Journal of Alzheimer's Disease - Volume 85, issue 2

Authors: Chen, Lei | Shen, Qianqian | Xu, Shunliang | Yu, Hongzhuan | Pei, Shengjie | Zhang, Yangting | He, Xin | Wang, QiuZhen | Li, Duo

Article Type: Research Article

Abstract: Background: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer’s disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material. Objective: However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date. Methods: We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to …detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control. Results: We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1 , CPNE4 , DNAJC15 , REEP3, ROR1 , CAMK1D , and RBFOX1 ) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects. Conclusion: The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD. Show more

Keywords: Alzheimer’s disease, biomarker, cell-free DNA, 5-hydroxymethylcytosine

DOI: 10.3233/JAD-215217

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 573-585, 2022

Authors: Turcotte, Valérie | Potvin, Olivier | Dadar, Mahsa | Hudon, Carol | Duchesne, Simon | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Evidence suggests birth cohort differences in cognitive performance of older adults. Proxies of cognitive reserve (CR), such as educational attainment and occupational complexity, could also partly account for these differences as they are influenced by the sociocultural environment of the birth cohorts. Objective: To predict cognitive performance using birth cohorts and CR and examine the moderating influence of CR on cognitive performance and structural brain health association. Methods: Using ADNI data (n  = 1628), four birth cohorts were defined (1915–1928; 1929–1938; 1939–1945; 1946–1964). CR proxies were education, occupational complexity, and verbal IQ. We predicted baseline cognitive …performances (verbal episodic memory; language and semantic memory; attention capacities; executive functions) using multiple linear regressions with CR, birth cohorts, age, structural brain health (total brain volume; total white matter hyperintensities volume) and vascular risk factors burden as predictors. Sex and CR interactions were also explored. Results: Recent birth cohorts, higher CR, and healthier brain structures predicted better performance in verbal episodic memory, language and semantic memory, and attention capacities, with large effect sizes. Better performance in executive functions was predicted by a higher CR and a larger total brain volume, with a small effect size. With equal score of CR, women outperformed men in verbal episodic memory and language and semantic memory in all cohorts. Higher level of CR predicted better performance in verbal episodic memory, only when total brain volume was lower. Conclusion: Cohort differences in cognitive performance favor more recent birth cohorts and suggests that this association may be partly explained by proxies of CR. Show more

Keywords: Aging, birth cohorts, cognition, cognitive impairments, cognitive reserve, generations

DOI: 10.3233/JAD-215044

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 587-604, 2022

Authors: Ge, Feifei | Dong, Lin | Zhu, Donglin | Lin, Xingjian | Shi, Jingping | Xiao, Ming

Article Type: Research Article

Abstract: Background: Accumulating studies have implicated thyroid dysfunction in the pathogenesis of Alzheimer’s disease (AD). Objective: This study aimed to explore the association between thyroid hormone (TH) levels and cerebrospinal fluid (CSF) biomarkers for AD continuum among euthyroid subjects. Methods: In all, 93 clinically euthyroid subjects with a cognitive decline were included in this prospective cross-sectional study and were divided into groups with abnormal AD biomarkers (belonging to the “Alzheimer’s continuum”; A+ patients) and those with “normal AD biomarkers” or “non-AD pathological changes” (A–patients), according to the ATN research framework classification for AD. A partial correlation analysis …of serum thyroid-stimulating hormone (TSH) or TH levels with CSF biomarkers was conducted. The predictor for A+ patients was analyzed via binary logistic regressions. Finally, the diagnostic significance of individual biochemical predictors for A+ patients was estimated via receiver operating characteristic curve analysis. Results: Serum total triiodothyronine (TT3) and free triiodothyronine (FT3) levels were found to affect the levels of CSF amyloid-β (Aβ)42 and the ratios of Aβ42/40 . Further, FT3 was found to be a significant predictor for A+ via binary logistic regression modeling. Moreover, FT3 showed a high diagnostic value for A+ in euthyroid subjects. Conclusion: Even in a clinical euthyroid state, low serum FT3 and TT3 levels appear to be differentially associated with AD-specific CSF changes. These data indicate that serum FT3 is a strong candidate for differential diagnosis between AD continuum and non-AD dementia, which benefits the early diagnosis and effective management of preclinical and clinical AD patients. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, cerebrospinal fluid, thyroid hormone

