Journal of Alzheimer's Disease - Volume 41, issue 3

Authors: Alegret, Montserrat | Cuberas-Borrós, Gemma | Espinosa, Ana | Valero, Sergi | Hernández, Isabel | Ruíz, Agustín | Becker, James T. | Rosende-Roca, Maitée | Mauleón, Ana | Sotolongo, Oscar | Castell-Conesa, Joan | Roca, Isabel | Tárraga, Lluís | Boada, Mercè

Article Type: Research Article

Abstract: Background: There is a range of factors that predict the development of Alzheimer’s disease (AD) dementia among patients with amnestic mild cognitive impairment (MCI). Objectives: To identify the neuropsychological, genetic, and functional brain imaging data that best predict conversion to AD dementia in patients with amnestic MCI. Methods: From an initial group of 42 amnestic MCI patients assessed with neurological, neuropsychological, and brain SPECT, 39 (25 converters, 14 non-converters) were followed for 4 years, and 36 had APOE ε4 genotyping. Baseline neuropsychological data and brain SPECT data were used to predict which of the MCI patients …would develop dementia by the end of the 4 years of observation. Results: The MCI patients who had converted to AD dementia had poorer performance on long-term visual memory and Semantic Fluency tests. The MCI subjects who developed dementia were more likely to carry at least one copy of the APOE ε4 allele (Hazard Risk = 4.22). There was lower brain perfusion in converters than non-converters, mainly in postcentral gyrus. An additional analysis of the SPECT data found differences between the MCI subjects and controls in the posterior cingulate gyrus and the basal forebrain. When the brain imaging and neuropsychological test data were combined in the same Cox regression model, only the neuropsychological test data were significantly associated with time to dementia. Conclusion: Although the presence of reduced brain perfusion in postcentral gyrus and basal forebrain indicated an at-risk condition, it was the extent of memory impairment that was linked to the speed of decline from MCI to AD. Show more

Keywords: Alzheimer's disease, brain SPECT, cerebral perfusion, four-year follow-up, longitudinal, mild cognitive impairment, prospective, visual memory

DOI: 10.3233/JAD-132516

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 739-748, 2014

Authors: Mak, Henry Ka-Fung | Qian, Wenshu | Ng, Kwok Sing | Chan, Queenie | Song, You-Qiang | Chu, Leung Wing | Yau, Kelvin Kai-Wing

Article Type: Research Article

Abstract: Background: Structural magnetic resonance imaging has been employed for evaluation of medial temporal atrophy in patients with Alzheimer’s disease (AD). Arterial spin labeling (ASL) technique could detect cerebral perfusion abnormalities in AD. Objective: We hypothesized that combination of hippocampal volumetry and cerebral blood flow yield higher accuracy than either method alone in discriminating AD patients from cognitively normal elderly adults. Materials and Methods: 13 AD patients and 15 healthy controls were studied using a 3-tesla scanner. Standardized T1W 3D volumetric Fast Field Echo and QUASAR ASL sequences were employed for cerebral volumetry and perfusion respectively. Manual …Right and left hippocampal volumetry was performed manually by ANALYZE software, with total intracranial volume normalization. ASL data were analyzed by institutional specially-design software to calculate cerebral blood flow of region-of-interests placed at the middle and posterior cingulate gyri. Results: Right and left hippocampal volumes and middle and posterior cingulate gyri cerebral blood flows were significantly lower in the patients than in the controls (independent-samples t-tests, p < 0.05), and prediction accuracies of 89.3%, 82.1%, 75.0% and 71.4% were achieved for each of the above parameters, respectively. In distinguishing patients from controls using corresponding optimized cut-off values, various combinations of these parameters were used to create the Receiver Operating Characteristic curves. The highest area under curve value was 0.944, by combining cerebral blood flow at the middle cingulate gyrus, normalized right and left hippocampal volumes. Conclusions: A ‘one-stop-shop’ magnetic resonance study of combined hippocampal volumetry and cerebral perfusion has improved efficacy in discriminating AD patients from cognitively normal elderly adults. Show more

Keywords: Alzheimer's disease, arterial spin labeling, cerebral blood flow, cerebral perfusion, hippocampal volumetry, medial temporal atrophy

DOI: 10.3233/JAD-131868

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 749-758, 2014

Authors: Ashford, J. Wesson | Furst, Ansgar J.

