Journal of Alzheimer's Disease - Volume 95, issue 3

Authors: Creavin, Samuel Thomas | Fish, Mark | Lawton, Michael | Cullum, Sarah | Bayer, Antony | Purdy, Sarah | Ben-Shlomo, Yoav

Article Type: Research Article

Abstract: Background: Many health systems are interested in increasing the number of uncomplicated and typical dementia diagnoses that are made in primary care, but the comparative accuracy of tests is unknown. Objective: Calculate diagnostic accuracy of brief cognitive tests in primary care. Methods: We did a diagnostic test accuracy study in general practice, in people over 70 years who had consulted their GP with cognitive symptoms but had no prior diagnosis of dementia. The reference standard was specialist assessment, adjudicated for difficult cases, according to ICD-10. We assessed 16 index tests at a research clinic, and additionally …analyzed referring GPs clinical judgement. Results: 240 participants had a median age of 80 years, of whom 126 were men and 132 had dementia. Sensitivity of individual tests at the recommended thresholds ranged from 56% for GP judgement (specificity 89%) to 100% for MoCA (specificity 16%). Specificity of individual tests ranged from 4% for Sniffin’ sticks (sensitivity 100%) to 91% for Timed Up and Go (sensitivity 23%). The 95% centile of test duration in people with dementia ranged from 3 minutes for 6CIT and Time and Change, to 16 minutes for MoCA. Combining tests with GP judgement increased test specificity and decreased sensitivity: e.g., MoCA with GP Judgement had specificity 87% and sensitivity 55%. Conclusions: Using GP judgement to inform selection of tests was an efficient strategy. Using IQCODE in people who GPs judge as having dementia and 6CIT in people who GPs judge as having no dementia, would be a time-efficient and accurate diagnostic assessment. The original protocol for the study is available at https://bmcfampract.biomedcentral.com/articles/10.1186/s12875-016-0475-2 Show more

Keywords: Alzheimer’s disease, dementia, general practice, sensitivity and specificity, symptom assessment

DOI: 10.3233/JAD-230320

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1189-1200, 2023

Authors: Zhang, Jingwen | Liu, Qing | Zhang, Haorui | Dai, Michelle | Song, Qianqian | Yang, Defu | Wu, Guorong | Chen, Minghan

Article Type: Research Article

Abstract: Background: Despite the striking efforts in investigating neurobiological factors behind the acquisition of amyloid-β (A), protein tau (T), and neurodegeneration ([N]) biomarkers, the mechanistic pathways of how AT[N] biomarkers spreading throughout the brain remain elusive. Objective: To disentangle the massive heterogeneities in Alzheimer’s disease (AD) progressions and identify vulnerable/critical brain regions to AD pathology. Methods: In this work, we characterized the interaction of AT[N] biomarkers and their propagation across brain networks using a novel bistable reaction-diffusion model, which allows us to establish a new systems biology underpinning of AD progression. We applied our model to large-scale …longitudinal neuroimages from the ADNI database and studied the systematic vulnerability and criticality of brains. Results: Our model yields long term prediction that is statistically significant linear correlated with temporal imaging data, produces clinically consistent risk prediction, and captures the Braak-like spreading pattern of AT[N] biomarkers in AD development. Conclusions: Our major findings include (i) tau is a stronger indicator of regional risk compared to amyloid, (ii) temporal lobe exhibits higher vulnerability to AD-related pathologies, (iii) proposed critical brain regions outperform hub nodes in transmitting disease factors across the brain, and (iv) comparing the spread of neuropathological burdens caused by amyloid-β and tau diffusions, disruption of metabolic balance is the most determinant factor contributing to the initiation and progression of AD. Show more

Keywords: Alzheimer’s disease, AT[N] biomarkers, brain network, reaction-diffusion model, vulnerable and critical regions

DOI: 10.3233/JAD-230027

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1201-1219, 2023

Authors: Oyarzún-González, Ximena | Abner, Erin L. | Toro, Pablo | Ferreccio, Catterina

Article Type: Research Article

Abstract: Background: Subjective memory complaints (SMC) are commonly studied in older adults and have been identified as potentially prodromal to dementia and Alzheimer’s disease. Studies among younger adults from South America are lacking. Objective: To estimate the prevalence of SMC and the factors associated with it among Maule Cohort (MAUCO) participants. Methods: We performed a cross-sectional analysis to estimate the prevalence of SMC and investigated its associated factors from MAUCO baseline data (N = 6,687). Within groups defined by age (38–59, 60–74) and global cognition (Mini-Mental State Examination: ≥26, 25-22, ≤21), multinomial logistic regression models evaluated risk factors for …SMC (Yes, Sometimes, No). Results: Overall, SMC prevalence was 16.4%; 15.9% (95% CI 14.9–16.9%) among younger and 17.6% (15.8–19.4%) among older participants. Female sex, comorbidities, and bad/fair self-reported health status (SRHS) were generally associated with higher odds of SMC. Conclusion: Overall prevalence of SMC was 16%. Different factors were associated with the odds of SMC depending on age and global cognitive status. Future SMC studies should include sex-specific assessments, evaluate SRHS as a moderator of SMC reporting, and the influence of the SARS-CoV-2 pandemic on SMC reporting. Show more

Keywords: Alzheimer’s disease, cohort, MAUCO, memory, multinomial, subjective memory complaint

DOI: 10.3233/JAD-230541

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1221-1231, 2023

Authors: Koppelmans, Vincent | Ruitenberg, Marit F.L. | Schaefer, Sydney Y. | King, Jace B. | Hoffman, John M. | Mejia, Amanda F. | Tasdizen, Tolga | Duff, Kevin

