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

Authors: Li, Gongbo | Kim, Chaeyoung | Kim, Jaekwang | Yoon, Hyejin | Zhou, Huadong | Kim, Jungsu

Article Type: Research Article

Abstract: While early-onset familial Alzheimer’s disease (AD) is caused by a genetic mutation, the vast majority of late-onset AD is likely caused by the combination of genetic and environmental factors. Unlike genetic studies, potential environmental factors affecting AD pathogenesis have not yet been thoroughly investigated. Among environmental factors, pesticides seem to be one of critical environmental contributors to late-onset AD. Recent studies reported that the serum and brains of AD patients have dramatically higher levels of a metabolite of dichlorodiphenyltrichloroethane (DDT). While these epidemiological studies provided initial clues to the environmental risks potentially contributing to disease pathogenesis, a functional approach is …required to determine whether they actually have a causal role in disease development. In our study, we addressed this critical knowledge gap by investigating possible mechanisms by which DDT affects amyloid-β (Aβ) levels. We treated H4-AβPPswe or H4 cells with DDT to analyze its effect on Aβ metabolism using Aβ production, clearance, and degradation assays. We found that DDT significantly increased the levels of amyloid-β protein precursor (AβPP) and β-site AβPP-cleaving enzyme1 (BACE1), affecting Aβ synthesis pathway in H4-AβPPswe cells. Additionally, DDT impaired the clearance and extracellular degradation of Aβ peptides. Most importantly, we identified for the first time that ATP-binding cassette transporter A1 (ABCA1) and insulin-degrading enzyme (IDE) are the downstream target genes adversely affected by DDT. Our findings provide insight into the molecular mechanisms by which DDT exposure may increase the risk of AD, and it further supports that ABCA1 and IDE may be potential therapeutic targets. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, ATP-binding cassette transporter A1, β-site AβPP-cleaving enzyme1, dichlorodiphenyldichloroethylene, dichlorodiphenyltrichloroethane, insulin-degrading enzyme, pesticides

DOI: 10.3233/JAD-150024

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 109-122, 2015

Authors: Bhattacharya, Soumee | Maelicke, Alfred | Montag, Dirk

Article Type: Research Article

Abstract: The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer’s disease (AD), providing cognitive and global relief in human patients. However, as an acetylcholinesterase inhibitor, gastrointestinal side effects limit the dosage and duration of treatment. Memogain (Gln-1062), a pro-drug, liberates galantamine on cleavage by a carboxyesterase in the brain. The possibility to deliver Memogain intranasally may further circumvent side effects, allowing higher dosing compared to galantamine. In this study, the 5X Familial Alzheimer’s Disease (5XFAD) mouse model was used to investigate the effect of chronic Memogain treatment on behavior and amyloid-β (Aβ) plaque deposition in the brain. Chronic …intranasal dosage of 6 mg/kg body weight twice daily was tolerated well, whereas the double dose caused body weight loss in males and was less effective in some behavioral tests. 8 weeks of chronic treatment resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, and in fear conditioning already at mildly affected stages at the age of 18 weeks compared to untreated controls. Furthermore, after treatment a significantly lower plaque density in the brain, i.e., in the entorhinal cortex (reduction 20% females, 40% males) and the hippocampus (19% females, 31% males) at the age of 18 weeks was observed. These results show that nasal application of Memogain effectively delivers the drug to the brain with the potential to retard plaque deposition and improve behavioral symptoms in AD similar to the approved galantamine. Show more

Keywords: Acetylcholinesterase inhibitor, Alzheimer’s disease, amyloid plaques, galantamine, nasal application, nicotinic enhancer

DOI: 10.3233/JAD-142421

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 123-136, 2015

Authors: Haratz, Salo | Weinstein, Galit | Molshazki, Noa | Beeri, Michal Schnaider | Ravona-Springer, Ramit | Marzeliak, Oleg | Goldbourt, Uri | Tanne, David