DOI: 10.3233/JAD-215092

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 605-614, 2022

Authors: Haoudy, Sarah | Jonveaux, Thérèse | Puisieux, Salomé | Epstein, Jonathan | Hopes, Lucie | Maillard, Louis | Aron, Olivier | Tyvaert, Louise

Article Type: Research Article

Abstract: Background: Epilepsy seems to be an important comorbidity in patients with early onset Alzheimer’s disease (EOAD). Currently, seizures are still underestimated in this population. However, seizures may interact with AD evolution with possible acceleration of cognitive decline. Objective: To better define the epileptic disorders observed in patients with EOAD. Methods: All patients diagnosed as EOAD in our hospital between 2013 and 2019 with positive CSF biomarkers for AD were selected. The usual follow-up was extended with a 3-h EEG and a consultation with an epilepsy expert. Information on epilepsy and AD were collected …and analyzed. Results: Among the 25 included patients, 10 (40%) were classified as epileptic. Seizure types were tonic-clonic (25%), typical temporal seizures (25%), myoclonus (25%), focal extra-temporal seizures (8%), and other seizure types (17%). AD-E patients had a significant lower MMSE (15.3±8.4 AD-E versus 22.1±5.1 AD-NE, p  = 0.036) and a lower autonomy (IADL 4.1±2.7 AD-E versus 6.4±1.9 AD-NE, p  = 0.046) at AD diagnosis with comparable ages between AD-E and AD-NE. Epileptic patients seemed to present a faster cognitive decline ([ΔMMSE per year 1.7±1.3 AD-E versus 0.9±1.4 AD-NE; p  = 0.09). All patients with severe cognitive impairment (MMSE ≤ 10) had an epileptic comorbidity. Conclusion: Epilepsy is a frequent comorbidity in EOAD patients, with a percentage of 40%in our study. This comorbidity may be associated with a severe form of EOAD. The role of epilepsy in the acceleration of cognitive decline and the positive impact of antiepileptic drugs on cognition need further research. Show more

Keywords: Cognitive decline, early onset Alzheimer’s disease, epilepsy, seizures

DOI: 10.3233/JAD-210681

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 615-626, 2022

Authors: Devlin, Kathryn N. | Brennan, Laura | Saad, Laura | Giovannetti, Tania | Hamilton, Roy H. | Wolk, David A. | Xie, Sharon X. | Mechanic-Hamilton, Dawn

Article Type: Research Article

Abstract: Background: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples. Objective: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators, among diverse older adults. Methods: Participants (N  = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations …with race/ethnicity, longitudinal cognitive and functional change, and incident dementia. Results: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants. Conclusion: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples. Show more

Keywords: Actuarial analysis, Alzheimer’s disease, cognitive aging, early diagnosis, latent class analysis, memory disorders, mild cognitive impairment, minority health, race factors, statistical models

DOI: 10.3233/JAD-210455

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 627-644, 2022

Authors: Neshan, Masoud | Malakouti, Seyed Kazem | Kamalzadeh, Leila | Makvand, Mina | Campbell, Arezoo | Ahangari, Ghasem

