Journal of Alzheimer's Disease - Volume 82, issue 1

Authors: Libon, David J. | Baliga, Ganesh | Swenson, Rod | Au, Rhoda

Article Type: Introduction

Abstract: Technology has transformed the science and practice of medicine. In this special mini-forum, data using digital neuropsychological technology are reported. All of these papers demonstrate how coupling digital technology with standard paper and pencil neuropsychological tests are able to extract behavior not otherwise obtainable. As digital assessment methods mature, early identification of persons with emergent neurodegenerative and other neurological illness may be possible.

Keywords: Boston Process Approach, digital assessment, neuropsychology

DOI: 10.3233/JAD-210513

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 1-4, 2021

Authors: Emrani, Sheina | Lamar, Melissa | Price, Catherine | Baliga, Satya | Wasserman, Victor | Matusz, Emily F. | Saunders, Johnathan | Gietka, Vaughn | Strate, James | Swenson, Rod | Baliga, Ganesh | Libon, David J.

Article Type: Research Article

Abstract: Background: The model of executive attention proposes that temporal organization, i.e., the time necessary to bring novel tasks to fruition is an important construct that modulates executive control. Subordinate to temporal organization are the constructs of working memory, preparatory set, and inhibitory control. Objective: The current research operationally-defined the constructs underlying the theory of executive attention using intra-component latencies (i.e., reaction times) from a 5-span backward digit test from patients with suspected mild cognitive impairment (MCI). Methods: An iPad-version of the Backward Digit Span Test (BDT) was administered to memory clinic patients. Patients with (n  = 22) …and without (n  = 36) MCI were classified. Outcome variables included intra-component latencies for all correct 5-span serial order responses. Results: Average total time did not differ. A significant 2-group by 5-serial order latency interaction revealed the existence of distinct time epochs. Non-MCI patients produced slower latencies on initial (position 2-working memory/preparatory set) and latter (position 4-inhibitory control) correct serial order responses. By contrast, patients with MCI produced a slower latency for middle serial order responses (i.e., position 3-preparatory set). No group differences were obtained for incorrect 5-span test trials. Conclusion: The analysis of 5-span BDT serial order latencies found distinct epochs regarding how time was allocated in the context of successful test performance. Intra-component latencies obtained from tests assessing mental re-ordering may constitute useful neurocognitive biomarkers for emergent neurodegenerative illness. Show more

Keywords: Digit span, executive control, intra-component latency, mild cognitive impairment, temporal organization

DOI: 10.3233/JAD-201125

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 5-16, 2021

Authors: Andersen, Stacy L. | Sweigart, Benjamin | Glynn, Nancy W. | Wojczynski, Mary K. | Thyagarajan, Bharat | Mengel-From, Jonas | Thielke, Stephen | Perls, Thomas T. | Libon, David J. | Au, Rhoda | Cosentino, Stephanie | Sebastiani, Paola | on behalf of the Long Life Family Study

Article Type: Research Article

Abstract: Background: Coupling digital technology with traditional neuropsychological test performance allows collection of high-precision metrics that can clarify and/or define underlying constructs related to brain and cognition. Objective: To identify graphomotor and information processing trajectories using a digitally administered version of the Digit Symbol Substitution Test (DSST). Methods: A subset of Long Life Family Study participants (n  = 1,594) completed the DSST. Total time to draw each symbol was divided into ‘writing ’ and non-writing or ‘thinking ’ time. Bayesian clustering grouped participants by change in median time over intervals of eight consecutively drawn symbols across the 90 s …test. Clusters were characterized based on sociodemographic characteristics, health and physical function data, APOE genotype, and neuropsychological test scores. Results: Clustering revealed four ‘thinking ’ time trajectories, with two clusters showing significant changes within the test. Participants in these clusters obtained lower episodic memory scores but were similar in other health and functional characteristics. Clustering of ‘writing ’ time also revealed four performance trajectories where one cluster of participants showed progressively slower writing time. These participants had weaker grip strength, slower gait speed, and greater perceived physical fatigability, but no differences in cognitive test scores. Conclusion: Digital data identified previously unrecognized patterns of ‘writing ’ and ‘thinking ’ time that cannot be detected without digital technology. These patterns of performance were differentially associated with measures of cognitive and physical function and may constitute specific neurocognitive biomarkers signaling the presence of subtle to mild dysfunction. Such information could inform the selection and timing of in-depth neuropsychological assessments and help target interventions. Show more

Keywords: Aging, bayesian approach, boston process approach, digit symbol substitution test, executive function, graphomotor performance, neuropsychological tests

DOI: 10.3233/JAD-201119

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 17-32, 2021

Authors: Parjane, Natalia | Cho, Sunghye | Ash, Sharon | Cousins, Katheryn A.Q. | Shellikeri, Sanjana | Liberman, Mark | Shaw, Leslie M. | Irwin, David J. | Grossman, Murray | Nevler, Naomi

