitability in both wild type and Aβ overproducing mice, whereas deficiency in TREM2 function exacerbates disruptive effects of Aβ on hippocampal network oscillations. Show more

Keywords: Alzheimer’s disease, hippocampus, microglia, theta oscillation, seizure, TREM2

DOI: 10.3233/JAD-210041

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: González-Alcaide, Gregorio | Fernández-Ríos, Mercedes | Redolat, Rosa | Serra, Emilia

Article Type: Research Article

Abstract: Background: The study of emotion recognition could be crucial for detecting alterations in certain cognitive areas or as an early sign of neurological disorders. Objective: The main objective of the study is to characterize research development on emotion recognition, identifying the intellectual structure that supports this area of knowledge, and the main lines of research attracting investigators’ interest. Methods: We identified publications on emotion recognition and dementia included in the Web of Science Core Collection, analyzing the scientific output and main disciplines involved in generating knowledge in the area. A co-citation analysis and an analysis of …the bibliographic coupling between the retrieved documents elucidated the thematic orientations of the research and the reference works that constitute the foundation for development in the field. Results: A total of 345 documents, with 24,282 bibliographic references between them, were included. This is an emerging research area, attracting the interest of investigators in Neurosciences, Psychology, Clinical Neurology, and Psychiatry, among other disciplines. Four prominent topic areas were identified, linked to frontotemporal dementia, autism spectrum disorders, Alzheimer’s disease, and Parkinson’s and Huntington disease. Many recent papers focus on the detection of mild cognitive impairment. Conclusion: Impaired emotion recognition may be a key sign facilitating the diagnosis and early treatment of different neurodegenerative diseases as well as for triggering the necessary provision of social and family support, explaining the growing research interest in this area. Show more

Keywords: Alzheimer’s disease, bibliometrics, dementia, emotions, facial recognition, knowledge discovery

DOI: 10.3233/JAD-210096

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021