Article Type: Research Article

Abstract: Background: Despite reports of gross motor problems in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), fine motor function has been relatively understudied. Objective: We examined if finger tapping is affected in AD, related to AD biomarkers, and able to classify MCI or AD. Methods: Forty-seven cognitively normal, 27 amnestic MCI, and 26 AD subjects completed unimanual and bimanual computerized tapping tests. We tested 1) group differences in tapping with permutation models; 2) associations between tapping and biomarkers (PET amyloid-β, hippocampal volume, and APOE ɛ 4 alleles) with linear regression; and 3) the predictive value …of tapping for group classification using machine learning. Results: AD subjects had slower reaction time and larger speed variability than controls during all tapping conditions, except for dual tapping. MCI subjects performed worse than controls on reaction time and speed variability for dual and non-dominant hand tapping. Tapping speed and variability were related to hippocampal volume, but not to amyloid-β deposition or APOE ɛ 4 alleles. Random forest classification (overall accuracy = 70%) discriminated control and AD subjects, but poorly discriminated MCI from controls or AD. Conclusions: MCI and AD are linked to more variable finger tapping with slower reaction time. Associations between finger tapping and hippocampal volume, but not amyloidosis, suggest that tapping deficits are related to neuropathology that presents later during the disease. Considering that tapping performance is able to differentiate between control and AD subjects, it can offer a cost-efficient tool for augmenting existing AD biomarkers. Show more

Keywords: Alzheimer’s disease, biomarkers, finger tapping, manual dexterity, motor function

DOI: 10.3233/JAD-221297

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1233-1252, 2023

Authors: Fazlollahi, Amir | Lee, Soohyun | Coleman, Felicia | McCann, Emily | Cloos, Martijn A. | Bourgeat, Pierrick | Nestor, Peter J.

Article Type: Research Article

Abstract: Background: Objective measurement of regional cortical atrophy in individual patients would be a highly desirable adjunct for diagnosis of degenerative dementias. Objective: We hypothesized that increasing the resolution of magnetic resonance scans would improve the sensitivity of cortical atrophy detection for individual patients. Methods: 46 participants including 8 semantic-variant primary progressive aphasia (svPPA), seven posterior cortical atrophy (PCA), and 31 cognitively unimpaired participants underwent clinical assessment and 3.0T brain scans. SvPPA and PCA were chosen because there is overwhelming prior knowledge of the expected atrophy pattern. Two sets of T1-weighted images with 0.8 mm3 (HighRes) …and conventional 1.0 mm3 (ConvRes) resolution were acquired. The cortical ribbon was segmented using FreeSurfer software to obtain surface-based thickness maps. Inter-sequence performance was assessed in terms of cortical thickness and sub-cortical volume reproducibility, signal-to-noise and contrast-to-noise ratios. For clinical cases, diagnostic effect size (Cohen’s d) and lesion distribution (z-score and t-value maps) were compared between HighRes and ConvRes scans. Results: The HighRes scans produced higher image quality scores at 90 seconds extra scan time. The effect size of cortical thickness differences between patients and cognitively unimpaired participants was 15–20% larger for HighRes scans. HighRes scans showed more robust patterns of atrophy in expected regions in each and every individual patient. Conclusions: HighRes T1-weighted scans showed superior precision for identifying the severity of cortical atrophy in individual patients, offering a proof-of-concept for clinical translation. Studying svPPA and PCA, two syndromes with well-defined focal atrophy patterns, offers a method to clinically validate and contrast automated algorithms. Show more

Keywords: Alzheimer’s disease, atrophy, cortical thickness, degeneration, dementia, dementia diagnosis, MPRAGE

DOI: 10.3233/JAD-230030

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1253-1262, 2023

Authors: Kim, Dong-Yun | Kim, Jae Sik | Seo, Young-Seok | Park, Woo-Yoon | Kim, Byoung Hyuck | Hong, Eun-Hee | Kim, Ji Young | Cho, Seong-Jun | Rhee, Hak Young | Kim, Aryun | Kim, Keun You | Oh, Dae Jong | Chung, Weon Kuu

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), the most common cause of dementia, is a neurodegenerative disease resulting from extracellular and intracellular deposits of amyloid-β (Aβ) and neurofibrillary tangles in the brain. Although many clinical studies evaluating pharmacological approaches have been conducted, most have shown disappointing results; thus, innovative strategies other than drugs have been actively attempted. Objective: This study aims to explore low-dose radiation therapy (LDRT) for the treatment of patients with AD based on preclinical evidence, case reports, and a small pilot trial in humans. Methods: This study is a phase II, multicenter, prospective, …single-blinded, randomized controlled trial that will evaluate the efficacy and safety of LDRT to the whole brain using a linear accelerator in patients with mild AD. Sixty participants will be randomly assigned to three groups: experimental I (24 cGy/6 fractions), experimental II (300 cGy/6 fractions), or sham RT group (0 cGy/6 fractions). During LDRT and follow-up visits after LDRT, possible adverse events will be assessed by the physician’s interview and neurological examinations. Furthermore, the effectiveness of LDRT will be measured using neurocognitive function tests and imaging tools at 6 and 12 months after LDRT. We will also monitor the alterations in cytokines, Aβ42 /Aβ40 ratio, and tau levels in plasma. Our primary endpoint is the change in cognitive function test scores estimated by the Alzheimer’s Disease Assessment Scale-Korea compared to baseline after 6 months of LDRT. Conclusions: This study is registered at ClinicalTrials.gov [NCT05635968] and is currently recruiting patients. This study will provide evidence that LDRT is a new treatment strategy for AD. Show more

Keywords: Alzheimer’s disease, low-dose radiation therapy, protocol, randomized controlled trial

DOI: 10.3233/JAD-230241

Citation: Journal of Alzheimer's Disease, vol. 95, no. 3, pp. 1263-1272, 2023