Journal of Alzheimer's Disease - Volume 90, issue 4

Authors: Xia, Xinyi | Qin, Qi | Peng, Yankun | Wang, Meng | Yin, Yunsi | Tang, Yi

Article Type: Review Article

Abstract: Patients with Alzheimer’s disease have difficulty maintaining independent living abilities as the disease progresses, causing an increased burden of care on family caregivers and the healthcare system and related financial strain. This patient group is expected to continue to expand as life expectancy climbs. Current diagnostics for Alzheimer’s disease are complex, unaffordable, and invasive without regard to diagnosis quality at early stages, which urgently calls for more technical improvements for diagnosis specificity. Optical coherence tomography or tomographic angiography has been shown to identify retinal thickness loss and lower vascular density present earlier than symptom onset in these patients. The retina …is an extension of the central nervous system and shares anatomic and functional similarities with the brain. Ophthalmological examinations can be an efficient tool to offer a window into cerebral pathology with the merit of easy operation. In this review, we summarized the latest observations on retinal pathology in Alzheimer’s disease and discussed the feasibility of retinal imaging in diagnostic prediction, as well as limitations in current retinal examinations for Alzheimer’s disease diagnosis. Show more

Keywords: Alzheimer’s disease, biomarkers, neurodegeneration, ocular abnormalities, retinal examinations

DOI: 10.3233/JAD-220596

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1341-1357, 2022

Authors: Giaquinto, Francesco | Battista, Petronilla | Angelelli, Paola

Article Type: Systematic Review

Abstract: Background: Touchscreen cognitive tools opened new promising opportunities for the early detection of cognitive impairment; however, most research studies are conducted in English-speaking populations and high-income countries, with a gap in knowledge about their use in populations with cultural, linguistic, and educational diversity. Objective: To review the touchscreen tools used in primary care settings for the cognitive assessment of mild cognitive impairment (MCI) and dementia, with a focus on populations of different cultures, languages, and literacy. Methods: This systematic review was conducted following the PRISMA guidelines. Studies were identified by searching across MEDLINE, EMBASE, EBSCO, OVID, …SCOPUS, SCIELO, LILACS, and by cross-referencing. All studies that provide a first-level cognitive assessment for MCI and dementia with any touchscreen tools suitable to be used in the context of primary care were included. Results: Forty-two studies reporting on 30 tools and batteries were identified. Substantial differences among the tools emerged, in terms of theoretical framework, clinical validity, and features related to the application in clinical practice. A small proportion of the tools are available in multiple languages. Only 7 out of the 30 tools have a multiple languages validation. Only two tools are validated in low-educated samples, e.g., IDEA and mSTS-MCI. Conclusion: General practitioners can benefit from touchscreen cognitive tools. However, easy requirements of the device, low dependence on the examiner, fast administration, and adaptation to different cultures and languages are some of the main features that we need to take into consideration when implementing touchscreen cognitive tools in the culture and language of underrepresented populations. Show more

Keywords: Alzheimer’s disease, dementia, detection, digital neuropsychological assessment, general practitioners, mild cognitive impairment

DOI: 10.3233/JAD-220547

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1359-1380, 2022

Authors: Roveta, Fausto | Cermelli, Aurora | Boschi, Silvia | Ferrandes, Fabio | Grassini, Alberto | Marcinnò, Andrea | Spina, Margherita | Rubino, Elisa | Borsello, Tiziana | Vercelli, Alessandro | Rainero, Innocenzo

Article Type: Systematic Review

Abstract: Background: Synaptic disruption precedes neuronal death and correlates with clinical features of Alzheimer’s disease (AD). The identification of fluid biomarkers of synaptic damage is emerging as a goal for early and accurate diagnosis of the disease. Objective: To perform a systematic review and meta-analysis to determine whether fluid biomarkers of synaptic damage are impaired in AD. Methods: PubMed, Scopus, EMBASE, and Web of Science were searched for articles reporting synaptic proteins as fluid biomarkers in AD and cognitively unimpaired (CU) individuals. Pooled effect sizes were determined using the Hedge G method with random effects. Questions adapted …from the Quality Assessment of Diagnostic Accuracy Studies were applied for quality assessment. A protocol for this study has been previously registered in PROSPERO (registration number: CRD42021277487). Results: The search strategy identified 204 articles that were assessed for eligibility. A total of 23 studies were included in the systematic review and 15 were included in the meta-analysis. For Neurogranin, 827 AD and 1,237 CU subjects were included in the meta-analysis, showing a significant increase in cerebrospinal fluid of patients with AD compared to CU individuals, with an effect size of 1.01 (p  < 0.001). A significant increase in SNAP-25 and GAP-43 levels in CSF of patients with AD was observed. Conclusion: Neurogranin, SNAP-25, and GAP-43 are possible biomarkers of synaptic damage in AD, and other potential synaptic biomarkers are emerging. This meta-analysis also revealed that there are still relatively few studies investigating these biomarkers in patients with AD or other dementias and showed wide heterogeneity in literature. Show more

Keywords: Alzheimer’s disease, blood, cerebrospinal fluid, GAP-43, meta-analysis, neurogranin, SNAP-25, synaptic dysfunction, synaptotagmin-1, systematic review

DOI: 10.3233/JAD-220515

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1381-1393, 2022

Authors: Høilund-Carlsen, Poul F. | Revheim, Mona-Elisabeth | Alavi, Abass | Satyamurthy, Nagichettiar | Barrio, Jorge R.

Article Type: Article Commentary

Abstract: Using amyloid PET imaging as a single primary surrogate efficacy measure in Alzheimer’s disease immunotherapy trials, as happened when the FDA granted accelerated approval of aducanumab, is unjustified. In vivo evidence indicates that PET quantification of amyloid deposition is distorted and misrepresents effects of anti-amyloid treatments due to lack of specificity of the PET imaging probe, effects of amyloid-related imaging abnormalities, spill-over from high white matter signals, and questionable quantification models. Before granting approval to other immunotherapy candidates, the FDA should require rigorous evidence of all imaging claims and irrefutable documentation that proposed treatments are clinically effective and harmless …to patients. Show more

Keywords: Alzheimer’s disease, amyloid-β , amyloid PET, ARIA, immunotherapy

DOI: 10.3233/JAD-220841

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1395-1399, 2022

Authors: Jacobs, Noortje | Theunissen, Bert

Article Type: Editorial

Abstract: For years now, Alzheimer’s disease (AD) research has been stuck in a Groundhog-Day scenario: an endless time loop with no breakthrough in sight. Disagreement about the validity of the field’s dominant approach, based on the Amyloid Cascade Hypothesis, has led to a seemingly unresolvable trench war between proponents and critics. Our paper evaluates the recent scientific literature on AD from a historical and philosophical perspective. We show that AD research is a classic example of the boundary work at play in a field in crisis: both parties deploy historical and philosophical references to illustrate what counts as good and bad …science, as proper scientific method and appropriate scientific conduct. We also show that boundary work has proved unable to point a way out of the deadlock and argue that the science system’s tools for establishing scientific quality, such as peer review and the grant system, are unlikely to resolve the crisis. Rather, they consolidate the dominant model’s position even more. In conclusion, we suggest that some kind of reverse boundary-work is needed that reopens the discussion on the nature of AD, an issue that has never been settled scientifically. Drawing on historical and philosophical work, we make clear that the definition of AD as a biomedical disease for which a cure can be found has consequences, not only for funding opportunities, but also for patients and their lives. A reconsideration of the desirability of these consequences may lead to different choices with respect to research priorities and patient care. Show more

Keywords: Alzheimer’s disease, Amyloid Cascade Hypothesis, boundary work, history and philosophy of science, science system

DOI: 10.3233/JAD-220569

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1401-1415, 2022

Authors: O’Caoimh, Rónán | Coghlan, Patrick | O’Donovan, Mark R | Mohd Zaki, Nurzakiah | Daly, Brian | Gao, Yang | Molloy, D. William