Article Type: Research Article

DOI: 10.3233/JAD-141100

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 759-763, 2014

Authors: Tarumi, Takashi | Dunsky, David I. | Khan, M. Ayaz | Liu, Jie | Hill, Candace | Armstrong, Kyle | Martin-Cook, Kristin | Cullum, C. Munro | Zhang, Rong

Article Type: Research Article

Abstract: Background: Vascular disease and dysfunction are associated with the higher risk of Alzheimer’s disease hypothetically due to cerebral hypoperfusion. Brain perfusion is protected by cerebral autoregulation, which, under normal conditions, maintains a constant cerebral blood flow and brain tissue oxygenation. Objective: To determine whether dynamic regulation of cerebral blood flow and tissue oxygenation is impaired in patients with amnestic mild cognitive impairment (aMCI). Methods: Twenty-seven patients with aMCI and 15 control subjects with normal cognitive function underwent the measurements of cerebral hemodynamics, brain MR imaging, and neurocognitive assessment. Dynamic regulation of cerebral blood flow and tissue …oxygenation were assessed by transfer function analysis of changes in mean blood pressure (MBP), normalized cerebral blood flow velocity (CBFV%), and cerebral tissue oxygenation index (TOI) at baseline and during a sit-stand maneuver. Results: Patients with aMCI demonstrated lower cognitive performance in memory and executive function, accompanied by smaller entorhinal cortex volumes. At baseline, cerebral TOI was lower in patients with aMCI than in control subjects. Lower cerebral TOI was also correlated with lower cognitive performance in memory and executive function in all subjects. Transfer function gain and phase between MBP and CBFV% and between CBFV% and cerebral TOI were not different between the groups. Within aMCI patients, greater oscillations of cerebral TOI and higher transfer function gain between cerebral TOI and CBFV% were associated with the lower scores on delayed recall. Conclusion: Dynamic regulation of cerebral tissue oxygenation is associated with neurocognitive dysfunction in aMCI patients. Show more

Keywords: Alzheimer's disease, cerebral autoregulation, cerebral blood flow, cerebral tissue oxygenation, mild cognitive impairment

DOI: 10.3233/JAD-132018

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 765-778, 2014

Authors: Engvig, Andreas | Fjell, Anders M. | Westlye, Lars T. | Skaane, Nina V. | Dale, Anders M. | Holland, Dominic | Due-Tønnessen, Paulina | Sundseth, Øyvind | Walhovd, Kristine B.

Article Type: Research Article

Abstract: Subjective memory impairment (SMI) is a common risk factor for Alzheimer's disease, with few established options for treatment. Here we investigate the effects of two months episodic memory training on regional brain atrophy in 19 memory clinic patients with SMI. We used a sensitive longitudinal magnetic resonance imaging protocol and compared the patients with 42 matched healthy volunteers randomly assigned to a group performing the same training, or a no-training control group. Following intervention, the SMI sample exhibited structural gray matter volume increases in brain regions encompassing the episodic memory network, with cortical volume expansion of comparable extent as healthy …training participants. Further, we found significant hippocampal volume increases in the healthy training group but not in the SMI group. Still, individual differences in left hippocampal volume change in the patient group were related to verbal recall improvement following training. The present results reinforce earlier studies indicating intact brain plasticity in aging, and further suggest that training-related brain changes can be evident also in the earliest form of cognitive impairment. Show more

Keywords: Aged, cognition disorders, episodic memory, hippocampus, intervention studies, longitudinal studies, magnetic resonance imaging, neuronal plasticity, training

DOI: 10.3233/JAD-131889

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 779-791, 2014

Authors: Lee, Grace J. | Lu, Po H. | Mather, Michelle J. | Shapira, Jill | Jimenez, Elvira | Leow, Alex D. | Thompson, Paul M. | Mendez, Mario F.

Article Type: Research Article

Abstract: Background: Emotional blunting is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD) and can help discriminate between patients with bvFTD and other forms of younger-onset dementia. Objective: We compared the presence of emotional blunting symptoms in patients with bvFTD and early-onset Alzheimer’s disease (AD), and investigated the neuroanatomical associations between emotional blunting and regional brain volume. Methods: Twenty-five individuals with bvFTD (n = 11) and early-onset AD (n = 14) underwent magnetic resonance imaging (MRI) and were rated on symptoms of emotional blunting using the Scale for Emotional Blunting (SEB). The two groups were compared …on SEB ratings and MRI-derived brain volume using tensor-based morphometry. Voxel-wise linear regression was performed to determine neuroanatomical correlates of SEB scores. Results: The bvFTD group had significantly higher SEB scores compared to the AD group. On MRI, bvFTD patients had smaller bilateral frontal lobe volume compared to AD patients, while AD patients had smaller bilateral temporal and left parietal volume than bvFTD patients. In bvFTD, SEB ratings were strongly correlated with right anterior temporal volume, while the association between SEB and the right orbitofrontal cortex was non-significant. Conclusions: Symptoms of emotional blunting were more prevalent in bvFTD than early-onset AD patients. These symptoms were particularly associated with right-sided atrophy, with significant involvement of the right anterior temporal region. Based on these findings, the SEB appears to measure symptoms of emotional blunting that are localized to the right anterior temporal lobe. Show more

