Journal of Alzheimer's Disease - Volume 60, issue 3

Authors: Stevenson, Anna | Lopez, Dianne | Khoo, Paul | Kalaria, Rajesh N. | Mukaetova-Ladinska, Elizabeta B.

Article Type: Review Article

Abstract: Peripheral biomarkers for dementia are few and far between. Despite research into blood plasma/serum biomarkers for dementia diagnostics, there is a lack of information on erythrocytes and their vast proteomes as potential biomarkers. This review identifies a number of relevant and potentially promising erythrocyte biomarkers for various subtypes of dementia. These include erythrocyte morphology, oxidative stress, and erythrocyte membrane proteins such as the glucose transporter (GLUT-1), amyloid-β, IgG, Hsp90, calpain-1, and band 3 protein. Of those proteins identified Hsp90, amyloid-β, calpain-1 and band 3 show the most promise as pre-clinical biomarkers. However, the most intriguing aspect of erythrocytes is their …changed morphology in dementia. The altered morphology not only could be used as a diagnostic biomarker but may be crucial in early pathogenesis of the disease. Further work must be done to establish the pathological connection between the periphery and central disease processes. Show more

Keywords: Alzheimer’s disease, amyloid, erythrocyte, membrane, oxidative stress, protein

DOI: 10.3233/JAD-170363

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 845-857, 2017

Authors: Vakalopoulos, Costa

Article Type: Research Article

Abstract: The pathognomonic feature of Alzheimer’s disease is a loss of declarative memory. This has generally been attributed to early involvement of medial temporal lobe structures with neurofibrillary tangles and loss of neurons in the entorhinal cortex. However, there has been a re-emerging emphasis on the causal role of brainstem monoaminergic nuclei as involvement of the cholinergic basal forebrain loses prominence. The rejection of this latter theory of cognitive decline is related to inconsistencies in time course and modest effects of treatment using cholinergic agents. The amyloid hypothesis of cortical dysfunction is also losing favor as current trials of plaque dissolution …are proving again disappointing. Recent pre-clinical studies on APP/PS1 (familial Alzheimer’s disease) transgenic mouse models using serotonergic receptor modulating agents, demonstrate clear neuroprotective effects. The involvement of midbrain raphe in the earliest stages of dementia requires a reassessment of relevant pathophysiology beyond behavioral and affective dimensions. Indeed, a theory of serotonergic modulation of explicit memory formation by direct enhancement of synaptic strength could change the view of the role of these nuclei in AD and lead to more effective treatments. Show more

Keywords: Alzheimer’s disease, dorsal raphe, explicit memory, locus coeruleus, tauopathy

DOI: 10.3233/JAD-170364

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 859-866, 2017

Authors: Chander, Russell Jude | Lim, Levinia | Handa, Sagarika | Hiu, Shaun | Choong, Angeline | Lin, Xuling | Singh, Rajinder | Oh, Daniel | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: While atrial fibrillation (AF) is an important risk factor for ischemic strokes and mild cognitive impairment (MCI) in Alzheimer’s disease, the association between AF and post-stroke cognitive impairment (PSCI), and the factors mediating this association, is unclear. Objective: To investigate the role of AF in PSCI, especially in relation to other markers of cerebrovascular disease. Methods: 445 subjects with mild ischemic stroke without pre-stroke cognitive decline were assessed 3–6 months post-stroke for cognitive deficits. MRIs were reviewed by trained raters for acute infarct characteristics, global cortical atrophy, white matter hyperintensities, cerebral microbleeds, and intracranial stenosis. …Logistic regression analysis was used to identify factors independently associated with PSCI. Subjects were also categorized according to paroxysmal (pAF) or persistent/chronic AF (p/cAF), and presence or absence of AF or large cortical infarcts (LCI) to study cognitive trends. Results: 80 (18.0%) subjects had AF. 76.3% of AF subjects and 42.7% of subjects without AF had PSCI. The odds ratio (OR) of AF in developing PSCI was 2.31 (95% CI: 1.12–4.75; p  = 0.035), after correcting for other risk factors. pAF subjects and AF subjects with LCIs had higher ORs for PSCI. AF subjects performed worse in neuropsychological tasks associated with global cognition, episodic memory, and executive function. Conclusion: AF is a significant risk factor for PSCI, even after correcting for AF-related infarcts. Other mechanisms, such as hypoperfusion, microhemorrhages, and neuroinflammation, may be at play. All stroke patients with AF, regardless of the type of infarction, should be closely monitored for PSCI. Show more

