Journal of Alzheimer's Disease - Volume 57, issue 4

Authors: O’Hare, Celia | Kenny, Rose-Anne | Aizenstein, Howard | Boudreau, Robert | Newman, Anne | Launer, Lenore | Satterfield, Suzanne | Yaffe, Kristine | Rosano, Caterina | for the Health ABC Study

Article Type: Research Article

Abstract: Background: Associations between orthostatic blood pressure and cognitive status (CS) have been described with conflicting results. Objective: We hypothesize that long-term exposure to lower orthostatic blood pressure is related to having worse CS later in life and that atrophy of regions involved in central regulation of autonomic function mediate these associations. Methods: Three-to-four measures of orthostatic blood pressure were obtained from 1997–2003 in a longitudinal cohort of aging, and average systolic orthostatic blood pressure response (ASOBPR) was computed as % change in systolic blood pressure from sit-to-stand measured at one minute post stand. CS was …determined in 2010–2012 by clinician-adjudication (n  = 240; age = 87.1±2.6; 59% women; 37% black) with a subsample also undergoing concurrent structural neuroimaging (n  = 129). Gray matter volume of regions related to autonomic function was measured. Multinomial regression was used to compare ASOBPR in those who were cognitively intact versus those with a diagnosis of mild cognitive impairment or dementia, controlling for demographics, trajectories of seated blood pressure, incident cardiovascular risk/events and medications measured from 1997 to 2012. Models were repeated in the subsample with neuroimaging, before and after adjustment for regional gray matter volume. Results: There was an inverse association between ASOBPR and probability of dementia diagnosis (9% lower probability for each % point higher ASOBPR: OR 0.91, CI95%  = 0.85–0.98; p  = 0.01). Associations were similar in the subgroup with neuroimaging before and after adjustment for regional gray matter volume. Conclusion: ASOBPR may be an early marker of risk of dementia in older adults living in the community. Show more

Keywords: Autonomic nervous system, blood pressure, cognition, dementia, hypotension, magnetic resonance imaging, orthostatic

DOI: 10.3233/JAD-161228

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1239-1250, 2017

Authors: Fernández-Matarrubia, Marta | Matías-Guiu, Jordi A. | Cabrera-Martín, María Nieves | Moreno-Ramos, Teresa | Valles-Salgado, María | Carreras, José Luis | Matías-Guiu, Jorge

Article Type: Research Article

Abstract: Background: Episodic memory disturbance is still considered as an exclusion criterion for behavioral variant frontotemporal dementia (bvFTD), but growing evidence suggests that memory can be impaired. Objective: Our main purposes were to assess episodic memory in a group of bvFTD patients comparatively with Alzheimer’s disease (AD) patients, and analyze the relationship between episodic memory and brain metabolism measured using positron emission tomography imaging with 18 F-fluorodeoxyglucose (FDG-PET). Methods: Twenty-six bvFTD, 29 AD, and 24 healthy controls were included. Episodic memory was assessed by the Free and Cued Selective Reminding Test (FCSRT), which controls for effective …encoding and measures memory consolidation processing. All participants underwent FDG-PET brain scans to provide data for voxel-based brain mapping analysis. Results: Half of bvFTD patients had a deficit of total, free delayed, and total free delayed recall as severe as AD patients (amnestic-FTD). The other half had FCSRT scores similar to controls (non-amnestic-FTD). Imaging analyses revealed that amnestic-FTD showed bilateral lower metabolism than non-amnestic-FTD in anterior parahippocampal and inferior temporal gyri. Additionally, FCSRT total and total delayed scores were inversely correlated with parahippocampal metabolism in both bvFTD and AD. Besides, bvFTD showed an inverse association among FCSRT and inferior temporal metabolism. Conclusions: Our findings support that bvFTD could present a genuine amnesia affecting storage and consolidation abilities, which involves structures implicated in the Papez circuit, as occurs in AD, and also inferior temporal regions. These results contribute to understanding the mechanisms underpinning memory dysfunction in bvFTD, and may be relevant to further revisions of the current diagnostic criteria. Show more

Keywords: Alzheimer’s disease, amnesia, diagnosis, episodic memory, FDG-PET, frontotemporal dementia, statistical parametric mapping

DOI: 10.3233/JAD-160874

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1251-1264, 2017

Authors: Dorey, Evan | Bamji-Mirza, Michelle | Najem, Dema | Li, Yan | Liu, Hong | Callaghan, Debbie | Walker, Douglas | Lue, Lih-Fen | Stanimirovic, Danica | Zhang, Wandong