Article Type: Research Article

Abstract: Background: Self or home-administered cognitive screening instruments (CSIs) can reduce barriers to the early detection of mild cognitive impairment (MCI) and dementia. Objective: To examine the acceptability and diagnostic accuracy of a caregiver-administered CSI, the Quick Memory Check (QMC). Methods: Components of the Quick Mild Cognitive impairment (Qmci ) screen (orientation, verbal fluency, and logical memory) were re-weighted to create the QMC, scored out of 100 points. Participants, attending a university hospital memory clinic, were provided administration instructions beforehand. Area under the curve (AUC) scores, adjusted for age and education, were compared with the Qmci …screen and Montreal Cognitive Assessment (MoCA). Caregivers or family scored the QMC. Results: In all, 366 participants were recruited; 53 with subjective memory complaints (SMC), 74 with MCI, 193 with dementia, and 46 normal controls. Median QMC scores for controls were 70±13 versus 60±20 for SMC, 52±18 for MCI, and 31±21 for dementia. The QMC had excellent accuracy (AUC 0.97) for cognitive impairment (MCI/dementia from controls), similar to the Qmci screen (AUC 0.98, p  = 0.17) and MoCA (AUC 0.95, p  = 0.13). At a cut-off of <52/100, the QMC had 83% sensitivity and 100% specificity for cognitive impairment. The QMC had lower accuracy differentiating MCI from SMC (AUC 0.73), albeit similar to the MoCA (AUC 0.70). Conclusion: The QMC, administered by caregivers in advance of clinic, compared favorably to established CSIs scored by trained raters. This caregiver, home-administered CSI is acceptable and can identify cognitive impairment, potentially improving efficiency by reducing testing time and patient stress in busy clinical settings. Show more

Keywords: Caregiver, cognitive screening instrument, dementia, diagnostic accuracy testing, mild cognitive impairment

DOI: 10.3233/JAD-220339

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1417-1427, 2022

Authors: Possin, Katherine L. | Rosen, Allyson C.

Article Type: Article Commentary

Abstract: O’Caoimh et al. demonstrated that caregivers or family members could administer and score a brief cognitive screening instrument and detect cognitive impairment with comparable accuracy to similar measures administered in-person by trained staff. This novel approach challenges us to consider the boundaries of how caregivers or other family members are used in remote testing. We discuss the potential risks of administration bias, test integrity, and impacts on the patient and caregiver or family member, and we recommend further research before incorporating this practice into routine clinical or research use.

Keywords: Cognitive assessment, ethics, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-220862

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1429-1431, 2022

Authors: O’Caoimh, Rónán

Article Type: Article Commentary

Abstract: Possin and Rosen provide a robust commentary exploring the challenges of using caregivers as cognitive testers. Informants have an important and often overlooked role in diagnosing cognitive impairment. O’Caoimh et al. show they can support cognitive screening in advance of clinic, suggesting new research avenues including the potential for home-monitoring. Although concerns testing may engender bias, introduce practice effects, and impact patient autonomy are valid and require examination, these should be viewed in light of patient preference, clinical need, and the broader ethics of assessing dementia. The importance of distinguishing concerns over accuracy and ethical appropriateness is also discussed.

Keywords: Cognition, cognitive screening, diagnosis, diagnostic techniques and procedures, ethics, health care, memory and learning, psychometrics

DOI: 10.3233/JAD-220989

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1433-1436, 2022

Authors: Segura-Uribe, Julia J. | García-de la Torre, Paola | Castillo-Mendieta, Tzayaka | Bribiesca-Cruz, Iván | Orozco-Suárez, Sandra | Soriano-Ursúa, Marvin A. | Pinto-Almazán, Rodolfo | Fuentes-Venado, Claudia E. | Guerra-Araiza, Christian

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) affects women more than men and consequently has been associated with menopause. Tibolone (TIB) has been used as a hormone replacement therapy to alleviate climacteric symptoms. Neuroprotective effects of TIB have also been reported in some animal models. Objective: This study aimed to assess the effect of TIB on memory and Aβ peptides and tau protein content in the hippocampus and cerebellum of transgenic 3xTgAD ovariectomized mice. Methods: Three-month-old female mice were ovariectomized. Ten days after surgery, animals were divided into four groups: wild-type (WT)+vehicle; WT+TIB (1 mg/kg); 3xTgAD+vehicle; and 3xTgAD+TIB (1 mg/kg). TIB …was administered for three months, and memory was evaluated using the object-in-context recognition task. Subsequently, animals were decapitated, and the hippocampus and cerebellum were dissected. Using commercial ELISA kits, these brain structures were homogenized in a PBS buffer for quantifying Aβ40 and Aβ42 and phosphorylated and total tau. Results A long-term memory deficit was observed in the 3xTgAD+vehicle group. In contrast, TIB treatment improved long-term memory in the 3xTgAD+TIB group than those treated with vehicle (p  < 0.05). Furthermore, TIB treatment decreased Aβ and tau content in the hippocampus of 3xTgAD mice compared to vehicle-treated groups (p  < 0.05). No significant changes were observed in the cerebellum. Conclusion: Chronic treatment with TIB showed neuroprotective effects and delayed AD neuropathology in the 3xTgAD mice. Our results support hormone replacement therapy with TIB in menopausal women for neuroprotection. Show more

Keywords: Hippocampus, hormone replacement therapy, menopause, neuroprotection, meta-analysis

DOI: 10.3233/JAD-220434

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1437-1447, 2022

Authors: Ehlen, John C. | Forman, Cassadi M. | Ostrowski, Daniela | Ostrowski, Tim D.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) patients frequently present with orthostatic hypotension. This inability to reflexively increase blood pressure on standing is a serious health concern and increases the risk of stroke and cardiovascular diseases. Objective: Since there are no clear mechanisms for orthostatic hypotension in human AD, the present study assessed the autonomic changes that could explain this comorbidity in an AD animal model. Methods: We used the established streptozotocin-induced rat model of AD (STZ-AD), which mimics many hallmark symptoms of sporadic AD in humans. Baroreflex responses were analyzed in anesthetized STZ-AD rats using femoral catheterization …for blood pressure and heart rate, and autonomic activity was assessed using specific blockers and splanchnic sympathetic nerve recordings. Expression levels of autonomic receptors at the heart were examined using the western blot technique. Results: Baroreflex function in STZ-AD showed a blunted heart rate (HR) response to low blood pressure challenges, and the maximal sympathetic nerve activity was reduced. Conversely, HR responses to high blood pressure were similar to control, indicating no change in parasympathetic nerve activity. Under resting conditions, autonomic blockade demonstrated a baseline shift to increased sympathetic tone in STZ-AD. Protein expression levels of beta-1 adrenergic receptor and muscarinic acetylcholine receptor M2 in the heart were unchanged. Conclusion: Our study provides the first data on the pathological influence of AD on baroreflex function, which primarily affected the sympathetic nervous system in STZ-AD. These results represent the first mechanisms that may correlate with the orthostatic hypotension in human AD. Show more

Keywords: Autonomic nervous system, blood pressure, heart rate, orthostatic hypotension, parasympathetic nervous system, streptozotocin, sympathetic nervous system

