Journal of Alzheimer's Disease Reports - Volume 7, issue 1

Authors: Ash, Sharon | Nevler, Naomi | Irwin, David J. | Shellikeri, Sanjana | Rascovsky, Katya | Shaw, Leslie | Lee, Edward B. | Trojanowski, John Q. | Grossman, Murray

Article Type: Research Article

Abstract: Background: Apraxia of speech (AOS) is a core feature of nonfluent/agrammatic primary progressive aphasia (naPPA), but its precise characteristics and the prevalence of AOS features in spontaneous speech are debated. Objective: To assess the frequency of features of AOS in the spontaneous, connected speech of individuals with naPPA and to evaluate whether these features are associated with an underlying motor disorder such as corticobasal syndrome or progressive supranuclear palsy. Methods: We examined features of AOS in 30 patients with naPPA using a picture description task. We compared these patients to 22 individuals with behavioral variant frontotemporal …dementia and 30 healthy controls. Each speech sample was evaluated perceptually for lengthened speech segments and quantitatively for speech sound distortions, pauses between and within words, and articulatory groping. We compared subgroups of naPPA with and without at least two features of AOS to assess the possible contribution of a motor impairment to speech production deficits. Results: naPPA patients produced both speech sound distortions and other speech sound errors. Speech segmentation was found in 27/30 (90%) of individuals. Distortions were identified in 8/30 (27%) of individuals, and other speech sound errors occurred in 18/30 (60%) of individuals. Frequent articulatory groping was observed in 6/30 (20%) of individuals. Lengthened segments were observed rarely. There were no differences in the frequencies of AOS features among naPPA subgroups as a function of extrapyramidal disease. Conclusion: Features of AOS occur with varying frequency in the spontaneous speech of individuals with naPPA, independently of an underlying motor disorder. Show more

Keywords: Language, phonetics, primary progressive nonfluent aphasia, speech, verbal apraxia

DOI: 10.3233/ADR-220089

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 589-604, 2023

Authors: Bussè, Cinzia | Zorzi, Giovanni | Pettenuzzo, Ilaria | Mozzetta, Stefano | Cagnin, Annachiara

Article Type: Short Communication

Abstract: Behavioral frontotemporal dementia (bvFTD) may present with episodic memory deficits. In 38 patients with bvFTD and 61 with Alzheimer’s disease (AD) specific measures of verbal memory (learning curves and serial position effects) were studied through the Rey Auditory Verbal Learning test. Forty-two percent of bvFTD showed deficits of delayed recall memory similar to that found in AD including the serial position effects. Amnestic bvFTD had more severe atrophy in the left mesial temporal lobe than non-amnestic bvFTD. AD-like memory deficits are not infrequent in bvFTD and may be in part related to mesial temporal lobe atrophy.

Keywords: Alzheimer’s disease, dementia, frontotemporal dementia, learning, memory

DOI: 10.3233/ADR-230015

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 605-612, 2023

Authors: Ratis, Renan C. | Dacoregio, Maria I. | Simão-Silva, Daiane P. | Mateus, Rogério P. | Machado, Luciana P.B. | Bonini, Juliana S. | Silva, Weber Claudio Francisco Nunes da

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) has several risk factors. APOE4 is the main one, and it has been suggested that there may be a synergy between it and BCHE-K as a risk factor. Objective: To investigate the association between APOE4 and BCHE-K as a risk factor for AD. Methods: We searched PubMed, Web of Science, Embase, and Scopus on August 8, 2021 for studies that analyzed the association of APOE4 and BCHE-K with AD. The random effect model was performed in meta-analysis according to age group. A chi-square was performed with …the meta-analysis data to verify if the effect found is not associated only with the E4 allele. Results: Twenty-one studies with 6,853 subjects (3,528 AD and 3,325 Controls) were included in the meta-analysis. The quality of the evidence is moderate. There is a positive E4-K association for subjects with AD as shown by the odds ratio of 3.43. The chi-square meta test, which measures the probability that the E4-K association is due to chance, has an odds ratio of 6.155, indicating that the E4-K association is not a random event. The odds ratio of an E4-K association in subjects with AD increases to OR 4.46 for the 65- to 75-year-old group and OR 4.15 for subjects older than 75 years. The probability that the E4-K association is due to chance is ruled out by chi-square meta test values of OR 8.638 and OR 9.558. Conclusion: The synergy between APOE4 and BCHE-K is a risk factor for late-onset AD. Show more

