Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Chow, Tiffany E. | Veziris, Christina R. | Mundada, Nidhi | Martinez-Arroyo, Alexis I. | Kramer, Joel H. | Miller, Bruce L. | Rosen, Howard J. | Gorno-Tempini, Maria Luisa | Rankin, Katherine P. | Seeley, William W. | Rabinovici, Gil D. | La Joie, Renaud | Sturm, Virginia E.

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD), the gradual accumulation of amyloid-β (Aβ) and tau proteins may underlie alterations in empathy. Objective: To assess whether tau aggregation in the medial temporal lobes relates to differences in cognitive empathy (the ability to take others’ perspectives) and emotional empathy (the ability to experience others’ feelings) in AD. Methods: Older adults (n  = 105) completed molecular Aβ positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aβ positive and symptomatic with diagnoses of mild cognitive impairment, dementia of the Alzheimer’s type, logopenic variant primary progressive aphasia, …or posterior cortical atrophy. The remaining 37 (22 women) were asymptomatic Aβ negative healthy older controls. Using the Interpersonal Reactivity Index, we compared current levels of informant-rated cognitive empathy (perspective-taking subscale) and emotional empathy (empathic concern subscale) in the Aβ positive and negative participants. The Aβ positive participants also underwent molecular tau-PET scans, which were used to investigate whether regional tau burden in the bilateral medial temporal lobes related to empathy. Results: Aβ positive participants had lower perspective-taking and higher empathic concern than Aβ negative healthy controls. Medial temporal tau aggregation in the Aβ positive participants had divergent associations with cognitive and emotional empathy. Whereas greater tau burden in the amygdala predicted lower perspective-taking, greater tau burden in the entorhinal cortex predicted greater empathic concern. Tau burden in the parahippocampal cortex did not predict either form of empathy. Conclusions: Across AD clinical syndromes, medial temporal lobe tau aggregation is associated with lower perspective-taking yet higher empathic concern. Show more

Keywords: Alzheimer’s disease, affective resonance, empathy, mentalization, social cognition, tau proteins

DOI: 10.3233/JAD-230367

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2023

Authors: Utz, Janine | Olm, Pauline | Jablonowski, Johannes | Siegmann, Eva-Maria | Spitzer, Philipp | Lewczuk, Piotr | Kornhuber, Johannes | Maler, Juan Manuel | Oberstein, Timo Jan

Article Type: Research Article

Abstract: Background: The established Erlangen Score (ES) for the interpretation of cerebrospinal fluid (CSF) biomarkers in the diagnostics of Alzheimer’s disease (AD) uses markers of amyloidopathy and tauopathy, equally weighted to form an easy-interpretable ordinal scale. However, these biomarkers are not equally predictive for AD. Objective: The higher weighting of the Aβ42 /Aβ40 ratio, as a reconceptualized ERlangen Score (ERS), was tested for advantages in diagnostic performance. Methods: Non-demented subjects (N  = 154) with a mean follow up of 5 years were assigned to a group ranging from 0 to 4 in ES or ERS. Psychometric trajectories …and dementia risk were assessed. Results: The distribution of subjects between ES and ERS among the groups differed considerably, as grouping allocated 32 subjects to ES group 2, but only 2 to ERS group 2. The discriminative accuracy between the ES (AUC 73.2%, 95% CI [64.2, 82.2]) and ERS (AUC 72.0%, 95% CI [63.1, 81.0]) for dementia risk showed no significant difference. Without consideration of the Aβ42 /Aβ40 ratio in ES grouping, the optimal cut-off of the ES shifted to ≥2. Conclusions: The ERS showed advantages over the ES in test interpretation with comparable overall test performance, as fewer cases were allocated to the intermediate risk group. The established cut-off of ≥2 can be maintained for the ERS, whereas it must be adjusted for the ES when determining the Aβ42 /Aβ40 ratio. Show more

Keywords: Alzheimer’s disease, dementia risk, Erlangen Score, longitudinal study, neuropsychological trajectories

DOI: 10.3233/JAD-230524

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Kero, Katherine | Halter, Colt M. | Moll, Allison C. | Hanna, Sophie M. | Woodard, John L. | Giordani, Bruno | Daugherty, Ana M. | Kavcic, Voyko

