Journal of Alzheimer's Disease Reports - Volume 4, issue 1

Authors: Moharrer, Mojtaba | Wang, Shuhang | Davis, Jennifer D. | Ott, Brian R. | Luo, Gang

Article Type: Research Article

Abstract: Background: Controlled naturalistic driving for examining impacts of cognitive impairment on driving safety is rare. Objective: Evaluating the safety among drivers with mild cognitive impairment based on near collision incidents using naturalistic driving, and investigating its correlation with cognitive measures. Methods: Frequency of near collisions of 44 cognitively impaired [Age = 75.1(±6.7), MMSE = 25.5(±2.5)] and 19 control group drivers [Age = 72.5(±7.8), MMSE = 29.3(±0.8)] were obtained from two weeks of recorded driving. Survival time free of predicted collision based on a previously established near-collision to collision estimate ratio of 11 : 1, for 140 hours of driving exposure was calculated. Participants were also tested …using Mini-Mental Status Examination (MMSE), Trail A, and Trail B. Spearman correlation and Cox survival analysis were conducted. Results: Near collision frequency per driving hour was correlated with MMSE (r  = –0.258, p  = 0.041). Survival analyses showed that cognitively impaired drivers might be prone to higher probability of having collision (p  = 0.056) with a hazard ratio of 5.78 (p  = 0.092). When all participants were combined, there was a significant difference (p  < 0.017) in all the three cognitive measures between drivers with and without predicted collision, which were not significant within patient or control group alone (p  > 0.186). Cox regression analysis showed MMSE as the only significant factor (p  < 0.025) for survival time of predicted collision, but not age, gender, or driving experience. Conclusion: The association between driving critical events and cognitive measures suggests that some drivers with mild cognitive impairment might have an elevated driving collision risk compared to control drivers. Standard clinical cognitive measures may be reasonable predictors. Show more

Keywords: Cognitive impairment, driving, naturalistic driving, near collision, surrogate measure

DOI: 10.3233/ADR-190159

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 1-7, 2020

Authors: Kostev, Karel | Osina, Galina

Article Type: Research Article

Abstract: Background: Studies on prevalence or the therapy of dementia are rare or non-existent in Russia. Objective: The purpose of this study was to analyze the prescription patterns of antidementia therapy in Russia in 2018. Methods: This retrospective cross-sectional study was based on the IQVIA Russia LRx database, which covers approximately 11% of all patients enrolled in federal or regional reimbursement state healthcare programs. We descriptively analyzed the proportions of patients treated with antidementia drugs, antipsychotics, antidepressants, and benzodiazepines. Results: A total of 12,051 dementia patients were available for analysis. Of those, 6,394 patients had …a vascular dementia (VaD) diagnosis, while 3,413 were diagnosed with dementia in other diseases (DOD), 1,128 with Alzheimer’s disease (AD), and 1,116 with unspecified dementia (UD). The therapy with the highest patient proportion was antipsychotics, with 74% of VaD patients, 73% of UD patients, and 47% of DOD patients receiving these drugs. The proportion of patients treated with antidementia drugs was 68% in AZ, 56% in VaD, 45% in UD, and only 9% in DOD. Antidepressants were a relatively rare therapy in dementia patients (between 4% and 12%), and 30% of DOD patients received benzodiazepines, while the proportions of patients receiving this therapy class in other dementias was low (7–10%). Most patients were treated with old-generation drugs. Conclusion: The proportion of older drugs prescribed in Russia is higher than in Western Europe, which may likely be due to their low prices, resulting in a higher chance for successful health insurance reimbursement claims. Show more

Keywords: Antidepressants, antipsychotics, benzodiazepine, dementia, Russia

DOI: 10.3233/ADR-190144

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 9-14, 2020

Authors: Stoye, Nicolai Maximilian | Jung, Patrick | Guilherme, Malena dos Santos | Lotz, Johannes | Fellgiebel, Andreas | Endres, Kristina

Article Type: Short Communication

Abstract: Apolipoprotein A1 (ApoA1) is the major protein component of the high-density lipoprotein and involved in cholesterol transport. Disruption of cholesterol homeostasis has been identified as a contributing factor for Alzheimer’s disease (AD). Moreover, polymorphisms of ApoA1 have been associated with higher risk of disease onset and cognitive decline. Therefore, ApoA1 has been suggested as a biomarker in AD. Here, we tested a small cohort of AD and non-AD dementia patients and measured levels of ApoA1 in cerebrospinal fluid. Our results indicate that ApoA1 might not be applicable to distinguish AD from other forms of dementia.

