Journal of Alzheimer's Disease - Volume 46, issue 1

Authors: Seaman, Jennifer Burgher | Terhorst, Lauren | Gentry, Amanda | Hunsaker, Amanda | Parker, Lisa S. | Lingler, Jennifer Hagerty

Article Type: Review Article

Abstract: Background: With the growing population of individuals affected by Alzheimer’s disease (AD) and related disorders, there is a pressing demand for research on late-life cognitive disorders. However, this population’s high risk for decisional incapacity necessitates evaluation of capacity to consent to research participation, adding cost and complexity to the research process. The University of California, San Diego Brief Assessment of Capacity to Consent (UBACC) was initially validated in a sample of persons with schizophrenia and healthy controls. Objective: To assess the psychometric properties of the UBACC when used in a sample of individuals contemplating participation in AD …research. Methods: The UBACC was administered to a convenience sample (n  = 132) consisting of individuals with mild to moderate cognitive impairment (n  = 52), their study partners (n  = 52), and healthy older adults control subjects (n  = 30), as part of a broader study to evaluate perceived burden of research participation. Reliability tests, correlational analyses, and exploratory factor analytic methods were used to examine the psychometric properties of the instrument. Results: UBACC scores were significantly associated with both global cognition (r s = 0.564, p  <  0.001) and verbal fluency (rs = 0.511, p  <  0.001), indicating concurrent validity with related constructs. The resulting factor structure differed from that reported by the developers in their initial testing. Items clustered almost entirely on one factor; items reflecting the construct of understanding accounted for 32.12% of total variance, with no evidence for distinct reasoning or appreciation scales. Conclusion: The UBACC shows promise when used to screen for decisional capacity among those considering participation in AD research. Show more

Keywords: Alzheimer’s disease, decisional capacity, informed consent, instrumentation

DOI: 10.3233/JAD-142559

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 1-9, 2015

Authors: Rosen, Allyson | Weitlauf, Julie C.

Article Type: Review Article

Abstract: A screening measure of capacity to consent can provide an efficient method of determining the appropriateness of including individuals from vulnerable patient populations in research, particularly in circumstances in which no caregiver is available to provide surrogate consent. Seaman et al. (2015) cross-validate a measure of capacity to consent to research developed by Jeste et al. (2007). They provide data on controls, caregivers, and patients with mild cognitive impairment and dementia. The study demonstrates the importance of validating measures across disorders with different domains of incapacity, as well as the need for timely and appropriate follow-up with potential participants who …yield positive screens. Ultimately clinical measures need to adapt to the dimensional diagnostic approaches put forward in DSM 5. Integrative models of constructs, such as capacity to consent, will make this process more efficient by avoiding the need to test measures in each disorder. Until then, cross-validation studies, such as the work by Seaman et al. (2015) are critical. Show more

Keywords: Alzheimer’s disease, decision making, ethics - research [N05.350.670], informed consent, mental competency, neuropsychology, vulnerable populations

DOI: 10.3233/JAD-143081

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 11-13, 2015

Authors: Lingler, Jennifer H. | Seaman, Jennifer B. | Parker, Lisa S.

Article Type: Review Article

DOI: 10.3233/JAD-150209

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 15-16, 2015

Authors: Theofilas, Panos | Dunlop, Sara | Heinsen, Helmut | Grinberg, Lea Tenenholz

Article Type: Review Article

Abstract: Pharmacological interventions in Alzheimer’s disease (AD) are likely to be more efficacious if administered early in the course of the disease, foregoing the spread of irreversible changes in the brain. Research findings underline an early vulnerability of the isodendritic core (IC) network to AD neurofibrillary lesions. The IC constitutes a phylogenetically conserved subcortical system including the locus coeruleus in pons, dorsal raphe nucleus, and substantia nigra in the midbrain, and nucleus basalis of Meynert in basal forebrain. Through their ascending projections to the cortex, the IC neurons regulate homeostasis and behavior by synthesizing aminergic and cholinergic neurotransmitters. Here we reviewed …the evidence demonstrating that neurons of the IC system show neurofibrillary tangles in the earliest stages of AD, prior to cortical pathology, and how this involvement may explain pre-amnestic symptoms, including depression, agitation, and sleep disturbances in AD patients. In fact, clinical and animal studies show a significant reduction of AD cognitive and behavioral symptoms following replenishment of neurotransmitters associated with the IC network. Therefore, the IC network represents a unique candidate for viable therapeutic intervention and should become a high priority for research in AD. Show more

Keywords: Aging, Alzheimer’s disease, brainstem nuclei, early diagnosis, human, monoamines, neurodegeneration, neurofibrillary tangles, neuromodulation, pathology

DOI: 10.3233/JAD-142682

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 17-34, 2015

Authors: Di Marco, Luigi Yuri | Farkas, Eszter | Martin, Chris | Venneri, Annalena | Frangi, Alejandro F.

