Journal of Alzheimer's Disease - Volume 80, issue 3

Authors: Johnson, Adrienne L. | Nystrom, Naomi C. | Piper, Megan E. | Cook, Jessica | Norton, Derek L. | Zuelsdorff, Megan | Wyman, Mary F. | Flowers Benton, Susan | Lambrou, Nickolas H. | O’Hara, John | Chin, Nathaniel A. | Asthana, Sanjay | Carlsson, Cynthia | Gleason, Carey E.

Article Type: Research Article

Abstract: Background: To fully characterize the risk for dementia associated with cigarette smoking, studies must consider competing risks that hinder the observation of dementia or modify the chance that dementia occurs (i.e., death). Extant research examining the competing risks fails to account for the occurrence of death following dementia, limiting our understanding of the relation between smoking and dementia. Objective: Examine the impact of smoking status, lifetime smoking exposure, and duration of abstinence on incident dementia, death following dementia, and death without dementia. Methods: Multi-state models estimated hazard ratios (HR) for 95% confidence interval (CI) of 10,681 …cognitively healthy adults for transition from baseline to dementia, baseline to death, and dementia to death based on smoking status, lifetime cigarette exposure, and abstinence duration. Results: Compared to never smokers, current smokers had increased risk of dementia (HR = 1.66; 95% CI 1.18– 2.32; p  = 0.004), and death from baseline (HR = 2.98; 95% CI 2.24– 3.98; p  < 0.001) and incident dementia (HR = 1.88; 95% CI 1.08– 3.27; p  = 0.03). Pack years increased risk of death from baseline (HR = 1.01; 95% CI 1.00– 1.01; p  < 0.001), but not dementia risk (HR = 1.00; 95% CI 1.00– 1.00; p  = 0.78) or death following dementia (HR = 1.01; 95% CI 1.00– 1.01; p  = 0.05). Recent quitters (quit < 10 years), compared to never smokers, had increased risk of death after baseline (HR = 2.31; 95% CI 1.55– 3.43; p  < 0.001), but not dementia (HR = 1.17; 95% CI 0.73– 1.88; p  = 0.52) or death following dementia (HR = 1.01; 95% CI 0.42– 2.41; p  = 0.99). Conclusion: Current smoking increases the risk for dementia and death, but dementia is better attributed to smoking recency than lifetime exposure. Smoking cessation at any age might reduce these risks for cognitively healthy individuals. Show more

Keywords: Cigarette smoking, dementia, mortality, smoking cessation, statistics

DOI: 10.3233/JAD-201332

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1013-1023, 2021

Authors: Arlati, Sara | Di Santo, Simona Gabriella | Franchini, Flaminia | Mondellini, Marta | Filiputti, Beatrice | Luchi, Matilde | Ratto, Federica | Ferrigno, Giancarlo | Sacco, Marco | Greci, Luca

Article Type: Research Article

Abstract: Background: Virtual reality (VR) has recently emerged as a promising means for the administration of cognitive training of seniors at risk of dementia. Immersive VR could result in increased engagement and performances; however, its acceptance in older adults with cognitive deficits still has to be assessed. Objective: To assess acceptance and usability of an immersive VR environment requiring real walking and active participants’ interaction. Methods: 58 seniors with mild cognitive impairment (MCI, n  = 24) or subjective cognitive decline (SCD, n  = 31) performed a shopping task in a virtual supermarket displayed through a head-mounted display. Subjective and …objective outcomes were evaluated. Results: Immersive VR was well-accepted by all but one participant (TAM3 positive subscales > 5.33), irrespective of the extent of cognitive decline. Participants enjoyed the experience (spatial presence 3.51±0.50, engagement 3.85±0.68, naturalness 3.85±0.82) and reported negligible side-effects (SSQ: 3.74; q1-q3:0–16.83). The environment was considered extremely realistic, such as to induce potentially harmful behaviors: one participant fell while trying to lean on a virtual shelf. Older participants needed more time to conclude trials. Participants with MCI committed more errors in grocery items’ selection and experienced less “perceived control” over the environment. Conclusion: Immersive VR was acceptable and enjoyable for older adults in both groups. Cognitive deficits could induce risky behaviors, and cause issues in the interactions with virtual items. Further studies are needed to confirm acceptance of immersive VR in individuals at risk of dementia, and to extend the results to people with more severe symptoms. Show more