Article Type: Research Article

Abstract: Background: Late-onset Alzheimer’s disease (LOAD) is associated with many environmental and genetic factors. The effect of systemic inflammation on the pathogenesis of neurodegenerative diseases such as AD has been strongly suggested. T helper cells (Th) are one of the important components of the immune system and can easily infiltrate the brain in pathological conditions. The development of each Th-subset depends on the production of unique cytokines and their main regulator. Objective: This study aimed to compare the mRNA levels of Th-related genes derived from peripheral blood mononuclear cells of LOAD patients with control. Also, the identification of the …most important Th1/Th2 genes and downstream pathways that may be involved in the pathogenesis of AD was followed by computational approaches. Methods: This study involved 30 patients with LOAD and 30 non-demented controls. The relative expression of T-cell cytokines (IFN-γ , TNF-α , IL-4, and IL-5) and transcription factors (T-bet and GATA-3) were assessed using Real-time PCR. Additionally, protein-protein interaction (PPI) was investigated by gene network construction. Results: A significant decrease at T-bet, IFN-γ , TNF-α , and GATA-3 mRNA levels was detected in the LOAD group, compared to the controls. However, there was no significant difference in IL-4 or IL-5 mRNA levels. Network analysis revealed a list of the highly connected protein (hubs) related to mitogen-activated protein kinase (MAPK) signaling and Th17 cell differentiation pathways. Conclusion: The findings point to a molecular dysregulation in Th-related genes, which can promising in the early diagnosis or targeted interventions of AD. Furthermore, the PPI analysis showed that upstream off-target stimulation may involve MAPK cascade activation and Th17 axis induction. Show more

Keywords: Alzheimer’s disease, cytokine, gene expression, LOAD, mitogen-activated protein kinase, protein-protein interaction, T helper cell, Th17 cell, transcription factor

DOI: 10.3233/JAD-210480

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 645-665, 2022

Authors: Sugawara, Norio | Yasui-Furukori, Norio | Maruo, Kazushi | Shimoda, Kazutaka | Sumiyoshi, Tomiki

Article Type: Research Article

Abstract: Background: Taking care of patients with dementia is often stressful and exhausting. The burden placed on caregivers (CGs) for care recipients with dementia (CRDs) has been reported to cause psychological distress. Objective: The aim of this study was to evaluate the psychological distress experienced by CGs for CRDs and identify the sociodemographic factors affecting that distress. Methods: We utilized the 2013 Comprehensive Survey of the Living Conditions for CRDs and CGs. Linked data from 643 pairs of CRDs and CGs were extracted. Serious psychological distress experienced by CGs was measured by Kessler’s Psychological Distress scale (K6) …with a cutoff point of 13. Factors predictive of psychological distress were evaluated using multivariable logistic regression analysis with the forward selection method. Results: Overall, the mean age of the CGs was 63.5±11.6 years, and 5.3%(34/643) experienced serious psychological distress. Male sex of CRDs, knowing how to access consulting services, spending almost all day for nursing care, and having subjective symptoms within a few days of completing the survey were associated with having serious psychological distress, while older age, participating in shopping as part of the nursing activities, and having their own house were related to freedom from serious psychological distress. Conclusion: Clinicians should be aware of the risk factors for psychological distress in CGs and consider providing support to reduce the distress imposed by modifiable factors. Further studies are warranted to examine whether such efforts would improve the mental health of CGs for CRDs. Show more

Keywords: Dementia, nursing care, psychological distress

DOI: 10.3233/JAD-210680

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 667-674, 2022

Authors: Foley, Éimear M. | Tripodis, Yorghos | Yhang, Eukyung | Koerte, Inga K. | Martin, Brett M. | Palmisano, Joseph | Makris, Nikos | Schultz, Vivian | Lepage, Chris | Muehlmann, Marc | Wróbel, Paweł P. | Guenette, Jeffrey P. | Cantu, Robert C. | Lin, Alexander P. | Coleman, Michael | Mez, Jesse | Bouix, Sylvain | Shenton, Martha E. | Stern, Robert A. | Alosco, Michael L.