Article Type: Research Article

Abstract: Background and Objective: Patients with pre-existing atherothrombotic disease are prone to cognitive impairment. We tested whether impaired cerebrovascular reactivity (CVR), a marker of cerebral microvascular hemodynamic dysfunction, is associated with poorer cognitive scores among patients with and without carotid large-vessel disease. Methods: A subgroup of non-demented patients with chronic coronary heart disease followed-up for 15 ± 3 years was assessed for cognitive function (Neurotrax Computerized Cognitive Battery; scaled to an IQ style scale with a mean of 100 and SD of 15) and for CVR using the breath-holding index (BHI) with transcranial Doppler and for carotid plaques …using ultrasound. We assessed cognitive scores in specific domains in patients with and without impaired CVR (BHI <0.47; bottom quartile). Results: Among 415 patients (mean age 71.7 ± 6.2 y) median BHI was 0.73 (25% 0.47, 75% 1.04). Impaired CVR was associated with diabetes and peripheral artery disease. Adjusting for potential confounders, impaired CVR was associated with lower executive function (p  = 0.02) and global cognitive scores (p  = 0.04). There was an interaction with carotid large-vessel disease for executive function (p  <  0.001), memory (p  = 0.03), and global cognitive scores (p  = 0.02). In the carotid large-vessel disease group there were pronounced differences by CVR status in executive function (p  <  0.001), memory (p  = 0.02), attention (p  <  0.001), and global cognitive scores (p  = 0.001). Conclusion: Impaired CVR, a marker of cerebral microvascular dysfunction, is associated with poorer cognitive functions and in particular executive dysfunction among non-demented patients with concomitant carotid large-vessel disease. These findings emphasize the importance of cerebral hemodynamics in cognitive performance. Show more

Keywords: Cerebrovascular disorders, dementia, hemodynamics, transcranial Doppler sonography, vascular dementia

DOI: 10.3233/JAD-150052

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 137-144, 2015

Authors: Bik-Multanowski, Miroslaw | Pietrzyk, Jacek J. | Midro, Alina

Article Type: Research Article

Abstract: Morphological abnormalities observed typically in the brains of adults with Down syndrome are identical with those present in patients with Alzheimer’s disease. However, only some adults with Down syndrome suffer from early dementia, whereas others remain unaffected. We aimed to identify the genomic background responsible for this observation. We performed cognitive assessment and genome expression analysis of blood mononuclear cells in seniors with Down syndrome. Unaffected elderly patients and younger patients with severe cognitive disability or cognitive deterioration differed significantly with regard to the MTRNR2L12 gene. Our findings suggest the potential value of this gene as a blood marker …of early dementia in individuals with Down syndrome. Show more

Keywords: Alzheimer’s disease, blood marker, cognitive assessment, Down syndrome, early dementia, microarrays

DOI: 10.3233/JAD-143030

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 145-150, 2015

Authors: Bregman, Noa | Regev, Keren | Moore, Orna | Giladi, Nir | Ash, Elissa

Article Type: Research Article

Abstract: Identification of individuals at high risk for developing dementia and Alzheimer’s disease is a major challenge. A “memory fair” is an enjoyable and affordable tool designed to reach local population at risk, mainly those with subjective cognitive impairment (SCI) or mild cognitive impairment. The fair included a free cognitive assessment and presentation on the importance of sleep, physical activity, cognitive training, and risk-factors and provided personalized recommendations. 160 individuals completed the evaluation (69.97 ± 9.01 y, 83% women). Average Montreal Cognitive Assessment Score (MoCA) was 24.73 ± 3.71. Six percent reported SCI and an upper estimate of mild cognitive impairment prevalence …was 30.7% . SCI was found to be a sensitive predictor for MoCA <26. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, prevention, screening, subjective cognitive impairment

DOI: 10.3233/JAD-142724

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 151-155, 2015

Authors: Terpening, Zoe | Lewis, Simon J.G. | Yee, Brendon J. | Grunstein, Ron R. | Hickie, Ian B. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Sleep-disordered breathing in middle-age and older adults has been shown to be linked to a range of neuropsychological deficits, but the extent to which these relationships are evident in older people ‘at risk’ of developing dementia in unknown. In this study, we aimed to determine whether changes in sleep-disordered breathing and sleep fragmentation during nocturnal sleep were related to neuropsychological dysfunction in patients with mild cognitive impairment. Forty-six patients with MCI (mean age = 66.1 y, sd = 8.4) and 40 age-matched healthy controls (mean age = 63.5 y, sd = 8.9) underwent psychiatric, medical, and neuropsychological assessment, in addition to overnight polysomnography and self-report questionnaires. Measures of …hypoxemia, sleep fragmentation, and sleep quality were derived including the apnoea-hypopnea index, oxygen desaturation index, percentage of total sleep time spent below 90% oxygen saturation, arousal index, sleep efficiency, and wake after sleep onset. Patients with MCI did not differ from healthy aging on any measure of sleep-disordered breathing or sleep fragmentation. In MCI, processing speed was negatively correlated with greater sleep time spent below 90% oxygen saturation and a higher apnoea-hypopnea index. In contrast, in the healthy aging, processing speed was negatively correlated with an increased oxygen desaturation index and the arousal index. Sleep-disordered breathing is evident in both healthy aging and MCI with associated decrements in processing speed. Future research is needed to determine the unique and synergistic effects of these differential associations, their potential to inform disease trajectory, and possible therapeutic interventions. Show more

