Journal of Alzheimer's Disease Reports - Volume 5, issue 1

Authors: Das, Subhrangshu | Panigrahi, Priyanka | Chakrabarti, Saikat

Article Type: Research Article

Abstract: Background: The total number of people with dementia is projected to reach 82 million in 2030 and 152 in 2050. Early and accurate identification of the underlying causes of dementia, such as Alzheimer’s disease (AD) is of utmost importance. A large body of research has shown that imaging techniques are most promising technologies to improve subclinical and early diagnosis of dementia. Morphological changes, especially atrophy in various structures like cingulate gyri, caudate nucleus, hippocampus, frontotemporal lobe, etc., have been established as markers for AD. Being the largest white matter structure with a high demand of blood supply from several main …arterial systems, anatomical alterations of the corpus callosum (CC) may serve as potential indication neurodegenerative disease. Objective: To detect mild and moderate AD using brain magnetic resonance image (MRI) processing and machine learning techniques. Methods: We have performed automatic detection and segmentation of the CC and calculated its morphological features to feed into a multivariate pattern analysis using support vector machine (SVM) learning techniques. Results: Our results using large patients’ cohort show CC atrophy-based features are capable of distinguishing healthy and mild/moderate AD patients. Our classifiers obtain more than 90%sensitivity and specificity in differentiating demented patients from healthy cohorts and importantly, achieved more than 90%sensitivity and > 80%specificity in detecting mild AD patients. Conclusion: Results from this analysis are encouraging and advocate development of an image analysis software package to detect dementia from brain MRI using morphological alterations of the CC. Show more

Keywords: Alzheimer’s disease, brain magnetic resonance imaging, corpus callosum atrophy, dementia, machine learning techniques, mild cognitive impairment

DOI: 10.3233/ADR-210314

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 771-788, 2021

Article Type: Correction

DOI: 10.3233/ADR-219005

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 789-789, 2021

Authors: Froelich, Lutz | Lladó, Albert | Khandker, Rezaul K. | Pedrós, Montse | Black, Christopher M. | Sánchez Díaz, Emilio J. | Chekani, Farid | Ambegaonkar, Baishali

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a significant burden on patients and caregivers. How this burden increases as disease progresses has not been well researched. Objective: To assess the association of caregiver burden and quality of life with Alzheimer’s disease severity and disease progression in community-dwelling patients in Germany, Spain, and the UK. Methods: This was a prospective observational longitudinal study of mild-to-moderate AD patients (assessed by Mini-Mental State Examination, MMSE), and their caregivers. The humanistic burden was assessed using these instruments: [Rapid Assessment of Physical Activity (RAPA), EuroQoL-5-Dimension Level (EQ-5D-5L)] and caregiver-reported [Dependence Scale (DS), EQ-5D-5L, …Zarit Burden Interview (ZBI)]. Caregiver-reported healthcare resource use was assessed using the Resource Use in Dementia (RUD) and ad-hoc questions. Results: Of 616 patients recruited, 338 and 99 were followed-up at 12 and 18 months, respectively. The caregiver-reported EQ-5D-5L scores of patients’ health-related quality of life (HRQoL) showed a negative trend over time (baseline: 0.76; 18 months: 0.67) while patient-reported HRQoL remained at 0.85. DS scores tended to worsen. Disease progression was an independent predictor of HRQoL and increased dependence. Mean ZBI score increased over time reflecting an increase in caregiver burden; MMSE being an independent predictor for caregiver burden. Patient resource utilization and caregiver time for caregiving tended to increase over time. Conclusion: We found significant association between disease progression and caregiver and patient burden. Independently, both disease-specific outcomes and disease burden measures increased over time, but as disease progresses, we also found incremental burden associated with it. Show more

Keywords: Alzheimer’s disease, caregivers, dementia, evidence-based medicine, global burden of disease, health-related quality of life, healthcare resources utilization