DOI: 10.3233/JAD-220496

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1449-1464, 2022

Authors: Zhou, Wen | Zhan, Libin | Xu, Huiying | Zhang, Lijing

Article Type: Research Article

Abstract: Background: Chronic psychological stress (PS) hinders the treatment of diabetes-associated cognitive decline (DACD). However, the impact of chronic PS on the risk of developing DACD remains unclear. There is growing evidence that gut flora interventions are promising targets for treating stress-related diseases. Objective: We examined whether chronic PS triggers or exacerbates the onset of DACD in rats and aimed to elucidate whether ZiBuPiYin recipe (ZBPYR) prevents and treats chronic PS-aggravated DACD by dynamically maintaining the components of the gut microbiota. Methods: We performed chronic PS (restraint, rotation, and congestion) on ZDF rats to establish a model. …Cognitive function was evaluated by behavioral experiments, and activation of the hypothalamic-pituitary-adrenal axis was detected by ELISA. Weekly feces from rats were collected for 16 S RNA sequencing. Results: We found that chronic PS promoted cognitive abnormalities and exacerbated DACD phenotypes. Additionally, chronic PS altered intestinal flora diversity, dynamically elevating the abundance of Alistipes and Coprococcus ; enriching Module 1 (Dorea, Blautia, Ruminococcus ) and Module 48 (Blautia ); and inhibiting Module 20 (Lactobacillus, SMB53 ), and Module 42 (Akkermansia ). ZBPYR significantly alleviated hyperglycemia and cognitive impairment in chronic PS-aggravated DACD rats and dynamically reduced the abundance of Alistipes and Coprococcus ; significantly enriched Module 3 (Ruminococcus ) and Module 45 (Lactobacillus, Coprococcus, SMB53 ); and suppressed Module 2 (Lactobacillus ), Module 16 (Turicibacter, Trichococcus, Lactobacillus, 02d06, Clostridium ), Module 23 (Bifidobacterium ), and Module 43 (Clostridium ). Conclusion: ZBPYR might prevent and treat chronic PS-aggravated DACD by dynamically regulating Lactobacillus, Alistipes , and Coprococcus . Show more

Keywords: Chronic psychological stress, diabetes-associated cognitive decline, gut microbiota, traditional Chinese medicine

DOI: 10.3233/JAD-220692

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1465-1483, 2022

Authors: Zhu, Chi | Zhu, Jie | Xiang, Yang | Bu, Xian-Le | Jin, Wang-Sheng | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: Abnormal intracellular expression and aggregation of α-synuclein (α-syn) is the histopathological hallmark of several neurodegenerative diseases especially Parkinson’s disease. However, safe and efficient approaches to clear α-syn remain unavailable. Objective: This study aimed to investigate the process of peripheral catabolism of brain-derived α-syn. Methods: Thirty patients with atrioventricular reentrant tachycardia (AVRT) (left accessory pathways) who underwent radiofrequency catheter ablation (RFCA) were enrolled in this study. Blood was collected via catheters from superior vena cava (SVC), inferior vena cava (IVC) proximal to the hepatic vein (HV), the right femoral vein (FV), and femoral artery (FA) simultaneously …during RFCA. Plasma α-syn levels of AVRT patients and soluble α-syn levels of the brain samples were measured using enzyme-linked immunosorbent assay kits. Results: The α-syn concentrations in different locations of veins were divided by time-matched arterial α-syn concentrations to generate the venous/arterial (V/A) ratio. The V/A ratio of α-syn from the SVC was 1.204 (1.069–1.339, 95% CI), while the V/A ratio of α-syn from IVC was 0.831 (0.734–0.928, 95% CI), suggesting that brain-derived α-syn in the arterial blood was physiologically cleared while going through the peripheral organs and tissues. And it was estimated that about half of brain soluble α-syn could efflux and be cleared in the periphery. Moreover, the glomerular filtration rate was found correlated with V-A difference (FA-ICV) (p  = 0.0272). Conclusion: Under physiological conditions, brain-derived α-syn could efflux into and be catabolized by the peripheral system. The kidney may play a potential role in the clearance of α-syn. Show more

Keywords: α-synuclein, kidney, peripheral clearance, plasma

DOI: 10.3233/JAD-220742

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1485-1492, 2022

Authors: Wang, Ye-Ran | Wang, Meng-Ting | Zeng, Xiao-Qin | Liu, Yu-Hui | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: Imbalance between the production and clearance of amyloid-β (Aβ) promotes the development of Alzheimer’s disease (AD). Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, which is involved in the process of Aβ production. The profiles of autoantibodies are dysregulated in AD patients. Objective: This study aims to investigate the relative levels and clinical relevance of naturally occurring antibodies to PS1 (NAbs-PS1) in AD. Methods: A total of 55 subjects with AD (including both dementia and mild cognitive impairment due to AD), 28 subjects with cognitive impairment (including both dementia and mild cognitive impairment) not due …to AD (non-AD CI), and 70 cognitively normal (CN) subjects were recruited. One-site ELISA was utilized to determine the relative levels of NAbs-PS1 in plasma. Results: AD subjects had lower plasma levels of NAbs-PS1 than CN and non-AD CI subjects. Plasma NAbs-PS1 were negatively associated with the brain Aβ load, as reflected by PET-PiB SUVR, and were positively associated with cognitive functions of participants. Plasma NAbs-PS1 discriminated AD patients from CN with an area under the curve (AUC) of 0.730, a sensitivity of 69.09%, and a specificity of 67.14%, and they discriminated AD patients from non-AD CI subjects with an AUC of 0.750, a specificity of 70.91%, and a sensitivity of 71.43%. Conclusion: This study found an aberrant immunological phenotype in AD patients. Further investigations are needed to determine the pathophysiological functions of NAbs-PS1 in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, γ-secretase, naturally occurring antibodies, presenilin-1

DOI: 10.3233/JAD-220775

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1493-1500, 2022

Authors: Pontrello, Crystal G. | McWhirt, Joshua M. | Glabe, Charles G. | Brewer, Gregory J.

Article Type: Research Article

Abstract: Background: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer’s disease (AD). Objective: To profile the progression of pathology in AD. Methods: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan. Results: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but …the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine. Conclusion: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by a pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes. Show more

Keywords: Alzheimer disease, glutathione, intracellular amyloid, lifespan, mechanism, pAkt, pathogenesis, redox

DOI: 10.3233/JAD-220824

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1501-1521, 2022

Authors: Röhr, Susanne | Pabst, Alexander | Baber, Ronny | Engel, Christoph | Glaesmer, Heide | Hinz, Andreas | Schroeter, Matthias L. | Witte, A. Veronica | Zeynalova, Samira | Villringer, Arno | Löffler, Markus | Riedel-Heller, Steffi G.

Article Type: Research Article

Abstract: Background: There are socioeconomic inequalities in dementia risk. Underlying pathways are not well known. Objective: To investigate whether modifiable health and lifestyle factors for brain health mediate the association of socioeconomic status (SES) and cognitive functioning in a population without dementia. Methods: The “LIfestyle for BRAin health” (LIBRA) score was computed for 6,203 baseline participants of the LIFE-Adult-Study. LIBRA predicts dementia in midlife and early late life, based on 12 modifiable factors. Associations of SES (education, net equivalence income, and occupational status) and LIBRA with cognitive functioning (composite score) were investigated using adjusted linear regression models. …Bootstrapped structural equation modelling (SEM) was used to investigate whether LIBRA mediated the association of SES and cognitive functioning. Results: Participants were M  = 57.4 (SD  = 10.6, range: 40-79) years old; 50.3% were female. Both, SES (Wald: F (2)=52.5, p  < 0.001) and LIBRA (Wald: F (1)=5.9, p  < 0.05) were independently associated with cognitive functioning; there was no interaction (Wald: F (2)=2.9, p  = 0.060). Lower SES and higher LIBRA scores indicated lower cognitive functioning. LIBRA partially mediated the association of SES and cognitive functioning (IE: =0.02, 95% CI [0.02, 0.03], p  < 0.001). The proportion mediated was 12.7%. Conclusion: Differences in cognitive functioning due to SES can be partially attributed to differences in modifiable health and lifestyle factors; but to a small extent. This suggests that lifestyle interventions could attenuate socioeconomic inequalities in cognitive functioning. However, directly intervening on the social determinants of health may yield greater benefits for dementia risk reduction. Show more

Keywords: Cognitive function, dementia, epidemiology, lifestyle, prevention, public health, risk factors, social inequalities, socioeconomic status