Article Type: Research Article

Abstract: Background: Repetitive head impacts (RHI) from contact sports have been associated with cognitive and neuropsychiatric disorders. However, not all individuals exposed to RHI develop such disorders. This may be explained by the reserve hypothesis. It remains unclear if the reserve hypothesis accounts for the heterogenous symptom presentation in RHI-exposed individuals. Moreover, optimal measurement of reserve in this population is unclear and likely unique from non-athlete populations. Objective: We examined the association between metrics of reserve and cognitive and neuropsychiatric functioning in 89 symptomatic former National Football League players. Methods: Individual-level proxies (e.g., education) defined reserve. We …additionally quantified reserve as remaining residual variance in 1) episodic memory and 2) executive functioning performance, after accounting for demographics and brain pathology. Associations between reserve metrics and cognitive and neuropsychiatric functioning were examined. Results: Higher reading ability was associated with better attention/information processing (β=0.25; 95% CI, 0.05–0.46), episodic memory (β=0.27; 95% CI, 0.06–0.48), semantic and phonemic fluency (β=0.24; 95% CI, 0.02–0.46; β=0.38; 95% CI, 0.17–0.59), and behavioral regulation (β=–0.26; 95% CI, –0.48, –0.03) performance. There were no effects for other individual-level proxies. Residual episodic memory variance was associated with better attention/information processing (β=0.45; 95% CI, 0.25, 0.65), executive functioning (β=0.36; 95% CI, 0.15, 0.57), and semantic fluency (β=0.38; 95% CI, 0.17, 0.59) performance. Residual executive functioning variance was associated with better attention/information processing (β=0.44; 95% CI, 0.24, 0.64) and episodic memory (β=0.37; 95% CI, 0.16, 0.58) performance. Conclusion: Traditional reserve proxies (e.g., years of education, occupational attainment) have limitations and may be unsuitable for use in elite athlete samples. Alternative approaches of reserve quantification may prove more suitable for this population. Show more

Keywords: Chronic traumatic encephalopathy, cognition, cognitive reserve, football, neurodegenerative diseases, repetitive head impacts, resilience

DOI: 10.3233/JAD-210379

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 675-689, 2022

Authors: Altomari, Natalia | Bruno, Francesco | Laganà, Valentina | Smirne, Nicoletta | Colao, Rosanna | Curcio, Sabrina | Di Lorenzo, Raffaele | Frangipane, Francesca | Maletta, Raffaele | Puccio, Gianfranco | Bruni, Amalia Cecilia

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer’s disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results. Objective: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years …onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1. Methods: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period. Results: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences. Conclusion: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia (BPSD), BPSD sub-syndromes, early-onset Alzheimer’s disease, late-onset Alzheimer’s disease, Neuropsychiatric Inventory, prevalence, prevalence over time, time of occurrence

DOI: 10.3233/JAD-215061

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 691-699, 2022

Authors: Zijlmans, Jendé L. | Lamballais, Sander | Vernooij, Meike W. | Ikram, M. Arfan | Luik, Annemarie I.

Article Type: Research Article

Abstract: Background: Cognitive reserve aims to explain individual differences in the susceptibility to the functional impact of dementia in the presence of equal amount of neuropathological damage. It is thought to be shaped by a combination of innate individual differences and lifetime exposures. Which determinants are associated with cognitive reserve remains unknown. Objective: The objective of this study was to investigate the associations of sociodemographic, lifestyle, physical, and psychosocial determinants with cognitive reserve, and potential sex differences. Methods: This cross-sectional study included 4,309 participants from the Rotterdam Study (mean age 63.9±10.7) between 2006–2016. Participants completed five cognitive …tests and a brain MRI-scan. Cognitive reserve was defined as a latent variable that captures variance common across five cognitive tests, while adjusting for demographic and MRI-inferred neuropathological factors. The associations of potential determinants and cognitive reserve, adjusted for relevant confounders, were assessed with structural equation models. Results: Current smoking (adjusted mean difference: –0.31, 95%confidence interval –0.42; –0.19), diabetes mellitus (–0.25, –0.40; –0.10) and depressive symptoms (–0.07/SD, –0.12; –0.03) were associated with a lower cognitive reserve whereas alcohol use (0.07/SD, 0.03; 0.12) was associated with higher cognitive reserve. Only smoking was associated with cognitive reserve in both men and women. Employment, alcohol use, diabetes, history of cancer, COPD, and depressive symptoms were only associated with cognitive reserve in women. Conclusion: Our study found that current smoking, diabetes mellitus, and depressive symptoms were associated with a lower cognitive reserve, whereas more alcohol use was associated with a higher cognitive reserve, but with clear differences between men and women. Show more

Keywords: Cognitive reserve, dementia, determinants, observational cohort, older adults

DOI: 10.3233/JAD-215122

Citation: Journal of Alzheimer's Disease, vol. 85, no. 2, pp. 701-713, 2022