Journal of Alzheimer's Disease - Volume 23, issue 3

Authors: Mazza, Marianna | Marano, Giuseppe | Traversi, Gianandrea | Bria, Pietro | Mazza, Salvatore

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a degenerative disorder characterized by a decreased regional cerebral blood flow (CBF). It is most likely that a reduction in CBF could displace a pathway leading to AD genesis, in so far neuron death explains a sustained reduction in the supply of oxygen, glucose, and nutrients. Nevertheless, the concept of secondary CBF deficiency cannot explain the critical stages of early memory loss while, on the other hand, the picture of progressive ischemia due to primary CBF decline sheds light on the course of AD in a most persuasive manner. The concept of primary CBF deficiency is …even more strengthened by the lack of correlation between degree of dementia and amount of CBF. Vascular abnormalities, frequently observed to co-occur with AD, might play a critical role in the initiation and aggravation of AD pathology given that the elimination of amyloid-β (Aβ) through a vascular route is an important brain Aβ clearance mechanism and its failure leads to formation of vascular amyloidosis and dense-core plaques. The goal of this review is to provide scientists comprehensive knowledge of the state-of the art influence vascular damage and reduced perfusion have on the final development of AD and to hopefully stimulate more research in this area of neuroscience. Show more

Keywords: Alzheimer's disease, amyloid-β, blood brain barrier, cerebral blood flow, nitric oxide, reactive oxygen species

DOI: 10.3233/JAD-2010-090700

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 375-389, 2011

Authors: Yang, Yuan-Han | Wu, Shey-Lin | Chou, Mei-Chuan | Lai, Chiou-Lian | Chen, Su-Hwei | Liu, Ching-Kuan

Article Type: Research Article

Abstract: Donepezil has been approved for the treatment for mild-to-moderate Alzheimer's disease (AD), but the therapeutic response rate varies from 20 to 60%. A higher oral dosage was suggested to have a better therapeutic response in reported results, but the plasma concentration of donepezil was not examined with respect to the therapeutic outcomes in those studies. Therefore, we analyzed the therapeutic responses, measured by neuropsychological assessments, among 70 newly diagnosed AD patients taking donepezil (5 mg daily) in relation to their plasma concentration of donepezil, apolipoprotein E genotype, and demographic characteristics. Our results have showed 60% of recruited AD patients improved …in cognition, measured by Mini-Mental Status Examination (MMSE), and 57.1% in global status, by Clinical Dementia Rating Scale (CDR) sum of boxes (CDR-SB). In cognition, compared to the improving group, the clinically worsening group had a significantly higher donepezil concentration [p = 0.022, odds ratio (OR) = 1.024, 95% CI = 1.003–1.045] and higher initial MMSE score (p = 0.007, OR = 1.330, 95% CI = 1.080–1.639). In global status, initially higher CDR-SB (p = 0.028, OR = 2.318, 95% CI = 1.096–4.903) and initially higher MMSE (p = 0.036, OR = 1.201, 95% CI = 1.012–1.425), not donepezil concentration (p = 0.883), were significantly associated with clinical worsening. Our results have indicated that the dosage of donepezil should be reconsidered for AD patients, especially those clinically worsening in cognition. Show more

Keywords: Alzheimer's disease, Clinical Dementia Rating Scale sum of boxes, donepezil, Mini-Mental Status Examination, Taiwanese

DOI: 10.3233/JAD-2010-100936

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 391-397, 2011

Authors: Head, Elizabeth | Doran, Eric | Nistor, Mihaela | Hill, MaryAnn | Schmitt, Frederick A. | Haier, Richard J. | Lott, Ira T.

Article Type: Research Article

Abstract: Adults with Down syndrome (DS) are at risk for developing Alzheimer's disease (AD). While plasma amyloid-β (Aβ) is known to be elevated in DS, its relationship to cognitive functioning is unknown. To assess this relationship, samples from two groups of subjects were used. In the first group, nondemented adults with DS were compared to: 1) a group of young and old individuals without DS and 2) to a group of patients with AD. Compared to these controls, there were significantly higher levels of plasma Aβ in nondemented adults with DS while AD patients showed lower levels of plasma Aβ. A …larger second group included demented and nondemented adults with DS, in order to test the hypothesis that plasma Aβ may vary as a function of dementia and Apolipoprotein E (ApoE) genotype. Plasma Aβ levels alone did not dissociate DS adults with and without dementia. However, in demented adults with DS, ApoE4 was associated with higher Aβ40 but not Aβ42 . After controlling for level of intellectual disability (mild, moderate, severe) and the presence or absence of dementia, there was an improved prediction of neuropsychological scores by plasma Aβ. In summary, plasma Aβ can help predict cognitive function in adults with DS independently of the presence or absence of dementia. Show more