Article Type: Research Article

Abstract: Background: Cognitive assessment of older adults typically includes symptom reports and objective evaluations. However, there is often poor agreement between these measures. Cultural norms, stress, and anxiety may also influence cognitive self-appraisal and performance. Little research describes how other factors affect the self-report/objective test discrepancies noted in the literature. Objective: This study investigated whether the disparity between subjective cognitive concerns and objective cognitive performance is related to measures of anxiety and stress in older Black and African American adults. Methods: Telephone screenings were administered to 206 older adults (ages 64–94) during the first year of the …pandemic. Demographic data, objective memory (Telephone Interview for Cognitive Status [TICS-m]), an adaptation of the subjective memory measure, the Cognitive Change Questionnaire, emphasizing executive functioning in everyday life [CCQ-e]), Generalized Anxiety Disorder-7 (GAD-7), and Perceived Stress Scale-4 (PSS4) were measured. Metacognition Discrepancy Index (MDI) was calculated from the standardized residual after regressing TICS-m on CCQ-e scores to quantify the discrepancy between cognitive self-appraisal and objective cognitive functioning. Results: Neither GAD-7 nor PSS-4 moderated the relationship between TICS-m and CCQ-e, and TICS-m scores weakly predicted subjective CCQ-e scores (F (1, 197)=4.37, p  = 0.038, R2  = 0.022). The MDI correlated with stress and anxiety (rs  = 0.294, 0.396, ps  <  0.001). Conclusion: Discrepancies exist between objectively measured and self-evaluated cognition. Elevations in stress and anxiety are associated with greater overestimation of cognitive difficulties relative to objective performance. Pandemic-related stressors may have worsened anxiety and diminished self-appraisal of cognitive abilities for some individuals, while others may remain reluctant to acknowledge impairments. Social and emotional factors are meaningful considerations in assessing cognitive difficulties. Show more

Keywords: affect, Alzheimer’s disease, anxiety, cognitive decline, metacognition, psychological stress

DOI: 10.3233/JAD-221140

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2023

Authors: Pase, Matthew P. | Pinheiro, Adlin | Rowsthorn, Ella | Demissie, Serkalem | Hurmez, Saoresho | Aparicio, Hugo | Rodriguez-Lara, Frances | Gonzales, Mitzi M. | Beiser, Alexa | DeCarli, Charles | Seshadri, Sudha | Romero, Jose Rafael

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) visible perivascular spaces (PVS) are associated with the risk of incident dementia but their association with the early stages of cognitive impairment remains equivocal. Objective: We examined the association between MRI visible PVS and the risk of incident mild cognitive impairment (MCI) in the community-based Framingham Heart Study (FHS). Methods: FHS participants aged at least 50 years free of stroke, cognitive impairment, and dementia at the time of MRI were included. PVS were rated according to severity in the basal ganglia and centrum semiovale (CSO) using established criteria. …Cox regression analyses were used to relate PVS to incident MCI adjusted for demographic and cardiovascular variables. Results: The mean age of the sample (1,314 participants) at MRI was 68 years (SD, 9; 54% women). There were 263 cases of incident MCI over a median 7.4 years follow-up (max, 19.8 years). MCI risk increased with higher PVS severity in the CSO. Relative to persons with the lowest severity rating, persons with the highest severity rating in the CSO had a higher risk of incident MCI (hazard ratio [HR] = 2.55; 95% confidence interval [CI], 1.48–4.37; p  = 0.0007). In secondary analysis, this association seemed stronger in women. Risk of incident MCI was nominally higher for participants with the highest severity grade of PVS in the basal ganglia, though not statistically significant relative to the lowest grade (HR = 2.19; 95% CI, 0.78–6.14; p  = 0.14). Conclusions: PVS burden in the CSO may be a risk marker for early cognitive impairment. Show more

Keywords: Alzheimer’s disease, cerebral small vessel disease, magnetic resonance imaging, mild cognitive impairment, perivascular spaces

DOI: 10.3233/JAD-230445

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023

Authors: Chen, Shihao | Huang, Wenting | He, Tao | Zhang, Mulan | Jin, Xing | Jiang, Lelin | Xu, Huiqin | Chen, Keyang