Keywords: Dementia, mild cognitive impairment, risk factors, sleep-disordered breathing

DOI: 10.3233/JAD-141860

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 157-165, 2015

Authors: Zeifman, Lubov E. | Eddy, William F. | Lopez, Oscar L. | Kuller, Lewis H. | Raji, Cyrus | Thompson, Paul M. | Becker, James T.

Article Type: Research Article

Abstract: The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer’s disease (AD) from normal cognition. We analyzed incident MCI (n  = 58) or AD (n  = 151) in 292 cognitively normal participants in the Cardiovascular Health Study–Cognition Study (mean age = 79.2 ± 3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine …the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p  <  0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5×10 −8 ). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person’s increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease. Show more

Keywords: Alzheimer’s disease, Cox survival model, incidence, mild cognitive impairment, MRI

DOI: 10.3233/JAD-150047

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 167-178, 2015

Authors: Bacchetti, Tiziana | Vignini, Arianna | Giulietti, Alessia | Nanetti, Laura | Provinciali, Leandro | Luzzi, Simona | Mazzanti, Laura | Ferretti, Gianna

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is associated with oxidative damage of low density lipoproteins (ox-LDL). In order to investigate whether higher levels of ox-LDL are related to alterations of the activity of enzymes involved in lipid metabolism, we studied the activity of paraoxonase-1 (PON1) and platelet activating factor acetylhydrolase (PAF-AH) in AD patients and the relationship between biochemical markers and severity of the disease. Levels of ox-LDL, PON1 (paraoxonase, arylesterase, and lactonase activities), and PAF-AH activity were evaluated in plasma from 49 patients affected by AD and from 34 control subjects matched for gender and age. Our results demonstrated alterations in the …activities of PON1 and PAF-AH in AD patients compared to controls and showed, for the first time, a relationship between the activities of these enzymes, ox-LDL levels, and severity of the disease. A significant negative correlation was observed between the ratio PON1/PAF-AH and ox-LDL. Whatever the causes that contribute to a systemic oxidative stress in AD, our results have shown that AD patients exhibit higher PAF-AH activity than control subjects and higher ox-LDL. This phenomenon, in combination with diminished PON1 in these patients and, consequently, the relatively lower ratio PON1/PAF-AH activity, could contribute to inflammation and oxidative stress of plasma lipoproteins. Show more

Keywords: Alzheimer’s disease, high density lipoproteins, lipid peroxidation, low density lipoproteins, oxidative stress, paraoxonase-1 (PON1), platelet activating factor acetyl hydrolase (PAF-AH)

DOI: 10.3233/JAD-143096

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 179-186, 2015

Authors: Savage, Sharon A. | Piguet, Olivier | Hodges, John R.

Article Type: Research Article

Abstract: Background: Reduced insight commonly occurs in dementia and can be specific to one area of functioning. Despite recent models identifying a role for semantic memory, little investigation of insight has been conducted in semantic dementia (SD), with patients often described as being aware of their language problems. Objective: This study aims to investigate language insight in SD. Method: Twenty-two SD (n  = 11 severe, n  = 11 mild-moderate) and 9 nonfluent primary progressive aphasic patients completed three experimental language tasks to assess knowledge and awareness of certain words. Skills in evaluating language were tested by comparing performance …ratings on the Cookie Theft task with objective scoring. Awareness regarding the existence and previous use of certain words was tested using two additional tasks. Results: While SD patients were as accurate as nonfluent patients in rating their own performance on the Cookie Theft immediately following the task, they were significantly poorer at evaluating the same content re-recorded, or other examples of poor language. Compared to nonfluent patients, severe SD patients also made more errors identifying previously known low frequency words. Lastly, when tested on labels for specific aspects of an object, only SD patients made errors regarding the existence, or their past knowledge, of certain words. Conclusion: SD patients show a general awareness of their language impairments, but have difficulty evaluating language content. These difficulties adversely affect the ability to reflect upon current and past language skills producing an under-awareness of language deficits. This mild, secondary form of anosognosia appears to increase with greater levels of semantic impairment. Show more

