Journal of Alzheimer's Disease - Volume 44, issue 1

Authors: Sieczkowski, Evelyn | Milenkovic, Ivan | Venkataramani, Vivek | Giera, Regina | Ströbel, Thomas | Höftberger, Romana | Liberski, Paweł P. | Auff, Eduard | Wirths, Oliver | Bayer, Thomas A. | Kovacs, Gabor G.

Article Type: Research Article

Abstract: Autosomal dominant familial Alzheimer's disease (AD) is associated with mutations in the AβPP, PSEN1, and PSEN2 genes. The clinical phenotype associated with AβPP mutations is mainly characterized by dementia or by strokes related to cerebral amyloid angiopathy (CAA). We present a comprehensive clinical, neuropathological, genetic, and biochemical study on a patient affected by familial AD associated with the I716F mutation in the AβPP gene. The clinical phenotype was characterized by early age of onset of 47 years, and rapidly progressive cerebellar ataxia, myoclonic jerks, rigidity, and dementia reminiscent of Creutzfeldt-Jakob disease (CJD), followed by a prolonged persistent vegetative state. Neuropathological …evaluation of the proband revealed AD-related pathology but also α-synucleinopathy compatible with dementia with Lewy bodies neocortical stage or Parkinson's disease corresponding to Braak stage 6. Tau-pathology in the form of neurofibrillary degeneration corresponded to stage VI according to the Braak classification. The severe Aβ pathology included CAA, numerous plaques, and deposition of N-truncated pyroglutamate-modified Aβ peptides. Remarkably, pyroglutamate Aβ oligomers were also present intracellularly in Purkinje cells corresponding to the ataxic phenotype. The detection of a CJD-like phenotype expands the spectrum of clinical presentations associated with familial AD. Our study supports the concept that the neuropathology of familial AD expands beyond the classical AD-related pathology as defined by plaques and tangles. Finally, we provide evidence for the first time that oligomeric pyroglutamate Aβ is present in a specific pattern correlating with the clinical symptoms of a patient with AβPP I716F mutation. Show more

Keywords: AβPP, α-synuclein, Alzheimer's disease, amyloid-β, dementia with Lewy bodies, N-truncated Aβ, oligomers, pyroglutamate Aβ, tau

DOI: 10.3233/JAD-141524

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 103-114, 2015

Authors: Wang, Hui-Fu | Tan, Lan | Hao, Xiao-Ke | Jiang, Teng | Tan, Meng-Shan | Liu, Ying | Zhang, Dao-Qiang | Yu, Jin-Tai | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Ephrin type-A receptor 1 (EPHA1) (11771145) was documented to be one of the most strongly associated locus with Alzheimer's disease (AD) in a recent meta-analysis of five genome wide association studies. However, its contribution to the pathogenesis of AD remains unclear to date. Here, we addressed the role of EPHA1 in AD by investigating the influence of EPHA1 on cerebrospinal fluid and neuroimaging biomarkers in three clinical stages from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We did not detect significant association of EPHA1 with amyloid-β deposition or tau protein. However, the A-allele in the mild cognitive impairment group remarkably …prevented hippocampal atrophy (partial correlation coefficient 2.812, 95% CI 0.651 to 4.973) at two-year follow-up. Additionally, AD subjects with the A-allele displayed less atrophy and greater cerebral metabolic rate for glucose (CMRgl) in the right lateral occipitotemporal gyrus (volume: partial correlation coefficient 540.10, 95% CI 247.26 to 832.95; CMRgl: partial correlation coefficient 0.056, 95% CI 0.024 to 0.087) and inferior temporal gyrus (volume: partial correlation coefficient 327.98, 95% CI 11.65 to 644.31; CMRgl: partial correlation coefficient 0.055, 95% CI 0.019 to 0.091) at baseline. This study suggests EPHA1 (rs11771145) interferes with the pathological alteration of the hippocampus and the lateral occipitotemporal and inferior temporal gyri throughout the AD process, leading to a lower risk of AD. However, the limited sample size and follow-up as well as the diversity across ethnicities precluded explanation of these findings. Show more

Keywords: Alzheimer's disease, Alzheimer's Disease Neuroimaging Initiative (ADNI), biomarker, cerebrospinal fluid, Ephrin type-A receptor 1 (EPHA1), neuroimaging

DOI: 10.3233/JAD-141488

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 115-123, 2015

Authors: Chang, Yu-Ling | Chen, Ta-Fu | Shih, Yao-Chia | Chiu, Ming-Jang | Yan, Sui-Hing | Tseng, Wen-Yih Isaac

