Journal of Alzheimer's Disease - Volume 60, issue 4

Authors: Ferro, Doeschka A. | van Veluw, Susanne J. | Koek, Huiberdina L. | Exalto, Lieza G. | Biessels, Geert Jan | on behalf of the Utrecht Vascular Cognitive Impairment (VCI) study group

Article Type: Research Article

Abstract: Background: Cerebral microinfarcts (CMIs) are small ischemic lesions that are a common neuropathological finding in patients with stroke or dementia. CMIs in the cortex can now be detected in vivo on 3 Tesla MRI. Objective: To determine the occurrence of CMIs and associated clinical features in patients with possible vascular cognitive impairment (VCI). Method: 182 memory-clinic patients (mean age 71.4±10.6, 55% male) with vascular injury on brain MRI (i.e., possible VCI) underwent a standardized work-up including 3 Tesla MRI and cognitive assessment. A control group consisted of 70 cognitively normal subjects (mean age 70.6±4.7, 60% …male). Cortical CMIs and other neuroimaging markers of vascular brain injury were rated according to established criteria. Result: Occurrence of CMIs was higher (20%) in patients compared to controls (10%). Among patients, the presence of CMIs was associated with male sex, history of stroke, infarcts, and white matter hyperintensities. CMI presence was also associated with a diagnosis of vascular dementia and reduced performance in multiple cognitive domains. Conclusion: CMIs on 3 Tesla MRI are common in patients with possible VCI and co-occur with imaging markers of small and large vessel disease, likely reflecting a heterogeneous etiology. CMIs are associated with worse cognitive performance, independent of other markers of vascular brain injury. Show more

Keywords: Cerebral small vessel disease, cerebrovascular disease, dementia, infarct, magnetic resonance imaging, neuropsychological test

DOI: 10.3233/JAD-170481

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1443-1450, 2017

Authors: Dumurgier, Julien | Hanseeuw, Bernard J. | Hatling, Frances B. | Judge, Kelly A. | Schultz, Aaron P. | Chhatwal, Jasmeer P. | Blacker, Deborah | Sperling, Reisa A. | Johnson, Keith A. | Hyman, Bradley T. | Gómez-Isla, Teresa

Article Type: Research Article

Abstract: Background: Identifying older adults at risk of cognitive decline represents a challenge as Alzheimer’s disease (AD) modifying therapies move toward preclinical stages. Objective: To investigate the relationship between AD biomarkers and subsequent change in cognition in a cohort of cognitively intact older adults. Methods: 84 cognitively normal subjects (mean age 72.0 years, 59% women) were recruited through the Massachusetts Alzheimer’s Disease Research Center and the Harvard Aging Brain Study and followed over 3 years. Measurements of amyloid-β 1–42 (Aβ42 ), total Tau (t-Tau), and Tau phosphorylated at threonine 181 (p-Tau181) in the cerebrospinal fluid (CSF) at …study entry were available in all cases. Baseline brain MRI, FDG-PET, and PiB-PET data were available in the majority of participants. Relationship between baseline AD biomarkers and longitudinal change in cognition was assessed using Cox proportional hazard regression and linear mixed models. Results: 14% participants increased their global Clinical Dementia Rating (CDR) score from 0 to 0.5 during follow-up. A CDR score increase was associated with higher baseline CSF t-Tau and p-Tau181, higher global cortical PiB retention, and lower hippocampal volume. The combination of high CSF t-Tau and low Aβ42 or low hippocampal volume was more strongly related to cognitive outcome than each single biomarker. Higher CSF t-Tau was the only biomarker associated with subsequent decline in MMSE score. Conclusions: Baseline CSF t-Tau and p-Tau181, in vivo amyloid load, and hippocampal volume were all independently associated with future decline in cognition. The discriminatory ability of these biomarkers to predict risk of cognitive decline, however, was only modest. Show more

Keywords: Biomarkers, cognitive decline, cerebrospinal fluid, epidemiology, neuroimaging