Keywords: Anosognosia, cognitive awareness, frontotemporal dementia, primary progressive aphasia, self-appraisal

DOI: 10.3233/JAD-142703

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 187-198, 2015

Authors: Suppa, Per | Hampel, Harald | Spies, Lothar | Fiebach, Jochen B. | Dubois, Bruno | Buchert, Ralph | and Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Hippocampus volumetry based on magnetic resonance imaging (MRI) has not yet been translated into everyday clinical diagnostic patient care, at least in part due to limited availability of appropriate software tools. In the present study, we evaluate a fully-automated and computationally efficient processing pipeline for atlas based hippocampal volumetry using freely available Statistical Parametric Mapping (SPM) software in 198 amnestic mild cognitive impairment (MCI) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI1). Subjects were grouped into MCI stable and MCI to probable Alzheimer’s disease (AD) converters according to follow-up diagnoses at 12, 24, and 36 months. Hippocampal grey matter volume …(HGMV) was obtained from baseline T1-weighted MRI and then corrected for total intracranial volume and age. Average processing time per subject was less than 4 minutes on a standard PC. The area under the receiver operator characteristic curve of the corrected HGMV for identification of MCI to probable AD converters within 12, 24, and 36 months was 0.78, 0.72, and 0.71, respectively. Thus, hippocampal volume computed with the fully-automated processing pipeline provides similar power for prediction of MCI to probable AD conversion as computationally more expensive methods. The whole processing pipeline has been made freely available as an SPM8 toolbox. It is easily set up and integrated into everyday clinical patient care. Show more

Keywords: ADNI, Alzheimer’s disease, atlas-based segmentation, fully automated, hippocampus volumetry, magnetic resonance imaging, mild cognitive impairment, prediction

DOI: 10.3233/JAD-142280

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 199-209, 2015

Authors: Balconi, Michela | Cotelli, Maria | Brambilla, Michela | Manenti, Rosa | Cosseddu, Maura | Premi, Enrico | Gasparotti, Roberto | Zanetti, Orazio | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Background: Previous studies have reported significant deficits in emotion recognition among individuals along the frontotemporal dementia (FTD) spectrum. The basis of emotional impairment is still poorly understood and explicit (emotion appraisal) and implicit (autonomic system activity) responses have not been carefully evaluated. Objective: We investigated explicit evaluation of emotions by testing valence and arousal using self-report measures and we also assessed automatic responses to emotional cues, using autonomic measures (skin conductance response and heart rate). Methods: 16 behavioral variant FTD and 12 agrammatic variants of primary progressive aphasia patients were included. The performance of these …patients was compared to a group of 14 patients with Alzheimer’s disease and 20 healthy controls. Each subject was required to observe and evaluate affective pictures while autonomic parameters were recorded. Results: FTD patients preserved a functional general competency in terms of valence (correct positive versus negative attribution) and arousal (correct dichotomy between high versus low arousal category) distinction. These patients showed significant changes in autonomic implicit response compared to the other groups. The mismatch between explicit and implicit responsiveness to emotional cues was found both in behavioral variant FTD and in agrammatic variants of primary progressive aphasia. Emotional responsiveness was related to the severity of behavioral abnormalities as measured by the Frontal Behavioral Inventory and associated with atrophy of the left putamen. Conclusion: The present findings indicate that FTD patients are able to explicitly “appraise” the emotion, but they cannot implicitly “feel” the emotion. This mismatch between the two levels may help explain the general emotional behavior impairment found in these patients. Show more

Keywords: Basal ganglia, dementia, emotional disturbances, putamen

DOI: 10.3233/JAD-142826

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 211-225, 2015

Authors: Nijholt, Diana A.T. | Ijsselstijn, Linda | van der Weiden, Marcel M. | Zheng, Ping-Pin | Sillevis Smitt, Peter A. E. | Koudstaal, Peter J. | Luider, Theo M. | Kros, Johan M.