Keywords: Alzheimer’s disease, APOE, BaβAC, cholinesterase, dementia, genetics, odds ratio

DOI: 10.3233/ADR-220084

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 613-625, 2023

Authors: Oh, Jean | Crockett, Rachel A. | Hsu, Chun-Liang | Dao, Elizabeth | Tam, Roger | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: As the aging population grows, there is an increasing need to develop accessible interventions against risk factors for cognitive impairment and dementia, such as cerebral small vessel disease (CSVD). The progression of white matter hyperintensities (WMHs), a key hallmark of CSVD, can be slowed by resistance training (RT). We hypothesize RT preserves white matter integrity and that this preservation is associated with improved cognitive and physical function. Objective: To determine if RT preserves regional white matter integrity and if any changes are associated with cognitive and physical outcomes. Methods: Using magnetic resonance imaging data from …a 12-month randomized controlled trial, we compared the effects of a twice-weekly 60-minute RT intervention versus active control on T1-weighted over T2-weighted ratio (T1w/T2w; a non-invasive proxy measure of white matter integrity) in a subset of study participants (N = 21 females, mean age = 69.7 years). We also examined the association between changes in T1w/T2w with two key outcomes of the parent study: (1) selective attention and conflict resolution, and (2) peak muscle power. Results: Compared with an active control group, RT increased T1w/T2w in the external capsule (p  = 0.024) and posterior thalamic radiations (p  = 0.013) to a greater degree. Increased T1w/T2w in the external capsule was associated with an increase in peak muscle power (p  = 0.043) in the RT group. Conclusion: By maintaining white matter integrity, RT may be a promising intervention to counteract the pathological changes that accompany CSVD, while improving functional outcomes such as muscle power. Show more

Keywords: Aged, Alzheimer’s disease, cerebral small vessel diseases, dementia, magnetic resonance imaging, randomized controlled trial, resistance training, white matter

DOI: 10.3233/ADR-220113

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 627-639, 2023

Authors: Cahan, Joshua G. | Vassar, Robert | Bonakdarpour, Borna

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers of amyloid-β42 (Aβ42 ) and phosphorylated-tau help clinicians accurately diagnose Alzheimer’s disease (AD). Whether biomarkers help prognosticate behavioral and psychological symptoms of dementia (BPSD) is unclear. Objective: Determine whether CSF biomarker levels aid prognostication of BPSD in AD. Methods: This retrospective cohort study included patients over 65 with a diagnosis of AD based on CSF biomarkers. We measured time from CSF testing to the first antipsychotic use in the following months. We then analyzed time to antipsychotic (AP) use with respect to Aβ42 , total tau, phosphorylated tau, and amyloid-to-tau …index using a survival analysis approach. Results: Of 86 AD patients (average 72±5 years, 46.5% male), 11 patients (12.7%) received APs following CSF testing. Patients with Aβ42 below the median had sooner time-to-AP use. This was significant on a log-rank test (p  = 0.04). There was no difference in time-to-AP use if the group was stratified by levels of total tau, phosphorylated tau, or amyloid-to-tau index. Conclusion: These results suggest a relationship between lower CSF Aβ42 levels and sooner AP use. This supports prior reports suggesting a correlation between BPSD and Aβ deposition on PET. These results highlight the need for further prospective studies on Aβ levels and BPSD. Show more

Keywords: Alzheimer’s disease, antipsychotic agents, behavioral and psychological symptoms of dementia, biomarkers, dementia, neurodegenerative disease