DOI: 10.3233/JAD-170511

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1451-1459, 2017

Authors: Yordanova, Kristina | Koldrack, Philipp | Heine, Christina | Henkel, Ron | Martin, Mike | Teipel, Stefan | Kirste, Thomas

Article Type: Research Article

Abstract: Background: Dementia impairs spatial orientation and route planning, thus often affecting the patient’s ability to move outdoors and maintain social activities. Situation-aware deliberative assistive technology devices (ATD) can substitute impaired cognitive function in order to maintain one’s level of social activity. To build such a system, one needs domain knowledge about the patient’s situation and needs. We call this collection of knowledge situation model. Objective: To construct a situation model for the outdoor mobility of people with dementia (PwD). The model serves two purposes: 1) as a knowledge base from which to build an ATD describing the mobility …of PwD; and 2) as a codebook for the annotation of the recorded behavior. Methods: We perform systematic knowledge elicitation to obtain the relevant knowledge. The OBO Edit tool is used for implementing and validating the situation model. The model is evaluated by using it as a codebook for annotating the behavior of PwD during a mobility study and interrater agreement is computed. In addition, clinical experts perform manual evaluation and curation of the model. Results: The situation model consists of 101 concepts with 11 relation types between them. The results from the annotation showed substantial overlapping between two annotators (Cohen’s kappa of 0.61). Conclusion: The situation model is a first attempt to systematically collect and organize information related to the outdoor mobility of PwD for the purposes of situation-aware assistance. The model is the base for building an ATD able to provide situation-aware assistance and to potentially improve the quality of life of PwD. Show more

Keywords: Alzheimer’s disease, assistance, data collection, dementia, knowledge base, mobility limitation, situationawareness

DOI: 10.3233/JAD-170105

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1461-1476, 2017

Authors: Handels, Ron L.H. | Wimo, Anders | Dodel, Richard | Kramberger, Milica G. | Visser, Pieter Jelle | Molinuevo, José Luis | Verhey, Frans R.J. | Winblad, Bengt

Article Type: Research Article

Abstract: Background: Diagnostic research criteria for Alzheimer’s disease support the use of biomarkers in the cerebrospinal fluid (CSF) to improve the accuracy of the prognosis regarding progression to dementia for people with mild cognitive impairment (MCI). Objective: The aim of this study was to estimate the potential incremental cost-effectiveness ratio of adding CSF biomarker testing to the standard diagnostic workup to determine the prognosis for patients with MCI. Methods: In an early technology assessment, a mathematical simulation model was built, using available evidence on added prognostic value as well as expert opinion to estimate the incremental costs …and quality-adjusted life years (QALYs) of 20,000 virtual MCI patients with (intervention strategy) and without (control strategy) relying on CSF, from a health-care sector perspective and with a 5-year time horizon. Results: Adding the CSF test improved the accuracy of prognosis by 11%. This resulted in an average QALY gain of 0.046 and € 432 additional costs per patient, representing an incremental cost-effectiveness ratio of € 9,416. Conclusion: The results show the potential of CSF biomarkers in current practice from a health-economics perspective. This result was, however, marked by a high degree of uncertainty, and empirical research is required into the impact of a prognosis on worrying, false-positive/negative prognosis, and stigmatization. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, cost-utility, economic evaluation, mild cognitive impairment, prognosis, risk

DOI: 10.3233/JAD-170324

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1477-1487, 2017

Authors: Sejunaite, Karolina | Lanza, Claudia | Riepe, Matthias W.