DOI: 10.3233/JAD-220474

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1523-1534, 2022

Authors: Waziry, Reem | Claus, Jacqueline J. | Hofman, Albert

Article Type: Research Article

Abstract: Background: The majority of stroke cases are ischemic in origin and ischemic stroke survivors represent a high-risk population for progression to dementia. Objective: To determine incidence rates and predictors of dementia after ischemic stroke. Methods: A systematic review and meta-analysis compliant with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Results: 5,843 studies were screened for title and abstract. 292 eligible studies were screened for full text. A total of 22 studies met the inclusion criteria and were included, representing 55,929 ischemic stroke survivors. Cumulative incidence of dementia after stroke was 20% at …5 years, 30% at 15 years, and 48% at 25 years of follow-up. Dementia incidence rates were 1.5 times higher among patients with recurrent ischemic stroke compared to patients with first-time stroke. Predictors of dementia after ischemic stroke included female gender (OR 1.2, 95% CI (1.1, 1.4)), hypertension (1.4, (1.1, 2.0)), diabetes mellitus (1.6, (1.3, 2.1)), atrial fibrillation (1.9, (1.2, 3.0)), previous stroke (2.0, (1.6, 2.6)), presence of stroke lesion in dominant hemisphere (2.4, (1.3, 4.5)), brain stem or cerebellum (OR 0.5, (0.3, 0.9)) or frontal lobe (3.7, (1.2, 12.0)), presence of aphasia (OR 7.9, (2.4, 26.0)), dysphasia (5.8, (3.0, 11.3)), gait impairment (1.7, (1.1, 2.7)), presence of white matter hyperintensities (3.2, (2.0, 5.3)), and medial temporal lobe atrophy (3.9, (1.9, 8.3)). Conclusion: Factors routinely collected for stroke patients are a useful resource for monitoring dementia progression in this population. In the present meta-analysis, cardiovascular factors, stroke location, stroke-related disability and chronic brain changes were predictors of dementia after ischemic stroke. Show more

Keywords: Dementia, ischemic stroke, meta-analysis, systematic review

DOI: 10.3233/JAD-220317

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1535-1546, 2022

Authors: Huang, Xiangyuan | Alcantara, Leicester Shawn | Tan, Chuen Seng | Ng, Yi Lin | van Dam, Rob M. | Hilal, Saima

Article Type: Research Article

Abstract: Background: Handgrip strength (HGS) is an important marker of frailty but there is limited research on lifestyle and vascular determinants of HGS and its relationship with cognitive impairment. Objective: To identify determinants of HGS and the association of HGS with cognitive impairment in a multiethnic cohort from Singapore. Methods: This study (n  = 2,109, median [Q1, Q3] age: 53 [48, 60] years, 59.6% women) was based on cross-sectional data from Singapore Multi-Ethnic Cohort. HGS was collected using hand-held Electronic Dynamometer. The potential determinants of HGS included age, sex, ethnicity, smoking, physical activity, serum cholesterol and history of …hypertension, diabetes, and stroke. Cognition, assessed with the Mini-Mental State Examination (MMSE), was analyzed as both continuous and binary outcome (cognitively impaired [scores < 26] and cognitively normal [scores≥26]). Results: In total, 239 (11.3%) participants were cognitively impaired. Older age, female sex, Malay or Indian compared with Chinese ethnicity, and diabetes history were associated with decreased HGS, whereas higher education, higher body mass index, and more physical activity were associated with higher HGS. Higher HGS was associated with higher MMSE scores (β: 0.34, 95% CI: 0.20, 0.49) and 37% lower odds of cognitive impairment (OR: 0.63, 95% CI: 0.49–0.82). These associations were significantly stronger in participants who were older (50–90 years), female, of Malay and Indian ethnicity (compared with Chinese), and less educated. Conclusion: In this multi-ethnic Asian population, demographics, vascular risk factors, and lifestyle behaviors were associated with HGS. Additionally, higher HGS was associated with substantially better cognitive function, which association was modified by age, sex, ethnicity, and education level. Show more

Keywords: Asians, cognitive dysfunction, hand strength, Mental Status and Dementia Tests

DOI: 10.3233/JAD-220531

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1547-1555, 2022

Authors: Gaitán, Julian M. | Asthana, Sanjay | Carlsson, Cynthia M. | Engelman, Corinne D. | Johnson, Sterling C. | Sager, Mark A. | Wang, Dan | Dubal, Dena B. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: Background: Klotho is a longevity and neuroprotective hormone encoded by the KLOTHO gene, and heterozygosity for the KL-VS variant confers a protective effect against neurodegenerative disease. Objective: Test whether klotho concentrations in serum or cerebrospinal fluid (CSF) vary as a function of KLOTHO KL-VS genotype, determine whether circulating klotho concentrations from serum and CSF differ from one another, and evaluate whether klotho levels are associated with Alzheimer’s disease risk factors. Methods: Circulating klotho was measured in serum (n  = 1,116) and CSF (n  = 183) of cognitively intact participants (aged 62.4 ± 6.5 years; 69.5% female). …KLOTHO KL-VS zygosity (non-carrier; heterozygote; homozygote) was also determined. Linear regression was used to test whether klotho hormone concentration varied as a function of KL-VS genotype, specimen source, and demographic and clinical characteristics. Results: Serum and CSF klotho were higher in KL-VS carriers than non-carriers. Klotho concentration was higher in CSF than in serum. Females had higher serum and CSF klotho, while younger age was associated with higher klotho in CSF. Conclusion: In a cohort enriched for risk for Alzheimer’s disease, heterozygotic and homozygotic carriers of the KL-VS allele, females, and younger individuals have higher circulating klotho. Fluid source, KL-VS genotype, age, and sex should be considered in analyses of circulating klotho on brain health. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, KL-VS, Klotho, serum

DOI: 10.3233/JAD-220571

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1557-1569, 2022

Authors: Dissanayake, Andrew S. | Tan, Yu Bin | Bowie, Christopher R. | Butters, Meryl A. | Flint, Alastair J. | Gallagher, Damien | Golas, Angela C. | Herrmann, Nathan | Ismail, Zahinoor | Kennedy, James L. | Kumar, Sanjeev | Lanctot, Krista L. | Mah, Linda | Mulsant, Benoit H. | Pollock, Bruce G. | Rajji, Tarek K. | Tau, Michael | Maraj, Anika | Churchill, Nathan W. | Tsuang, Debby | Schweizer, Tom A. | Munoz, David G. | Fischer, Corinne E.

Article Type: Research Article

Abstract: Background: Recent work suggests that APOE ɛ 4/4 females with Alzheimer’s disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS). Objective: To examine the interaction of sex and APOE ɛ 4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n  = 252) and 2) patients with probable AD (n  = 7,261). Methods: Regression models examined the interactive effects of sex and APOE ɛ 4 on the number of NPS experienced and NPS Severity. APOE ɛ 3/4 and APOE …ɛ 4/4 were pooled in the at-risk cohort due to the sample size. Results: In the at-risk cohort, there was a significant sex*APOE ɛ 4 interaction (p  = 0.007) such that the association of APOE ɛ 4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOE ɛ 4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOE ɛ 4/4 females had significantly more NPS (IRR = 1.1, p  = 0.001, mean = 3.1) and higher severity scores (b  = 0.31, p  = 0.015, mean = 3.7) than APOE ɛ 3/3 females (meanNPS  = 2.9, meanSeverity  = 3.3). No association was found in males. Conclusion: Our study suggests that sex modifies the association of APOE ɛ 4 on NPS burden. APOE ɛ 4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed. Show more

Keywords: Alzheimer’s disease, APOE4, behavioral and psychological symptoms of dementia, biomarkers, gender differences, major depressive disorder, mild cognitive impairment, neuropsychiatry, Neuropsychiatric Inventory Questionnaire, psychosis

DOI: 10.3233/JAD-220586

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1571-1588, 2022

Authors: Hughes, Timothy M. | Lockhart, Samuel N. | Suerken, Cynthia K. | Jung, Youngkyoo | Whitlow, Christopher T. | Bateman, James R. | Williams, Benjamin J. | Espeland, Mark A. | Sachs, Bonnie C. | Williamson, Jeff | Cleveland, Maryjo | Yang, Mia | Rogers, Samantha | Hayden, Kathleen M. | Baker, Laura D. | Craft, Suzanne