Article Type: Research Article

Abstract: Background: Brain-derived neurotrophic factor (BDNF) is a protein synthesized in the brain and widely expressed in the nervous system. Previous studies have demonstrated a controversial role of BDNF in neurological diseases. Objective: In this study, we aimed to assess the association between BDNF levels and the risk of neurological diseases by Mendelian randomization analysis. Methods: From a genome-wide association analysis of plasma proteins comprising 3,301 European participants, we isolated 25 genetic variations as instrumental variables for BDNF levels. Summary statistics data on six common neurological diseases as outcome variables. Two-sample Mendelian randomization (MR) analysis was used …to assess whether plasma BDNF is causally related to neurological diseases. We also performed sensitivity analysis to ensure the robustness of the results and reverse MR to exclude potential reverse causality. Results: We confirmed the significant causal relationship between BDNF levels and the risk of Alzheimer’s disease (AD) (OR, 0.91; 95% CI, 0.83, 0.99; p  = 0.033). Other methods have also shown similar results. We infer that BDNF also reduces the risk of epilepsy (OR, 0.94; 95% CI, 0.90, 0.99; p  = 0.0103). In reverse MR analysis, we also found that AD can affect the level of BDNF. Conclusions: Our study suggests higher plasma BDNF was associated with the reduced risk of AD. Moreover, higher plasma BDNF is a protective factor on AD and focal epilepsy. The results provide credence to the idea that BDNF may play a significant role in the development of focal epilepsy and AD. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, epilepsy, genome-wide association studies, Mendelian randomization

DOI: 10.3233/JAD-230693

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Bruinsma, Jeroen | Heger, Irene | Loukas, Vasileios S. | Kassiotis, Thomas | Karanasiou, Georgia | Fotiadis, Dimitrios I. | Hanke, Sten | Crutzen, Rik

Article Type: Research Article

Abstract: Background: There is accumulating evidence that addressing modifiable risk and protective factors has an impact on dementia rates. Insight into the public’s perspectives on dementia risk reduction is needed to inform future individual-level interventions and public health approaches. Objective: This study explores the publics’ openness towards dementia risk reduction and willingness towards changing lifestyle behavior to reduce the future risk for dementia. Methods: Using a screening questionnaire, participants were purposively selected based on lifestyle behaviors that are associated with dementia risk. One-on-one interviews were used to explore their openness towards dementia risk reduction and willingness towards …behavior change. Independently, two researchers performed an inductive content analysis. Results: Interviews were conducted with 23 participants aged from 40 to 79 years. Main themes that were identified from the data were: 1) abstractness of dementia risk reduction, 2) ambivalence towards changing behavior, 3) negative self-image and low behavioral control, and 4) all-or-nothing thinking about lifestyle change. Conclusions: The concept of dementia risk reduction seems difficult to translate to the personal context, particularly if individuals perceive that dementia would occur decades in the future. This is problematic because a large proportion of the public needs a healthier lifestyle to reduce the incidence of dementia. Translating healthy intentions into behavior is complex and involves overcoming a variety of barriers that complicate dementia risk reduction initiatives. Support is needed for individuals who experience additional obstacles that obstruct commencing to a healthier lifestyle (e.g., negative self-image, engaging in multiple unhealthy behaviors, unrealistic perceptions about lifestyle change). Show more

Keywords: Alzheimer’s disease, behavior change, dementia, health promotion, prevention, public health

DOI: 10.3233/JAD-230217

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2023

Authors: Bramen, Jennifer E. | Siddarth, Prabha | Popa, Emily S. | Kress, Gavin T. | Rapozo, Molly K. | Hodes, John F. | Ganapathi, Aarthi S. | Slyapich, Colby B. | Glatt, Ryan M. | Pierce, Kyron | Porter, Verna R. | Wong, Claudia | Kim, Mihae | Dye, Richelin V. | Panos, Stella | Bookheimer, Tess | Togashi, Tori | Loong, Spencer | Raji, Cyrus A. | Bookheimer, Susan Y. | Roach, Jared C. | Merrill, David A.

Article Type: Research Article

Abstract: Background: A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimer’s disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis. Objective: We tested the hypothesis that individuals with AD and confirmed amyloid burden eating a carbohydrate-restricted diet have thicker cortex than those eating a moderate-to-high carbohydrate diet. Methods: A …total of 31 patients (mean age 71.4±7.0 years) with AD and confirmed amyloid burden were divided into two groups based on a 130 g/day nCHO cutoff. Cortical thickness was estimated from T1-weighted MRI using FreeSurfer. Cortical surface analyses were corrected for multiple comparisons using cluster-wise probability. We assessed group differences using a two-tailed two-independent sample t -test. Linear regression analyses using nCHO as a continuous variable, accounting for confounders, were also conducted. Results: The lower nCHO group had significantly thicker cortex within somatomotor and visual networks. Linear regression analysis revealed that lower nCHO intake levels had a significant association with cortical thickness within the frontoparietal, cingulo-opercular, and visual networks. Conclusions: Restricting carbohydrates may be associated with reduced atrophy in patients with AD. Lowering nCHO to under 130 g/day would allow patients to follow the well-validated MIND diet while benefiting from lower insulin levels. Show more

Keywords: Alzheimer’s disease, amyloid, atrophy, carbohydrates, carbohydrate-restricted, cerebral cortical thinning, cognitive dysfunction, diet, magnetic resonance imaging

DOI: 10.3233/JAD-230458

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2023

Authors: Alkon, Daniel L. | Sun, Miao-Kun | Tuchman, Alan J. | Thompson, Richard E.