Keywords: Alzheimer’s disease, Apolipoprotein A1, biomarker, cerebrospinal fluid, dementia

DOI: 10.3233/ADR-190165

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 15-19, 2020

Authors: Hameed, Shahul | Fuh, Jong-Ling | Senanarong, Vorapun | Ebenezer, Esther Gunaseli M. | Looi, Irene | Dominguez, Jacqueline C. | Park, Kyung Won | Karanam, Ananda Krishna | Simon, Oliver

Article Type: Review Article

Abstract: Clinical diagnosis of Alzheimer’s disease (AD) is based on symptoms; however, the challenge is to diagnose AD at the preclinical stage with the application of biomarkers and initiate early treatment (still not widely available). Currently, cerebrospinal fluid (CSF) amyloid-β 42 (Aβ42 ) and tau are used in the clinical diagnosis of AD; nevertheless, blood biomarkers (Aβ42 and tau) are less predictive. Amyloid-positron emission tomography (PET) imaging is an advancement in technology that uses approved radioactive diagnostic agents (florbetapir, flutemetamol, or florbetaben) to estimate Aβ neuritic plaque density in adults with cognitive impairment evaluated for AD and other causes of …cognitive decline. There is no cure for AD to date—the disease progression cannot be stopped or reversed; approved pharmacological agents (donepezil, galantamine, and rivastigmine; memantine) provide symptomatic treatment. However, the disease-modifying therapies are promising; aducanumab and CAD106 are in phase III trials for the early stages of AD. In conclusion, core CSF biomarkers reflect pathophysiology of AD in the early and late stages; the application of approved radiotracers have potential in amyloid-PET brain imaging to detect early AD. Show more

Keywords: Alzheimer’s disease, biomarker, blood, cerebrospinal fluid, early diagnosis, positron emission tomography

DOI: 10.3233/ADR-190143

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 21-37, 2020

Authors: Rodriguez (Then), Francisca S. | Jackson, Jonathan | Ware, Caitlin | Churchyard, Rebekah | Hanseeuw, Bernard | for the International Interdisciplinary Young Investigators Alzheimer’s & Dementia ()

Article Type: Review Article

Abstract:  Dementia, of which the most frequent form is Alzheimer’s disease, is a chronic and terminal condition with multi-factorial causes and numerous consequences on a patient’s life. Combining perspectives from different disciplines seems necessary for unraveling dementia’s entangled issues. Current dementia management is a multidisciplinary effort; however, integrating different disciplines as a holistic treatment process is often hindered due to different responsibilities, various conceptual approaches, and distinctive research methods. With this paper, we raise some of the challenges that need to be addressed in order to initiate an interdisciplinary or even transdisciplinary research agenda. We also outline recommendations on how to …integrate multiple disciplinary perspectives in dementia care and research. We see opportunities for young investigators to draw from different fields of research in dementia as their research focus is still developing. By establishing common objectives with investigators from other fields, we can pursue the goal of improving treatment and care as a team—meaning accomplishing different tasks but sharing a common purpose. It is necessary to address the communication between fields that limits the understanding of connections between cognitive symptoms, biological processes, treatment, lifestyle, and care giving in order to reach the aim of developing a holistic, person-centered, patient-first approach. Associating biomedical research to field experience from care professionals and the study of human science will promote a more independent, social, and sustainable lifestyle for people with dementia. Show more

Keywords: Alzheimer’s disease, dementia, interdisciplinary, research methods, treatment