Article Type: Research Article

Abstract: Neuroinflammation plays a critical role in neuronal dysfunction and death of Alzheimer’s disease (AD). ApoE4 is a major risk factor of AD, while ApoE2 is neuroprotective. Little is known about the roles of ApoE isoforms in the neuroinflammation seen in AD. Their roles and mechanisms in Aβ-induced/neuroinflammation were investigated in this study using in vivo and in vitro models. Rat astrocytes were treated with lipid-poor recombinant hApoE and/or Aβ42 . Mouse astrocyte lines-expressing lipidated hApoE were treated with Aβ42 and/or vitamin D receptor (VDR) agonist, 1α,25-dihydroxyvitamin D3 . Cells and media were harvested for cytokine ELISA, RNA …isolated for qRT-PCR, and nuclear protein for transcription factor (TF) arrays and EMSA. hApoE-transgenic and AD mice were mated to generate hApoE2/AD and hApoE4/AD mice. Mice were euthanized at 6 months of age. Brain tissues were collected for cytokine ELISA array, Aβ ELISA, immunoblotting, and immunohistochemistry. hApoE4/AD mice had significantly higher levels of inflammatory cytokines than hApoE2/AD mice. Lipidated hApoE4 significantly promoted inflammatory gene expression induced by Aβ42 but not recombinant hApoE4 in astrocytes as compared to controls. Lipidated hApoE3 provided a certain degree of protection against Aβ42 -induced inflammatory response but not recombinant hApoE3 as compared to controls. Both lipidated and recombinant hApoE2 provided protection against Aβ42 -induced inflammatory response compared to controls. TF array revealed that ApoE2 strongly activated VDR in Aβ42 -treated astrocytes. Application of 1α,25-dihydroxyvitamin D3 completely inhibited Aβ-induced inflammatory gene expression in hApoE4-expressing astrocytes. The results suggest that ApoE4 promotes, but ApoE2 inhibits, AD/Aβ-induced neuroinflammation via VDR signaling. Targeting VDR signaling or active form of VD3 may relieve AD neuroinflammation or/and neurodegeneration. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, ApoE isoform proteins, neuroinflammation, vitamin D receptorsignaling

DOI: 10.3233/JAD-160133

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1265-1279, 2017

Authors: Lopez-Font, Inmaculada | Boix, Claudia P. | Zetterberg, Henrik | Blennow, Kaj | Sáez-Valero, Javier

Article Type: Research Article

Abstract: We recently demonstrated that soluble forms of the amyloid-β protein precursor (sAβPP) assemble into multimeric complexes in cerebrospinal fluid (CSF), which contributes to the underestimation of specific sAβPP species when assessed by ELISA. To circumvent this issue, we analyzed by SDS-PAGE large fragments of sAβPP and their variants in the CSF from Alzheimer’s disease (AD; n  = 20) and control (n  = 20) subjects, probing with specific antibodies against particular domains. Similar levels of sAβPPα and sAβPPβ protein were found in CSF samples from AD and controls, yet there appeared to be a shift in the balance of the soluble full-length AβPP …(sAβPPf) species in AD samples, with a decrease in the proportion of the lower (∼100 kDa) band relative to the upper (∼120 kDa) band. Similar differences were observed in the contribution of the major KPI-immunoreactive AβPP species. CSF samples also displayed differences in the correlations of AβPP species with classical AD biomarkers, particularly with respect to the Aβ42 peptide. The differences reveal alterations that probably reflect pathophysiological changes in the brain. Show more

Keywords: AβPP, Alzheimer’s disease, biomarker, cerebrospinal fluid, KPI, sAβPPα, sAβPPβ, sAβPPf

DOI: 10.3233/JAD-161275

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1281-1291, 2017

Authors: Stott, Joshua | Scior, Katrina | Mandy, William | Charlesworth, Georgina

Article Type: Research Article

Abstract: Background: Scores on cognitive screening tools for dementia are associated with premorbid IQ. It has been suggested that screening scores should be adjusted accordingly. However, no study has examined whether premorbid IQ variation affects screening accuracy. Objective: To investigate whether the screening accuracy of a widely used cognitive screening tool for dementia, the Addenbrooke’s cognitive examination-III (ACE-III), is improved by adjusting for premorbid IQ. Methods: 171 UK based adults (96 memory service attendees diagnosed with dementia and 75 healthy volunteers over the age of 65 without subjective memory impairments) completed the ACE-III and the Test …of Premorbid Function (TOPF). The difference in screening performance between the ACE-III alone and the ACE-III adjusted for TOPF was assessed against a reference standard; the presence or absence of a diagnosis of dementia (Alzheimer’s disease, vascular dementia, or others). Results: Logistic regression and receiver operating curve analyses indicated that the ACE-III has excellent screening accuracy (93% sensitivity, 94% specificity) in distinguishing those with and without a dementia diagnosis. Although ACE-III scores were associated with TOPF scores, TOPF scores may be affected by having dementia and screening accuracy was not improved by accounting for premorbid IQ, age, or years of education. Conclusion: ACE-III screening accuracy is high and screening performance is robust to variation in premorbid IQ, age, and years of education. Adjustment of ACE-III cut-offs for premorbid IQ is not recommended in clinical practice. The analytic strategy used here may be useful to assess the impact of premorbid IQ on other screening tools. Show more

Keywords: Dementia, neuropsychology, screening, sensitivity, specificity

DOI: 10.3233/JAD-161218

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1293-1302, 2017

Authors: Ochmann, Sina | Dyrba, Martin | Grothe, Michel J. | Kasper, Elisabeth | Webel, Steffi | Hauenstein, Karlheinz | Teipel, Stefan J.