Article Type: Research Article

Abstract: Background: Cardiometabolic disorders (hypertension, diabetes) are key modifiable risk factors for Alzheimer’s disease and related disorders. They often co-occur; yet, the extent to which they independently affect brain structure and function is unclear. Objective: We hypothesized their combined effect is greater in associations with cognitive function and neuroimaging biomarkers of white matter (WM) health and cerebral perfusion in a diverse older adult cohort. Methods: Participants aged 50-85 years received: clinical evaluation, oral glucose tolerance testing, neuroimaging, cognitive testing, and adjudication. Neuroimaging included: T1 (gray [GM]/WM segmentation, regional volumes/thicknesses); FLAIR (WM hyperintensity volume [WMHv]; arterial spin labeling …(cerebral blood flow); diffusion tensor imaging (fractional anisotropy [FA]); and neurite orientation dispersion and density imaging (Free Water). Hypertension (HTN) and impaired glucose tolerance (IGT) were staged and cardiometabolic status was categorized (HTN only, IGT only, IGT+HTN, neither). Multivariable linear regression modeled associations with cognitive and neuroimaging measures (covariates: age, gender, race). Results: MRI was available for 478 participants (35% mild cognitive impairment, 10% dementia) with mean age 70±8 years, 74% with HTN, 61% with IGT, and 15% self-identified as Black/African-American. IGT+HTN was significantly associated with cognitive impairment, higher WM Free Water and WMHv, lower FA, and lower GM perfusion compared to neither factor. HTN alone was associated with poorer cognition and lower GM perfusion. Cardiometabolic factors were not associated with GM macrostructure (volumes, temporal lobe cortical thickness) or cognitive status. Conclusion: HTN and its co-occurrence with IGT (HTN+IGT) were associated with lower global cognitive performance and reduced GM perfusion and impaired WM microstructure. Show more

Keywords: Brain, cognition, hyperglycemia, hypertension

DOI: 10.3233/JAD-220646

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1589-1599, 2022

Authors: Libard, Sylwia | Giedraitis, Vilmantas | Kilander, Lena | Ingelsson, Martin | Alafuzoff, Irina

Article Type: Research Article

Abstract: Background: There are more than 300 presenilin-1 (PSEN1 ) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed. Objective: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer’s disease (sAD). Methods: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations. Results: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, …although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations. Conclusion: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness. Show more

Keywords: Alpha-synuclein, amyloid-β, cross-seeding, hyperphosphorylated tau, neuroinflammation, PSEN1, TDP43

DOI: 10.3233/JAD-220655

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1601-1614, 2022

Authors: Chaudhary, Shefali | Zhornitsky, Simon | Chao, Herta H. | van Dyck, Christopher H. | Li, Chiang-Shan R.

Article Type: Research Article

Abstract: Background: Earlier studies have described the neural markers of apathy in Alzheimer’s disease (AD) and mild cognitive impairment (MCI), but few focused on the motivation circuits. Here, we targeted hypothalamus, a hub of the motivation circuit. Objective: To examine hypothalamic resting state functional connectivity (rsFC) in relation to apathy. Methods: We performed whole-brain regression of hypothalamic rsFC against Apathy Evaluation Scale (AES) total score and behavioral, cognitive, and emotional subscores in 29 patients with AD/MCI and 28 healthy controls (HC), controlling for age, sex, education, cognitive status, and depression. We evaluated the results at a corrected …threshold and employed path analyses to assess possible interaction between hypothalamic rsFCs, apathy and depression/memory. Finally, we re-examined the findings in a subsample of amyloid-β-verified AD. Results: AES total score correlated negatively with hypothalamic precuneus (PCu)/posterior cingulate cortex (PCC) and positively with left middle temporal gyrus (MTG) and supramarginal gyrus rsFCs. Behavioral subscore correlated negatively with hypothalamic PCu/PCC and positively with middle frontal gyrus rsFC. Cognitive subscore correlated positively with hypothalamic MTG rsFC. Emotional subscore correlated negatively with hypothalamic calcarine cortex rsFC. In path analyses, hypothalamic-PCu/PCC rsFC negatively modulated apathy and, in turn, depression. The model where hypothalamic MTG rsFC and memory independently modulated apathy also showed a good fit. The findings of diminished hypothalamic-PCu/PCC rsFC in relation to apathy and, in turn, depression were confirmed in amyloid-verified AD. Conclusion: The findings together support a role of altered hypothalamic connectivity in relation to apathy and depression, and modulation of apathy by memory dysfunction. Show more

Keywords: Alzheimer’s disease, apathy, depression, hypothalamus, memory, resting state functional connectivity

DOI: 10.3233/JAD-220708

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1615-1628, 2022

Authors: Kochan, Nicole A. | Heffernan, Megan | Valenzuela, Michael | Sachdev, Perminder S. | Lam, Ben C.P. | Fiatarone Singh, Maria | Anstey, Kaarin J. | Chau, Tiffany | Brodaty, Henry

Article Type: Research Article

Abstract: Background: Self-administered computerized neuropsychological assessments (CNAs) provide lower cost, more accessible alternatives to traditional in-person assessments but lack critical information on psychometrics and subjective experience of older adults in remote testing environments. Objective: We used an online brief battery of computerized tasks selected from the Cogstate Brief Battery (CBB) and Cambridge Brain Sciences (CBS) to 1) determine test-retest reliability in an unsupervised setting; 2) examine convergent validity with a comprehensive ‘gold standard’ paper-and-pencil neuropsychological test battery administered in-person; and 3) explore user-experience of remote computerized testing and individual tests. Methods: Fifty-two participants (mean age 65.8±5.7 years) …completed CBB and CBS tests on their own computer, unsupervised from home, on three occasions, and visited a research center for an in-person paper-and-pencil assessment. They also completed a user-experience questionnaire. Results: Test-retest reliabilities varied for individual measures (ICCs = 0.20 to 0.83). Global cognition composites showed excellent reliability (ICCs > 0.8 over 1-month follow-up). A strong relationship between a combination of CNA measures and paper-and-pencil battery was found (canonical correlation R  = 0.87, p  = 0.04). Most tests were rated as enjoyable with easy-to-understand instructions. Ratings of general experience with online testing were mostly favorable; few had difficulty concentrating (17%) or using the computer for tasks (10%), although over one-third experienced performance anxiety (38%). Conclusion: A combined brief online battery selected from two CNAs demonstrated robust psychometric standards for reliability (global composite), and convergent validity with a gold standard battery, and mostly good usability and acceptability in the remote testing environment. Show more

Keywords: Healthcare acceptability, mental status and dementia tests, neuropsychological tests, psychometrics

DOI: 10.3233/JAD-220665

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1629-1645, 2022

Authors: Gao, Fan | Zhang, Peng-Fei | Gao, Jing | Song, Jinghui | Chi, Song

Article Type: Research Article

Abstract: Background: CC-chemokine ligand 2 (CCL2), the key immunomodulatory chemokine for microglial activation, has been implicated in the pathogenesis of Alzheimer’s disease (AD). Whether the association of CCL2 single nucleotide polymorphisms (SNPs) and the risk of AD is still controversial. Objective: We aimed to investigate whether CCL2 rs4586 SNP is associated with the pathological changes and cognitive decline of AD. Methods: A total of 486 participants with longitudinal cerebrospinal fluid (CSF) amyloid-β (Aβ) and phospho-tau (P-tau) biomarkers, 18 F-Florbetapir and 18 F-flortaucipir-positron emission tomography (PET), and cognitive assessments from the Alzheimer’s disease Neuroimaging Initiative were …included in the study. The effects of CCL2 rs4586 SNP on the pathological changes and cognitive decline of AD were assessed with linear mixed-effects models and evaluated according to the Aβ-status so as to identify whether the effects were independent of Aβ status. Results: CCL2 rs4586-CC carriers exhibited a slower global Aβ-PET accumulation, particularly within stage I and stage II. However, they exhibited a faster accumulation of CSF P-tau and global tau-PET standard uptake value ratios, especially in Braak I and Braak III/IV and the inferior temporal gyrus. The congruent effects of CCL2 rs4586 on tau accumulation existed only in the Aβ–group, as is shown in global tau-PET and Braak I. However, CCL2 rs4586 was not associated with the cognitive decline. Conclusion: Our findings showed that the CCL2 rs4586-CC (versus TT/TC) genotype was associated with slower Aβ deposition and faster tau accumulation, and the latter of which was independent of Aβ status. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, amyloid-β, CCL2, tau