Keywords: Alzheimer's disease, early onset, emotional blunting, frontotemporal dementia, magnetic resonance imaging

DOI: 10.3233/JAD-132219

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 793-800, 2014

Authors: Zwan, Marissa | van Harten, Argonde | Ossenkoppele, Rik | Bouwman, Femke | Teunissen, Charlotte | Adriaanse, Sofie | Lammertsma, Adriaan | Scheltens, Philip | van Berckel, Bart | van der Flier, Wiesje

Article Type: Research Article

Abstract: Background: Two approaches are available for measuring Alzheimer’s disease (AD) pathology in vivo. Biomarkers in cerebrospinal fluid (CSF) include amyloid-β1-42 (Aβ42 ) and tau. Furthermore, amyloid deposition can be visualized using positron emission tomography (PET) and [11 C]Pittsburgh compound-B ([11 C]PIB). Objective: We investigated concordance between CSF biomarkers and [11 C]PIB PET as markers for AD pathology in a memory clinic cohort. Methods: We included 64 AD patients, 34 non-AD dementia patients, 22 patients with mild cognitive impairment (MCI), and 16 controls. [11 C]PIB scans were visually rated as positive or negative. CSF biomarkers were …considered abnormal based on Aβ42 alone (<550 ng/L), a more lenient Aβ42 cut-off (<640 ng/L) or a combination of both Aβ42 and tau ((373 + 0.82tau)/Aβ42 > 1). Concordance between CSF biomarkers and [11 C]PIB PET was determined. Results: Overall, concordance between [11 C]PIB PET and CSF Aβ42 (<550 ng/L) was 84%. In discordant cases, [11 C]PIB PET was more often AD-positive than Aβ42 . When a more lenient Aβ42 cut-point (<640 ng/L) or a combination of Aβ42 and tau was used, concordance with [11 C]PIB PET appeared to be even higher (90% and 89%). This difference is explained by a subgroup of mostly MCI and AD patients with Aβ42 levels just above cut-off. Now, in discordant cases, CSF was more often AD-positive than [11 C]PIB PET. Conclusion: Concordance between CSF Aβ42 and [11 C]PIB PET was good in all diagnostic groups. Discordance was mostly seen in MCI and AD patients close to the cut-point. These results provide convergent validity for the use of both types of biomarkers as measures of AD pathology. Show more

Keywords: Alzheimer's disease, amyloid, cerebrospinal fluid, positron-emission tomography, tau

DOI: 10.3233/JAD-132561

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 801-807, 2014

Authors: Zlatar, Zvinka Z. | Wierenga, Christina E. | Bangen, Katherine J. | Liu, Thomas T. | Jak, Amy J.

Article Type: Research Article

Abstract: Resting cerebral blood flow (CBF) decreases with age; however regulatory increases in hippocampal CBF have been associated with genetic risk (Apolipoprotein E [APOE] ε4 carriers) for Alzheimer's disease (AD). Although physical activity exerts beneficial effects on CBF in healthy elderly, the effects of sedentary behaviors on CBF remain unknown. We measured resting hippocampal CBF (via arterial spin labeling magnetic resonance imaging) and sedentary time/physical activity (via accelerometry) on 33 cognitively healthy adults (ages 52–81), 9 of which were APOE ε4 carriers. Results indicate that the relationship between sedentary time and CBF in the left hippocampus differs by APOE status, whereby …APOE ε4 carriers show higher CBF as a function of longer sedentary time (B = 10.8, SE = 3.17, β = 0.74, t = 3.41, p < 0.01) compared to noncarriers (B = 1.4, SE = 2.7, β = 0.096, t = 0.51, p = 0.61), possibly suggesting a CBF regulatory response to compensate for metabolic alterations in dementia risk. These preliminary data suggest that the relationship between CBF and sedentary time is different in APOE ε4 carriers and noncarriers and that sedentary time may act as a behavioral risk factor for CBF dysregulation in those at genetic risk for developing AD. More research is needed to further understand the role of sedentary behaviors and physical activity on CBF, especially in individuals at genetic risk of developing AD. Show more

Keywords: Apolipoprotein E, arterial spin labeling, biological aging, cerebral blood flow, hippocampus, magnetic resonance imaging, physical activity, sedentary behavior

DOI: 10.3233/JAD-132252

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 809-817, 2014

Authors: Vermeiren, Yannick | Van Dam, Debby | Aerts, Tony | Engelborghs, Sebastiaan | De Deyn, Peter P.

