Journal of Alzheimer's Disease - Volume 69, issue 2

Authors: Petukhova, Elena O. | Mukhamedshina, Yana O. | Salafutdinov, Ilnur I. | Garanina, Ekaterina E. | Kaligin, Maxim S. | Leushina, Alina V. | Rizvanov, Albert A. | Reis, Helton J. | Palotás, András | Zefirov, Andrey L. | Mukhamedyarov, Marat A.

Article Type: Research Article

Abstract: Background/Objective: Alzheimer’s disease (AD) is a progressive incurable neurodegenerative disorder. Glial cell line-derived neurotrophic factor (GDNF) is a prominent regulator of brain tissue and has an impressive potential for use in AD therapy. While its metabolism is still not fully understood, delivering neuropeptides such as GDNF via umbilical cord blood mononuclear cells (UCBMCs) to the sites of neurodegeneration is a promising approach in the development of innovative therapeutic avenues. Methods: UCBMCs were transduced with adenoviral vectors expressing GDNF and injected into AD transgenic mice. Various parameters including homing and survival of transplanted cells, expression of GDNF and synaptic …proteins, as well as spatial memory were evaluated. Results: UCBMCs were observed in the hippocampus and cortex several weeks after transplantation, and their long-term presence was associated with improved spatial memory. Post-synaptic density protein 95 (PSD-95) and synaptophysin levels in the hippocampus were also effectively restored following the procedure in AD mice. Conclusions: Our data indicate that gene-cell therapy with GDNF-overexpressing UCBMCs may produce long-lasting neuroprotection and stimulation of synaptogenesis. Such adenoviral constructs could potentially possess a high therapeutic potential for the treatment of AD. Show more

Keywords: Alzheimer’s disease, glial cell line-derived neuro-trophic factor, post-synaptic density protein 95, synaptophysin, umbilical cord blood mono-nuclear cells

DOI: 10.3233/JAD-190150

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 443-453, 2019

Authors: Roheger, Mandy | Eriksdotter, Maria | Westling, Karin | Kalbe, Elke | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Life in rural areas differs from life in urban areas not only in geographical conditions, but also in health care structure. Objective: Our aim is to compare the diagnostic process and the management of dementia in rural and urban areas of Sweden. Methods: We performed a cross-sectional study of patients with dementia living in rural (n  = 16,428), intermediate (n  = 18,033), and urban (n  = 23,680) areas in Sweden including patients registered from 2007 through 2014 in the Swedish Dementia Registry (SveDem). Descriptive statistics are shown. Odds ratios with 95% CI are presented for basic diagnostic examinations …in rural compared to intermediate and urban areas, adjusted for age, sex, type of care (primary versus specialist), and comorbidities. Analyses were also stratified for diagnostic care unit (primary versus specialist). Results: Patients who lived in rural areas were more likely to receive a complete basic examination, MMSE examination, Clock test, blood analysis, and neuro-imaging, compared to patients living in urban areas, and also compared to patients living in intermediate areas. Sex differences were seen in nearly all domains, with men receiving more diagnostic work-up than women. Stratified analyses show that in primary care, the complete basic examination is less frequently performed in urban and intermediate areas compared to rural areas. Conclusion: There are differences in diagnostic work-up for dementia between rural, intermediate, and urban areas in Sweden. These results should be considered in future healthcare decisions to ensure equality of health care across rural and urban areas. Show more

Keywords: Dementia, diagnostic work-up, epidemiology, living typology, SveDem

DOI: 10.3233/JAD-190017

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 455-462, 2019

Authors: Akerman, S. Can | Hossain, Shireen | Shobo, Adeola | Zhong, Yifei | Jourdain, Roland | Hancock, Mark A. | George, Kelly | Breton, Lionel | Multhaup, Gerhard

