Journal of Alzheimer's Disease - Volume 59, issue 1

Authors: Robillard, Julie M. | Feng, Tanya L.

Article Type: Review Article

Abstract: The importance of patient engagement in research has been gaining recognition since the turn of the 21st century. However, little is known about the perspectives of people with dementia on the process of discovery. To fill this gap and to inform priorities in patient engagement in the context of dementia research, the Clinic for Alzheimer Disease and Related Disorders at the University of British Columbia hosted an interactive session for members of the patient community and of the general public to share their views on various ethical aspects of the research process. Results from the session indicate that several current …research ethics policies and norms in dementia research are not in line with participants’ preferences. Here we discuss the importance of bridging the gap between researchers and patients and call for reforms in current standards of dementia research. Show more

Keywords: Alzheimer’s disease, dementia, ethics, informed consent, public policy, research ethics

DOI: 10.3233/JAD-161285

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 1-10, 2017

Authors: Forlini, Cynthia

Article Type: Research Article

Abstract: Robillard and Feng highlight incongruence between patient preferences and the procedural aspects of research ethics as they relate to protocols for dementia research. Their findings break ground for a reassessment of how research ethics, researchers, and participants (including patients and caregivers) approach participation in dementia research. However, it is unclear whether patient preferences may also herald a normative gap between how dementia research is being conducted and how it should be done. This response uses one of Robillard and Feng’s findings to illustrate how descriptive empirical data might be reinterpreted into normative questions that reframe current practices in the context …of dementia research. Show more

Keywords: Alzheimer’s disease, dementia, empirical ethics, ethics, neuroethics, normative ethics, research ethics

DOI: 10.3233/JAD-170328

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 11-12, 2017

Authors: Cagnin, Annachiara | Mariotto, Sara | Fiorini, Michele | Gaule, Marina | Bonetto, Nicola | Tagliapietra, Matteo | Buratti, Emanuele | Zanusso, Gianluigi | Ferrari, Sergio | Monaco, Salvatore

Article Type: Short Communication

Abstract: A novel neuronal tauopathy, mainly confined to hypothalamus and brainstem tegmentum, has recently been reported in patients with autoantibodies to the neuronal cell-adhesion molecule IgLON5. We describe a patient with anti-IgLON5 syndrome, who presented with dysautonomia and sleep disorder, followed by subacute dementia. Postmortem brain examination disclosed neuronal tau pathology prevailing in the hippocampus, amygdala, and locus coeruleus, in addition to microglial/neuronal TDP-43 pathology, with overexpression of aberrantly phosphorylated forms and neurotoxic truncated fragments, in basal ganglia, nucleus basalis, thalamus, and midbrain. These findings suggest that neurodegeneration in anti-IgLON5 syndrome might also occur via a microglia-triggered non-cell autonomous pathway.

Keywords: IgLON5, microglia, non-cell autonomous neurodegeneration, tauopathy, TDP-43 pathology

DOI: 10.3233/JAD-170189

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 13-20, 2017

Authors: Yun, Chang-Ho | Lee, Ho-Young | Lee, Seung Ku | Kim, Hyun | Seo, Hyung Suk | Bang, Seong Ae | Kim, Sang Eun | Greve, Douglas N. | Au, Rhoda | Shin, Chol | Thomas, Robert J.

Article Type: Research Article

Abstract: To test the hypothesis that excessive amyloid deposition is a biological link between obstructive sleep apnea (OSA) and Alzheimer’s disease, we determined whether OSA increases cerebral amyloid burden, relative to controls, using Pittsburgh Compound B (PiB) PET imaging. The subjects were adult participants (age 50–65 years) from the Korean Genome and Epidemiology Study. Polysomnography, brain MRI including 3D images, and a detailed neuro-cognitive function test battery were done in 2011–2012. Nineteen OSA subjects (Apnea–Hypopnea Index [AHI] ≥15/h, 21.2±5.1/h; age 58.5±4.1 years; 9 male) and 19 controls (AHI 1.8±1.3/h; age 58.5±4.2 years; 9 male) underwent 60-min dynamic 11 C-PiB PET. All …subjects were right-handed with normal cognitive function and brain MRI. Controls were matched by age, gender, education, and APOE genotype. A voxel-wise comparison of PiB-PET images between the two groups was performed after spatial and count normalization with cerebellar gray matter as a reference. Covariates included the status of sleep duration, hypertension, diabetes, body mass index, exercise, depressive mood, smoking, and alcohol drinking. Cortical thickness on 3D MRI was also measured and compared between the two groups. The OSA group showed a higher PiB deposition in the right posterior cingulate gyrus and right temporal cortex (corrected p  < 0.05). There was no area of higher uptake in the control compared with OSA. Regional differences in cortical thickness were not significant. The study suggests that OSA accelerates amyloid deposition and may contribute to the development or progression of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cerebral cortex, dementia, positron-emission tomography, sleep

DOI: 10.3233/JAD-161047

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 21-29, 2017

Authors: Tarraf, Wassim | Rodríguez, Carlos J. | Daviglus, Martha L. | Lamar, Melissa | Schneiderman, Neil | Gallo, Linda | Talavera, Gregory A. | Kaplan, Robert C. | Fornage, Myriam | Conceicao, Alan | González, Hector M.