Keywords: Acceptance, cybersickness, immersive virtual reality, mild cognitive impairment, subjective cognitive decline, usability

DOI: 10.3233/JAD-201431

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1025-1038, 2021

Authors: Li, Bingyu | Bi, Jiefeng | Wei, Chang | Sha, Feng

Article Type: Research Article

Abstract: Background: How specific activities influence cognitive decline among different age groups, especially the late middle-aged and the early old, remains inadequately studied. Objective: To examine the association between specific activities with trajectories of cognitive functions in different age groups in China. Methods: A longitudinal cohort study was conducted based on data from the China Health and Retirement Longitudinal Study (CHARLS). Mixed effects growth models were applied to analyze the association between specific activities and cognitive functions. Results: Interacting with friends (infrequent: β= 0.13, confidence interval [CI] = 0.03 to 0.22; daily: β= 0.19, CI = 0.09 to 0.28), playing Mah-jong …or other games (infrequent: β= 0.12, CI = 0.02 to 0.22; daily:β= 0.26, CI = 0.10 to 0.42), infrequent providing help to others (β= 0.24, CI = 0.11 to 0.37), and going to a sport (infrequent: β= 0.31, CI = 0.08 to 0.54); daily: β= 0.22, CI = 0.05 to 0.38) are significantly associated with participants’ memory. Infrequently playing Mah-jong or other games (β= 0.30, CI = 0.17 to 0.43) and daily sports (β= 0.24, CI = 0.03 to 0.45) are significantly associated with better mental status. Effect of each activity varies among population of different age, education level, gender, and residence. Conclusion: This study identifies four social activities that are associated with better cognitive functions, and provides a comprehensive, in-depth understanding on the specific protective effect of each activity among different subgroups. Show more

Keywords: Activities, cognitive functions, dementia

DOI: 10.3233/JAD-201268

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1039-1050, 2021

Authors: Klein, Julia | Yan, Xinyu | Johnson, Aubrey | Tomljanovic, Zeljko | Zou, James | Polly, Krista | Honig, Lawrence S. | Brickman, Adam M. | Stern, Yaakov | Devanand, D.P. | Lee, Seonjoo | Kreisl, William C.

Article Type: Research Article

Abstract: Background: Olfactory impairment is evident in Alzheimer’s disease (AD); however, its precise relationships with clinical biomarker measures of tau pathology and neuroinflammation are not well understood. Objective: To determine if odor identification performance measured with the University of Pennsylvania Smell Identification Test (UPSIT) is related to in vivo measures of tau pathology and neuroinflammation. Methods: Cognitively normal and cognitively impaired participants were selected from an established research cohort of adults aged 50 and older who underwent neuropsychological testing, brain MRI, and amyloid PET. Fifty-four participants were administered the UPSIT. Forty-one underwent 18 F-MK-6240 PET (measuring …tau pathology) and fifty-three underwent 11 C-PBR28 PET (measuring TSPO, present in activated microglia). Twenty-three participants had lumbar puncture to measure CSF concentrations of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ42 ). Results: Low UPSIT performance was associated with greater18 F-MK-6240 binding in medial temporal cortex, hippocampus, middle/inferior temporal gyri, inferior parietal cortex, and posterior cingulate cortex (p  < 0.05). Similar relationships were seen for 11 C-PBR28. These relationships were primarily driven by amyloid-positive participants. Lower UPSIT performance was associated with greater CSF concentrations of t-tau and p-tau (p  < 0.05). Amyloid status and cognitive status exhibited independent effects on UPSIT performance (p  < 0.01). Conclusion: Olfactory identification deficits are related to extent of tau pathology and neuroinflammation, particularly in those with amyloid pathophysiology. The independent association of amyloid-positivity and cognitive impairment with odor identification suggests that low UPSIT performance may be a marker for AD pathophysiology in cognitive normal individuals, although impaired odor identification is associated with both AD and non-AD related neurodegeneration. NCT Registration Numbers: NCT03373604; NCT02831283 Show more