Article Type: Research Article

Abstract: Background: Cognitive rehabilitation (CR) is a cognitive intervention for patients with Alzheimer’s disease (AD) that aims to maintain everyday competences. The analysis of functional connectivity (FC) in resting-state functional MRI has been used to investigate the effects of cognitive interventions. Objectives: We evaluated the effect of CR on the default mode network FC in a group of patients with mild AD, compared to an active control group. Methods: We performed a three-month interventional study including 16 patients with a diagnosis of AD. The intervention group (IG) consisted of eight patients, performing twelve sessions of CR. …The active control group (CG) performed a standardized cognitive training. We used a seed region placed in the posterior cingulate cortex (PCC) for FC analysis, comparing scans acquired before and after the intervention. Effects were thresholded at a significance of p  < 0.001 (uncorrected) and a minimal cluster size of 50 voxels. Results: The interaction of group by time showed a higher increase of PCC connectivity in IG compared to CG in the bilateral cerebellar cortex. CG revealed widespread, smaller clusters of higher FC increase compared with IG. Across all participants, an increase in quality of life was associated with connectivity increase over time in the bilateral precuneus. Conclusions: CR showed an effect on the FC of the DMN in the IG. These effects need further study in larger samples to confirm if FC analysis may suit as a surrogate marker for the effect of cognitive interventions in AD. Show more

Keywords: Alzheimer’s disease, cognitive rehabilitation, default mode network, dementia, functional connectivity, functional MRI

DOI: 10.3233/JAD-160773

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1303-1313, 2017

Authors: Brueggen, Katharina | Kasper, Elisabeth | Ochmann, Sina | Pfaff, Henrike | Webel, Steffi | Schneider, Wolfgang | Teipel, Stefan

Article Type: Research Article

Abstract: Background: Cognitive Rehabilitation for Alzheimer’s disease (AD) is an integrative multimodal intervention. It aims to maintain autonomy and quality of life by enhancing the patients’ abilities to compensate for decreased cognitive functioning. Objective: We evaluated the feasibility of a group–based Cognitive Rehabilitation approach in mild AD dementia and assessed its effect on activities of daily living (ADL). Methods: We included 16 patients with AD dementia in a controlled partial–randomized design. We adapted the manual–guided Cognitive Rehabilitation program (CORDIAL) to a group setting. Over the course of three months, one group received the Cognitive Rehabilitation intervention …(n  = 8), while the other group received a standardized Cognitive Training as an active control condition (n  = 8). ADL–competence was measured as primary outcome. The secondary outcome parameters included cognitive abilities related to daily living, functional cognitive state, and non–cognitive domains, e.g., quality of life. For each scale, we assessed the interaction effect ‘intervention by time’, i.e., from pre–to post–intervention. Results: We found no significant interaction effect of intervention by time on the primary outcome ADL–competence. The interaction effect was significant for quality of life (Cohen’s d: –1.43), showing an increase in the intervention group compared with the control group. Conclusions: Our study demonstrates the feasibility of a group–based Cognitive Rehabilitation program for patients with mild AD dementia. The Cognitive Rehabilitation showed no significant effect on ADL, possibly reflecting a lack of transfer between the therapy setting and real life. However, the group setting enhanced communication skills and coping mechanisms. Effects on ADL may not have reached statistical significance due to a limited sample size. Furthermore, future studies might use an extended duration of the intervention and integrate caregivers to a greater extent to increase transfer to activities of daily living. Show more

Keywords: Alzheimer’s disease, cognitive rehabilitation, cognitive training, dementia, mild cognitive impairment

DOI: 10.3233/JAD-160771

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1315-1324, 2017

Authors: Craft, Suzanne | Claxton, Amy | Baker, Laura D. | Hanson, Angela J. | Cholerton, Brenna | Trittschuh, Emily H. | Dahl, Deborah | Caulder, Erin | Neth, Bryan | Montine, Thomas J. | Jung, Youngkyoo | Maldjian, Joseph | Whitlow, Christopher | Friedman, Seth

Article Type: Research Article

Abstract: Background: Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer’s disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers. Objective: The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD. Methods: This randomized, double-blind, placebo-controlled trial …included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n  = 12), 40 IU of insulin detemir (n  = 12), or 40 IU of regular insulin (n  = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n  = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer’s Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers. Results: The regular insulin treated group had better memory after two and four months compared with placebo (p  < 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio. Conclusion: Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin. Show more

Keywords: Alzheimer’s disease, clinical trial, insulin, intranasal, magnetic resonance imaging, memory

DOI: 10.3233/JAD-161256

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1325-1334, 2017

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1335-1346, 2017