Article Type: Research Article

Abstract: Background: Progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) as well as non-fluent/agrammatic primary progressive aphasia (naPPA) are often associated with misfolded 4-repeat tau pathology, but the diversity of the associated speech features is poorly understood. Objective: Investigate the full range of acoustic and lexical properties of speech to test the hypothesis that PSPS-CBS show a subset of speech impairments found in naPPA. Methods: Acoustic and lexical measures, extracted from natural, digitized semi-structured speech samples using novel, automated methods, were compared in PSPS-CBS (n  = 87), naPPA (n  = 25), and healthy controls (HC, n  = 41). We …related these measures to grammatical performance and speech fluency, core features of naPPA, to neuropsychological measures of naming, executive, memory and visuoconstructional functioning, and to cerebrospinal fluid (CSF) phosphorylated tau (pTau) levels in patients with available biofluid analytes. Results: Both naPPA and PSPS-CBS speech produced shorter speech segments, longer pauses, higher pause rates, reduced fundamental frequency (f0) pitch ranges, and slower speech rate compared to HC. naPPA speech was distinct from PSPS-CBS with shorter speech segments, more frequent pauses, slower speech rate, reduced verb production, and higher partial word production. In both groups, acoustic duration measures generally correlated with speech fluency, measured as words per minute, and grammatical performance. Speech measures did not correlate with standard neuropsychological measures. CSF pTau levels correlated with f0 range in PSPS-CBS and naPPA. Conclusion: Lexical and acoustic speech features of PSPS-CBS overlaps those of naPPA and are related to CSF pTau levels. Show more

Keywords: Corticobasal syndrome, language, non-fluent primary progressive aphasia, progressive supranuclear palsy, speech, tauopathy

DOI: 10.3233/JAD-201132

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 33-45, 2021

Authors: Davoudi, Anis | Dion, Catherine | Amini, Shawna | Tighe, Patrick J. | Price, Catherine C. | Libon, David J. | Rashidi, Parisa

Article Type: Research Article

Abstract: Background: Advantages of digital clock drawing metrics for dementia subtype classification needs examination. Objective: To assess how well kinematic, time-based, and visuospatial features extracted from the digital Clock Drawing Test (dCDT) can classify a combined group of Alzheimer’s disease/Vascular Dementia patients versus healthy controls (HC), and classify dementia patients with Alzheimer’s disease (AD) versus vascular dementia (VaD). Methods: Healthy, community-dwelling control participants (n  = 175), patients diagnosed clinically with Alzheimer’s disease (n  = 29), and vascular dementia (n  = 27) completed the dCDT to command and copy clock drawing conditions. Thirty-seven dCDT command and 37 copy dCDT features were …extracted and used with Random Forest classification models. Results: When HC participants were compared to participants with dementia, optimal area under the curve was achieved using models that combined both command and copy dCDT features (AUC = 91.52%). Similarly, when AD versus VaD participants were compared, optimal area under the curve was, achieved with models that combined both command and copy features (AUC = 76.94%). Subsequent follow-up analyses of a corpus of 10 variables of interest determined using a Gini Index found that groups could be dissociated based on kinematic, time-based, and visuospatial features. Conclusion: The dCDT is able to operationally define graphomotor output that cannot be measured using traditional paper and pencil test administration in older health controls and participants with dementia. These data suggest that kinematic, time-based, and visuospatial behavior obtained using the dCDT may provide additional neurocognitive biomarkers that may be able to identify and tract dementia syndromes. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease/vascular spectrum dementia, digital clock drawing test, executive control, kinematics, vascular dementia

DOI: 10.3233/JAD-201129

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 47-57, 2021

Authors: Davoudi, Anis | Dion, Catherine | Formanski, Erin | Frank, Brandon E. | Amini, Shawna | Matusz, Emily F. | Wasserman, Victor | Penney, Dana | Davis, Randall | Rashidi, Parisa | Tighe, Patrick J. | Heilman, Kenneth M. | Au, Rhoda | Libon, David J. | Price, Catherine C.

Article Type: Research Article

Abstract: Background: Relative to the abundance of publications on dementia and clock drawing, there is limited literature operationalizing ‘normal’ clock production. Objective: To operationalize subtle behavioral patterns seen in normal digital clock drawing to command and copy conditions. Methods: From two research cohorts of cognitively-well participants age 55 plus who completed digital clock drawing to command and copy conditions (n  = 430), we examined variables operationalizing clock face construction, digit placement, clock hand construction, and a variety of time-based, latency measures. Data are stratified by age, education, handedness, and number anchoring. Results: Normative data are provided …in supplementary tables . Typical errors reported in clock research with dementia were largely absent. Adults age 55 plus produce symmetric clock faces with one stroke, with minimal overshoot and digit misplacement, and hands with expected hour hand to minute hand ratio. Data suggest digitally acquired graphomotor and latency differences based on handedness, age, education, and anchoring. Conclusion: Data provide useful benchmarks from which to assess digital clock drawing performance in Alzheimer’s disease and related dementias. Show more

Keywords: Older adult, aging, attention, cognition, dementia, digital technology, executive function, laterality, middle aged, neuropsychological tests, reference standards, short-term memory, clock drawing test