Keywords: Atrial fibrillation, cognitive impairments, ischemic stroke, magnetic resonance imaging, risk factors

DOI: 10.3233/JAD-170313

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 867-875, 2017

Authors: Inui, Yoshitaka | Ito, Kengo | Kato, Takashi | SEAD-J Study Group

Article Type: Research Article

Abstract: Background: The value of fluorine-18-fluorodeoxyglucose positron emission tomography (18 F-FDG-PET) and magnetic resonance imaging (MRI) for predicting conversion of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) in longer-term is unclear. Objective: To evaluate longer-term prediction of MCI to AD conversion using 18 F-FDG-PET and MRI in a multicenter study. Methods: One-hundred and fourteen patients with MCI were followed for 5 years. They underwent clinical and neuropsychological examinations, 18 F-FDG-PET, and MRI at baseline. PET images were visually classified into predefined dementia patterns. PET scores were calculated as a semi quantitative index. For structural MRI, z-scores …in medial temporal area were calculated by automated volume-based morphometry (VBM). Results: Overall, 72% patients with amnestic MCI progressed to AD during the 5-year follow-up. The diagnostic accuracy of PET scores over 5 years was 60% with 53% sensitivity and 84% specificity. Visual interpretation of PET images predicted conversion to AD with an overall 82% diagnostic accuracy, 94% sensitivity, and 53% specificity. The accuracy of VBM analysis presented little fluctuation through 5 years and it was highest (73%) at the 5-year follow-up, with 79% sensitivity and 63% specificity. The best performance (87.9% diagnostic accuracy, 89.8% sensitivity, and 82.4% specificity) was with a combination identified using multivariate logistic regression analysis that included PET visual interpretation, educational level, and neuropsychological tests as predictors. Conclusion: 18 F-FDG-PET visual assessment showed high performance for predicting conversion to AD from MCI, particularly in combination with neuropsychological tests. PET scores showed high diagnostic specificity. Structural MRI focused on the medial temporal area showed stable predictive value throughout the 5-year course. Show more

Keywords: Alzheimer’s disease, fluorodeoxyglucose F18, magnetic resonance imaging, mild cognitive impairment, multicenter studies, positron-emission tomography

DOI: 10.3233/JAD-170395

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 877-887, 2017

Authors: Bahar-Fuchs, Alex | Webb, Shannon | Bartsch, Lauren | Clare, Linda | Rebok, George | Cherbuin, Nicolas | Anstey, Kaarin J.

Article Type: Research Article

Abstract: Background: Computerized Cognitive Training (CCT) has been shown to improve cognitive function in older adults with mild cognitive impairment (MCI) or mood-related neuropsychiatric symptoms (MrNPS), but many questions remain unresolved. Objective: To evaluate the extent to which CCT benefits older adults with both MCI and MrNPS, and its effects on meta-cognitive and non-cognitive outcomes, as well as establish whether adapting difficulty levels and tailoring to individuals’ profile is superior to generic training. Methods: Older adults with MCI (n  = 9), MrNPS (n  = 11), or both (MCI+, n  = 25) were randomized into a home-based individually-tailored and adaptive CCT …(n  = 21) or an active control condition (AC; n  = 23) in a double-blind design. Interventions lasted 8–12 weeks and outcomes were assessed after the intervention, and at a 3-month follow-up. Results: Participants in both conditions reported greater satisfaction with their everyday memory following intervention and at follow-up. However, participants in the CCT condition showed greater improvement on composite measures of memory, learning, and global cognition at follow-up. Participants with MrNPS in the CCT condition were also found to have improved mood at 3-month follow-up and reported using fewer memory strategies at the post-intervention and follow-up assessments. There was no evidence that participants with MCI+ were disadvantaged relative to the other diagnostic conditions. Finally, informant-rated caregiver burden declined at follow-up assessment in the CCT condition relative to the AC condition. Conclusions: Home-based CCT with adaptive difficulty and personal tailoring appears superior to more generic CCT in relation to both cognitive and non-cognitive outcomes. Mechanisms of treatment effect and future directions are discussed. Show more

Keywords: Behavior change techniques, cognitive training, mild cognitive impairment, randomized controlled trial