Article Type: Research Article

Abstract: Background: Errors of omission are an established hallmark of memory impairment in Alzheimer’s disease (AD). Much less is known about other memory errors in AD such as false memories. Objective: We investigated false memories in healthy elderly controls (HC; n  = 23) and patients with AD (n  = 20) using real-life tasks of watching news and commercials. Methods: Participants received a comprehensive neuropsychological assessment and were shown original news and commercials with a subsequent recognition task to assess veridical and false memories. Results: Subjective estimate of the number of errors were alike in HC and patients …with AD. However, memory performance in both the news and the commercials task was significantly worse in patients with AD. Trail-Making Test and Symbol-Span Test were significant predictors of false memories on viewing news and commercials. In patients with AD, levels of Aβ1 - 42 , but not levels of tau-protein were correlated with false memories in both tasks. Conclusions: Everyday life in patients with AD is impeded not due to the incompleteness of memory but also due to its distortions. Furthermore, it is hindered by the lack of awareness towards these deficits. False memory content in patients with AD is associated with Aβ42 levels in the CSF as a surrogate of the overall extent to which the brain has been affected by AD pathology. Future studies will need to address the impact of this duality of memory failure on everyday life of patients with AD and their proxies in greater detail. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid markers, episodic memory, everyday life, false memories, memory disorders, neuropsychology

DOI: 10.3233/JAD-170493

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1489-1498, 2017

Authors: Stelmokas, Julija | Yassay, Lance | Giordani, Bruno | Dodge, Hiroko H. | Dinov, Ivo D. | Bhaumik, Arijit | Sathian, K. | Hampstead, Benjamin M.

Article Type: Research Article

Abstract: NeuroQuant (NQ) is a fully-automated program that overcomes several existing limitations in the clinical translation of MRI-derived volumetry. The current study characterized differences between the original (NQ1) and an updated NQ version (NQ2) by 1) replicating previously identified relationships between neuropsychological test performance and medial temporal lobe volumes, 2) evaluating the level of agreement between NQ versions, and 3) determining if the addition of NQ2 age-/sex-based z-scores hold greater clinical utility for prediction of memory impairment than standard percent of intracranial volume (% ICV) values. Sixty-seven healthy older adults and 65 mild cognitive impairment patients underwent structural MRI and completed …cognitive testing, including the Immediate and Delayed Memory indices from the Repeatable Battery for the Assessment of Neuropsychological Status. Results generally replicated previous relationships between key medial temporal lobe regions and memory test performance, though comparison of NQ regions revealed statistically different values that were biased toward one version or the other depending on the region. NQ2 hippocampal z-scores explained additional variance in memory performance relative to % ICV values. Findings indicate that NQ1/2 medial temporal lobe volumes, especially age- and sex-based z-scores, hold clinical value, though caution is warranted when directly comparing volumes across NQ versions. Show more

Keywords: Alzheimer’s disease, amygdala, hippocampus, memory, neuroimaging

DOI: 10.3233/JAD-170306

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1499-1510, 2017

Authors: Hares, Kelly | Miners, James Scott | Cook, Amelia Jane | Rice, Claire | Scolding, Neil | Love, Seth | Wilkins, Alastair

Article Type: Research Article

Abstract: Defects in motor protein-mediated neuronal transport mechanisms have been implicated in a number of neurodegenerative disorders but remain relatively little studied in Alzheimer’s disease (AD). Our aim in the present study was to assess the expression of the anterograde kinesin superfamily motor proteins KIF5A, KIF1B, and KIF21B, and to examine their relationship to levels of hyperphosphorylated tau, amyloid-β protein precursor (AβPP), and amyloid-β (Aβ) in human brain tissue. We used a combination of qPCR, immunoblotting, and ELISA to perform these analyses in midfrontal cortex from 49 AD and 46 control brains. Expression of KIF5A, KIF1B, and KIF21B at gene and …protein level was significantly increased in AD. KIF5A protein expression correlated inversely with the levels of AβPP and soluble Aβ in AD brains. Upregulation of KIFs may be an adaptive response to impaired axonal transport in AD. Show more

Keywords: Alzheimer’s disease, amyloid, kinesin, tau

DOI: 10.3233/JAD-170094

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1511-1524, 2017

Authors: Devanand, D.P. | Lentz, Cody | Chunga, Richard E. | Ciarleglio, Adam | Scodes, Jennifer M. | Andrews, Howard | Schofield, Peter W. | Stern, Yaakov | Huey, Edward D. | Bell, Karen | Pelton, Gregory H.