Article Type: Research Article

Abstract: Background: In pre-clinical studies, Bryostatin, MW (molecular weight) 904, has demonstrated synaptogenic, anti-apoptotic, anti-amyloid, and anti-tau tangle efficacies. Objective: To identify AD patients who show significant cognitive benefit versus placebo when treated in a trial with chronic Bryostatin dosing. Methods: In this 6-month 122 AD patient Bryostatin trial, there were two cohorts: the Moderate Cohort (MMSE, Mini-Mental Status Exam: 15-18) and the Moderately Severe Cohort (MMSE 10-14) as pre-specified secondary endpoints. Patient randomization was stratified by baseline SIB to insure balance in baseline cognitive ability between treatment arms. Results: With no safety events noted …by the data safety and monitoring board, the Moderately Severe (MMSE 10-14) Bryostatin-treated patients were significantly improved above the placebo patients for Weeks #13 through Week #42. After two cycles of 7 x i.v. Bryostatin doses over a 26-week period, the 10-14 Cohort Severe Impairment Battery (SIB), measured every 2 weeks, showed significant benefit using a Mixed Model Repeated Measures model (MMRM, 2-tailed, p  < 0.05) for Weeks #13 through #42, even 16 weeks after dosing completion by Week #26. Placebo 10-14 patients showed no benefit, declining to negative 12.8 points by Week #42. Trend analyses confirmed the MMRM data for this Cohort, with a significant downward slope (equivalent to Cognitive Decline) for the placebo group, p  < 0.001, 2-tailed, but no significant decline for the Bryostatin-treated group (p  = 0.409, NS), treatment versus placebo p  < 0.007. The Moderate Cohort patients showed no significant benefit. Conclusions: The Bryostatin-treated MMSE 10-14 patients showed no significant cognitive decline throughout the 10-month trial, versus placebo patients’ decline of -12.8 SIB points. Show more

Keywords: Alzheimer’s disease, Bryostatin, moderately severe AD patients, prevention, safety

DOI: 10.3233/JAD-230868

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2023

Authors: Ding, Huitong | Mandapati, Amiya | Hamel, Alexander P. | Karjadi, Cody | Ang, Ting F.A. | Xia, Weiming | Au, Rhoda | Lin, Honghuang

Article Type: Research Article

Abstract: Background: Early prediction of dementia risk is crucial for effective interventions. Given the known etiologic heterogeneity, machine learning methods leveraging multimodal data, such as clinical manifestations, neuroimaging biomarkers, and well-documented risk factors, could predict dementia more accurately than single modal data. Objective: This study aims to develop machine learning models that capitalize on neuropsychological (NP) tests, magnetic resonance imaging (MRI) measures, and clinical risk factors for 10-year dementia prediction. Methods: This study included participants from the Framingham Heart Study, and various data modalities such as NP tests, MRI measures, and demographic variables were collected. CatBoost was …used with Optuna hyperparameter optimization to create prediction models for 10-year dementia risk using different combinations of data modalities. The contribution of each modality and feature for the prediction task was also quantified using Shapley values. Results: This study included 1,031 participants with normal cognitive status at baseline (age 75±5 years, 55.3% women), of whom 205 were diagnosed with dementia during the 10-year follow-up. The model built on three modalities demonstrated the best dementia prediction performance (AUC 0.90±0.01) compared to single modality models (AUC range: 0.82–0.84). MRI measures contributed most to dementia prediction (mean absolute Shapley value: 3.19), suggesting the necessity of multimodal inputs. Conclusion: This study shows that a multimodal machine learning framework had a superior performance for 10-year dementia risk prediction. The model can be used to increase vigilance for cognitive deterioration and select high-risk individuals for early intervention and risk management. Show more

Keywords: Alzheimer’s disease, dementia risk prediction, machine learning, magnetic resonance imaging, multimodal data, neuropsychological test

DOI: 10.3233/JAD-230496

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2023

Authors: Dinnerstein, Eric

Article Type: Correction

DOI: 10.3233/JAD-239010

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2023