Article Type: Research Article

Abstract: There is increasing evidence suggesting that amyloidogenic proteins might form deposits in non-neuronal tissues in neurodegenerative disorders such as Alzheimer’s or Parkinson’s diseases. However, the detection of these aggregation-prone proteins within the human skin has been controversial. Using immunohistochemistry (IHC) and mass spectrometry tissue imaging (MALDI-MSI), fresh frozen human skin samples were analyzed for the expression and localization of neurodegenerative disease-related proteins. While α-synuclein was detected throughout the epidermal layer of the auricular samples (IHC and MALDI-MSI), tau and Aβ34 were also localized to the epidermal layer (IHC). In addition to Aβ peptides of varying length (e.g., Aβ40 , …Aβ42 , Aβ34 ), we also were able to detect inflammatory markers within the same sample sets (e.g., thymosin β-4, psoriasin). While previous literature has described α-synuclein in the nucleus of neurons (e.g., Parkinson’s disease), our current detection of α-synuclein in the nucleus of skin cells is novel. Imaging of α-synuclein or tau revealed that their presence was similar between the young and old samples in our present study. Future work may reveal differences relevant for diagnosis between these proteins at the molecular level (e.g., age-dependent post-translational modifications). Our novel detection of Aβ34 in human skin suggests that, just like in the brain, it may represent a stable intermediate of the Aβ40 and Aβ42 degradation pathway. Show more

Keywords: Aging, α-synuclein, amyloid-β, human skin, neurodegenerative proteins, tau

DOI: 10.3233/JAD-181191

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 463-478, 2019

Authors: Kvello-Alme, Marte | Bråthen, Geir | White, Linda R. | Sando, Sigrid Botne

Article Type: Research Article

Abstract: Background: Young onset dementia poses several challenges for the individual, health care, and society that are not normally relevant for late onset dementia, but is little researched. Objective: To determine the prevalence and subtypes of young onset dementia in a defined catchment area in central Norway. Methods: The main sources of patient identification were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav’s Hospital), and Department of Psychiatry, Levanger Hospital. Both departments are the main sites for referral of young onset dementia (onset before age 65 years) in the county, covering approximately …90% of the catchment area of the study. Other sources included key persons in the communities, collaborating hospital departments examining dementia, and review of hospital records of all three hospitals in the area. Included patients met the DSM-IV criteria for dementia. The prevalence of dementias was calculated by sex and age. Results: All patients identified with dementia and onset before 65 years on census date were included in the study (n  = 390). Patients younger than 65 on census date were included in the calculation of prevalence, giving a result of 76.3 per 100 000 persons at risk in the age category of 30–65 years, and 163.1 per 100,000 for the category 45–64 years. Etiology was heterogeneous, but the main subtype of dementia was Alzheimer’s disease. Conclusions: Young onset dementia affects a significant number of people in central Norway. Prevalence figures are higher than previously reported from England and Japan, but are similar to a more recent study from Australia. Show more

Keywords: Alzheimer’s disease, early onset dementia, epidemiology, prevalence

DOI: 10.3233/JAD-181223

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 479-487, 2019

Authors: Mustapic, Maja | Tran, Joyce | Craft, Suzanne | Kapogiannis, Dimitrios

Article Type: Research Article

Abstract: Background: Insulin resistance is implicated in Alzheimer’s disease (AD), whereas intranasal insulin is an experimental treatment in clinical trials. We previously proposed insulin signaling mediators in plasma neuronal-enriched extracellular vesicles (EVs) as biomarkers of brain insulin resistance. Objective: We sought to demonstrate the capacity of neuronal-enriched EV biomarkers to demonstrate target engagement in response to intranasal insulin and their ability to track treatment-associated cognitive changes in AD. Methods: We isolated neuronal-enriched EVs from plasma samples of participants with amnestic mild cognitive impairment or probable AD involved in a 4-month duration placebo-controlled clinical trial of 20 or …40 IU intranasal insulin. We measured insulin signaling mediators as biomarkers and examined treatment-associated changes and their relationship with cognitive performance (ADAS-Cog). Results: There were no EV biomarker changes from baseline in any of the treatment groups. In participants treated with 20 IU insulin, EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) showed strong positive correlations with ADAS-Cog changes, especially in ApoE ɛ 4 non-carriers. Conclusion: Neuronal EV biomarkers of insulin resistance (pS312-IRS-1, pY-IRS-1) were associated with cognitive changes in response to low dose intranasal insulin suggesting engagement of the insulin cascade in neurons of origin. Show more

Keywords: Alzheimer’s disease, biomarkers, brain insulin resistance, extracellular vesicles, exosomes, intranasal insulin

DOI: 10.3233/JAD-180578

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 489-498, 2019

Authors: Kumar, Sourav | Srivastav, Saurabh | Fatima, Mahino | Giri, Rajat Subhra | Mandal, Bhubaneswar | Mondal, Amal Chandra