DOI: 10.3233/JAD-201249

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 59-70, 2021

Authors: Alves, Suélen Santos | Silva-Junior, Rui Milton Patrício da | Servilha-Menezes, Gabriel | Homolak, Jan | Šalković-Petrišić, Melita | Garcia-Cairasco, Norberto

Article Type: Review Article

Abstract: Almost 115 years ago, Alois Alzheimer described Alzheimer’s disease (AD) for the first time. Since then, many hypotheses have been proposed. However, AD remains a severe health public problem. The current medical approaches for AD are limited to symptomatic interventions and the complexity of this disease has led to a failure rate of approximately 99.6%in AD clinical trials. In fact, no new drug has been approved for AD treatment since 2003. These failures indicate that we are failing in mimicking this disease in experimental models. Although most studies have focused on the amyloid cascade hypothesis of AD, the literature has …made clear that AD is rather a multifactorial disorder. Therefore, the persistence in a single theory has resulted in lost opportunities. In this review, we aim to present the striking points of the long scientific path followed since the description of the first AD case and the main AD hypotheses discussed over the last decades. We also propose insulin resistance as a common link between many other hypotheses. Show more

Keywords: Alzheimer’s disease, biomarkers, insulin resistance, memory, metabolism

DOI: 10.3233/JAD-210234

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 71-105, 2021

Authors: Massett, Holly A. | Mitchell, Alexandra K. | Alley, Leah | Simoneau, Elizabeth | Burke, Panne | Han, Sae H. | Gallop-Goodman, Gerda | McGowan, Melissa

Article Type: Review Article

Abstract: Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) disproportionally affect Hispanic and Latino populations, yet Hispanics/Latinos are substantially underrepresented in AD/ADRD clinical research. Diverse inclusion in trials is an ethical and scientific imperative, as underrepresentation reduces the ability to generalize study findings and treatments across populations most affected by a disease. This paper presents findings from a narrative literature review (N = 210) of the current landscape of Hispanic/Latino participation in clinical research, including the challenges, facilitators, and communication channels to conduct culturally appropriate outreach efforts to increase awareness and participation of Hispanics/Latinos in AD/ADRD clinical research studies. Many challenges identified were systemic …in nature: lack of culturally relevant resources; staffing that does not represent participants’ cultures/language; eligibility criteria that disproportionately excludes Hispanics/Latinos; and too few studies available in Hispanic/Latino communities. The paper also details facilitators and messaging strategies to improve engagement and interest among Hispanics/Latinos in AD/ADRD research, starting with approaches that recognize and address the heterogeneity of the Hispanic/Latino ethnicity, and then, tailor outreach activities and programs to address their diverse needs and circumstances. The needs identified in this article represent longstanding failures to improve engagement and interest among Hispanics/Latinos in AD/ADRD research; we discuss how the field can move forward learning from the experiences of the COVID-19 pandemic. Show more

Keywords: Alzheimer’s disease, clinical trial, dementia, Hispanic, Latino, research subject recruitment

DOI: 10.3233/JAD-201463

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 107-127, 2021

Authors: Woodworth, Davis C. | Scambray, Kiana A. | Corrada, María M. | Kawas, Claudia H. | Sajjadi, S. Ahmad

Article Type: Review Article

Abstract: The oldest-old, those 85 years and older, are the fastest growing segment of the population and present with the highest prevalence of dementia. Given the importance of neuroimaging measures to understand aging and dementia, the objective of this study was to review neuroimaging studies performed in oldest-old participants. We used PubMed, Google Scholar, and Web of Science search engines to identify in vivo CT, MRI, and PET neuroimaging studies either performed in the oldest-old or that addressed the oldest-old as a distinct group in analyses. We identified 60 studies and summarized the main group characteristics and findings. Generally, oldest-old …participants presented with greater atrophy compared to younger old participants, with most studies reporting a relatively stable constant decline in brain volumes over time. Oldest-old participants with greater global atrophy and atrophy in key brain structures such as the medial temporal lobe were more likely to have dementia or cognitive impairment. The oldest-old presented with a high burden of white matter lesions, which were associated with various lifestyle factors and some cognitive measures. Amyloid burden as assessed by PET, while high in the oldest-old compared to younger age groups, was still predictive of transition from normal to impaired cognition, especially when other adverse neuroimaging measures (atrophy and white matter lesions) were also present. While this review highlights past neuroimaging research in the oldest-old, it also highlights the dearth of studies in this important population. It is imperative to perform more neuroimaging studies in the oldest-old to better understand aging and dementia. Show more

Keywords: Aged 80 and over, aging, Alzheimer’s disease, cognitive aging, magnetic resonance imaging, memory disorders, neuroimaging, neuropathology, positron emission tomography, tomography, x-ray computed

DOI: 10.3233/JAD-201578

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 129-147, 2021

Authors: Ye, Fan | Wu, Anshi

Article Type: Review Article

Abstract: Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer’s disease, which may be correlated with the role of …SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, mitochondrial autophagy, protective mechanism, SIRT1

DOI: 10.3233/JAD-210132

Citation: Journal of Alzheimer's Disease, vol. 82, no. 1, pp. 149-157, 2021