Article Type: Research Article

Abstract: Background: Hispanics/Latinos are at increased risk for cardiovascular disease and cognitive decline and dementias. High blood pressure (BP) has been implicated in both stroke and dementias. Associations between BP and cognition among diverse Latinos are still unpublished. Objective: We examined associations between cognition and four BP based measures among diverse Hispanics/Latinos. We hypothesized that higher BP, particularly systolic pressure, and increased arterial stiffness (i.e., pulse pressure), would be associated with lower cognitive function. Methods: We used baseline (2008–2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; n  = 9,019; ages 45–74 years) data to examine cognition in …relation to BP measures. Results: In age, sex, and education adjusted models, systolic, pulse, and mean arterial pressure were consistently negatively associated with executive function, psychomotor speed and sustained attention, verbal episodic learning and memory, speech fluency, and mental status measures. These associations were attenuated but remained statistically significant in fully adjusted models. Conclusion: Among middle-aged and older diverse Hispanics/Latinos, we found modest but consistent associations between indicators of arterial stiffness, and compromised blood flow and lower cognitive function. Clinical management and public health interventions to raise awareness and enhance BP management beginning in midlife could reduce disparities and improve population health by reducing cognitive decline burdens. Show more

Keywords: Arterial stiffness, bloodpressure, cardiovascular health, cognitive, Hispanic/Latino, hypertension, neurocognitive

DOI: 10.3233/JAD-170017

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 31-42, 2017

Authors: Leino, Marina | Popova, Svetlana N. | Alafuzoff, Irina

Article Type: Research Article

Abstract: A link between diabetes mellitus (DM) related islet amyloid polypeptide (IAPP) and Alzheimer’s disease (AD) related amyloid-β (Aβ) has been suggested in epidemiological and clinical studies. In 2017, proof for existing interaction between type 2 DM and AD on a molecular level was provided based on research carried out in experimental animal models. We assessed aging-related neurodegenerative lesions, i.e., misfolded proteins, associated with dementia such as hyperphosphorylated τ (HPτ ), Aβ, α-synuclein (αS), and phosphorylated transactive DNA binding protein 43 (pTDP43) seen in the brain and IAPP seen in the pancreas in subjects with and without DM applying immunohistochemical …techniques. HPτ in the brain and IAPP in the pancreas were observed in most subjects. The prevalence and the extent of all misfolded proteins increased with age but this increase was not influenced by DM. Interestingly the extent of misfolded proteins in the brain was higher in non-diabetics when compared with diabetics in demented. A significant correlation was observed between HPτ , Aβ, αS, and pTDP43, whereas IAPP showed no association with HPτ , Aβ, and αS. In subjects with DM, the extent of pTDP43 in brain correlated with the extent of IAPP in pancreas. Thus, there is no evidence of a link between AD-related pathology and DM in humans, whereas an association was found between pTDP43 and IAPP in DM. TDP43 is ubiquitously expressed in all organs but whether TDP43 is phosphorylated in other organs in DM or whether the phosphorylation of TDP43 is influenced by glucose metabolism is yet unknown. Show more

Keywords: α-synuclein, amyloid-β, diabetes mellitus, islet amyloid polypeptide, hyperphosphorylated τ, phosphorylated transactive DNA binding protein 43

DOI: 10.3233/JAD-170192

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 43-56, 2017

Authors: Ferguson, Sherry A. | Panos, John J. | Sloper, Daniel | Varma, Vijayalakshmi

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) presents with an earlier onset age and increased symptom severity in African Americans and Hispanics. Objective: Although the prevalence of plaques and tangles may not exhibit ethnicity-related differences, levels of neurodegenerative proteins have not been described. Methods: Here, levels of five proteins (i.e., S100B, sRAGE, GDNF, Aβ40 , and Aβ42 ) and the Aβ42 /Aβ40 ratio were measured in postmortem samples of the middle temporal gyrus (BA21) from age-matched African Americans and Caucasians with AD (n  = 6/gender/ethnicity). Results: S100B levels were increased 17% in African Americans (p  < 0.003) …while sRAGE was mildly decreased (p  < 0.09). Aβ42 levels were increased 121% in African Americans (p  < 0.02), leading to a 493% increase in the Aβ42 /Aβ40 ratio (p  < 0.002). Analysis of GDNF levels did not indicate any significant effects. There were no significant effects of gender and no significant ethnicity with gender interactions on any analyte. Effect size calculations indicated “medium” to “very large” effects. Conclusion: S100B is typically elevated in AD cases; however, the increased levels in African Americans here may be indicative of increased severity in specific populations. Increased Aβ42 /Aβ40 ratios in the current study are compatible with increased disease severity and might indicate increased AD pathogenesis in African Americans. Overall, these results are compatible with a hypothesis of increased neuroinflammation in African Americans with AD. Show more