Article Type: Research Article

Abstract: Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are present during the disease course of nearly all AD patients and consist of psychosis, agitation/aggression, and depression, among others. Given their detrimental consequences regarding life expectancy, cognition, and socio-economic costs, it is essential to elucidate their neurochemical etiology to facilitate the development of novel and effective pharmacotherapeutics. This study attempted to identify brain region-specific monoaminergic correlates of NPS by measuring the levels of eight monoamines and metabolites in nine relevant postmortem brain regions of 40 behaviorally characterized AD patients, i.e., dopamine (DA), serotonin (5-HT), (nor)epinephrine and their respective metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) …and homovanillic acid, 5-hydroxy-3-indoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), using RP-HPLC-ECD. Likewise, Mini-Mental State Examination (MMSE) score correlates of monoaminergic neurotransmitter alterations were calculated. As a result, MMSE scores, used as a measure of dementia severity, correlated positively with hippocampal 5-HIAA levels as well as with 5-HT levels of the superior temporal gyrus and cerebellar cortex. Furthermore, hippocampal 5-HIAA levels inversely correlated with agitation scores, whereas thalamic MHPG levels comparably did with the presence of hallucinations. Finally, in the cerebellar cortex, DOPAC/DA ratios, indicative of DA turnover, correlated with physically agitated behavior while MHPG levels correlated with affective disturbances. These findings support the assumption that specific NPS features in AD might be (in)directly related to brain region-specific monoaminergic neurotransmitter alterations. Additionally, the effect of AD pathology on neurochemical alterations in the cerebellum requires further examination due to its important but underestimated role in the neurochemical pathophysiology of NPS in AD. Show more

Keywords: Alzheimer's disease, dementia, behavior, brain tissue, correlations, monoamines and metabolites, neurochemistry, neuropsychiatric symptoms

DOI: 10.3233/JAD-140309

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 819-833, 2014

Authors: Zhao, Yan | Zhao, Hailin | Lobo, Niyati | Guo, Xiangyang | Gentleman, Steve M. | Ma, Daqing

Article Type: Research Article

Abstract: Background: Neuroinflammation is a notable hallmark of Alzheimer’s disease pathogenesis and can markedly exacerbate amyloid pathology. Celastrol, a pentacyclic-triterpene, has been found to possess anti-inflammatory properties. Objective: The purpose of this study was to characterize the effects of celastrol on cell viability and amyloid-β (Aβ) peptide production induced by lipopolysaccharide (LPS) administration in H4 human neuroglioma cells stably transfected to overexpress human full length APP (H4-APP). Methods: H4-APP cells were exposed to 1, 10, and 100 nM of celastrol in the presence of 0.1 µg/ml or 100 µg/ml of LPS for 24 hours. The effects of …celastrol were determined using MTT cell viability assay, immunohistochemistry, western blot, and ELISA. Results: Cell viability tests revealed that a dose-dependent death of H4-APP cells following administration of LPS. Moreover, celastrol significantly reduced (p < 0.05) cell death induced by LPS compared to LPS alone. Furthermore, the administration of celastrol was associated with a significant reduction in LPS-stimulated Aβ production compared to LPS alone. Western blot and immunofluorescence analysis showed that exposure to celastrol increased HSP-70 and Bcl-2 expression but decreased NFκB activity, phosphorylated glycogen synthase kinase-3β (GSK-3β) at tyrosine 216 and cyclooxygenase-2 (COX-2) expression, Aβ accumulation together with a reduction of superoxide and hydrogen peroxide generation. HSP-70 siRNA abolished celastrol mediated cytoprotection. Conclusion: This study demonstrates that celastrol reduced both LPS-induced cell death and Aβ production in vitro through increasing HSP-70 and Bcl-2 expression and reducing NFκB, COX-2, and GSK-3β expression and oxidative stress. Show more

Keywords: Alzheimer's disease, amyloid-β, celastrol, cell signal, lipopolysaccharide, neuroinflammation

DOI: 10.3233/JAD-131799

Citation: Journal of Alzheimer's Disease, vol. 41, no. 3, pp. 835-844, 2014