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