DOI: 10.3233/JAD-170404

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 889-911, 2017

Authors: Bae, Seongryu | Shimada, Hiroyuki | Lee, Sangyoon | Makizako, Hyuma | Lee, Sungchul | Harada, Kazuhiro | Doi, Takehiko | Tsutsumimoto, Kota | Hotta, Ryo | Nakakubo, Sho | Park, Hyuntae | Suzuki, Takao

Article Type: Research Article

Abstract: Background: The associations between components of metabolic syndrome (MetS) and mild cognitive impairment (MCI) subtypes remain unclear. Objective: The study aim was to identify the prevalence of MetS for MCI subtypes and to investigate sex differences in the association between MetS and MCI subtypes in older Japanese adults. Methods: The study analyzed data from 3,312 men and women aged 70 years or more. MetS was diagnosed according to International Diabetes Federation criteria. Participants completed cognitive tests and were categorized into normal cognition, amnestic MCI (aMCI), and non-amnestic MCI (naMCI). The associations between MetS and its components …and MCI subtypes were analyzed using multiple logistic regression. Results: MetS prevalence was greater in participants with naMCI (men: p  = 0.030; women: p  = 0.040). Participants with naMCI showed higher odds ratios (OR) of MetS (men: 2.45, 95% confidence intervals (CI): 1.13–5.32; women: OR: 1.94, 95% CI: 1.12–3.39) compared with participants with normal cognition. MetS was not associated with aMCI. Analysis of MetS components showed that raised glucose (OR: 1.62, 95% CI: 1.19–2.22) and reduced high-density lipoprotein cholesterol (OR: 1.97, 95% CI: 1.25–3.12) were associated with naMCI in men. In women, raised blood pressure (OR: 1.42, 95% CI: 1.03–1.94) and raised glucose (OR: 1.32, 95% CI: 1.02–1.71) were associated with naMCI. Conclusion: MetS was associated only with naMCI regardless of sex, which suggests etiologic differences in MCI subtypes. We also found sex differences in the relationship between naMCI risk and MetS and its components. Show more

Keywords: Elderly population, metabolic syndrome, mild cognitive impairment, sex differences

DOI: 10.3233/JAD-161230

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 913-921, 2017

Authors: Cascella, Roberta | Evangelisti, Elisa | Bigi, Alessandra | Becatti, Matteo | Fiorillo, Claudia | Stefani, Massimo | Chiti, Fabrizio | Cecchi, Cristina

Article Type: Research Article

Abstract: An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer’s disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-β peptide (Aβ42 ), with intracellular flux of Ca2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca2+ …ions induced by Aβ42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by Aβ42 oligomers with low solvent-exposed hydrophobicity (A-) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD. Show more

Keywords: Alzheimer’s disease, AMPA, calcium dysregulation, glutamatergic receptors, GM1, lipid rafts, membrane permeabilization, NMDA

DOI: 10.3233/JAD-170340

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 923-938, 2017

Authors: Lan, Martin J. | Ogden, R. Todd | Kumar, Dileep | Stern, Yaakov | Parsey, Ramin V. | Pelton, Gregory H. | Rubin-Falcone, Harry | Pradhaban, Gnanavalli | Zanderigo, Francesca | Miller, Jeffrey M. | Mann, J. John | Devanand, D.P.

Article Type: Research Article

Abstract: This project compares three neuroimaging biomarkers to predict progression to dementia in subjects with mild cognitive impairment (MCI). Eighty-eight subjects with MCI and 40 healthy controls (HCs) were recruited. Subjects had a 3T magnetic resonance imaging (MRI) scan, and two positron emission tomography (PET) scans, one with Pittsburgh compound B ([11 C]PIB) and one with fluorodeoxyglucose ([18 F]FDG). MCI subjects were followed for up to 4 y and progression to dementia was assessed on an annual basis. MCI subjects had higher [11 C]PIB binding potential (BPND ) than HCs in multiple brain regions, and lower hippocampus volumes. [11 C]PIB BPND, …[18 F]FDG standard uptake value ratio (SUVR), and hippocampus volume were associated with time to progression to dementia using a Cox proportional hazards model. [18 F]FDG SUVR demonstrated the most statistically significant association with progression, followed by [11 C]PIB BPND and then hippocampus volume. [11 C]PIB BPND and [18 F]FDG SUVR were independently predictive, suggesting that combining these measures is useful to increase accuracy in the prediction of progression to dementia. Hippocampus volume also had independent predictive properties to [11 C]PIB BPND , but did not add predictive power when combined with the [18 F]FDG SUVR data. This work suggests that PET imaging with both [11 C]PIB and [18 F]FDG may help to determine which MCI subjects are likely to progress to AD, possibly directing future treatment options. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, prognosis, PET, volumetric MRI

