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

Authors: Gonzales, Eric B. | Sumien, Nathalie

Article Type: Research Article

Abstract: Alzheimer’s disease prevalence has reached epidemic proportion with very few treatment options, which are associated with a multitude of side effects. A potential avenue of research for new therapies are protons, and their associated receptor: acid-sensing ion channels (ASIC). Protons are often overlooked neurotransmitters, and proton-gated currents have been identified in the brain. Furthermore, ASICs have been determined to be crucial for proper brain function. While there is more work to be done, this review is intended to highlight protons as neurotransmitters and their role along with the role of ASICs within physiological functioning of the brain. We will also …cover the pathophysiological associations between ASICs and modulators of ASICs. Finally, this review will sum up how the studies of protons, ASICs and their modulators may generate new therapeutic molecules for Alzheimer’s disease and other neurodegenerative diseases. Show more

Keywords: Acid-sensing ion channels, acidity, Alzheimer’s disease, ASIC, cognitive function, pH, protons

DOI: 10.3233/JAD-161131

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1137-1144, 2017

Authors: Huang, Chia-Chi | Isidoro, Ciro

Article Type: Review Article

Abstract: The continuous increasing rate of patients suffering of Alzheimer’s disease (AD) worldwide requires the adoption of novel techniques for non-invasive early diagnosis and monitoring of the disease. Here we review the various Raman spectroscopic techniques, including Fourier Transform-Raman spectroscopy, surface-enhanced Raman scattering spectroscopy, coherent anti-Stokes Raman scattering spectroscopy, and confocal Raman microspectroscopy, that could be used for the diagnosis of AD. These techniques have shown the potential to detect AD biomarkers, such as the amyloid-β peptide and the tau protein, or the neurotransmitters involved in the disease (e.g., Glutamate and γ -Aminobutyric acid), or the typical structural alterations in specific …brain areas. The possibility to detect the specific biomarkers in liquid biopsies and to obtain high resolution 3D microscope images of the affected area make the Raman spectroscopy a valuable ally in the early diagnosis and monitoring of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, brain tissue, diagnosis, Raman spectroscopy, tau protein

DOI: 10.3233/JAD-161238

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1145-1156, 2017

Authors: Liu, Xin-jun | Wei, Jun | Shang, Ying-hui | Huang, Han-chang | Lao, Feng-xue

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a dementia disease with neuronal loss and synaptic impairment. This impairment is caused, at least partly, by the generation of two main AD hallmarks, namely the hyperphosphorylated tau protein comprising neurofibrillary tangles and senile plaques containing amyloid-β (Aβ) peptides. The amyloid-β protein precursor (AβPP) and glycogen synthase kinase-3β (GSK3β) are two main proteins associated with AD and are closely correlated with these hallmarks. Recently, both of the proteins were reported to be modulated by endoplasmic reticulum stress (ERS) and are involved in the pathogenesis of AD. The mechanism of ERS plus the modulation of AβPP processing …and GSK3β activity by ERS in AD are summarized and explored in this review. Show more

Keywords: Alzheimer’s disease, amyloid-β, apoptosis, endoplasmic reticulum stress, neurofibrillary tangles

DOI: 10.3233/JAD-161111

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1157-1170, 2017

Authors: Esquerda-Canals, Gisela | Montoliu-Gaya, Laia | Güell-Bosch, Jofre | Villegas, Sandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that nowadays affects more than 40 million people worldwide and it is predicted to exponentially increase in the coming decades. Because no curative treatment exists, research on the pathophysiology of the disease, as well as the testing of new drugs, are mandatory. For these purposes, animal models constitute a valuable, although perfectible tool. This review takes a tour through several aspects of mouse models of AD, such as the generation of transgenic models, the relevance of the promoter driving the expression of the transgenes, and the concrete transgenes used to simulate AD pathophysiology. …Then, transgenic mouse lines harboring mutated human genes at several loci such as APP , PSEN1 , APOE ɛ 4 , and ob (leptin) are reviewed. Therefore, not only the accumulation of the Aβ peptide is emulated but also cholesterol and insulin metabolism. Further novel information about the disease will allow for the development of more accurate animal models, which in turn will undoubtedly be helpful for bringing preclinical research closer to clinical trials in humans. Show more

Keywords: Alzheimer’s disease, amyloid-β, animal models, apoE, APP, ob mutation, PS1

DOI: 10.3233/JAD-170045

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1171-1183, 2017

Authors: Gazzina, Stefano | Archetti, Silvana | Alberici, Antonella | Bonomi, Elisa | Cosseddu, Maura | Di Lorenzo, Diego | Padovani, Alessandro | Borroni, Barbara