DOI: 10.3233/JAD-220716

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1647-1657, 2022

Authors: Ma, Yanzhen | Li, Weizu | Fan, Chang | Wang, Yongzhong | Jiang, Hui | Yang, Wenming

Article Type: Research Article

Abstract: Background: N4-acetylcytidine (ac4C), an important posttranscriptional modification, is involved in various disease processes. Long noncoding RNAs (lncRNAs) regulate gene expression mainly through epigenetic modification, transcription, and posttranscriptional modification. Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloidosis of the brain. However, the role of lncRNA ac4C modification in AD remains unclear. Objective: In this study, we investigated the association between ac4C modification and AD, and the underlying mechanisms of ac4C modification in AD. Methods: The male 9-month-old APP/PS1 double transgenic mice, age- and sex-matched wild type (WT) mice were used in this study. Then, ac4C-RIP-seq …and RNA-seq were used to comprehensively analyze lncRNA ac4C modification in AD mice. The lncRNA-miRNA-mRNA regulatory networks using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed the regulatory relationships among these three lncRNAs and AD. Results: The results showed that there were 120 significantly different ac4C peaks located on 102 lncRNAs in AD, of which 55 were hyperacetylated and 47 were hypoacetylated. Simultaneously, 231 differentially expressed lncRNAs were identified, including 138 upregulated lncRNAs and 93 downregulated lncRNAs. Moreover, 3 lncRNAs, lncRNA Gm26508, lncRNA A430046D13Rik, and lncRNA 9530059O14Rik, showed significant changes in both the ac4C and RNA levels using conjoint analysis. Conclusion: The abundance of lncRNA ac4C modification is significantly different in AD and indicates that lncRNA ac4C is associated with the occurrence and development of AD, which could provide a basis for further exploration of the related regulatory mechanisms. Show more

Keywords: ac4C acetylation, Alzheimer’s disease, high-throughput sequencing, lncRNAs

DOI: 10.3233/JAD-220564

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1659-1675, 2022

Authors: Ng, Ted Kheng Siang | Tan, Xiang Ren | Todd, Michael | Chen, Angela Chia-Chen | Feng, Lei | Lu, Yanxia | Yu, Fang | Kua, Ee Heok | Mahendran, Rathi

Article Type: Research Article

Abstract: Background: Few randomized controlled trials (RCTs) investigated the effects of mindfulness intervention on affective and cognitive symptoms in older adults with mild cognitive impairment (MCI). Furthermore, no RCTs on mindfulness followed participants beyond two years. Objective: To examine the longitudinal effects of a mindful awareness practice (MAP) intervention on depressive, anxiety, and cognitive symptoms in MCI. Methods: In this parallel-arm and assessor-blinded RCT, 55 community-dwelling older adults with MCI were randomized into the MAP or active control, i.e., health education program (HEP). Intervention sessions were conducted weekly for three months and monthly for the subsequent six …months. Assessments and follow-up were conducted at baseline, 3-month, 9-month, and 5-year time points. Depressive, anxiety, and cognitive symptoms were measured using the Geriatric Depression Scale-15 (GDS-15), Geriatric Anxiety Inventory-20 (GAI-20), and Mini-Mental State Examination (MMSE), respectively. Linear-mixed models, following the intention-to-treat principle, were used for data analyses. Results: A total of 55 participants aged 60 to 86 (Mean age: 71.3±6 years old) was recruited, with n  = 28 allocated to the MAP arm and n  = 27 allocated to the HEP arm. Compared to HEP, GDS-15, GAI-20, and MMSE scores did not differ significantly in MAP during follow-ups. Conclusion: Compared to HEP, MAP did not improve affective symptoms nor delay deteriorations in general cognition in community-dwelling older adults with MCI. Compared to our previous findings showing domain-specific improvements in MAP over HEP in attention and memory up to 9 months, this study highlights the importance of examining domain-specificity using detailed cognitive measures in non-pharmacological intervention with MCI. Show more

Keywords: Geriatric anxiety inventory, health education, mild cognitive impairment, mindfulness, mini-mental state examination, geriatric depression scale, non-pharmacological intervention, preclinical dementia

DOI: 10.3233/JAD-220641

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1677-1688, 2022

Authors: Ayton, Darshini | Pirotta, Stephanie | Morello, Renata | Rosenich, Emily | Barton, Chris | Lavale, Alexandra | Pase, Matthew P. | Maruff, Paul | Yassi, Nawaf | Brodtmann, Amy | Lim, Yen Ying | Barker, Anna

Article Type: Research Article

Abstract: Background: The BetterBrains Randomized Controlled Trial (RCT) will evaluate the effectiveness of an online, person-centered, risk factor management, coaching intervention in community-dwelling, healthy adults at risk of cognitive decline. Multi-component interventions are challenging to evaluate due to program complexity and personalization to individual needs and contexts. This paper describes a multi-level process evaluation conducted alongside the BetterBrains RCT. Objective: To understand how and why the BetterBrains intervention was effective or ineffective at reducing cognitive decline in healthy adults whilst considering the context in which it was implemented. Methods: 1,510 non cognitively-deteriorated community-dwelling adults aged 40–70 years …old at risk of cognitive decline will be recruited and randomly assigned to the intervention or control group. All BetterBrains intervention participants, coaches, and the research team will be included in the evaluation. A mixed-methods design will be used, guided by The Framework for Implementation Fidelity and the program logic model. Data will be sourced from interviews, focus groups, surveys, BetterBrains coach notes, participant weekly check-in surveys, and audio recordings of intervention coaching sessions. Quantitative data will be analyzed via descriptive and inferential statistics and qualitative data will be analyzed using content and thematic analysis. Results: The process evaluation will provide information about contextual and influencing factors related to the implementation of BetterBrains and the RCT outcomes. Conclusion: Understanding how BetterBrains was implemented and its associated impacts will inform the translation of the program into community and clinical settings, providing easy access to online, personalized dementia prevention services. Show more

Keywords: Chronic disease prevention, cognitive decline, implementation, process evaluation

DOI: 10.3233/JAD-220341

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1689-1703, 2022

Authors: Restifo, Daniel | Zhao, Chen | Kamel, Hooman | Iadecola, Costantino | Parikh, Neal S.

Article Type: Research Article

Abstract: Background: The detrimental impact of tobacco smoking on brain health is well recognized. Objective: To evaluate whether smoking acts synergistically with hypertension and diabetes to influence cognitive performance. Methods: We performed a cross-sectional analysis using the US National Health and Nutrition Examination Survey. Participants were tested for serum cotinine, a validated cigarette smoking/exposure biomarker, and had standardized blood pressure and hemoglobin A1c measurements. Participants were administered four cognitive tests: Digit Symbol Substitution (DSST), Animal Fluency, Immediate Recall, and Delayed Recall. Multivariable linear regression models adjusted for demographics and confounders evaluated the association of cotinine with cognition. …Interaction testing evaluated effect modification by hypertension, diabetes, and their continuous measures (systolic blood pressure and hemoglobin A1c). Results: For 3,007 participants, mean age was 69.4 years; 54% were women. Using cotinine levels, 14.9% of participants were categorized as active smokers. Higher cotinine levels were associated with worse DSST performance when modeling cotinine as a continuous variable (β, -0.70; 95% CI, -1.11, -0.29; p  < 0.01) and when categorizing participants as active smokers (β, -5.63; 95% CI, -9.70, -1.56; p  < 0.01). Cotinine was not associated with fluency or memory. Effect modification by hypertension and diabetes were absent, except that cotinine was associated with worse Immediate Recall at lower blood pressures. Conclusion: Higher levels of a smoking and secondhand exposure biomarker were associated with worse cognitive performance on a multidomain test. Overall, the relationship of cotinine with cognition was not contingent on or amplified by hypertension or diabetes; smoking is detrimental for brain health irrespective of these comorbidities. Show more

