Journal of Alzheimer's Disease - Volume 86, issue 2

Authors: Cardoso, Sandra | Silva, Dina | Alves, Luísa | Guerreiro, Manuela | de Mendonça, Alexandre

Article Type: Research Article

Abstract: Background: Patients with amnestic mild cognitive impairment (aMCI) are usually at an initial stage of Alzheimer’s disease (AD). However, some patients with aMCI do not present biomarkers of amyloid pathology characteristic of AD. The significance of amyloid-negative aMCI is not presently clear. Objective: To know the etiology and prognosis of amyloid-negative aMCI. Methods: Patients who fulfilled criteria for aMCI and were amyloid negative were selected from a large cohort of non-demented patients with cognitive complaints and were followed with clinical and neuropsychological assessments. Results: Few amyloid-negative aMCI had evidence of neurodegeneration at the baseline, …as reflected in cerebrospinal fluid elevated tau protein levels. About half of the patients remained essentially stable for long periods of time. Others manifested a psychiatric disorder that was not apparent at baseline, namely major depression or bipolar disorder. Remarkably, about a quarter of patients developed neurodegenerative disorders other than AD, mostly frontotemporal dementia or Lewy body disease. Conclusion: Amyloid-negative aMCI is a heterogeneous condition. Many patients remain clinically stable, but others may later manifest psychiatric conditions or evolve to neurodegenerative disorders. Prudence is needed when communicating to the patient and family the results of biomarkers, and clinical follow-up should be advised. Show more

Keywords: Amnestic mild cognitive impairment, amyloid-beta, amyloid-negative, biomarkers, dementia, follow-up

DOI: 10.3233/JAD-215465

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 629-640, 2022

Authors: Ceyzériat, Kelly | Tournier, Benjamin B. | Millet, Philippe | Dipasquale, Giovanna | Koutsouvelis, Nikolaos | Frisoni, Giovanni B. | Garibotto, Valentina | Zilli, Thomas

Article Type: Research Article

Abstract: Background: Low-dose radiation therapy (LD-RT) has been shown to decrease amyloidosis or inflammation in systemic diseases and has recently been proposed as possible treatment of Alzheimer’s disease (AD). A positive effect of LD-RT on tauopathy, the other marker of AD, has also been suggested. These effects have been shown in preclinical studies, but their mechanisms are still not well understood. Objective: This study aimed to evaluate if anti-amyloid and anti-inflammatory effects of LD-RT can be observed at an early stage of the disease. Its impact on tauopathy and behavioral alterations was also investigated. Methods: The whole …brain of 12-month-old 3xTg-AD mice was irradiated with 10 Gy in 5 daily fractions of 2 Gy. Mice underwent behavioral tests before and 8 weeks post treatment. Amyloid load, tauopathy, and neuroinflammation were measured using histology and/or ELISA. Results: Compared with wild-type animals, 3xTg-AD mice showed a moderate amyloid and tau pathology restricted to the hippocampus, a glial reactivity restricted to the proximity of amyloid plaques. LD-RT significantly reduced Aβ42 aggregated forms (–71%) in the hippocampus and tended to reduce other forms in the hippocampus and frontal cortex but did not affect tauopathy or cognitive performance. A trend for neuroinflammation markers reduction was also observed. Conclusion: When applied at an early stage, LD-RT reduced amyloid load and possibly neuroinflammation markers, with no impact on tauopathy. The long-term persistence of these beneficial effects of LD-RT should be evaluated in future studies. Show more

Keywords: Alzheimer’s disease, amyloid, neuroinflammation, radiation therapy, tau

DOI: 10.3233/JAD-215510

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 641-653, 2022

Authors: Bernstein Sideman, Alissa | Chalmer, Rachel | Ayers, Emmeline | Gershon, Richard | Verghese, Joe | Wolf, Michael | Ansari, Asif | Arvanitis, Marina | Bui, Nhat | Chen, Pei | Chodos, Anna | Corriveau, Roderick | Curtis, Laura | Ehrlich, Amy R. | Tomaszewski Farias, Sarah E. | Goode, Collette | Hill-Sakurai, Laura | Nowinski, Cindy J. | Premkumar, Mukund | Rankin, Katherine P. | Ritchie, Christine S. | Tsoy, Elena | Weiss, Erica | Possin, Katherine L.