Keywords: Apolipoprotein E, cognition, mental status, neuropsychology, trisomy 21

DOI: 10.3233/JAD-2010-101335

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 399-409, 2011

Authors: Santos, Vasco Dos | Thomann, Philipp A. | Wüstenberg, Torsten | Seidl, Ulrich | Essig, Marco | Schröder, Johannes

Article Type: Research Article

Abstract: The objective of this study was to investigate the association between structural cerebral changes and neuropsychological deficits in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Sixty patients with MCI, 34 patients with mild to moderate AD, and 32 healthy controls underwent both extensive neuropsychological assessment (CERAD test battery) and high-resolution structural magnetic resonance imaging. We used optimized voxel based morphometry to investigate (i) differences in gray matter density between the three aforementioned groups and (ii) the putative relations of CERAD test performance with atrophic brain changes. When compared to the healthy controls, the AD patients and, to a lesser …extent, patients with MCI showed significant density losses predominantly in the medial temporal lobe. Deficits in verbal fluency and word finding were significantly correlated with left fronto-temporal and left temporal (including hippocampal) changes, respectively. Decreased scores in immediate and delayed recall and in delayed recognition were associated with several cortical and subcortical sites including the parahippocampal and posterior cinguli gyri, the right thalamus, and the right hippocampus, whereas deficits in constructional praxis and constructional praxis recall referred to sites in the left thalamus and cerebellum, and the temporal cortices (bilaterally), respectively. Our findings lend further support for medial temporal lobe degeneration in MCI and AD and demonstrate that cognitive deficits as assessed on the CERAD do not simply refer to specific changes in discrete cerebral sites but rather reflect morphological alterations in widespread networks. Show more

Keywords: Alzheimer's disease, CERAD, magnetic resonance imaging, mild cognitive impairment, voxel based morphometry

DOI: 10.3233/JAD-2010-100156

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 411-420, 2011

Authors: Licastro, Federico | Chiappelli, Martina | Caldarera, Claudio Marcello | Porcellini, Elisa | Carbone, Ilaria | Caruso, Calogero | Lio, Domenico | Corder, Elizabeth H.

Article Type: Research Article

Abstract: Gene variants that promote inflammation and cholesterol metabolism have been associated with acute myocardial infarction (AMI) and Alzheimer's disease (AD). We investigated a panel of relevant polymorphisms to distinguish genetic backgrounds for AMI and AD: IL10 −1082G/A, IL6 −174G/C, TNF −308G/A, IFNG +874T/A, SERPINA3 −51G/T, HMGCR −911C/A, APOE ε2/3/4 (280 AMI cases, 257 AD cases, and 1307 population controls, all Italian (presumed risk alleles are shown in bold). Six genetic risk sets I to VI were identified by fuzzy latent classification: I had low risk; II and III had low risk before age 65 (II, III); low risk sets lacked …pro-inflammatory alleles for HMGCR-TNF-APOE. Pro-inflammatory alleles for SERPINA3–IL10–IFNG were found for high risk sets IV to VI. Set IV ‘AMI < age 40, AD < age 65’ included risk alleles for HMGCR. Set V ‘AMI over a broad range of age’ included risk alleles for TNF+IL6. Set VI ‘AMI at ages 40 to 55, AD ages 65+’ included APOE ε4. Close resemblance to the high risk sets, as indicated by membership scores close to one, defined high relative risks. We conclude that AMI and AD share genetic backgrounds involving cholesterol metabolism and the upregulation of inflammation and that gene-gene interactions in relevant sets of genes may be useful in defining inherited risk for common disorders. Show more

Keywords: Acute myocardial infarction, Alzheimer's disease, APOE, cholesterol, gene polymorphism, genetic epidemiology, grade-of-membership analysis, inflammation