Keywords: Cigarette smoking, cognition, cotinine, diabetes, hypertension

DOI: 10.3233/JAD-220647

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1705-1712, 2022

Authors: Musaeus, Christian Sandøe | Waldemar, Gunhild | Andersen, Birgitte Bo | Høgh, Peter | Kidmose, Preben | Hemmsen, Martin Christian | Rank, Mike Lind | Kjær, Troels Wesenberg | Frederiksen, Kristian Steen

Article Type: Research Article

Abstract: Background: Previous studies have reported that epileptiform activity may be detectible in nearly half of patients with Alzheimer’s disease (AD) on long-term electroencephalographic (EEG) recordings. However, such recordings can be uncomfortable, expensive, and difficult. Ear-EEG has shown promising results for long-term EEG monitoring, but it has not been used in patients with AD. Objective: To investigate if ear-EEG is a feasible method for long-term EEG monitoring in patients with AD. Methods: In this longitudinal, single-group feasibility study, ten patients with mild to moderate AD were recruited. A total of three ear-EEG recordings of up to 48 …hours three months apart for six months were planned. Results: All patients managed to wear the ear-EEG for at least 24 hours and at least one full night. A total of 19 ear-EEG recordings were performed (self-reported recording, mean: 37.15 hours (SD: 8.96 hours)). After automatic pre-processing, a mean of 27.37 hours (SD: 7.19 hours) of data with acceptable quality in at least one electrode in each ear was found. Seven out of ten participants experienced mild adverse events. Six of the patients did not complete the study with three patients not wanting to wear the ear-EEG anymore due to adverse events. Conclusion: It is feasible and safe to use ear-EEG for long-term EEG monitoring in patients with AD. Minor adjustments to the equipment may improve the comfort for the participants. Show more

Keywords: Alzheimer’s disease, ear-EEG, electroencephalography, long-term EEG, wearable

DOI: 10.3233/JAD-220491

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1713-1723, 2022

Authors: Bartels, Claudia | Abdel-Hamid, Mona | Wiltfang, Jens | Schneider, Anja | Belz, Michael

Article Type: Research Article

Abstract: Background: The multimodal CORDIAL treatment concept for mild dementia, combining cognitive rehabilitation, cognitive behavioral and humanistic psychology interventions, has proven its feasibility and demonstrated a reduction of depressive symptoms in individual dyadic/triadic settings. Objective: We investigate antidepressant effects of an adapted group-based CORDIAL program in clinical routine care. Methods: During 2013 and 2017, 51 outpatients with mild dementia (45% female, mean age 72.4 years, 67% Alzheimer’s dementia, mean MMST 24.8) periodically received a modified CORDIAL group treatment as part of our regular outpatient care. Treatment comprised 10 bi-weekly sessions, partly involving caregivers. Systematic pre- and post-treatment …assessments of clinical routine data were evaluated retrospectively (median time-interval of 6.6 months). Results: Depressive symptoms as measured by the Geriatric Depression Scale significantly decreased over time (p  = 0.007, Cohen’s d  = 0.39), and irrespective of gender. Patients with longer disease duration before treatment start showed significantly higher initial levels of depressive symptoms (p  = 0.044), followed by a reduction to a level of those with shorter disease duration (ns ). Most secondary outcomes (cognitive symptoms, disease severity, quality of life, caregiver burden) remained unchanged (ns ), while competence in activities of daily living declined from pre- to post-measurement (p  = 0.033). Conclusion: A group-based CORDIAL treatment is feasible in a clinical routine setting and demonstrated antidepressant effects comparable to those of the individual treatment design, further suggesting its implementation in regular care. Future trials might also investigate its potentially preventive effects by reducing depressive symptoms in pre-dementia stages, even at a subsyndromal level. Show more

Keywords: Dementia, depression, cognitive rehabilitation, cognitive behavioral therapy, reminiscence, group therapy, activities of daily living, caregiver burden

DOI: 10.3233/JAD-220578

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1725-1737, 2022

Authors: Laton, Jorne | Van Schependom, Jeroen | Goossens, Joery | Wiels, Wietse | Sieben, Anne | De Deyn, Peter Paul | Goeman, Johan | Streffer, Johannes | van der Zee, Julie | Martin, Jean-Jacques | Van Broeckhoven, Christine | De Vos, Maarten | Bjerke, Maria | Nagels, Guy | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Distinguishing between Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) results in poor diagnostic accuracy. Objective: To investigate the utility of electroencephalography (EEG)-based biomarkers in comparison and in addition to established cerebrospinal fluid (CSF) biomarkers in the AD versus FTLD differential diagnosis. Methods: The study cohort comprised 37 AD and 30 FTLD patients, of which 17 AD and 9 FTLD patients had definite diagnoses. All participants had CSF neurochemical (NCM) biomarker analyses (Aβ1-42 , T-tau, P-tau181 , and Nf-L) and underwent 19-channel resting-state EEG. From the EEG spectra, dominant frequency peaks were extracted in four …regions resulting in four dominant frequencies. This produced eight features (4 NCM + 4 EEG). Results: When NCM and EEG markers were combined, the diagnostic accuracy increased significantly. In the whole group, the accuracy went up from 79% (NCM) to almost 82%, while in the definite group only, it went up from around 85% to almost 95%. Two differences in the occurrence of the dominant EEG frequency were discovered: people lacking a clear dominant peak almost all had definite AD, while people with two peaks more often had FTLD. Conclusion: Combining EEG with NCM biomarkers resulted in differential diagnostic accuracies of 82% in clinically diagnosed AD and FTD patients and of 95% in patients having a definite diagnosis, which was significantly better than with EEG or NCM biomarkers alone. This suggests that NCM and EEG markers are complementary, revealing different aspects of the disease and therefore confirms again their relevance in developing additional diagnosis tools. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebrospinal fluid, dementia, EEG, frontotemporal dementia, neurofilament light, random forest, tau protein

DOI: 10.3233/JAD-220693

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1739-1747, 2022

Authors: Ren, Shuhua | Hu, Jingchao | Huang, Lin | Li, Junpeng | Jiang, Donglang | Hua, Fengchun | Guan, Yihui | Guo, Qihao | Xie, Fang | Huang, Qi

Article Type: Research Article

Abstract: Background: Subjects with subjective cognitive decline (SCD) are proposed as a potential population to screen for Alzheimer’s disease (AD). Objective: Investigating brain topologies would help to mine the neuromechanisms of SCD and provide new insights into the pathogenesis of AD. Methods: Objectively cognitively unimpaired subjects from communities who underwent resting-state BOLD-fMRI and clinical assessments were included. The subjects were categorized into SCD and normal control (NC) groups according to whether they exhibited self-perceived cognitive decline and were worried about it. The minimum spanning tree (MST) of the functional brain network was calculated for each subject, based …on which the efficiency and centrality of the brain network organization were explored. Hippocampal/parahippocampal volumes were also detected to reveal whether the early neurodegeneration of AD could be seen in SCD. Results: A total of 49 subjects in NC and 95 subjects in SCD group were included in this study. We found the efficiency and centrality of brain network organization, as well as the hippocampal/parahippocampal volume were preserved in SCD. Besides, SCD exhibited normal cognitions, including memory, language, and execution, but increased depressive and anxious levels. Interestingly, language and execution, instead of memory, showed a significant positive correlation with the maximum betweenness centrality of the functional brain organization and hippocampal/parahippocampal volume. Neither depressive nor anxious scales exhibited correlations with the brain functional topologies or hippocampal/parahippocampal volume. Conclusion: SCD exhibited preserved efficiency and centrality of brain organization. In clinical practice, language and execution as well as depression and anxiety should be paid attention in SCD. Show more

Keywords: Alzheimer’s disease, functional brain topologies, hippocampal volume, minimum spanning tree, subjective cognitive decline