Article Type: Research Article

Abstract: Amnestic mild cognitive impairment (aMCI), which has a high risk of progression to Alzheimer's disease (AD), can be classified into single domain (S-aMCI) and multiple domain (M-aMCI) subtypes. We investigated the integrity of regional gray matter and segments of the cingulum bundle with diffusion spectrum imaging tract-specific analysis, and their relationships to neuropsychological functioning, in 46 individuals with aMCI (S-aMCI n = 24; M-aMCI n = 22) and 36 healthy controls (HC). Results demonstrated that although both aMCI groups were impaired on all memory measures relative to HCs, the M-aMCI group demonstrated worse performance on paired association memory and on …selective executive function relative to the S-aMCI group. The two aMCI groups did not show significant atrophy in regional gray matter indices as compared to the HC group, but the M-aMCI group showed significant disruption in white matter of the left anterior and inferior cingulum bundles relative to the S-aMCI and HC groups. Furthermore, disruption in the inferior cingulum bundles was significantly associated with executive function and attention/processing speed in all aMCI participants above and beyond the contribution of bilateral hippocampal volumes. Overall, these results indicate that the degeneration of cingulum fibers did not appear to arise from degeneration of the corresponding cerebral cortex. It also suggests relatively greater sensitivity of a white matter biomarker and comprehensive neuropsychological evaluation over gray matter biomarkers in early detection of AD. Show more

Keywords: Alzheimer's disease, cognition, diffusion magnetic resonance imaging, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-141839

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 125-138, 2015

Authors: Semrau, Maya | Burns, Alistair | Djukic-Dejanovic, Slavica | Eraslan, Defne | Han, Changsu | Lecic-Tosevski, Dusica | Lobo, Antonio | Mihai, Adriana | Morris, Julie | Palumbo, Claudia | Robert, Philippe | Stiens, Gerthild | Stoppe, Gabriela | Volpe, Umberto | Rikkert, Marcel Olde | Sartorius, Norman | on behalf of the International Dementia Alliance (IDEAL) study group

Article Type: Research Article

Abstract: Background: A reliable and valid global staging scale has been lacking within dementia care. Objective: To develop an easy-to-use multi-dimensional clinical staging schedule for dementia. Methods: The schedule was developed through: i) Two series of focus groups (40 and 48 participants, respectively) in Denmark, France, Germany, Netherlands, Spain, Switzerland, and UK with a multi-disciplinary group of professionals working within dementia care, to assess the need for a dementia-staging tool and to obtain suggestions on its design and characteristics; ii) A pilot-study over three rounds to test inter-rater reliability of the newly developed schedule using written case …histories, with five members of the project's steering committee and 27 of their colleagues from Netherlands, France, and Spain as participants; and iii) A field-study to test the schedule's inter-rater reliability in clinical practice in France, Germany, Netherlands, Spain, Italy, Turkey, South Korea, Romania, and Serbia, which included 209 dementia patients and 217 of their caregivers as participants. Results: Focus group participants indicated a clear need for a culture-fair international dementia staging scale and reached consensus on face validity and content validity. Accordingly, the schedule has been composed of seven dimensions including behavioral, cognitive, physical, functional, social, and care aspects. Overall, the schedule showed adequate face validity, content validity, and inter-rater reliability; in the nine field-sites, intraclass correlation coefficients (ICCs; absolute agreement) for individual dimensions ranged between 0.38 and 1.0, with 84.4% of ICCs over 0.7. ICCs for total sum scores ranged between 0.89 and 0.99 in the nine field-sites. Conclusion: The IDEAL schedule looks promising as tool for the clinical and social management of people with dementia globally, though further reliability and validity testing is needed. Show more

Keywords: Dementia, mental status schedule, patient schedule, psychometrics, reliability, validity

DOI: 10.3233/JAD-141599

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 139-151, 2015

Authors: Jochemsen, Hadassa M. | van der Flier, Wiesje M. | Ashby, Emma L. | Teunissen, Charlotte E. | Jones, Ruth E. | Wattjes, Mike P. | Scheltens, Philip | Geerlings, Mirjam I. | Kehoe, Patrick G. | Muller, Majon