DOI: 10.3233/JAD-2010-090871

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 421-431, 2011

Authors: Lu, Po H. | Thompson, Paul M. | Leow, Alex | Lee, Grace J. | Lee, Agatha | Yanovsky, Igor | Parikshak, Neelroop | Khoo, Theresa | Wu, Stephanie | Geschwind, Daniel | Bartzokis, George

Article Type: Research Article

Abstract: Apolipoprotein E (ApoE) ε4 genotype is a strong risk factor for developing Alzheimer's disease (AD). Conversely, the presence of the ε2 allele has been shown to mitigate cognitive decline. Tensor-based morphometry (TBM), a novel computational approach for visualizing longitudinal progression of brain atrophy, was used to determine whether cognitively intact elderly participants with the ε4 allele demonstrate greater volume reduction than those with the ε2 allele. Healthy “younger elderly” volunteers, aged 55–75, were recruited from the community and hospital staff. They were evaluated with a baseline and follow-up MRI scan (mean scan interval = 4.72 years, s.d. = 0.55) and …completed ApoE genotyping. Twenty-seven participants were included in the study of which 16 had the ε4 allele (all heterozygous ε3ε4 genotype) and 11 had the ε2ε3 genotype. The two groups did not differ significantly on any demographic characteristics and all subjects were cognitively “normal” at both baseline and follow-up time points. TBM was used to create 3D maps of local brain tissue atrophy rates for individual participants; these spatially detailed 3D maps were compared between the two ApoE groups. Regional analyses were performed and the ε4 group demonstrated significantly greater annual atrophy rates in the temporal lobes (p = 0.048) and hippocampus (p = 0.016); greater volume loss was observed in the right hippocampus than the left. TBM appears to be useful in tracking longitudinal progression of brain atrophy in cognitively asymptomatic adults. Possession of the ε4 allele is associated with greater temporal and hippocampal volume reduction well before the onset of cognitive deficits. Show more

Keywords: Aging, Alzheimer's disease, Apolipoprotein E, asymmetry, healthy elderly, hippocampus, magnetic resonance imaging, tensor-based morphometry, temporal lobe, white matter

DOI: 10.3233/JAD-2010-101398

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 433-442, 2011

Authors: Jefferson, Angela L. | Lambe, Susan | Chaisson, Christine | Palmisano, Joseph | Horvath, Kathy J. | Karlawish, Jason

Article Type: Research Article

Abstract: In light of our limited understanding of what motivates older adults to participate in clinical studies of Alzheimer's disease (AD), the current study examines incentives and barriers to participating in AD clinical research among older adults. 235 participants enrolled in the Boston University Alzheimer's Disease Center research registry (75 ± 8 years, range 58–99 years, 60% female), a longitudinal registry from which individuals are recruited into other clinical studies, completed a survey assessing registry participation satisfaction, religiousness, trust in healthcare institutions, and medical research attitudes. Most participants reported initially enrolling in the registry for societal benefit. Insufficient time was a …commonly endorsed barrier to enrolling in other Center-approved studies, particularly among younger participants. Driving and a lack of transportation to the medical facility were also barriers, particularly for older participants. Transportation was the most popular incentive, followed by home-based visits (particularly for older participants and participants with less formal education) and compensation (particularly among respondents from racial/ethnic minority groups). Participation interest in other studies was associated with favorable medical research attitudes (r = 0.34, p = 0.00003) but not religiousness (r = −0.09, p = 0.21), or trust in healthcare institutions (r = 0.09, p = 0.17). Among older adults, societal benefit is a motivating factor for registry enrollment; however, participation in additional studies is hindered by insufficient time among younger participants and transportation barriers among older participants. Providing transportation, home-based visits, and modest compensation may improve participation rates. Furthermore, favorable attitudes toward medical research are strongly associated with interest in enrolling in additional studies and may serve as a beneficial outreach triage technique. Show more

Keywords: Alzheimer's disease, barriers, clinical research, incentives, participation

DOI: 10.3233/JAD-2010-101536

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 443-452, 2011

Authors: Marner, Lisbeth | Knudsen, Gitte M. | Madsen, Karine | Holm, Søren | Baaré, William | Hasselbalch, Steen G.