DOI: 10.3233/JAD-220527

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1749-1759, 2022

Authors: Ganapathi, Aarthi S. | Glatt, Ryan M. | Bookheimer, Tess H. | Popa, Emily S. | Ingemanson, Morgan L. | Richards, Casey J. | Hodes, John F. | Pierce, Kyron P. | Slyapich, Colby B. | Iqbal, Fatima | Mattinson, Jenna | Lampa, Melanie G. | Gill, Jaya M. | Tongson, Ynez M. | Wong, Claudia L. | Kim, Mihae | Porter, Verna R. | Kesari, Santosh | Meysami, Somayeh | Miller, Karen J. | Bramen, Jennifer E. | Merrill, David A. | Siddarth, Prabha

Article Type: Research Article

Abstract: Background: Distinguishing between subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia in a scalable, accessible way is important to promote earlier detection and intervention. Objective: We investigated diagnostic categorization using an FDA-cleared quantitative electroencephalographic/event-related potential (qEEG/ERP)-based cognitive testing system (eVox® by Evoke Neuroscience) combined with an automated volumetric magnetic resonance imaging (vMRI) tool (Neuroreader® by Brainreader). Methods: Patients who self-presented with memory complaints were assigned to a diagnostic category by dementia specialists based on clinical history, neurologic exam, neuropsychological testing, and laboratory results. In addition, qEEG/ERP (n  = 161) and quantitative vMRI (n … = 111) data were obtained. A multinomial logistic regression model was used to determine significant predictors of cognitive diagnostic category (SCD, MCI, or dementia) using all available qEEG/ERP features and MRI volumes as the independent variables and controlling for demographic variables. Area under the Receiver Operating Characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the prediction models. Results: The qEEG/ERP measures of Reaction Time, Commission Errors, and P300b Amplitude were significant predictors (AUC = 0.79) of cognitive category. Diagnostic accuracy increased when volumetric MRI measures, specifically left temporal lobe volume, were added to the model (AUC = 0.87). Conclusion: This study demonstrates the potential of a primarily physiological diagnostic model for differentiating SCD, MCI, and dementia using qEEG/ERP-based cognitive testing, especially when combined with volumetric brain MRI. The accessibility of qEEG/ERP and vMRI means that these tools can be used as adjuncts to clinical assessments to help increase the diagnostic certainty of SCD, MCI, and dementia. Show more

Keywords: Dementia, electroencephalography, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-220616

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1761-1769, 2022

Authors: Giraldo, Diana L. | Smith, Robert E. | Struyfs, Hanne | Niemantsverdriet, Ellis | De Roeck, Ellen | Bjerke, Maria | Engelborghs, Sebastiaan | Romero, Eduardo | Sijbers, Jan | Jeurissen, Ben

Article Type: Research Article

Abstract: Background: Most studies using diffusion-weighted MRI (DW-MRI) in Alzheimer’s disease (AD) have focused their analyses on white matter (WM) microstructural changes using the diffusion (kurtosis) tensor model. Although recent works have addressed some limitations of the tensor model, such as the representation of crossing fibers and partial volume effects with cerebrospinal fluid (CSF), the focus remains in modeling and analyzing the WM. Objective: In this work, we present a brain analysis approach for DW-MRI that disentangles multiple tissue compartments as well as micro- and macroscopic effects to investigate differences between groups of subjects in the AD continuum and …controls. Methods: By means of the multi-tissue constrained spherical deconvolution of multi-shell DW-MRI, underlying brain tissue is modeled with a WM fiber orientation distribution function along with the contributions of gray matter (GM) and CSF to the diffusion signal. From this multi-tissue model, a set of measures capturing tissue diffusivity properties and morphology are extracted. Group differences were interrogated following fixel-, voxel-, and tensor-based morphometry approaches while including strong FWE control across multiple comparisons. Results: Abnormalities related to AD stages were detected in WM tracts including the splenium, cingulum, longitudinal fasciculi, and corticospinal tract. Changes in tissue composition were identified, particularly in the medial temporal lobe and superior longitudinal fasciculus. Conclusion: This analysis framework constitutes a comprehensive approach allowing simultaneous macro and microscopic assessment of WM, GM, and CSF, from a single DW-MRI dataset. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cognitive dysfunction, dementia, diffusion MRI, gray matter, white matter

DOI: 10.3233/JAD-220551

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1771-1791, 2022

Authors: Gaubert, Fanny | Borg, Céline | Chainay, Hanna

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) negatively impacts patients’ ability to make advantageous decisions, i.e., a core ability contributing to the preservation of autonomy. Objective: The present study aims to analyze the changes that occur in the decision-making competence (DMC) in AD patients and to determine if these changes are related to the deterioration of executive functions and working memory. Method: To this end, 20 patients with AD and 20 elderly control adults were assessed using executive, working memory, and DMC tasks. The latter comprised the Iowa Gambling Task (IGT) and a scenarios task based on situations inspired …by everyday life and performed under conditions of risk and ambiguity. Results: Results revealed lower performances in AD patients than in elderly control adults for all the tasks assessing cognitive functions. The AD patients also made more strategy changes during the IGT. In the scenarios tasks, the two groups took as many ambiguous or risky decisions, but AD patients tended to take more risks in the context of gain than elderly control adults did. Switching and updating ability, as well as working memory, appeared to be involved in decisions in tasks inspired by everyday life, while inhibition was more related to the IGT performances. Conclusion: Working memory and executive functions seem to be involved in decision-making, but in different ways in gambling and daily-life situations. Show more

Keywords: Alzheimer’s disease, decision making, executive function, working memory

DOI: 10.3233/JAD-220581

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1793-1815, 2022

Authors: Kleiman, Michael J. | Chang, Lun-Ching | Galvin, James E.

Article Type: Research Article

Abstract: Background: It is difficult to assess brain health status and risk of cognitive impairment, particularly at the initial evaluation. To address this, we developed the Brain Health Platform to quantify brain health and identify Alzheimer’s disease and related disorders (ADRD) risk factors by combining a measure of brain health: the Resilience Index (RI), a measure of risk of ADRD; the Vulnerability Index (VI); and the Number-Symbol Coding Task (NSCT), a measure of brain performance. Objective: The Brain Health Platform is intended to be easily and quickly administered, providing an overview of a patient’s risk of developing future impairment …based on modifiable and non-modifiable factors as well as current cognitive performance. Methods: This cross-sectional study comprehensively evaluated 230 participants (71 controls, 71 mild cognitive impairment, 88 ADRD). VI and RI scores were derived from physical assessments, lifestyle questionnaires, demographics, medical history, and neuropsychological examination including the NSCT. Results: Individuals with abnormal scores were 95.7% likely to be impaired, with a misclassification rate of 9.7%. The combined model had excellent discrimination (AUC:0.923±0.053; p  < 0.001), performing better than the Montreal Cognitive Assessment. Conclusion: The Brain Health Platform combines measures of resilience, vulnerability, and performance to provide a cross-sectional snapshot of overall brain health. The Brain Health Platform can effectively and accurately identify even the very mildest impairments due to ADRD, leveraging brief yet powerful and actionable indices of brain health and risk that could be used to develop personalized, precision medicine-like interventions. Show more

Keywords: Alzheimer’s disease, brain health, cognitive assessment, dementia, dementia with Lewy bodies, mild cognitive impairment, resilience, screening, vascular cognitive impairment, vulnerability

DOI: 10.3233/JAD-220927

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1817-1830, 2022

Authors: Whitehouse, Peter J. | George, Daniel R.

Article Type: Book Review

DOI: 10.3233/JAD-221066

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1831-1833, 2022

Article Type: Other

DOI: 10.3233/JAD-229012

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1835-1849, 2022

Authors: Prema, Asokan | Justin Thenmozhi, Arokiasamy | Manivasagam, Thamilarasan | Mohamed Essa, Musthafa | Guillemin, Gilles J.

Article Type: Correction

DOI: 10.3233/JAD-229017

Citation: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1851-1852, 2022