DOI: 10.3233/ADR-220064

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 641-647, 2023

Authors: Saiyed, Nazia | Yilmaz, Ali | Vishweswariah, Sangeetha | Maiti, Amit K. | Ustun, Ilyas | Bartolone, Sarah | Brown-Hughes, Travonia | Thorpe Jr , Roland J. | Osentoski, Tammy | Ruff, Stacey | Pai, Amita | Maddens, Michael | Imam, Khaled | Graham, Stewart F.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia, accounting for 80% of all cases. Mild cognitive impairment (MCI) is a transitional state between normal aging and AD. Early detection is crucial, as irreversible brain damage occurs before symptoms manifest. Objective: This study aimed to identify potential biomarkers for early detection of AD by analyzing urinary cytokine concentrations. We investigated 37 cytokines in AD, MCI, and cognitively normal individuals (NC), assessing their associations with AD development. Methods: Urinary cytokine concentrations were measured in AD (n  = 25), MCI (n  = 25), and NC (n  = 26) patients. …IL6ST and MMP-2 levels were compared between AD and NC, while TNFRSF8, IL6ST, and IL-19 were assessed in AD versus MCI. Diagnostic models distinguished AD from NC, and in-silico analysis explored molecular mechanisms related to AD. Results: Significant perturbations in IL6ST and MMP-2 concentrations were observed in AD urine compared to NC, suggesting their potential as biomarkers. TNFRSF8, IL6ST, and IL-19 differed significantly between AD and MCI, implicating them in disease progression. Diagnostic models exhibited promising performance (AUC: 0.59–0.79, sensitivity: 0.72–0.80, specificity: 0.56–0.78) in distinguishing AD from NC. In-silico analysis revealed molecular insights, including relevant non-coding RNAs, microRNAs, and transcription factors. Conclusion: This study establishes significant associations between urinary cytokine concentrations and AD and MCI. IL6ST, MMP-2, TNFRSF8, IL6ST, and IL-19 emerge as potential biomarkers for early detection of AD. In-silico analysis enhances understanding of molecular mechanisms in AD. Further validation and exploration of these biomarkers in larger cohorts are warranted to assess their clinical utility. Show more

Keywords: Alzheimer’s disease, biomarkers, cytokines, inflammation, mild cognitive impairment, urine

DOI: 10.3233/ADR-220081

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 649-657, 2023

Authors: Roth, Sophie | Burnie, Nerida | Suridjan, Ivonne | Yan, Jessie T. | Carboni, Margherita

Article Type: Research Article

Abstract: Background: Diagnostic pathways for patients presenting with cognitive complaints may vary across geographies. Objective: To describe diagnostic pathways of patients presenting with cognitive complaints across 6 countries. Methods: This real-world, cross-sectional study analyzed chart-extracted data from healthcare providers (HCPs) for 6,744 patients across China, France, Germany, Spain, UK, and the US. Results: Most common symptoms at presentation were cognitive (memory/amnestic; 89.86%), followed by physical/behavioral (87.13%). Clinical/cognitive tests were used in > 95%, with Mini-Mental State Examination being the most common cognitive test (79.0%). Blood tests for APOE ɛ4/other mutations, or to rule out treatable causes, …were used in half of the patients. Clinical and cognitive tests were used at higher frequency at earlier visits, and amyloid PET/CSF biomarker testing at higher frequency at later visits. The latter were ordered at low rates even by specialists (across countries, 5.7% to 28.7% for amyloid PET and 5.0% to 27.3% for CSF testing). Approximately half the patients received a diagnosis (52.1% of which were Alzheimer’s disease [AD]). Factors that influenced risk of not receiving a diagnosis were HCP type (higher for primary care physicians versus specialists) and region (highest in China and Germany). Conclusion: These data highlight variability in AD diagnostic pathways across countries and provider types. About 45% of patients are referred/told to ‘watch and wait’. Improvements can be made in the use of amyloid PET and CSF testing. Efforts should focus on further defining biomarkers for those at risk for AD, and on dismantling barriers such low testing capacity and reimbursement challenges. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, diagnosis, neurology, neuropsychological tests, standard of care, surveys and questionnaires

DOI: 10.3233/ADR230007

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 659-674, 2023

Authors: Fotuhi, Majid | Khorrami, Noah D. | Raji, Cyrus A.

Article Type: Research Article

Abstract: Background: Non-pharmacologic interventions can potentially improve cognitive function, sleep, and/or mood in patients with attention-deficit/hyperactive disorder (ADHD), post-concussion syndrome (PCS), or memory loss. Objective: We evaluated the benefits of a brain rehabilitation program in an outpatient neurology practice that consists of targeted cognitive training, lifestyle coaching, and electroencephalography (EEG)-based neurofeedback, twice weekly (90 minutes each), for 12 weeks. Methods: 223 child and adult patients were included: 71 patients with ADHD, 88 with PCS, and 64 with memory loss (mild cognitive impairment or subjective cognitive decline). Patients underwent a complete neurocognitive evaluation, including tests for Verbal Memory, …Complex Attention, Processing Speed, Executive Functioning, and Neurocognition Index. They completed questionnaires about sleep, mood, diet, exercise, anxiety levels, and depression—as well as underwent quantitative EEG—at the beginning and the end of the program. Results: Pre-post test score comparison demonstrated that all patient subgroups experienced statistically significant improvements on most measures, especially the PCS subgroup, which experienced significant score improvement on all measures tested (p ≤0.0011; d z ≥0.36). After completing the program, 60% to 90% of patients scored higher on cognitive tests and reported having fewer cognitive and emotional symptoms. The largest effect size for pre-post score change was improved executive functioning in all subgroups (ADHD d z = 0.86; PCS d z = 0.83; memory d z = 1.09). Conclusion: This study demonstrates that a multimodal brain rehabilitation program can have benefits for patients with ADHD, PCS, or memory loss and supports further clinical trials in this field. Show more