Article Type: Research Article

Abstract: Background: Cognitive impairment, including dementia, is frequently under-detected in primary care. The Consortium for Detecting Cognitive Impairment, including Dementia (DetectCID) convenes three multidisciplinary teams that are testing novel paradigms to improve the frequency and quality of patient evaluations for detecting cognitive impairment in primary care and appropriate follow-up. Objective: Our objective was to characterize the three paradigms, including similarities and differences, and to identify common key lessons from implementation. Methods: A qualitative evaluation study with dementia specialists who were implementing the detection paradigms. Data was analyzed using content analysis. Results: We identified core components …of each paradigm. Key lessons emphasized the importance of engaging primary care teams, enabling primary care providers to diagnose cognitive disorders and provide ongoing care support, integrating with the electronic health record, and ensuring that paradigms address the needs of diverse populations. Conclusion: Approaches are needed that address the arc of care from identifying a concern to post-diagnostic management, are efficient and adaptable to primary care workflows, and address a diverse aging population. Our work highlights approaches to partnering with primary care that could be useful across specialties and paves the way for developing future paradigms that improve differential diagnosis of symptomatic cognitive impairment, identifying not only its presence but also its specific syndrome or etiology. Show more

Keywords: Cognitive assessment, dementia, detection, diagnosis, implementation evaluation, mild cognitive impairment, primary care

DOI: 10.3233/JAD-215106

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 655-665, 2022

Authors: Jo, Sungyang | Cheong, E-Nae | Kim, Nayoung | Oh, Jungsu S. | Shim, Woo Hyun | Kim, Hyung-Ji | Lee, Sun Ju | Lee, Yoojin | Oh, Minyoung | Kim, Jae Seung | Kim, Bum Joon | Roh, Jee Hoon | Kim, Sang Joon | Lee, Jae-Hong

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy (CAA) often presents as cognitive impairment, but the mechanism of cognitive decline is unclear. Recent studies showed that number of microbleeds were associated with cognitive decline. Objective: We aimed to investigate how microbleeds contribute to cognitive impairment in association with white matter tract abnormalities or cortical thickness in CAA. Methods: This retrospective comparative study involved patients with probable CAA according to the Boston criteria (Aβ+ CAA) and patients with Alzheimer’s disease (Aβ+ AD), all of whom showed severe amyloid deposition on amyloid PET. Using mediation analysis, we investigated how FA …or cortical thickness mediates the correlation between the number of lobar microbleeds and cognition. Results: We analyzed 30 patients with Aβ+ CAA (age 72.2±7.6, female 53.3%) and 30 patients with Aβ+ AD (age 71.5±7.6, female 53.3%). The two groups showed similar degrees of cortical amyloid deposition in AD-related regions. The Aβ+ CAA group had significantly lower FA values in the clusters of the posterior area than did the Aβ+ AD group (family-wise error-corrected p  < 0.05). The correlation between the number of lobar microbleeds and visuospatial function was indirectly mediated by white matter tract abnormality of right posterior thalamic radiation (PTR) and tapetum, while lobar microbleeds and language function was indirectly mediated by the abnormality of left PTR and sagittal stratum. Cortical thickness did not mediate the association between lobar microbleeds and cognition. Conclusion: This result supports the hypothesis that microbleeds burden leads to white matter tract damage and subsequent cognitive decline in CAA. Show more