Keywords: Alzheimer’s disease, anosmia, microglia, olfaction, tau proteins

DOI: 10.3233/JAD-201149

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1051-1065, 2021

Authors: Monllor, Paloma | Giraldo, Esther | Badia, Mari-Carmen | de la Asuncion, Jose Garcia | Alonso, Maria-Dolores | Lloret, Ana | Vina, Jose

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia and biomarkers are essential to help in the diagnosis of this disease. Image techniques and cerebrospinal fluid (CSF) biomarkers are limited in their use because they are expensive or invasive. Thus, the search for blood-borne biomarkers is becoming central to the medical community. Objective: The main objective of this study is the evaluation of three serum proteins as potential biomarkers in AD patients. Methods: We recruited 27 healthy controls, 19 mild cognitive impairment patients, and 17 AD patients. Using the recent A/T/N classification we split …our population into two groups (AD and control). We used ELISA kits to determine Aβ42 , tau, and p-tau in CSF and clusterin, PKR, and RAGE in serum. Results: The levels of serum clusterin, PKR, and RAGE were statistically different in the AD group compared to controls. These proteins showed a statistically significant correlation with CSF Aβ42 . So, they were selected to generate an AD detection model showing an AUC-ROC of 0.971 (CI 95%, 0.931–0.998). Conclusion: The developed model based on serum biomarkers and other co-variates could reflect the AD core pathology. So far, not one single blood-biomarker has been described, with effectiveness offering high sensitivity and specificity. We propose that the complexity of AD pathology could be reflected in a set of biomarkers also including clinical features of the patients. Show more

Keywords: Alzheimer’s disease, biomarkers, clusterin, dementia, RAGE (receptor for advanced glycation end products), ROC curve

DOI: 10.3233/JAD-201443

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1067-1077, 2021

Authors: Nagaraj, Sanjay | Duong, Tim Q.

Article Type: Research Article

Abstract: Background: Many neurocognitive and neuropsychological tests are used to classify early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and Alzheimer’s disease (AD) from cognitive normal (CN). This can make it challenging for clinicians to make efficient and objective clinical diagnoses. It is possible to reduce the number of variables needed to make a reasonably accurate classification using machine learning. Objective: The goal of this study was to develop a deep learning algorithm to identify a few significant neurocognitive tests that can accurately classify these four groups. We also derived a simplified risk-stratification score model for diagnosis. …Methods: Over 100 variables that included neuropsychological/neurocognitive tests, demographics, genetic factors, and blood biomarkers were collected from 383 EMCI, 644 LMCI, 394 AD patients, and 516 cognitive normal from the Alzheimer’s Disease Neuroimaging Initiative database. A neural network algorithm was trained on data split 90% for training and 10% testing using 10-fold cross-validation. Prediction performance used area under the curve (AUC) of the receiver operating characteristic analysis. We also evaluated five different feature selection methods. Results: The five feature selection methods consistently yielded the top classifiers to be the Clinical Dementia Rating Scale - Sum of Boxes, Delayed total recall, Modified Preclinical Alzheimer Cognitive Composite with Trails test, Modified Preclinical Alzheimer Cognitive Composite with Digit test, and Mini-Mental State Examination. The best classification model yielded an AUC of 0.984, and the simplified risk-stratification score yielded an AUC of 0.963 on the test dataset. Conclusion: The deep-learning algorithm and simplified risk score accurately classifies EMCI, LMCI, AD and CN patients using a few common neurocognitive tests. Show more

Keywords: Alzheimer’s disease, artificial intelligence, deep learning, dementia, machine learning, mild cognitive impairment

DOI: 10.3233/JAD-201438

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1079-1090, 2021

Authors: Devous Sr., Michael D. | Fleisher, Adam S. | Pontecorvo, Michael J. | Lu, Ming | Siderowf, Andrew | Navitsky, Michael | Kennedy, Ian | Southekal, Sudeepti | Harris, Thomas S. | Mintun, Mark A.