DOI: 10.3233/ADR-210025

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 791-804, 2021

Authors: Tan, Yi Jayne | Wong, Benjamin Y.X. | Vaidyanathan, Ramanathan | Sreejith, Sivaramapanicker | Chia, Sook Yoong | Kandiah, Nagaendran | Ng, Adeline S.L. | Zeng, Li

Article Type: Research Article

Abstract: Background: micro-RNAs (miRNAs) are stable, small, non-coding RNAs enriched in exosomes. Their variation in levels according to different disease etiologies have made them a promising diagnostic biomarker for neurodegenerative diseases such as Alzheimer’s disease (AD). Altered expression of miR-320a, miR-328-3p, and miR-204-5p have been reported in AD and frontotemporal dementia (FTD). Objective: To determine their reliability, we aimed to examine the expression of three exosomal miRNAs isolated from cerebrospinal fluid (CSF) of patients with young-onset AD and FTD (< 65 years), correlating with core AD biomarkers and cognitive scores. Methods: Exosomes were first isolated from CSF samples …of 48 subjects (8 controls, 28 AD, and 12 FTD), followed by RNA extraction and quantitative PCR to measure the expression of miR-320a, miR-328-3p, and miR-204-5p. Results: Expression of all three markers (miR-320a (p  = 0.005), miR-328-3p (p  = 0.049), and miR-204-5p (p  = 0.036)) were significantly lower in AD versus controls. miR-320a was reduced in FTD versus controls (p  = 0.049) and miR-328-3p was lower in AD versus FTD (p  = 0.054). Notably, lower miR-328-3p levels could differentiate AD from FTD and controls with an AUC of 0.702, 95% CI: 0.534– 0.870, and showed significant correlation with lower CSF Aβ42 levels (r  = 0.359, p  = 0.029). Pathway enrichment analysis identified potential targets of miR-328-3p implicated in the AMPK signaling pathway linked to amyloid-β and tau metabolism in AD. Conclusion: Overall, we demonstrated miR-320a and miR-204-5p as reliable biomarkers for AD and FTD and report miR-328-3p as a novel AD biomarker. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, exosome, frontotemporal dementia, miRNAs, young-onset Alzheimer’s disease

DOI: 10.3233/ADR-210311

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 805-813, 2021

Authors: Geerts, Hugo | van der Graaf, Piet

Article Type: Review Article

Abstract: With the approval of aducanumab on the “Accelerated Approval Pathway” and the recognition of amyloid load as a surrogate marker, new successful therapeutic approaches will be driven by combination therapy as was the case in oncology after the launch of immune checkpoint inhibitors. However, the sheer number of therapeutic combinations substantially complicates the search for optimal combinations. Data-driven approaches based on large databases or electronic health records can identify optimal combinations and often using artificial intelligence or machine learning to crunch through many possible combinations but are limited to the pharmacology of existing marketed drugs and are highly dependent upon …the quality of the training sets. Knowledge-driven in silico modeling approaches use multi-scale biophysically realistic models of neuroanatomy, physiology, and pathology and can be personalized with individual patient comedications, disease state, and genotypes to create ‘virtual twin patients’. Such models simulate effects on action potential dynamics of anatomically informed neuronal circuits driving functional clinical readouts. Informed by data-driven approaches this knowledge-driven modeling could systematically and quantitatively simulate all possible target combinations for a maximal synergistic effect on a clinically relevant functional outcome. This approach seamlessly integrates pharmacokinetic modeling of different therapeutic modalities. A crucial requirement to constrain the parameters is the access to preferably anonymized individual patient data from completed clinical trials with various selective compounds. We believe that the combination of data- and knowledge driven modeling could be a game changer to find a cure for this devastating disease that affects the most complex organ of the universe. Show more

Keywords: Drug development, quantitative systems pharmacology, trial design

DOI: 10.3233/ADR-210039

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 815-826, 2021

Authors: Lewis, Leslie A. | Urban, Carl M. | Hashim, Sami A.