Article Type: Review Article

Abstract: A substantial body of evidence supports the hypothesis of a vascular component in the pathogenesis of Alzheimer’s disease (AD). Cerebral hypoperfusion and blood-brain barrier dysfunction have been indicated as key elements of this pathway. Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder, frequent in AD, characterized by the accumulation of amyloid-β (Aβ) peptide in cerebral blood vessel walls. CAA is associated with loss of vascular integrity, resulting in impaired regulation of cerebral circulation, and increased susceptibility to cerebral ischemia, microhemorrhages, and white matter damage. Vasomotion— the spontaneous rhythmic modulation of arterial diameter, typically observed in arteries/arterioles in various vascular beds …including the brain— is thought to participate in tissue perfusion and oxygen delivery regulation. Vasomotion is impaired in adverse conditions such as hypoperfusion and hypoxia. The perivascular and glymphatic pathways of Aβ clearance are thought to be driven by the systolic pulse. Vasomotion produces diameter changes of comparable amplitude, however at lower rates, and could contribute to these mechanisms of Aβ clearance. In spite of potential clinical interest, studies addressing cerebral vasomotion in the context of AD/CAA are limited. This study reviews the current literature on vasomotion, and hypothesizes potential paths implicating impaired cerebral vasomotion in AD/CAA. Aβ and oxidative stress cause vascular tone dysregulation through direct effects on vascular cells, and indirect effects mediated by impaired neurovascular coupling. Vascular tone dysregulation is further aggravated by cholinergic deficit and results in depressed cerebrovascular reactivity and (possibly) impaired vasomotion, aggravating regional hypoperfusion and promoting further Aβ and oxidative stress accumulation. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, cerebral autoregulation, endothelium, perivascular drainage, vascular smooth muscle cell, vasomotion

DOI: 10.3233/JAD-142976

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 35-53, 2015

Authors: Dinkins, Michael B. | Dasgupta, Somsankar | Wang, Guanghu | Zhu, Gu | He, Qian | Kong , Ji Na | Bieberich, Erhard

Article Type: Short Communication

Abstract: We present evidence that 5XFAD Alzheimer’s disease model mice develop an age-dependent increase in antibodies against ceramide, suggesting involvement of autoimmunity against ceramide in Alzheimer’s disease pathology. To test this, we increased serum anti-ceramide IgG (2-fold) by ceramide administration and analyzed amyloid plaque formation in 5XFAD mice. There were no differences in soluble or total amyloid-β levels. However, females receiving ceramide had increased plaque burden (number, area, and size) compared to controls. Ceramide-treated mice showed an increase of serum exosomes (up to 3-fold using Alix as marker), suggesting that systemic anti-ceramide IgG and exosome levels are correlated with enhanced plaque …formation. Show more

Keywords: Alzheimer’s disease, amyloid, antibodies, ceramide, exosomes, mice

DOI: 10.3233/JAD-150088

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 55-61, 2015

Authors: Donovan, Nancy J. | Hsu, David C. | Dagley, Alexander S. | Schultz, Aaron P. | Amariglio, Rebecca E. | Mormino, Elizabeth C. | Okereke, Olivia I. | Rentz, Dorene M. | Johnson, Keith A. | Sperling, Reisa A. | Marshall, Gad A.

Article Type: Research Article

Abstract: Even low levels of depressive symptoms are associated with an increased risk of cognitive decline in older adults without overt cognitive impairment (CN). Our objective was to examine whether very low, “subthreshold symptoms of depression” are associated with Alzheimer’s disease (AD) biomarkers of neurodegeneration in CN adults and whether these associations are specific to particular depressive symptoms. We analyzed data from 248 community-dwelling CN older adults, including measurements of cortical amyloid burden, neurodegeneration markers of hippocampal volume (HV) and cerebral 18 F-fluorodeoxyglucose (FDG) metabolism in a composite of AD-related regions and the 30-item Geriatric Depression Scale (GDS). Participants with GDS …>10 were excluded. General linear regression models evaluated the cross-sectional relations of GDS to HV or FDG in separate backward elimination models. Predictors included GDS total score, age, gender, premorbid intelligence, a binary amyloid variable and its interaction with GDS. Principal component analyses of GDS item scores revealed three factors (the Dysphoria, Apathy-Anhedonia, and Anxiety-Concentration Factors). In secondary analyses, GDS total score was replaced with the three factor scores in repeated models. Higher GDS score (p  = 0.03) was significantly associated with lower HV and was marginally related (p  = 0.06) to FDG hypometabolism. In secondary models, higher Dysphoria (p  = 0.02) and Apathy-Anhedonia (p  = 0.05) were related to lower HV while higher Apathy-Anhedonia (p  = 0.003) was the sole factor related to FDG hypometabolism. Amyloid was not a significant predictor in any model. In conclusion, very low-level dysphoria, apathy and anhedonia may point to neurodegeneration in AD-related regions but this association appears to be independent of amyloid burden. Show more