Article Type: Research Article

Abstract: Background: Tau neurofibrillary tangle burden increases with Alzheimer’s disease (AD) stage and correlates with degree of cognitive impairment. Tau PET imaging could facilitate understanding the relationship between tau pathology and cognitive impairment. Objective: Evaluate the relationship between 18 F flortaucipir uptake patterns and cognition across multiple cognitive domains. Methods: We acquired flortaucipir PET scans in 84 amyloid-positive control, mild cognitive impairment (MCI), and AD subjects. Flortaucipir standardized uptake value ratio (SUVr) values were obtained from a neocortical volume of interest (VOI), a precuneus VOI, and VOIs defined by the correlation between flortaucipir SUVr images and domain-specific …cognitive tests. Cognitive assessments included Mini-Mental State Exam (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and a neuropsychological test battery (i.e., Wechsler Memory Scale-Revised Logical Memory (WMS-R), Trail Making Test, Boston Naming Test, Digit Symbol Substitution Test, Animal List Generation, WMS-R Digit Span, American National Adult Reading Test, Clock Drawing Test, Judgment of Line Orientation, and WMS-R Logical Memory II (Delayed Recall)) and the Functional Activities Questionnaire (FAQ). Correlation analyses compared regional and voxel-wise VOIs to cognitive scores. Results: Subjects included 5 controls, 47 MCI, and 32 AD subjects. Significant correlations were seen between both flortaucipir and florbetapir SUVrs and MMSE, ADAS-Cog, and FAQ. Cognitive impairment was associated with increased flortaucipir uptake in regionally specific patterns consistent with the neuroanatomy underlying specific cognitive tests. Conclusion: Flortaucipir SUVr values demonstrated significant inverse correlations with cognitive scores in domain-specific patterns. Findings support the hypothesis that PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD. Show more

Keywords: Alzheimer’s disease, AV-1451, cognition, flortaucipir, PET, tau imaging

DOI: 10.3233/JAD-200808

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1091-1104, 2021

Authors: Merighi, Stefania | Battistello, Enrica | Casetta, Ilaria | Gragnaniello, Daniela | Poloni, Tino Emanuele | Medici, Valentina | Cirrincione, Alice | Varani, Katia | Vincenzi, Fabrizio | Borea, Pier Andrea | Gessi, Stefania

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative pathology covering about 70%of all cases of dementia. Adenosine, a ubiquitous nucleoside, plays a key role in neurodegeneration, through interaction with four receptor subtypes. The A2A receptor is upregulated in peripheral blood cells of patients affected by Parkinson’s and Huntington’s diseases, reflecting the same alteration found in brain tissues. However, whether these changes are also present in AD pathology has not been determined. Objective: In this study we verified any significant difference between AD cases and controls in both brain and platelets and we evaluated whether peripheral A2A receptors …may reflect the status of neuronal A2A receptors. Methods: We evaluated the expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, in postmortem AD patients and control subjects, through [3 H]ZM 241385 binding experiments. The same analysis was performed in peripheral platelets from AD patients versus controls. Results: The expression of A2A receptors in frontal white matter, frontal gray matter, and hippocampus/entorhinal cortex, revealed a density (Bmax) of 174±29, 219±33, and 358±84 fmol/mg of proteins, respectively, in postmortem AD patients in comparison to 104±16, 103±19, and 121±20 fmol/mg of proteins in controls (p  < 0.01). The same trend was observed in peripheral platelets from AD patients versus controls (Bmax of 214±17 versus 95±4 fmol/mg of proteins, respectively, p  < 0.01). Conclusion: AD subjects show significantly higher A2A receptor density than controls. Values on platelets seem to correlate with those in the brain supporting a role for A2A receptor as a possible marker of AD pathology and drug target for novel therapies able to modify the progression of dementia. Show more

Keywords: A2A adenosine receptor antagonist, A2A adenosine receptor overexpression, Alzheimer’s disease, biomarker, drug target, platelets