DOI: 10.3233/ADR-180070

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 39-48, 2020

Authors: Bigham, Bahare | Zamanpour, Seyed Amir | Zemorshidi, Fariba | Boroumand, Farzaneh | Zare, Hoda | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Diffusion tensor imaging (DTI) estimates the microstructural alterations of the brain, as a magnetic resonance imaging (MRI)-based neuroimaging technique. Prior DTI studies reported decreased structural integrity of the superficial white matter (SWM) in the brain diseases. Objective: This study aimed to determine the diffusion characteristics of SWM in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) using tractography and region of interest (ROI) approaches. Methods: The diffusion MRI data were downloaded from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database on 24 patients with AD, 24 with MCI, and 24 normal control (NC) subjects. DTI processing …was performed using DSI Studio software. First, for ROI-based analysis, The superficial white matter was divided into right and left frontal, parietal, temporal, insula, limbic and occipital regions by the Talairach Atlas, Then, for tractography-based analysis, the tractography of each of these regions was performed with 100000 seeds. Finally, the average diffusion values were extracted from voxels within the ROIs and tracts. Results: Both tractography and ROI analyses showed a significant difference in radial, axial and mean diffusivity values between the three groups (p  < 0.05) across most of the SWM. Furthermore, The Mini-Mental State Examination was significantly correlated with radial, axial, and mean diffusivity values in parietal and temporal lobes SWM in the AD group (p  < 0.05). Conclusion: DTI provided information indicating microstructural changes in the SWM of patients with AD and MCI. Therefore, assessment of the SWM using DTI may be helpful for the clinical diagnosis of patients with AD and MCI. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, mild cognitive impairment, superficial white matter, tractography

DOI: 10.3233/ADR-190149

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 49-59, 2020

Authors: Sasaki, Shoichi

Article Type: Short Communication

Abstract: A 69-year-old right-handed woman developed difficulty naming objects and word-finding. The clinical features of language disorder and predominant atrophy on MRI and predominant hypoperfusion on 123 I-IMP SPECT in the left temporo-parietal junction area were consistent with the diagnostic criteria for the logopenic variant of primary progressive aphasia (lvPPA). Neurological examination showed slight right-side rigidity and resting tremor (UPDRS-III: 4). 123 I-FP-CIT SPECT showed presynaptic dopamine transporter reduction in the posterior putamina with left-side predominance. The odor-stick identification test for Japanese exhibited complete loss of the sense of smell (anosmia). These findings suggest that lvPPA may be accompanied by parkinsonism …and anosmia. Show more

Keywords: Anosmia, 123I-FP-CIT SPECT, 123I-IMP SPECT, logopenic variant of primary progressive aphasia, magnetic resonance imaging, parkinsonism, primary progressive aphasia

DOI: 10.3233/ADR-190158

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 61-66, 2020

Authors: Tsao, Francis H.C. | Barnes, Jill N. | Amessoudji, Amy | Li, Zhanhai | Meyer, Keith C.

Article Type: Research Article

Abstract: Aging-related protein misfolding and aggregation may play critical roles in the pathogenesis of numerous diseases. In the brain, extracellular aggregated amyloid-β (Aβ) is closely related to the death of neurons in individuals with Alzheimer’s disease (AD). Albumin-Aβ binding is important in preventing Aβ fibril aggregation. However, because albumin is the most abundant and important antioxidant in the circulation, aging-related oxidative stress could have a significant effect on the molecular conformation and binding capacities of albumin. To investigate the link between misfolded albumin and AD, we developed fluorescent assays to determine the effects of misfolded albumin on membrane integrity in the …presence of a lipolytic, inflammatory response-like enzyme, secretory phospholipase A2 (sPLA2). We found that misfolded albumin increased degradation of phospholipids in highly fluid bilayer membranes in the presence of sPLA2 due to hydrophobic effects of misfolded albumin. High amounts of misfolded albumin were present in sera of elderly (average 74 years) versus young (average 24 years) subjects (p  < 0.0001). Albumin in cerebrospinal fluid (CSF) of elderly subjects, though present in small concentrations, had a 2- to 3-fold increased capacity to promote sPLA2-catalyzed membrane phospholipid degradation as compared with the same amount of albumin in serum (p  < 0.0001). In addition, the fatty acid binding capacity of albumin in CSF from female subjects was considerably lower than values obtained for men, especially for individuals diagnosed with AD (p  = 0.0006). This study suggests that inflammation, misfolded albumin and/or other dysfunctional proteins, and changes in membrane fluidity could alter cell membrane integrity and homeostasis and contribute to the pathogenesis of aging-related dementia and AD. Show more