Keywords: African American, amyloid-beta, Caucasian, ethnic groups, racial differences, S100B, sRAGE, temporal gyrus

DOI: 10.3233/JAD-170204

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 57-66, 2017

Authors: Viticchi, Giovanna | Falsetti, Lorenzo | Buratti, Laura | Sajeva, Giulia | Luzzi, Simona | Bartolini, Marco | Provinciali, Leandro | Silvestrini, Mauro

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) often represents the clinical manifestation of cognitive deterioration preceding Alzheimer’s disease (AD). Currently, there are no reliable approaches for an objective evaluation of the risk of developing AD in MCI patients. Objective: The aim of this study was to verify whether the Framingham cardiovascular risk profile (FCRP) could be useful to identify patients at the highest risk of conversion from MCI to AD. Methods: Patients with amnestic MCI (aMCI) were carefully investigated to assess their vascular risk profile. They were also submitted to a comprehensive neuropsychological evaluation. The FCRP was …calculated for each patient and the apolipoprotein E (ApoE) genotype was determined from peripheral blood cells. The main outcome was defined as a conversion to AD within 24 months after inclusion. Results: 385 consecutive aMCI subjects were included. Age, FCRP, and vascular age showed a fairly predictive value on conversion to AD. Selecting the subpopulation of ApoE ɛ 4 carriers, we observed that FCRP had an increased performance in predicting the conversion. The rate of conversion increased from 12.5% in the FCRP low-risk group to 43.2% in the high-risk group (p  < 0.0001). ApoE ɛ 4 carriers had a 3.7-times increased probability of conversion with respect to the other subjects (p  < 0.0001). Conclusions: FCRP assessment could be considered a reliable approach to predict conversion to AD in aMCI subjects. The presence of ApoE ɛ 4 increases significantly the risk of conversion. These data confirm the narrow relationship between genetic and vascular risk factors in influencing the evolution of cognitive impairment. Show more

Keywords: Alzheimer’s disease, apolipoproteins, cognitive dysfunction, dementia, risk factors

DOI: 10.3233/JAD-170160

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 67-75, 2017

Authors: Doi, Takehiko | Shimada, Hiroyuki | Makizako, Hyuma | Tsutsumimoto, Kota | Verghese, Joe | Suzuki, Takao

Article Type: Research Article

Abstract: Background: It is important to examine the etiology of motoric cognitive risk syndrome (MCR) and its association with dementia and disability to obtain biological insights and to develop preventive strategies. Objective: This study aimed to examine the association of MCR with incidence of dementia and disability in a Japanese community-dwelling sample of older adults. Methods: Participants were 4,235 older adults (50% women, mean age: 72.0 years). MCR was diagnosed at baseline using established criteria in non-demented seniors with self-reported cognitive complaints and slow gait. Incident cases of dementia were identified from insurance data monthly. Disability …was regarded as certification by long-term care insurance. Results: At baseline, 265 participants (6.3%) met criteria for MCR. During follow-up (mean duration: 29 months), there were 138 incident cases of dementia (3.3%) and 207 incident cases of disability (4.9%). Cox-proportional hazards models, adjusted for demographical data, lifestyle, and medical conditions, showed that presence of MCR at baseline was a major risk factor for developing dementia (HR 2.49, 95% CI 1.52–4.10, p  < 0.001). MCR also predicted risk for disability (HR 1.69, 95% CI 1.08–2.02, p  < 0.001). Conclusions: MCR is helpful in the short-term prediction of risk for dementia and disability in the elderly Japanese population. Identification of seniors with MCR is recommended for early detection and instituting preventive measures for reducing the risk of dementia and disability. Show more

Keywords: Cognition, dementia, mobility, risk factors

DOI: 10.3233/JAD-170195

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 77-84, 2017

Authors: Lupton, Michelle K. | Benyamin, Beben | Proitsi, Petroula | Nyholt, Dale R. | Ferreira, Manuel A. | Montgomery, Grant W. | Heath, Andrew C. | Madden, Pamela A. | Medland, Sarah E. | Gordon, Scott D. | GERAD1 Consortium | the Alzheimer’s Disease Neuroimaging Initiative | Lovestone, Simon | Tsolaki, Magda | Kloszewska, Iwona | Soininen, Hilkka | Mecocci, Patrizia | Vellas, Bruno | Powell, John F. | Bush, Ashley I. | Wright, Margaret J. | Martin, Nicholas G. | Whitfield, John B.

Article Type: Research Article

Abstract: Iron deposition in the brain is a prominent feature of Alzheimer’s disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n∼10,000). Conversely, we test …whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n∼9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology. Show more

Keywords: Alzheimer’s disease, apolipoproteins E, dementia, ferritin, genetic profile scores, genome-wide association study, iron, population genetics, transferrin

DOI: 10.3233/JAD-170027

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 85-99, 2017