DOI: 10.3233/JAD-201437

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1105-1117, 2021

Authors: Cuttler, Jerry M. | Abdellah, Eslam | Goldberg, Yael | Al-Shamaa, Sarmad | Symons, Sean P. | Black, Sandra E. | Freedman, Morris

Article Type: Research Article

Abstract: Background: In 2015, a patient in hospice with Alzheimer’s disease (AD) was treated with ionizing radiation to her brain using repeated CT scans. Improvement in cognition, speech, movement, and appetite was observed. These improvements were so momentous that she was discharged from the hospice to a long-term care home. Based on this case, we conducted a pilot clinical trial to examine the effect of low-dose ionizing radiation (LDIR) in severe AD. Objective: To determine whether the previously reported benefits of LDIR in a single case with AD could be observed again in other cases with AD when the …same treatments are given. Methods: In this single-arm study, four patients were treated with three consecutive treatments of LDIR, each spaced two weeks apart. Qualitative changes in communication and behavior with close relatives were observed and recorded. Quantitative measures of cognition and behavior were administered pre and post LDIR treatments. Results: Minor improvements on quantitative measures were noted in three of the four patients following treatment. However, the qualitative observations of cognition and behavior suggested remarkable improvements within days post-treatment, including greater overall alertness. One patient showed no change. Conclusion: LDIR may be a promising, albeit controversial therapy for AD. Trials of patients with less severe AD, double-blind and placebo-controlled, should be carried out to determine the benefits of LDIR. Quantitative measures are needed that are sensitive to the remarkable changes induced by LDIR, such as biological markers of oxidative stress that are associated with AD. Show more

Keywords: Adaptive protection systems, Alzheimer’s disease, low-dose ionizing radiation, oxidative damage, therapy

DOI: 10.3233/JAD-200620

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1119-1128, 2021

Authors: Wright, Clinton B. | DeRosa, Janet T. | Moon, Michelle P. | Strobino, Kevin | DeCarli, Charles | Cheung, Ying Kuen | Assuras, Stephanie | Levin, Bonnie | Stern, Yaakov | Sun, Xiaoyan | Rundek, Tatjana | Elkind, Mitchell S.V. | Sacco, Ralph L.

Article Type: Research Article

Abstract: Background: Variability in dementia rates across racial and ethnic groups has been estimated at 60%. Studies suggest disparities in Caribbean Hispanic and Black populations, but community-based data are limited. Objective: Estimate the prevalence of mild cognitive impairment (MCI) and dementia in the racially and ethnically diverse community-based Northern Manhattan Study cohort and examine sociodemographic, vascular risk factor, and brain imaging correlates. Methods: Cases of MCI and dementia were adjudicated by a team of neuropsychologists and neurologists and prevalence was estimated across race/ethnic groups. Ordinal proportional odds models were used to estimate race/ethnic differences in the prevalence …of MCI or dementia adjusting for sociodemographic variables (model 1), model 1 plus potentially modifiable vascular risk factors (model 2), and model 1 plus structural imaging markers of brain integrity (model 3). Results: There were 989 participants with cognitive outcome determinations (mean age 69±9 years; 68% Hispanic, 16% Black, 14% White; 62% women; mean (±SD) follow-up five (±0.6) years). Hispanic and Black participants had greater likelihood of MCI (20%) and dementia (5%) than White participants accounting for age and education differences. Hispanic participants had greater odds of MCI or dementia than both White and Black participants adjusting for sociodemographic variables, vascular risk factors, and brain imaging factors. White matter hyperintensity burden was significantly associated with greater odds of MCI or dementia (OR = 1.3, 1.1 to 1.6), but there was no significant interaction by race/ethnicity. Conclusion: In this diverse community-based cohort, cross-sectional data revealed significant race/ethnic disparities in the prevalence of MCI and dementia. Longer follow-up and incidence data are needed to further clarify these relationships. Show more

Keywords: African American, cohort studies, dementia, Hispanic American, mild cognitive impairment

DOI: 10.3233/JAD-201370

Citation: Journal of Alzheimer's Disease, vol. 80, no. 3, pp. 1129-1138, 2021