Article Type: Research Article

Abstract: Background: The study involved a female patient diagnosed with late-stage dementia, with chronic daytime somnolence (CDS) as a prominent symptom. Objective: To explore whether her dementia resulted from Type 3 diabetes, and whether it could be reversed through ketosis therapy. Methods: A ketogenic diet (KD) generating low-dose 100 μM Blood Ketone Levels (BKL) enhanced by a brief Ketone Mono Ester (KME) regimen with high-dose 2–4 mM BKLs was used. Results: Three sets of data describe relief (assessed by % days awake) from CDS: 1) incremental, slow, time-dependent KD plus KME-induced sigmoid curve responses which resulted …in partial wakefulness (0–40% in 255 days) and complete wakefulness (40–85% in 50 days); 2) both levels of wakefulness were shown to be permanent; 3) initial permanent relief from CDS with low-dose ketosis from 6.7% to 40% took 87 days. Subsequent low-dose recovery from illness-induced CDS (6.9% to 40%) took 10 days. We deduce that the first restoration involved permanent repair, and the second energized the repaired circuits. Conclusion: The results suggest a role for ketosis in the elimination of CDS with the permanent functional restoration of the awake neural circuits of the Sleep-Wake cycle. We discuss whether available evidence supports ketosis-induced bioenergetics alone or whether other mechanisms of functional renewal were the basis for the elimination of CDS. Given evidence for permanent repair, two direct links between ketosis and neurogenesis in the adult mammalian brain are discussed: Ketosis-induced 1) brain-derived neurotrophic factor, resulting in neural progenitor/stem cell proliferation, and 2) mitochondrial bioenergetics-induced stem cell biogenesis. Show more

Keywords: Chronic daytime somnolence, hypothesis for induced neurogenesis, insulin resistance, ketosis therapy, logarithmic increase of wakefulness, mitochondrial bioenergetics, sleep-wake-cycle, type 3 diabetes

DOI: 10.3233/ADR-210315

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 827-846, 2021

Authors: Gutman, Gloria | Vashisht, Avantika | Kaur, Taranjot | Karbakhsh, Mojgan | Churchill, Ryan | Moztarzadeh, Amir

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) exhibited by persons with dementia (PwD) in nursing home communal areas are generally managed by segregation and/or pharmacological interventions. Objective: This study trialed MindfulGarden (MG), a novel digital calming device, in a Canadian nursing home. Methods: Participants were 15 PwD (mean age = 87.67; 5m,10f; mean MMSE = 11.64±7.85). Each was observed by a research assistant (RA) for an average of 8–10 hours on two separate days. The RA followed them during time spent in communal areas of the nursing home including their unit’s dining space, lounges, and corridors and spaces shared …with other units (e.g., gym and gift shop) and documented any BPSD exhibited. Day-1 provided baseline data; on Day-2, residents were exposed to MG if nursing staff considered their BPSD were sufficiently intense or sustained to warrant intervention. Staff rated the impact as positive, neutral, or negative. Results: On Day-1, 9 participants exhibited both aggressive and non-aggressive behaviors, 4 non-aggressive behaviors only, and 2 no BPSD. On Day-2, 7 exhibiting aggressive behaviors were exposed to MG. Staff reported MG as having distracting/calming effects and gave positive impact ratings to 6/13 exposures; there were no negative ratings. The most common aggressive BPSD on days of observation were pushing/shoving and screaming. Conclusion: MG may have value as a “psychiatric crash cart” in de-escalating agitation and aggression in care home settings. Show more

Keywords: Aggression, agitation, dementia, digital technology, feasibility studies, long-term care, nursing homes, pilot projects

DOI: 10.3233/ADR-210054

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 847-853, 2021

Authors: Pitera, Aleksandra P. | Hartnell, Iain J. | Scullard, Lucy | Williamson, Kirsten L. | Boche, Delphine | O’Connor, Vincent | Deinhardt, Katrin