Article Type: Short Communication

Abstract: Progranulin is a multifunctional growth factor mainly expressed in neurons and microglia. Loss-of-function mutations in the Granulin (GRN) gene are causative of frontotemporal dementia with TAR DNA-binding protein-43 inclusions. We reported the case of a 51-year-old male patient affected by sporadic agrammatic variant of primary progressive aphasia, in whom we identified a novel heterozygous deletion in the exon 6 (g.10338_39delAG, p.Arg161GlyfsX36). Plasma progranulin levels were significantly reduced and in silico analysis predicted a premature termination codon. This case expands our knowledge on GRN mutations in frontotemporal dementia.

Keywords: Frontotemporal dementia, granulin, mutation, progranulin

DOI: 10.3233/JAD-170066

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1185-1189, 2017

Authors: Wingbermühle, Robin | Wen, Ke-xin | Wolters, Frank J. | Ikram, M. Arfan | Bos, Daniel

Article Type: Short Communication

Abstract: The association of smoking with preclinical cognitive decline remains unclear and may be modified by the APOE ɛ 4 genotype. In 5,705 participants (mean age: 63.9±9.1 years; 57.4% women) from the population-based Rotterdam Study, we investigated the relationship between smoking and cognitive decline over a 5.5-year period and examined potential effect modification by APOE ɛ 4 genotype. We found that current smoking was related to decline in global cognition [difference compared to never smoking: –0.06 (95% C.I.–0.10;–0.01)], as well as decline on specific cognitive tests including the Letter Digit Substitution Task, the 15-Word Learning Test, and …the Purdue Pegboard. We found no evidence for effect modification by APOE ɛ 4 genotype on this relation. Show more

Keywords: APOE ɛ4 genotype, cognitive decline, epidemiology, smoking

DOI: 10.3233/JAD-170063

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1191-1195, 2017

Authors: Anstey, Kaarin J. | Eramudugolla, Ranmalee | Chopra, Sidhant | Price, Jasmine | Wood, Joanne M.

Article Type: Research Article

Abstract: Background: With population aging, drivers with mild cognitive impairment (MCI) are increasing; however, there is little evidence available regarding their safety. Objective: We aimed to evaluate risk of unsafe on-road driving performance among older adults with MCI. Method: The study was a cross-sectional observational study, set in Canberra, Australia. Participants were non-demented, current drivers (n  = 302) aged 65 to 96 years (M  = 75.7, SD = 6.18, 40% female) recruited through the community and primary and tertiary care clinics. Measures included a standardized on-road driving test (ORT), a battery of screening measures designed to evaluate older driver safety …(UFOV® , DriveSafe, Multi-D), a neurocognitive test battery, and questionnaires on driving history and behavior. Results: Using Winblad criteria, 57 participants were classified as having MCI and 245 as cognitively normal (CN). While the MCI group had a significantly lower overall safety rating on the ORT (5.61 versus 6.05, p  = 0.03), there was a wide range of driving safety scores in the CN and MCI groups. The MCI group performed worse than the CN group on the off-road screening tests. The best fitting model of predictors of ORT performance across the combined sample included age, the Multi-D, and DriveSafe, classifying 90.4% of the sample correctly. Conclusion: Adults with MCI exhibit a similar range of driving ability to CN adults, although on average they scored lower on off-road and on-road assessments. Driving specific tests were more strongly associated with safety ratings than traditional neuropsychological tests. Show more

Keywords: Driving safety, mild cognitive impairment, neuropsychological assessment, older drivers, on-road drivingperformance

DOI: 10.3233/JAD-161209

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1197-1205, 2017

Authors: Yin, Huajing | Wang, Weiping | Yu, Wenwen | Li, Jiang | Feng, Nan | Wang, Ling | Wang, Xiaoliang