Keywords: Aging, albumin, Alzheimer’s disease, cerebrospinal fluid, membrane degradation, phospholipase A2, protein misfolding

DOI: 10.3233/ADR-200168

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 67-77, 2020

Authors: Kennedy, Greg | Meyer, Denny | Hardman, Roy J. | Macpherson, Helen | Scholey, Andrew B. | Pipingas, Andrew

Article Type: Research Article

Abstract: Background: Previous modelling found that fitness and aortic stiffness both independently predicted spatial working memory (SWM) performance in older people. There is also evidence that greater engagement in moderate intensity exercise contributes to better cognitive performance, potentially working through improving fitness and aortic stiffness. Objective: To investigate the effect of exercise on the previously established relationships between fitness, aortic stiffness, and SWM, and whether these associations differ between older adults of higher and lower fitness. Methods: One hundred and two residents of independent living facilities, aged 60–90 (M  = 77.5, SD = 6.9) participated in the study. Measures included …computerized cognitive assessment, the Six-Minute Walk fitness test, the CHAMPS physical activity questionnaire, and aortic pulse wave analysis. Multiple structural equation models were used to test hypotheses. Results: Overall, exercise levels had a small additional effect in predicting SWM, working exclusively through fitness, although this was only true for those of lower than average fitness. Additionally, it was found that while fitness was the most important factor in predicting SWM in those of lower fitness, aortic stiffness was the strongest predictor in those of higher fitness. Conclusion: Fitness and aortic stiffness are strong predictors of cognition in older people, and greater engagement in exercise predicted better cognition in those who were of lower fitness. Fitter older people may benefit more from interventions which target aortic stiffness in order to preserve cognitive performance as they age, while those who are less fit may benefit most from improving fitness first, including through increased physical activity. Show more

Keywords: Aging, aortic stiffness, arterial stiffness, cognition, exercise, physical activity, physical fitness, working memory

DOI: 10.3233/ADR-190164

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 79-89, 2020

Authors: Sanders, Owen

Article Type: Review Article

Abstract: Nitric oxide/cyclic guanosine monophosphate (cGMP) signaling is compromised in Alzheimer’s disease (AD), and phosphodiesterase 5 (PDE5), which degrades cGMP, is upregulated. Sildenafil inhibits PDE5 and increases cGMP levels. Integrating previous findings, we determine that most doses of sildenafil (especially low doses) likely activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) via protein kinase G-mediated cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) phosphorylation and/or Sirtuin-1 activation and PGC1α deacetylation. Via PGC1α signaling, low-dose sildenafil likely suppresses β-secretase 1 expression and amyloid-β (Aβ) generation, upregulates antioxidant enzymes, and induces mitochondrial biogenesis. Plus, sildenafil should increase brain perfusion, insulin sensitivity, long-term potentiation, …and neurogenesis while suppressing neural apoptosis and inflammation. A systematic review of sildenafil in AD was undertaken. In vitro, sildenafil protected neural mitochondria from Aβ and advanced glycation end products. In transgenic AD mice, sildenafil was found to rescue deficits in CREB phosphorylation and memory, upregulate brain-derived neurotrophic factor, reduce reactive astrocytes and microglia, decrease interleukin-1β, interleukin-6, and tumor necrosis factor-α, decrease neural apoptosis, increase neurogenesis, and reduce tau hyperphosphorylation. All studies that tested Aβ levels reported significant improvements except the two that used the highest dosage, consistent with the dose-limiting effect of cGMP-induced phosphodiesterase 2 (PDE2) activation and cAMP depletion on PGC1α signaling. In AD patients, a single dose of sildenafil decreased spontaneous neural activity, increased cerebral blood flow, and increased the cerebral metabolic rate of oxygen. A randomized control trial of sildenafil (ideally with a PDE2 inhibitor) in AD patients is warranted. Show more

Keywords: Alzheimer’s disease, cyclic GMP, mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, sildenafil citrate

DOI: 10.3233/ADR-200166

Citation: Journal of Alzheimer's Disease Reports, vol. 4, no. 1, pp. 91-106, 2020