Keywords: Amyloid PET, cerebral amyloid angiopathy, cognition, microbleeds

DOI: 10.3233/JAD-215094

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 667-678, 2022

Authors: Chen, Wan-Ting | Chi, Nai-Fang | Cheng, Hao-Min | Ko, Yu-Ting | Chuang, Shao-Yuan | Pan, Wen-Harn | Chen, Chen-Huan | Chung, Chih-Ping | Wang, Pei-Ning

Article Type: Research Article

Abstract: Background: Increasing evidence shows early vascular dysregulation in the pathophysiology of Alzheimer’s disease (AD) in elderly population. Objective: We wondered about the relationship between vascular health and cognitive performance in middle-aged adults. The present study aims to evaluate whether and which brain vascular hemodynamic parameters are associated with cognitive functions in a middle-aged, non-demented population. Methods: We recruited 490 middle-aged community-based participants (30–60 years). Transcranial color-coded sonography was used to measure cerebral vascular hemodynamics, including mean flow velocity, pulsatility index, and breath-holding index (BHI) in the middle cerebral arteries (MCAs). Cognitive functions were assessed using the …Montreal Cognitive Assessment (MoCA). A multivariate linear regression model was used to determine the association between the MoCA scores and each intracranial hemodynamic parameter. Results: In 369 participants (median age 52 years [IQR 47–56], 48.8% men) with robust acoustic windows, the factors related to poorer MoCA scores were older age, less education extent, and the habitats of cigarette smoking or alcohol consumption. Multivariate analyses did not show a significant association between any intracranial hemodynamic parameters in both MCAs and MoCA scores in the total study population. Left MCA BHI was found to be significantly and independently correlated with the MoCA scores only in people aged 55–60 years (n  = 111, B  = 0.70, 95% confidence interval, 0.13–1.26, p  = 0.017), however, not in people younger than 55 years. Conclusion: Our results emphasize the role of neurovascular abnormalities in the early pathophysiology of cognitive impairment and suggest cerebral vasoreactivity as the earliest detectable cognition-associated hemodynamic parameter. Show more

Keywords: Alzheimer’s disease, cerebrovascular reactivity, cognitive impairment, vasomotor system, vasoreactivity

DOI: 10.3233/JAD-215317

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 679-690, 2022

Authors: Ni, Ling | Sun, Wenshan | Yang, Dan | Huang, Lili | Shao, Pengfei | Wang, Chong | Xu, Yun

Article Type: Research Article

Abstract: Background: The BOLD signal is regulated by neuronal activity and vascular physiology. The evolution pattern of brain activities after modulating the vascular factors in white matter hyperintensities (WMHs) related cognitive impairment (CI) was unknown. Objective: To explore the “pure” low-frequency fluctuation (ALFF) alterations after adjusting the cerebrovascular reactivity (CVR) factor. Methods: In this study, 111 WMHs subjects including 55 with CI (WMH-CI) and 56 without CI (WMH-no-CI), and 72 normal controls (NCs) underwent resting-state fMRI. The CVR and ALFF maps were derived using BOLD data. A voxel-wise Pearson analysis was performed to detect the relationship between …CVR and ALFF maps. The ANCOVA analysis with and without CVR as a covariate was conducted to explore the effect of CVR on ALFF analysis. Correlation between the ALFF alterations and cognitive performance was conducted in WMH-CI subjects. The receiver operating characteristic curve was constructed to assess the diagnostic performance of ALFF indexes to determine the occurrence of CI. Results: There was a significant widespread correlation between the CVR and ALFF maps. The ALFF alterations between the WMH groups and NC group with CVR as covariate were more than those without CVR as covariate. WMH-CI subjects showed further ALFF alterations when compared with WMH-no-CI subjects. The abnormal ALFF values were significantly associated with poor performance. The combination of inferior frontal gyrus and middle frontal gyrus to PCC provided an incremental contribution to the occurrence of CI. Conclusion: More areas with abnormal ALFF values which were specific to the WMHs related cognitive dysfunction were detected when considering the impact of CVR. Show more