Article Type: Research Article

Abstract: We previously demonstrated a 20–30% reduction in cortical 5-HT2A receptor binding in patients with mild cognitive impairment (MCI) as compared to healthy subjects. Here we present a two-year follow-up of 14 patients and 12 healthy age-matched subjects. Baseline and follow-up partial volume corrected levels of 5-HT2A in four neocortical lobes and the posterior cingulate gyrus were investigated using [18 F]altanserin positron emission tomography with a bolus-infusion approach. In the two-year follow-up period, 8 of 14 patients with MCI had progressed to fulfill diagnostic criteria for probable Alzheimer's disease (AD). In both patients and healthy subjects, no significant change …in 5-HT2A receptor binding was found as compared to baseline values. In MCI patients, the average BPP in neocortex ranged from 1.49 to 2.45 at baseline and 1.38 to 2.29 at two-year follow-up; and in healthy subjects BPP ranged from 1.85 to 3.10 at baseline and 1.81 to 2.98 at two-year follow-up. The BPP of the patients that converted to AD during the follow-up period did not differ significantly from the patients that had not (yet) converted, neither at baseline, nor at follow-up. We conclude that the reduced levels of 5-HT2A receptor binding in MCI patients decrease only slowly and non-significantly, even in patients who convert to AD. Our finding suggests that profoundly reduced cortical 5-HT2A receptor binding is an early feature in MCI whereas the clinical progression from MCI to AD is less associated with further decrease in binding. Show more

Keywords: 5-HT 2A receptor, [18F]altanserin, Alzheimer's disease, brain, humans, neurodegenerative disease, positronemission tomography, PET

DOI: 10.3233/JAD-2010-100903

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 453-459, 2011

Authors: Keller, Lina | Xu, Weili | Wang, Hui-Xin | Winblad, Bengt | Fratiglioni, Laura | Graff, Caroline

Article Type: Research Article

Abstract: The FTO gene has been shown to have a small but robust effect on body mass index (BMI) and to increase the risk for diabetes. Both high BMI and diabetes are vascular risk factors that might play a role in the development of Alzheimer's disease (AD) and dementia. Thus, our aim was to explore the impact of FTO on AD and dementia risk. Nine years of follow-up data was gathered from the Kungsholmen project, a prospective population-based study on 1,003 persons without dementia. Cox-regression models were used to assess the relative risks of developing AD and dementia (DSM-III-R criteria) according …to FTO genotypes (rs9939609), taking into account APOE, physical inactivity, BMI, diabetes, and cardiovascular disease (CVD). Compared to carriers of the FTO TT-genotype, AA-carriers had a higher risk for AD (RR 1.58, 95% CI: 1.11–2.24) and for dementia (RR 1.48, 95% CI: 1.09–2.02) after adjustment for age, gender, education, and APOE genotype. This effect remained after additional adjustment for physical inactivity, BMI, diabetes, and CVD. An interaction between FTO and APOE was found, with increased risk for dementia for those carrying both FTO AA and APOE ϵ4. Importantly, the effect of the AA-genotype on dementia/AD risk seems to act mostly through the interaction with APOE ϵ4. Our findings suggest that the FTO AA-genotype increases the risk for dementia, and in particular AD, independently of physical inactivity, BMI, diabetes, and CVD measured at baseline. Our results are in line with the recently reported association between FTO and reduced brain volume in cognitively healthy subjects. Show more

Keywords: Alzheimer's disease, APOE, body mass index, cardiovascular disease, dementia, diabetes, FTO, physical activity

DOI: 10.3233/JAD-2010-101068

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 461-469, 2011

Authors: Lockrow, Jason | Boger, Heather | Gerhardt, Greg | Aston-Jones, Gary | Bachman, David | Granholm, Ann-Charlotte

Article Type: Research Article

Abstract: Individuals with Down syndrome (DS) acquire Alzheimer's-like dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However, biological mechanisms have not been discovered and there is currently limited therapy for either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits, neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice …exhibit progressive loss of norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies. Show more

Keywords: Alzheimer's disease, cholinergic neurons, cytokines, Down syndrome, hippocampus, memory, neuroinflammation, neurotoxins, noradrenergic

DOI: 10.3233/JAD-2010-101218

Citation: Journal of Alzheimer's Disease, vol. 23, no. 3, pp. 471-489, 2011