Article Type: Research Article

Abstract: Background: Tauopathies are a group of neurodegenerative diseases associated with the accumulation of misfolded tau protein. The mechanisms underpinning tau-dependent proteinopathy remain to be elucidated. A protein quality control pathway within the endoplasmic reticulum, the unfolded protein response (UPR), has been suggested as a possible pathway modulating cellular responses in a range of neurodegenerative diseases, including those associated with misfolded cytosolic tau. Objective: In this study we investigated three different clinically defined tauopathies to establish whether these diseases are accompanied by the activation of UPR. Methods: We used PCR and western blotting to probe for the …modulation of several reliable UPR markers in mRNA and proteins extracted from three distinct tauopathies: 20 brain samples from Alzheimer’s disease patients, 11 from Pick’s disease, and 10 from progressive supranuclear palsy. In each disease samples from these patients were compared with equal numbers of age-matched non-demented controls. Results: Our investigation showed that different markers of UPR are not changed at the late stage of any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. Conclusion: These data from late-stage human cortical tissue report an activation of UPR markers within the aged brain across all cohorts investigated and further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a disease-associated activation of UPR. Show more

Keywords: Alzheimer’s disease, BiP, endoplasmic reticulum, Pick’s disease, progressive supranuclear palsy, tau, XBP-1

DOI: 10.3233/ADR-210050

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 855-869, 2021

Authors: Rijksen, Dirk O.C. | Zuidema, Sytse U. | de Haas, Esther C.

Article Type: Research Article

Abstract: Background: Guidelines worldwide recommend restricted prescription of benzodiazepine receptor agonists (BZRAs), i.e., benzodiazepines and Z-drugs, for the treatment of dementia-associated behavioral and psychological symptoms and insomnia. Objective: To assess the prevalence and appropriateness of BZRA use among nursing home residents with dementia. Methods: This is a post-hoc analysis of BZRA prescriptions from two intervention studies on psychotropic drug use, conducted from 2016 to 2018. It includes 1,111 residents of dementia special care units from 24 Dutch long-term care organizations. We assessed the prevalence of use of continuous and as-needed BZRA prescriptions and their association with …registered symptoms. Continuous BZRA prescriptions were evaluated for appropriateness, i.e., whether indication, dosage, duration, and evaluation accorded with guidelines for the treatment of challenging behavior in dementia and sleep disorders. Results: The prevalence of BZRA use is 39.2% (95% CI: 36.3%–42.0%): continuous 22.9%; only as-needed 16.3%. Combinations of preferred BZRAs and appropriate indications occur in 19.0% of continuous anxiolytic prescriptions and 44.8% of hypnotic prescriptions. Frequently registered inappropriate indications are aggression/agitation for anxiolytics (continuous: 75.7%; as-needed: 75.2%) and nighttime agitation for hypnotics (continuous: 40.3%; as-needed: 26.7%). None of the continuous prescriptions with appropriate indications were appropriate for all other items. For most of the prescriptions, duration and time to evaluation exceeded 4 weeks. Conclusion: BZRA use in nursing home residents with dementia is highly frequent. A large proportion of prescriptions do not follow the guidelines with regard to indication, exceed the recommended duration and are not evaluated in a timely manner. The discrepancy between evidence-based guidelines and daily practice calls for an exploration of factors maintaining inappropriate use. Show more

Keywords: Behavioral and psychological symptoms of dementia, benzodiazepines, dementia, inappropriate prescribing, insomnia, nursing homes, Z-drugs

DOI: 10.3233/ADR-210041

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 871-879, 2021

Authors: Posada Rodríguez, Camilo | Rodríguez-Araña, Sofía | Oviedo, Diana C. | Carreira, María B. | Flores-Cuadra, Julio | Villarreal, Alcibiades E. | Rangel, Giselle | Britton, Gabrielle B.