Article Type: Research Article

Abstract: Increased levels of pregnancy zone protein (PZP) were found in the serum of persons who later developed Alzheimer’s disease (AD) in comparison to controls who remained dementia free. We suggested that this increase is due to brain derived PZP entering the blood stream during the early phase of the disease. Here we investigate the possible involvement of PZP in human AD pathogenesis. We observed increased PZP immunoreactivity in AD postmortem brain cortex compared to non-demented controls. In the AD cortex, PZP immunoreactivity localized to microglial cells that interacted with senile plaques and was occasionally observed in neurons. Our data link …the finding of elevated serum PZP levels with the characteristic AD pathology and identify PZP as a novel component in AD. Show more

Keywords: Alzheimer’s disease, microglia, pregnancy zone protein

DOI: 10.3233/JAD-131628

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 227-238, 2015

Authors: Liu, Huanliang | Jin, Xiaoxia | Yin, Xiaomin | Jin, Nana | Liu, Fei | Qian, Wei

Article Type: Research Article

Abstract: Accumulated and abnormally hyperphosphorylated tau aggregates into neurofibrillary tangles in the brains of patients with Alzheimer’s disease (AD). cAMP response binding protein (CREB), a constitutively expressed nuclear transcription factor, is a critical component of the neuroprotective transcriptional network. Numerous studies have shown that cAMP-dependent protein kinase (PKA)-CREB signaling is down-regulated in AD brain. In the present study, we studied the regulation of tau expression by PKA-CREB signaling. We found that the promoter of human tau gene contains three potential cAMP response element (CRE)-like elements, CRE1, CRE2, and CRE3. Overexpression of CREB or activation of PKA significantly suppressed the expression of …tau at mRNA and protein levels. ChIP (Chromatin immunoprecipitation) and EMSA (electrophoretic mobility shift assay) revealed that CREB interacted with these three CRE cis-element and that CRE1, among the three elements, plays the most important role in the suppression of tau expression. Furthermore, upregulation of PKA-CREB signaling suppressed expression of endogenous tau. Collectively, these results suggest that PKA-CREB signaling down-regulates tau expression by reducing tau transcription, which may provide a novel insight into the regulation of tau expression and a molecular mechanism involved in tau pathogenesis in AD. Show more

Keywords: CRE, CREB, PKA, tau, transcriptional regulation

DOI: 10.3233/JAD-142610

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 239-248, 2015

Authors: Kim, Hak-Su | Moon, Sohee | Paik, Jin-Hwe | Shin, Dong Wun | Kim, Lindsay S. | Park, Chang-Shin | Ha, Joohun | Kang, Ju-Hee

Article Type: Research Article

Abstract: The 5′-AMP-activated protein kinase (AMPK), which is a sensor of cellular energy, regulates neuronal survival and energy homeostasis. However, the roles of AMPK in the pathogenesis of Alzheimer's disease (AD) are unclear. The senescence-accelerated mouse prone 8 (SAMP8) strain is characterized by deficits in learning and memory, exhibits pathological characteristics of AD as early as 5 months of age, and is being increasingly recognized as a model of AD. Here, we investigated the relationship between AMPK activation and phosphorylation of the tau protein in the brain of young (2-month-old) SAMP8 animals and in differentiated SH-SY5Y cells. Upregulation of p-AMPK, p-ACC, …and p-GSK3βS9 and downregulation of p-tau396 and sirtuin 1 (Sirt1) were observed in the cerebral cortex of young SAMP8 mice compared with that of age-matched SAMR1 animals. The hippocampal levels of p-AMPK and p-tau396 in SAMP8 animals were not significantly different from those of SAMR1, whereas upregulation of p-GSK3βS9 and downregulation of sirt1 was observed in the hippocampus of SAMP8 mice. Consistent with in vivo findings in the cortex, AMPK activation in SH-SY5Y cells upregulated p-GSK3βS9 but downregulated p-tau396 , whereas it had no significant effect on p-tau262 expression. In addition, the AMPK-mediated inhibition of p-tau396 expression was attenuated by okadaic acid, a protein phosphatase 2A (PP2A) inhibitor. Taken together, our data showed that AMPK activation inhibits p-tau396 expression in a GSK3β- and PP2A-dependent manner, and suggest that differential regulation of tau phosphorylation in young SAMP8 mice by AMPK plays a compensatory role against accelerated senescence in this AD animal model. Show more

Keywords: 5′-AMP-activated protein kinase, GSK3β, p-tau, protein phosphatase 2A, senescence-accelerated mice, sirtuin 1, tau protein