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, involves the formation of the extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles. The current therapies against AD are symptomatic with limited benefits but associated with major side effects. Inhibition of self-aggregation of Aβ peptides into higher order cross-β structure is one of the potential therapeutic approach which may counter oligomerization of Aβ peptide. Objective: The present study aimed to evaluate the neuroprotective and anti-inflammatory potential of a synthetic Pro-Drug type peptide (PDp) against Aβ-induced toxicity in rat model of AD. Methods: Intra-hippocampal microinjection of toxic Aβ40 …(IHAβ40 ) by stereotaxic surgery was performed in the male Sprague-Dawley rats to generate an Aβ-induced AD model. Sub-chronic toxicity of synthetic PDp using hematological, biochemical, and histopathological parameters was investigated. Evaluation of PDp on Aβ-induced neurodegeneration and neuroinflammation was performed. Results: PDp inhibits plaque formation with increase in Nissl granule staining in the rat hippocampus. Aβ-induced toxicity associated imbalance in reactive oxygen species and antioxidant enzymes activity such as superoxide dismutase and catalase in the rat brain was overcome by PDp treatment. Tau protein hyperphosphorylation was normalized with PDp treatment. Also, the neuroinflammatory response was suppressed with PDp treatment. Conclusion: The present study depicts the potential neuroprotective role of PDp against Aβ-induced toxicity in rat. PDp inhibits plaque formation thereby normalizing oxidative stress, inhibiting tau protein hyperphosphorylation, and suppressing neuroinflammatory responses. Future studies done in this direction will pave way for new therapeutic strategies. Show more

Keywords: Alzheimer’s disease, amyloid-β40, neuroinflammation, neuroprotection, Pro-Drug type peptide, rat model of AD

DOI: 10.3233/JAD-181273

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 499-512, 2019

Authors: Zakarias, Johanne Købstrup | Jensen-Dahm, Christina | Nørgaard, Ane | Roos, Peter | Gasse, Christiane | Phung, Thien Kieu Thi | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Early and accurate diagnosis of dementia opens the door to appropriate treatment, support, and counseling. Despite availability of evidence-based guidelines for diagnostic evaluation of dementia, the diagnostic rate in people with dementia is low and the quality of dementia diagnoses is unknown. Objective: The overall aim of this register-based study was to analyze the quality of diagnostic evaluation of dementia by assessing nationwide geographical variations in a range of indicators. Methods: A register-based cross-sectional study of the entire Danish population aged 65 years or older in 2015 was conducted. The surrogate indicators for diagnostic quality …included 1) prevalence rates of dementia diagnoses, 2) incidence rates of dementia diagnoses, 3) age at first diagnosis of dementia, 4) medical specialty responsible for diagnosis, 5) diagnostic rate of dementia subtypes, and 6) use of anti-dementia medication. The indicators were compared across the five Danish regions. Results: The national prevalence and incidence of registered dementia diagnoses was 3.0% and 0.5%, respectively. The proportion of patients diagnosed at a dementia specialist department ranged from 60.9% to 90.5% across the five regions, subtype specific diagnosis ranged from 45.3% to 75.5%, and use of anti-dementia medication ranged from 29.2% to 58.3%. Conclusion: The observed geographical variations in dementia diagnoses and treatment indicate inequality in the access to appropriate diagnostic evaluation and care for patients with dementia. Our findings call for more awareness of the benefits of timely diagnosis and for improvement in the quality of diagnostic evaluation of dementia. Show more

Keywords: Dementia, diagnosis, geography, health care quality assessment, register

DOI: 10.3233/JAD-190030

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 513-520, 2019

Authors: Pyun, Jung-Min | Kang, Min Ju | Yun, Younghwa | Park, Young Ho | Kim, SangYun

Article Type: Research Article

Abstract: Background: Sundown syndrome (SS) in patients with Alzheimer’s disease (AD) is characterized by aggravation of behavioral problems at sunset. Disturbance of the circadian rhythm, a possible cause of SS, also facilitates amyloidopathy and reduces sleep quality. However, the associations of SS with amyloidopathy and sleep quality remain unclear. Objective: To investigate the prevalence of SS in patients with AD, the association between SS and APOE ɛ 4 carrier, representing an enhanced amyloid pathology, and the relationship between SS and sleep quality in AD. Methods: We included 104 patients with late-onset AD and known APOE …genotype. All participants underwent a structured interview via informant-based questionnaires to assess sleep quality and the presence of SS. Binary logistic regression analysis was performed to determine odds ratios (ORs) of APOE ɛ 4 carrier and parameters of sleep quality for SS. Results: The prevalence of SS in AD was 27.8% (n  = 29). Patients with SS were significantly more likely to be APOE ɛ 4 carriers and to have rapid eye movement sleep behavior disorder (RBD) and a higher Clinical Dementia Rating (CDR) score compared to those without SS. In the multivariate regression analysis, APOE ɛ 4 carrier (OR 3.158, CI 1.022–9.758), RBD (OR 2.166, CI 1.073–4.371), and higher CDR score (OR 2.453, CI 1.084–5.550) were associated with an increased risk of SS. Conclusion: The prevalence of SS in patients with AD was 27.8%. The presence of the APOE ɛ 4 allele, RBD, and more severe dementia are associated with an increased risk of SS in AD. Show more