Keywords: Amplitude of low-frequency fluctuation, cerebrovascular reactivity, cognitive impairment, white matter hyperintensities

DOI: 10.3233/JAD-215216

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 691-701, 2022

Authors: Bohlken, Jens | Peters, Oliver | Kostev, Karel

Article Type: Research Article

Abstract: Background: Clinical trials have demonstrated a significant effectiveness of Ginkgo biloba therapy versus placebo in patients with dementia. Objective: The present study aims to analyze the impact of Ginkgo biloba drug prescriptions on dementia incidence in patients with mild cognitive impairment (MCI) in a real-world setting. Methods: This retrospective study was based on the IQVIA Disease Analyzer database and included patients aged 65 or older with a first diagnosis of MCI from January 2000 to December 2019. Each patient was followed for up to 20 years after MCI diagnosis until February …2021. Date of the first diagnosis of dementia or loss to follow-up, whichever occurred first, was noted. To estimate the association between Ginkgo biloba prescriptions during the follow-up and dementia incidence, a multivariable Cox regression analysis was performed, adjusted for age, sex, health insurance, documented co-diagnoses, and prescription of cholinesterase inhibitors. Results: Overall, 24,483 MCI patients (mean age: 77.0 years, 56.3% women) were included. It was found that > 2 prescriptions of Ginkgo biloba were significantly associated with a reduced dementia incidence (HR: 0.71 (95% CI: 0.55–0.91), p  = 0.007), as compared with no Ginkgo biloba prescription. The effect of receiving > 3 Ginkgo biloba prescriptions was even stronger, with an HR of 0.64 (95% CI: 0.48–0.86), p  = 0.003), while for > 4 prescriptions the HR was 0.58 (95% CI: 0.41–0.82) (p  = 0.002). Conclusion: All-cause dementia incidence decreased with higher numbers of Ginkgo biloba prescriptions in MCI patients. Show more

Keywords: Dementia, Ginkgo biloba extract, mild cognitive impairment, outpatients

DOI: 10.3233/JAD-215348

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 703-709, 2022

Authors: Diaz Baquero, Angie A. | Franco-Martín, Manuel A. | Parra Vidales, Esther | Toribio-Guzmán, José Miguel | Bueno-Aguado, Yolanda | Martínez Abad, Fernando | Perea Bartolomé, María V. | Asl, Aysan Mahmoudi | van der Roest, Henriëtte G.

Article Type: Research Article

Abstract: Background: Computer-based cognitive training programs have been developed with promising results on the maintenance/improvement of cognitive performance in people with dementia. Objective: The objective was to evaluate the effectiveness of the cognitive rehabilitation program “GRADIOR” in people with mild cognitive impairment and mild dementia. Method: This study was a single-blind multicenter randomized clinical trial. Participants were recruited from hospitals/day centers. The experimental group (EG) and control group (CG) received computer-based cognitive training (CCT) and routine daily care, respectively. Outcome measures at T0 : baseline, T1 : at 4 months, T2 : at 12 …months were compared within and between-groups. Results: Significant differences or important effect sizes were detected at the intragroup and intergroup level for most variables, observing a trend of improvement and/or maintenance at 4 months by Visual Reasoning of Cambridge Cognitive Examination (CAMCOG), Digit and Arithmetic of WAIS-III, Semantic Verbal Fluency, Mini-Mental State Exam (MMSE), Trail Making Test (TMT)-A-Mistakes and at 12 months by Visual Reasoning of CAMCOG, Digit Symbol of WAIS-III, TMT-B-mistakes, Visual Memory of Rivermead Behavioural Memory Test, Lexical Verbal Fluency-P, Yesavage’s Geriatric Depression Scale (GDS), TMT-A-time scales whose objective was to evaluate some executive functions and/or the memory. The CG presented a worsening trend for most of the measures towards 12 months. There was also a significant interaction between “time and group” for MMSE (F = 8.971; p  = 0.03; η2  = 0.019) and the GDS (F = 3.414; p  = 0.04; η2  = 0.041), as well as small effect sizes for TMT-A-time (F = 1.641; p  = 0.21; η2  = 0.021) and TMT-A-mistakes (F = 0.908; p  = 0.41; η2  = 0.019). Conclusion: CCT with GRADIOR has been proved to benefit cognitive functions (ISRCTN:15742788). Show more