Article Type: Short Communication

Abstract: There is a dearth of research in Latin America regarding risk and protective factors affecting older adults’ cognition. This study aimed to investigate the factors mediating the association between occupational complexity and late-life cognition and daily function in a sample of Hispanic older adults. Participants (n  = 588) aged 65 years and older underwent clinical, functional, and cognitive assessments. Mediation analyses revealed that depressive symptoms mediated the relationship between occupational complexity and cognitive as well as functional outcomes. Results provide evidence that depression may act as a risk factor for worse outcomes, even if older adults had a cognitively demanding occupation.

Keywords: Aging, cognitive reserve, executive functions, Latin America, risk factors

DOI: 10.3233/ADR-210040

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 881-886, 2021

Authors: Monoranu, Camelia-Maria | Hartmann, Tim | Strobel, Sabrina | Heinsen, Helmut | Riederer, Peter | Distel, Luitpold | Bohnert, Simone

Article Type: Research Article

Abstract: Background: The role of neuroinflammation has become more evident in the pathogenesis of neurodegenerative diseases. Increased expression of microglial markers is widely reported in Alzheimer’s disease (AD), but much less is known about the role of monocytes in AD pathogenesis. In AD animal models, bone marrow-derived monocytes appear to infiltrate the parenchyma and contribute to the phagocytosis of amyloid-β depositions, but this infiltration has not been established in systematic studies of the human brain postmortem. Objective: In addition to assessing the distribution of different subtypes of microglia by immunostaining for CD68, HLA-DR, CD163, and CD206, we focused on …the involvement of C-chemokine receptor type2 (CCR2) positive monocytes during the AD course. Methods: We used formalin-fixed and paraffin-embedded tissue from four vulnerable brain regions (hippocampus, occipital lobe, brainstem, and cerebellum) from neuropathologically characterized AD cases at different Braak stages and age-matched controls. Results: Only singular migrated CCR2-positive cells were found in all brain regions and stages. The brainstem showed the highest number of positive cells overall, followed by the hippocampus. This mechanism of recruitment seems to work less efficiently in the human brain at an advanced age, and the ingress of monocytes obviously takes place in much reduced numbers or not at all. Conclusion: In contrast to studies on animal models, we observed only a quite low level of myeloid monocytes associated with AD pathology. Furthermore, we provide evidence associating early microglial reactions carried out in particular by pro-inflammatory cells with early effects on tangle- and plaque-positive vulnerable brain regions. Show more

Keywords: Alzheimer’s disease, bone marrow–derived monocytes, CCR2, microglia, neuroinflammation

DOI: 10.3233/ADR-210052

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 887-897, 2021

Authors: Patel, Kavita | Srivastava, Siwangi | Kushwah, Shikha | Mani, Ashutosh

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease that is coupled with chronic cognitive dysfunction. AD cases are mostly late onset, and genetic risk factors like the Apolipoprotein E (APOE ) play a key role in this process. APOE ɛ 2, APOE ɛ 3, and APOE ɛ 4 are three key alleles in the human APOE gene. For late onset, APOE ɛ 4 has the most potent risk factor while APOE ɛ 2 plays a defensive role. Several studies suggests that APOE ɛ 4 causes AD via different processes like neurofibrillary tangle formation by …amyloid-β accumulation, exacerbated neuroinflammation, cerebrovascular disease, and synaptic loss. But the pathway is still unclear that which actions of APOE ɛ 4 lead to AD development. Since APOE was found to contribute to many AD pathways, targeting APOE ɛ 4 can lead to a hopeful plan of action in development of new drugs to target AD. In this review, we focus on recent studies and perspectives, focusing on APOE ɛ 4 as a key molecule in therapeutic strategies. Show more

Keywords: Alzheimer’s disease, apolipoprotein, clearance, dementia, insoluble amyloid, regulation, treatment

DOI: 10.3233/ADR-210027

Citation: Journal of Alzheimer's Disease Reports, vol. 5, no. 1, pp. 899-910, 2021