Keywords: Alzheimer’s disease, biomarkers, neurodegeneration, normal cognition, preclinical, subthreshold depressivesymptoms

DOI: 10.3233/JAD-142940

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 63-73, 2015

Authors: Ventriglia, Mariacarla | Brewer, George J. | Simonelli, Ilaria | Mariani, Stefania | Siotto, Mariacristina | Bucossi, Serena | Squitti, Rosanna

Article Type: Research Article

Abstract: To evaluate whether zinc levels in serum, plasma, and cerebrospinal fluid are altered in Alzheimer’s disease (AD), we performed meta-analyses of 27 studies on the topic published from 1983 to 2014. The subjects’ sample obtained by merging studies was a pooled total of 777 AD subjects and 1,728 controls for serum zinc studies, 287 AD subjects and 166 controls for plasma zinc, and of 292 AD subjects and 179 controls for CSF zinc. The main result of this meta-analysis is the very high heterogeneity among the studies either in demographic terms or in methodological approaches. Although we considered these effects …in our analyses, the heterogeneity persisted and it has to be taken into account in the interpretation of the results. Our meta-analysis indicated that serum zinc appears significantly decreased in AD patients compared with healthy controls, and this result is confirmed when serum and plasma studies were analyzed together. If we considered the age-matched studies, the meta-analysis carried out on only six studies showed no significant difference in zinc levels between AD and healthy controls (SMD =−0.55, 95% CI (−1.18; 0.09); p  = 0.094; I2  = 91%). In the light of these findings, we speculated about the possibility that the decreases observed could indicate a possible dietary zinc deficiency and we suggested that the possible involvement of zinc alterations in AD may have an interplay with copper metabolism. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, meta-analysis, plasma, serum, zinc

DOI: 10.3233/JAD-141296

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 75-87, 2015

Authors: Avan, Abolfazl | Hoogenraad, Tjaard U.

Article Type: Article Commentary

Abstract: In a recent meta-analysis by Ventriglia and colleagues studying the association of zinc levels with Alzheimer’s disease (AD), serum zinc has been found significantly decreased in AD patients compared with healthy controls. However, such a finding does not necessarily propose the causal role of low zinc in the pathophysiology of this neurodegenerative disease. On the basis of available evidence, free copper toxicosis may play a causal role in age-related AD, and zinc therapy can be a rational causal treatment. Nevertheless, a randomized controlled clinical trial testing a definite hypothesis is needed before conclusions can be drawn about the value of …zinc supplements in the treatment of AD. Show more

Keywords: Alzheimer’s disease, ceruloplasmin, copper, free copper, metallothionein, neurodegeneration, underreporting, Wilson’s disease, zinc

DOI: 10.3233/JAD-150186

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 89-92, 2015

Authors: Le Page, Aurélie | Bourgade, Karine | Lamoureux, Julie | Frost, Eric | Pawelec, Graham | Larbi, Anis | Witkowski, Jacek M. | Dupuis, Gilles | Fülöp, Tamás

Article Type: Research Article

Abstract: Alzheimerś disease (AD) is a progressive irreversible neurological brain disorder characterized by accumulation of amyloid-β, amyloid plaques, and neurofibrillary tangles. Inflammation and immune alterations have been linked to AD, suggesting that the peripheral immune system plays a role during the asymptomatic period of AD. NK cells participate in innate immune surveillance against intracellular pathogens and malignancy but their role in AD remains controversial. We have investigated changes in peripheral NK cell phenotypes and functions in amnestic mild cognitive impairment (aMCI, n  = 10), patients with mild AD (mAD, n  = 11), and healthy elderly controls (n  = 10). Patients selected according to NINCDS-ADRDA …criteria were classified using neuropsychological assessment tests. Phenotype analysis revealed differences in expression of CD16 (increased in mAD), NKG2A (decreased in aMCI), and TLR2 and TLR9 (both decreased in mAD). Functional assays revealed that NK cell killing activity and degranulation (CD107 expression) were unchanged in the three groups. In contrast, expression of the CD95 receptor was increased in aMCI and mAD. Granzyme B expression and cytokine production (TNFα , IFNγ ) were increased in aMCI but not in mAD. CCL19- but not CCL21-dependent chemotaxis was decreased in aMCI and mAD, despite the fact that CCR7 expression was increased in aMCI. Our data suggest that the number of alterations observed in peripheral NK cells in aMCI represent an activation state compared to mAD patients and that may reflect an active immune response against a still to be defined aggression. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, cell cytotoxicity, chemotaxis, natural killer cells, phenotyping, toll-like receptors

DOI: 10.3233/JAD-143054

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 93-107, 2015