Keywords: Alzheimer’s disease, APOE , circadian rhythm, REM sleep behavior disorder, sundown syndrome

DOI: 10.3233/JAD-190032

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 521-528, 2019

Authors: Bunai, Tomoyasu | Kakimoto, Akihiro | Yoshikawa, Etsuji | Terada, Tatsuhiro | Ouchi, Yasuomi

Article Type: Research Article

Abstract: Background: Amyloid imaging with positron emission tomography (PET) often comes with glucose metabolic imaging in diagnosis of Alzheimer’s disease (AD). Objective: The present purpose was to explore the clinical valence of early amyloid-β (Aβ) PET scans to determine whether they could substitute for other imaging biomarkers (early and delayed Aβ images of 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) images) in the AD spectrum. Methods: Thirty healthy control subjects, 20 patients with mild cognitive impairment, and 45 patients with AD underwent 11 C-PIB and 18 F- FDG PET. Image analyses were performed with three-dimensional …stereotactic surface projection and Brodmann’s area regions-of-interest methods. Since early accumulation of PIB (ePIB) reflects blood flow, we classified all subjects according to the level of ePIB in the posterior cingulate gyrus, precuneus, and lateral parietal cortex. We compared the PET parameters (ePIB, delayed-phase PIB accumulation or dPIB, FDG) to determine whether ePIB-based categorization reflected Aβ deposition in a Braak stage-related fashion. Results: We found that ePIB images were similar to 18 F-FDG images and that the progress of Aβ deposition deduced from the reduction in ePIB index was similar to the pathological progress of Braak staging. A decrease in the ePIB level in the posterior cingulate gyrus, precuneus, and parietal cortex was shown to correspond to greater and wider Aβ deposition in the medial frontal, anterior, and posterior cingulate gyri. Conclusions: The early-phase 11 C-PIB index can be an alternative to the neurogenerative markers of glucose hypometabolism and reflects the Braak stage of Aβ deposition in the living AD brain. Show more

Keywords: Alzheimer’s disease, amyloid, Braak stage, 11C-PIB, 18F-FDG, glucose, positron emission tomography

DOI: 10.3233/JAD-181188

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 529-538, 2019

Authors: Dourado, Marcia Cristina Nascimento | Torres Mendonça de Melo Fádel, Bianca | Simões Neto, José Pedro | Alves, Gilberto | Alves, Cândida

Article Type: Research Article

Abstract:  Facial expression recognition is one of the essential abilities for social cognition. We aimed to compare facial expression recognition among people with mild and moderate Alzheimer’s disease (AD) and to identify which factors were associated with impairment according to disease severity. We included 52 participants with either mild or moderate AD. FACES includes four subtasks requiring matching expressions with picture stimuli (tasks 1 and 2), labelling emotions (task 3), and recognizing situations with evident emotional content (task 4). There were significant differences between groups in FACES global scores, task 2 and task 4. In the mild AD group, FACES global …score was influenced by educational background and cognitive performance, task 1 was associated with comprehension and constructive praxis, task 2 was associated with cognitive flexibility, and task 3 was associated with word finding. In subtask 4, no significant associations were found after adjusting for level of cognitive decline. In the moderate AD group, the awareness of emotional state domain was associated with FACES global score, task 1 was associated with constructive praxis, task 3 was associated with neuropsychiatric symptoms, and task 4 was associated with the ability to recognize emotions through situations. No significant associations were found on task 2, after adjusting for level of cognitive decline. Our findings suggest emotional processing difficulties across AD stages. However, when participants needed to recognize the most preponderant emotion in a situation with evident emotional content, our results suggest that in both groups there was no influence of cognitive impairment. Show more

Keywords: Alzheimer’s disease, cognition, emotion, facial expression, facial recognition

DOI: 10.3233/JAD-181101

Citation: Journal of Alzheimer's Disease, vol. 69, no. 2, pp. 539-549, 2019