Article Type: Research Article

Abstract: In the present study, the progressive alteration of cognition and the mechanisms of reduction in long-term potentiation (LTP) in spontaneous obese KK-Ay type 2 diabetic mice were investigated. In the study, 3-, 5-, and 7-month-old KK-Ay mice were used. The results indicated that KK-Ay mice showed cognitive deficits in the Morris water maze test beginning at the age of 3 months. LTP was significantly impaired in KK-Ay mice during whole study period (3 to 7 months). The above deficits were reversible at an early stage (3 to 5 months old) by diet intervention. Moreover, we found the underlying mechanisms of …LTP impairment in KK-Ay mice might be attributed to abnormal phosphorylation or expression of postsynaptic glutamate receptor subunits instead of alteration of basal synaptic transmission. The expression levels of NR1, NR2A, and NR2B subunits of N-methyl-d-aspartate receptors (NMDARs) were unchanged while the Tyr-dependent phosphorylation of both NR2A and NR2B subunits were significantly reduced in KK-Ay mice. The level of p-Src expression mediating this process was decreased, and the level of αCaMKII autophosphorylation was also reduced. Meanwhile, the GluR1 of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) was decreased, and GluR2 was significantly increased. These data suggest that deficits in synaptic plasticity in KK-Ay mice may arise from the abnormal phosphorylation of the NR2 subunits and the alteration of subunit composition of AMPARs. Diet intervention at an early stage of diabetes might alleviate the cognitive deficits and LTP reduction in KK-Ay mice. Show more

Keywords: AMPA receptor, diabetic encephalopathy, KK-Ay mice, long-term potentiation, NMDA receptor, type 2 diabetes mellitus

DOI: 10.3233/JAD-160858

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1207-1220, 2017

Authors: Shinagawa, Shunichiro | Shigenobu, Kazue | Tagai, Kenji | Fukuhara, Ryuji | Kamimura, Naoto | Mori, Takaaki | Yoshiyama, Kenji | Kazui, Hiroaki | Nakayama, Kazuhiko | Ikeda, Manabu

Article Type: Research Article

Abstract: Although violations of laws, such as shoplifting, are considered to be common in frontotemporal dementia (FTD) patients, there have been few studies on this subject and the frequencies and types of such violations have not been clarified. The objective of this study was to conduct a retrospective investigation of FTD patients in the psychiatry departments of multiple institutions to determine the types and frequencies of any law violations and compare them with those of AD patients. All patients were examined between January 2011 and December 2015 at the specialized dementia outpatient clinics of 10 facilities (5 psychiatry departments of university …hospitals, 5 psychiatric hospitals). According to diagnostic criteria, 73 behavior variant FTD (bvFTD) patients, 84 semantic variant of primary progressive aphasia (svPPA) patients, and 255 age- and sex-matched AD subjects as the control group were selected. The findings revealed a higher rate of law violations in the bvFTD and svPPA patients before the initial consultation as compared to the AD group (bvFTD: 33%, svPPA: 21%, AD: 6%) and that many patients had been referred due to such violations. Laws had been broken 4 times or 5 or more times in several cases in the FTD group before the initial consultation. Regarding rates for different types of violation, in bvFTD subjects, the highest rate was for theft, followed by nuisance acts and hit and run. In svPPA, theft had the highest rate, followed by ignoring road signs. There was no gender difference in law violations but they were more frequent when the disease was severe at the initial consultation in the FTD group. As the rates of law violations after the initial consultation were lower than before it, interventions were considered to have been effective. These findings may be useful for future prevention as well as to the legal system. Show more

Keywords: Behavioral symptoms, frontotemporal dementia, legal system, violation of laws

DOI: 10.3233/JAD-170028

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1221-1227, 2017

Authors: Czaja, Sara J. | Loewenstein, David A. | Sabbag, Samir A. | Curiel, Rosie E. | Crocco, Elizabeth | Harvey, Philip D.

Article Type: Research Article

Abstract: Background: Recent findings indicate that impairments in functional performance do occur among individuals diagnosed with mild cognitive impairment (MCI). Most assessment strategies for everyday competence are associated with challenges with reliability, are typically in paper and pencil format, or require in-person administration by a trained professional. Objective: This paper reports on a novel technology-based assessment battery of everyday competence that includes ecologically valid simulations of daily activities important to independence. Methods: The sample included 85 non-cognitively impaired older adults aged 65+ and 62 older adults diagnosed with amnestic MCI (aMCI). Participants completed standard measures of …cognitive abilities and the computerized battery of everyday tasks, which included simulations of a doctor’s visit; and medication and financial management tasks. Results: The older adults with aMCI performed significantly poorer on all three tasks in the everyday task battery. Performance on these measures were also moderately correlated with standard measures of cognitive abilities and showed good test-retest reliability. Conclusions: The results show that it is feasible to use a technology-based assessment battery of everyday tasks with both non-cognitively impaired older adults and older adults with MCI. The use of this type of battery can overcome many of the logistic constraints associated with current functional assessment protocols. Show more

Keywords: Assessment, cognition, everyday competence, mild cognitive impairment, technology

DOI: 10.3233/JAD-161183

Citation: Journal of Alzheimer's Disease, vol. 57, no. 4, pp. 1229-1238, 2017

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