Article Type: Research Article

Abstract: Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer’s disease pathology. Objective: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI). Methods: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate …recall and ADAS-Cog total score from baseline to 26 and 52 weeks. Results: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (p  < 0.03). This effect remained after adjusting for time, age, education, gender, APOE ɛ 4 status, and baseline cognitive score (p  < 0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (p  < 0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (p  = 0.07). Conclusions: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment. Show more

Keywords: Acetylcholine, Alzheimer’s disease, mild cognitive impairment, olfaction

DOI: 10.3233/JAD-170497

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1525-1531, 2017

Authors: van Duijn, Sara | Bulk, Marjolein | van Duinen, Sjoerd G. | Nabuurs, Rob J.A. | van Buchem, Mark A. | van der Weerd, Louise | Natté, Remco

Article Type: Research Article

Abstract: Abnormal iron distribution in the isocortex is increasingly recognized as an in vivo marker for Alzheimer’s disease (AD). However, the contribution of iron accumulation to the AD pathology is still poorly understood. In this study, we investigated: 1) frontal cortical iron distribution in AD and normal aging and 2) the relation between iron distribution and degree of AD pathology. We used formalin fixed paraffin embedded frontal cortex from 10 AD patients, 10 elder, 10 middle aged, and 10 young controls and visualized iron with a modified Perl’s histochemical procedure. AD and elderly subjects were not different with respect to …age and sex distribution. Iron distribution in the frontal cortex was not affected by normal aging but was clearly different between AD and controls. AD showed accumulation of iron in plaques, activated microglia, and, in the most severe cases, in the mid-cortical layers along myelinated fibers. The degree of altered iron accumulations was correlated to the amount of amyloid-β plaques and tau pathology in the same block, as well as to Braak stage (p  < 0.001). AD and normal aging show different iron and myelin distribution in frontal cortex. These changes appear to occur after the development of the AD pathological hallmarks. These findings may help the interpretation of high resolution in vivo MRI and suggest the potential of using changes in iron-based MRI contrast to indirectly determine the degree of AD pathology in the frontal cortex. Show more

Keywords: Alzheimer’s disease, iron, magnetic resonance imaging, myelin

DOI: 10.3233/JAD-161143

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1533-1545, 2017

Authors: André, Séverine | Ansciaux, Emilie | Saidi, Elamine | Larbanoix, Lionel | Stanicki, Dimitri | Nonclercq, Denis | Vander Elst, Luce | Laurent, Sophie | Muller, Robert N. | Burtea, Carmen

Article Type: Research Article

Abstract: The diagnosis of Alzheimer’s disease (AD) is a critical step in the management of patients. We have developed a non-invasive diagnosis tool based on magnetic resonance molecular imaging (MRMI) of amyloid-β peptide using ultra-small particles of iron oxide (USPIO) functionalized with a disulfide constrained cyclic heptapeptide (PHO) identified by phage display (USPIO-PHO). After previously demonstrating the optimal pharmacologic properties of USPIO-PHO and its capacity to cross the blood-brain barrier (BBB), the ability of USPIO-PHO to target amyloid plaques (AP) by MRMI has been validated in the present work on AD transgenic mice. The immunohistochemistry and immunofluorescent detection of USPIO-PHO on …brain sections collected after in vivo MRMI studies enabled its colocalization with AP, confirming the BBB passage and specific targeting. The AP targeting by USPIO-PHO has been moreover corroborated by the good correlation between the number of AP detected with anti-amyloid β antibody and Perls’-DAB staining. Finally, the crossing mechanism of USPIO-PHO through the BBB was elucidated, revealing the involvement of non-degradation pathway of caveolae, while the control contrast agent USPIO-PEG was not endocytosed by the human brain endothelial cells. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, blood-brain barrier, contrast agents, functionalized iron oxide nanoparticles, magnetic resonance imaging

DOI: 10.3233/JAD-170563

Citation: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1547-1565, 2017