Keywords: Alzheimer’s disease, attention-deficit/hyperactivity disorder, electroencephalography, memory, neurofeedback, post-concussion syndrome, rehabilitation, subjective cognitive decline, subjective cognitive impairment, traumatic brain injury

DOI: 10.3233/ADR-220091

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 675-697, 2023

Authors: Guarnera, Jade | Yuen, Eva | Macpherson, Helen

Article Type: Review Article

Abstract: Social concepts such as loneliness and social isolation are fairly new factors that have been recently gaining attention as to their involvement in changes in cognitive function and association with dementia. The primary aim of this narrative review was to describe the current understanding of how loneliness and social isolation influence cognitive aging and how they are linked to dementia. Studies have shown that there is an association between loneliness, social isolation, and reduced cognitive function, in older adults, across multiple cognitive domains, as well as a heightened risk of dementia. Numerous changes to underlying neural biomechanisms including cortisol secretion …and brain volume alterations (e.g., white/grey matter, hippocampus) may contribute to these relationships. However, due to poor quality research, mixed and inconclusive findings, and issues accurately defining and measuring loneliness and social isolation, more consistent high-quality interventions are needed to determine whether studies addressing loneliness and social isolation can impact longer term risk of dementia. This is especially important given the long-term impact of the COVID-19 pandemic on social isolation in older people is yet to be fully understood. Show more

Keywords: Aging, alzheimer’s disease, cognition, dementia, loneliness, social isolation

DOI: 10.3233/ADR-230011

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 699-714, 2023

Authors: Michaelian, Johannes C. | McCade, Donna | Hoyos, Camilla M. | Brodaty, Henry | Harrison, Fleur | Henry, Julie D. | Guastella, Adam J. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Individuals living with Alzheimer’s disease (AD) demonstrate extensive deficits in social cognition. To date, no studies have investigated the feasibility of an intranasal oxytocin (INOT) treatment to improve social cognition in individuals living with AD. Objective: We conducted a pilot trial to determine recruitment feasibility, enrolment acceptability, and adherence to an INOT treatment to inform on the subsequent design of a future randomized controlled trial (RCT). We also estimated the effect sizes of potential social cognitive function outcome measures related to participants and their caregivers. Methods: Four individuals with AD were enrolled in a single-center, …randomized, double-blind, placebo-controlled crossover trial involving a one-week treatment period with both INOT (72 IU twice daily) and placebo. Results: All participants reported no treatment-causative or serious adverse events following repeated INOT administration. While enrolment acceptability (100%) and INOT adherence (placebo, 95%; INOT, 98%) were excellent, feasibility of recruitment was not acceptable (i.e., n  = 4/58 individuals screened met inclusion criteria). However, positive/large effects were associated with secondary outcomes of self-reported health and wellbeing, caregiver ‘burden’, intimacy and interpersonal-bonding, following repeated INOT administration. No positive effects were associated with participant outcomes of social cognition. Conclusion: This pilot RCT provides first evidence that INOT administration in individuals living with AD is safe and well-tolerated. Despite limitations in sample size, moderate-to-large effect size improvements were identified in participant health outcomes as well as core social cognitive functions and ‘burden’ as reported by a caregiver. This suggests potential broad-ranging beneficial effects of INOT which should be assessed in future RCTs. Show more

Keywords: Alzheimer’s disease, dementia, intranasal oxytocin, oxytocin nasal spray, social cognition

DOI: 10.3233/ADR-230013

Citation: Journal of Alzheimer's Disease Reports, vol. 7, no. 1, pp. 715-729, 2023