Keywords: Cognitive training, dementia, mild cognitive impairment, randomized controlled trial, rehabilitation

DOI: 10.3233/JAD-215350

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 711-727, 2022

Authors: Tu, Min-Chien | Chung, Hsiao-Wen | Hsu, Yen-Hsuan | Yang, Jir-Jei | Wu, Wen-Chau

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and subcortical ischemic vascular disease (SIVD) have both been associated with white matter hyperintensities (WMHs) and altered cerebral blood flow (CBF) although the etiology of AD is still unclear. Objective: To test the hypothesis that CBF and WMHs have differential effects on cognition and that the relationship between CBF and WMHs changes with the subtypes and stages of dementia. Methods: Forty-two patients with SIVD, 50 patients with clinically-diagnosed AD, and 30 cognitively-normal subjects were included. Based on the Clinical Dementia Rating (CDR), the patients were dichotomized into early-stage (CDR = 0.5) …and late-stage (CDR = 1 or 2) groups. CBF and WMH metrics were derived from magnetic resonance imaging and correlated with cognition. Results: Hierarchical linear regression revealed that CBF metrics had distinct contribution to global cognition, memory, and attention, whereas WMH metrics had distinct contribution to executive function (all p  < 0.05). In SIVD, the WMHs in frontotemporal areas correlated with the CBF in bilateral thalami at the early stage; the correlation then became between the WMHs in basal ganglia and the CBF in frontotemporal areas at the late stage. A similar corticosubcortical coupling was observed in AD but involved fewer areas. Conclusion: A stage-dependent coupling between CBF and WMHs was identified in AD and SIVD, where the extent of cortical WMHs correlated with subcortical CBF for CDR = 0.5, whereas the extent of subcortical WMHs correlated with cortical CBF for CDR = 1–2. Show more

Keywords: Alzheimer’s disease, cerebral blood flow, magnetic resonance imaging, vascular dementia

DOI: 10.3233/JAD-215405

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 729-739, 2022

Authors: Zhu, Zili | Zeng, Qingze | Zhang, Ruiting | Luo, Xiao | Li, Kaicheng | Xu, Xiaopei | Zhang, Minming | Yang, Yunjun | Huang, Peiyu | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Vascular pathology is an important partner of Alzheimer’s disease (AD). Both total cerebral small vessel disease (CSVD) score and white matter free water (FW) are useful markers that could reflect cerebral vascular injury. Objective: We aim to investigate the efficacy of these two metrics in predicting cognitive declines in patients with mild cognitive impairment (MCI). Methods: We enrolled 126 MCI subjects with 3D T1-weighted images, fluid-attenuated inversion recovery images, T2* images, diffusion tensor imaging images, cerebrospinal fluid biomarkers and neuropsychological tests from the Alzheimer’s Disease Neuroimaging Initiative database. The total CSVD …score and FW values were calculated. Simple and multiple linear regression analyses were applied to explore the association between vascular and cognitive impairments. Linear mixed effect models were constructed to investigate the efficacy of total CSVD score and FW on predicting cognitive decline. Results: FW was associated with baseline cognition and could predict the decline of executive and language functions in MCI subjects, while no association was found between total CSVD score and cognitive declines. Conclusion: FW is a promising imaging marker for investigating the effect of CSVD on AD progression. Show more

Keywords: Cerebral small vessel disease, cognitive decline, diffusion tensor imaging, mild cognitive impairment

DOI: 10.3233/JAD-215541

Citation: Journal of Alzheimer's Disease, vol. 86, no. 2, pp. 741-751, 2022