DOI: 10.3233/JAD-161284

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 939-947, 2017

Authors: Kuttner-Hirshler, Yafit | Venkatasubramanian, Palamadai N. | Apolinario, Joan | Bonds, Jacqueline | Wyrwicz, Alice M. | Lazarov, Orly

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by progressive loss of memory and cognitive deterioration. It is thought that the onset of the disease takes place several decades before memory deficits are apparent. Reliable biomarkers for the diagnosis or prognostication of the disease are highly desirable. Neural stem cells (NSC) exist in the adult brain throughout life and give rise to neural progenitor cells (NPC), which differentiate into neurons or glia. The level of NPC proliferation and new neuron formation is significantly compromised in mouse models of familial Alzheimer’s disease (FAD). These deficits are readily detected in young adults, at 2-3 months …of age, preceding amyloid deposition and cognitive impairments, which may indicate that impaired neurogenesis can be an early biomarker for cognitive deficits in AD. Recent studies suggest that NSC can be detected in live rodents, noninvasively, using proton magnetic resonance spectroscopy (1 H-MRS) signal at 1.28 ppm. Here we examined the use of 1 H-MRS for determining the extent of neurogenesis in the brains of FAD mice. We observed that the reduction in neurogenesis in the FAD mice as observed by immunohistochemistry, was not manifested by a reduction in the 1.28 ppm signal, suggesting that this marker is either not specific for neurogenesis or not sensitive enough for the detection of alterations in hippocampal neurogenesis in the brains of FAD mice. Show more

Keywords: Alzheimer’s disease, brain biomarkers, 1H-MRS, mouse models, neurogenesis

DOI: 10.3233/JAD-170269

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 949-958, 2017

Authors: Krudop, Welmoed A. | Dols, Annemieke | Kerssens, Cora J. | Eikelenboom, Piet | Prins, Niels D. | Möller, Christiane | Schouws, Sigfried | Rhebergen, Didi | van Exel, Eric | van der Flier, Wiesje M. | Sikkes, Sietske | Scheltens, Philip | Stek, Max L. | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: Background: The behavioral variant of frontotemporal dementia (bvFTD) has a broad differential diagnosis including other neurological and psychiatric disorders. Psychiatric misdiagnoses occur in up to 50% of bvFTD patients. Numbers on misdiagnosis of bvFTD in psychiatric disorders are lacking. Objective: The aim of our study was to investigate the frequency and characteristics of bvFTD misdiagnoses in psychiatric disorders and other neurologic disorders. Methods: Thirty-five patients with a (possible or probable ) bvFTD diagnosis made by specialized memory clinic neurologists were included. Change in diagnosis after consulting a psychiatrist at baseline was recorded as well as …change in diagnosis after two years of multidisciplinary neuropsychiatric follow-up. Differences in cognitive and behavioral profiles were investigated per diagnostic group after follow-up (bvFTD, psychiatry, other neurologic disorders). Clinical profiles are described in detail. Results: In 17 patients (48.5%), the bvFTD baseline diagnosis changed: Two at baseline after psychiatric consultation, and 15 after two years of multidisciplinary follow-up. Eleven (64.5%) of these 17 patients (31.5% of total) were reclassified with a psychiatric diagnosis. We found no differences for cognitive baseline profiles between patients with bvFTD versus psychiatric diagnoses. Conclusion: In almost half of cases, the initial bvFTD diagnosis was changed after follow-up, most often into a psychiatric disorder. A multidisciplinary neuropsychiatric approach in the diagnostic process of bvFTD results in the identification of treatable disorders. Our findings illustrate a limited specificity of the [18 F]FDG-PET-scan and the bvFTD criteria in a neuropsychiatric cohort, especially combined with certain clinical symptoms, like disinhibition, apathy, or loss of empathy. Show more

Keywords: Behavioral variant FTD, differential diagnosis, frontotemporal dementia, psychiatry

DOI: 10.3233/JAD-170608

Citation: Journal of Alzheimer's Disease, vol. 60, no. 3, pp. 959-975, 2017