DOI: 10.3233/JAD-150035

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 249-259, 2015

Authors: Herukka, Sanna-Kaisa | Rummukainen, Jaana | Ihalainen, Jouni | von und zu Fraunberg, Mikael | Koivisto, Anne M. | Nerg, Ossi | Puli, Lakshman K. | Seppälä, Toni T. | Zetterberg, Henrik | Pyykkö, Okko T. | Helisalmi, Seppo | Tanila, Heikki | Alafuzoff, Irina | Hiltunen, Mikko | Rinne, Jaakko | Soininen, Hilkka | Jääskeläinen, Juha E. | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ1 - 42 ), total tau (T-tau), and phosphorylated tau (P-tau181 ) in the cerebrospinal fluid (CSF) are the most promising biomarkers of Alzheimer’s disease (AD). Still, little is known about the dynamics of these molecules in the living brain. In a transgenic mouse brain, soluble Aβ decreases with increasing age and advanced Aβ pathology as seen similarly in CSF. Objective: To assess the relationship between AD-related pathological changes in human brain tissue, ventricular and lumbar CSF, and brain interstitial fluid (ISF). Methods: Altogether 11 patients with suspected idiopathic normal pressure hydrocephalus underwent frontal cortical …brain biopsy, 24-h intraventricular pressure monitoring, and a microdialysis procedure. AD-related biomarkers were analyzed from brain tissue, CSF, and ISF. Results: ISF T-tau levels decreased strongly within the first 12 h, then plateauing until the end of the experiment. Aβ1 - 42 and P-tau181 remained stable during the experiment (n  = 3). T-tau and P-tau were higher in the ISF than in ventricular or lumbar CSF, while Aβ1 - 42 levels were within similar range in both CSF and ISF samples. ISF P-tau correlated with the ventricular CSF T-tau (r  = 0.70, p  = 0.017) and P-tau181 (r  = 0.64, p  = 0.034). Five patients with amyloid pathology in the brain biopsy tended to reveal lower ISF Aβ1 - 42 levels than those six without amyloid pathology. Conclusions: This is the first study to report ISF Aβ and tau levels in the human brain without significant brain injury. The set-up used enables sampling from the brain ISF for at least 24 h without causing adverse effects due to the microdialysis procedure to follow the dynamics of the key molecules in AD pathogenesis in the living brain at various stages of the disease. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarkers, normal pressure hydrocephalus, tau

DOI: 10.3233/JAD-142862

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 261-269, 2015

Authors: Petersen, Robert B. | Lissemore, Frances M. | Appleby, Brian | Aggarwal, Neelum | Boyatzis, Richard | Casadesus, Gemma | Cummings, Jeff | Jack, Anthony | Perry, George | Safar, Jiri | Sajatovic, Martha | Surewicz, Witold K. | Wang, Yanming | Whitehouse, Peter | Lerner, Alan

Article Type: Brief Report

Abstract: The term “brain health” integrates general health and well-being with cognitive fitness, in the context of an environment that includes the spectrum of positive and negative factors affecting the individual. Brain health incorporates the effects of neurodegeneration in an ecological sense and the effects of environment and health practices on brain function. It also provides a framework for understanding and maximizing cognitive function across the lifespan. Despite decades of research into the pathogenesis of neurodegenerative disorders, our understanding of how to treat them is relatively rudimentary. Unidimensional approaches, such as medication monotherapies, have generally produced negative results in treatment trials. …New integrative paradigms that cut across the molecular and cellular level to the individual and societal level may provide new approaches to understand and treat these disorders. This report on proceedings of a multi-disciplinary conference held in Cleveland, Ohio, in October 2013 summarizes research progress in understanding neurodegenerative disorders in a brain health context. A new “brain health” paradigm is essential to finally understand neurodegenerative disorders such as Alzheimer’s disease and overcome the relative stand-still in therapeutics research that has characterized the last decade. The authors summarize progress in these emerging areas with the aim of producing new integrated scientific models for understanding brain health, potentially modifying disease course and advancing care for individuals and families affected by neurodegenerative conditions. Show more

Keywords: Alzheimer’s disease, brain health, neurodegeneration, Parkinson’s disease, psychosocial approaches

DOI: 10.3233/JAD-150043

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 271-283, 2015

Article Type: Meeting Report

DOI: 10.3233/JAD-150239

Citation: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 285-287, 2015