Article Type: Research Article

Abstract: Background: Higher angiotensin-converting enzyme (ACE) activity might increase the risk of Alzheimer's disease by increasing blood pressure, and subsequent development of cerebral small vessel disease (CSVD). Yet, it may also decrease this risk, as it functions to degrade amyloid-β, thereby reducing brain atrophy. Objective: To examine the cross-sectional associations of serum and cerebrospinal fluid (CSF) ACE protein levels and activity with brain atrophy and CSVD in a memory clinic cohort. Methods: In 118 subjects from the memory clinic based Amsterdam Dementia Cohort (mean age 66 ± 8 years), ACE protein levels (ng/ml) and activity in CSF …and serum were investigated. Poisson regression analyses were used to associate ACE measurements with rated global cortical atrophy, medial temporal lobe atrophy, lacunar infarcts, white matter hyperintensities, and microbleeds on brain MRI. Results: Higher CSF ACE activity was associated with a reduced risk of global brain atrophy. The relative risk (95% CI) of having global cortical atrophy ≥2 per SD increase in CSF ACE activity was 0.67 (0.49; 0.93). ACE levels were not significantly related to measures of CSVD. Conclusions: These results show that high ACE might have protective effects on the brain. This could suggest that ACE inhibitors, which may lower CSF ACE levels, are not preferred as antihypertensive treatment in patients at risk for Alzheimer's disease. Show more

Keywords: Alzheimer's disease, angiotensin-converting enzyme, brain atrophy, cerebral small vessel disease, hypertension

DOI: 10.3233/JAD-131496

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 153-162, 2015

Authors: Zhu, Xi-Chen | Yu, Yang | Wang, Hui-Fu | Jiang, Teng | Cao, Lei | Wang, Chong | Wang, Jun | Tan, Chen-Chen | Meng, Xiang-Fei | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Many studies reported that physiotherapy interventions are available to treat Alzheimer's disease (AD), but the efficacy remains uncertain. Objective: To evaluate the effectiveness of physiotherapy intervention on AD. Methods: he data sources were searched from literature databases, journals, and reference lists from 1 January 1990 to the end of 1 April 2014. Randomized and non-randomized controlled trials with physiotherapy intervention were included in our meta-analysis. Jadad score and Newcastle-Ottawa scale were used to assess the quality of included trials. Outcome measures were cognition function, physical function, activity of daily life (ADL) and neuropsychiatric inventory (NPI). …Results: 23 trials met the inclusion standard finally. Significant changes were seen in cognitive function: Mini-Mental State Examination score (weighted mean difference (WMD): 1.84, 95% confidence interval (CI): [0.76, to, 2.93], p < 0.0001), and verbal fluency (standard mean difference (SMD): 0.34, 95% CI: [0.01 to 0.66], p = 0.04). Other outcomes are also significant, they were timed up and go test (SMD: 0.56, 95% CI: [0.30 to 0.83], p < 0.0001), berg functional balance scale (SMD: 1.11, 95% CI: [0.37 to 1.84], p = 0.003), 6-min walk distance test (SMD: 141.45, 95% CI: [11.72 to 271.18], p = 0.03), ADL (SMD: 0.78, 95% CI: [0.33 to 1.23], p = 0.0007) and NPI (SMD: −0.69, 95% CI: [−1.31 to −0.07], p = 0.03). Conclusion: The available data indicate that physiotherapy intervention may have benefits in AD. However, current data are not definitive; more carefully designed and conducted observational studies are needed to definitively establish that whether physiotherapy intervention can effectively alleviate symptoms of AD. Show more

Keywords: Activity of daily life, Alzheimer's disease, cognitive function, meta-analysis, neuropsychiatric inventory, physical function, physiotherapy intervention

DOI: 10.3233/JAD-141377

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 163-174, 2015

Authors: Lazarus, Jessica | Mather, Karen A. | Armstrong, Nicola J. | Song, Fei | Poljak, Anne | Thalamuthu, Anbupalam | Lee, Teresa | Kochan, Nicole A. | Brodaty, Henry | Wright, Margaret J. | Ames, David | Sachdev, Perminder S. | Kwok, John B.J.

Article Type: Research Article

Abstract: Background: DNA methylation variation has been implicated in memory, cognitive performance, and dementia. Plasma apolipoprotein-A1 (ApoA1) levels may act as a biomarker of age-associated cognitive performance and decline. Objectives: To estimate the heritability of plasma ApoA1 protein levels; to examine DNA methylation variation within the APOA1 gene; and to investigate whether APOA1 methylation is associated with plasma ApoA1 levels and episodic memory performance. Method: Heritability of ApoA1 protein levels in Older Australian Twins Study (OATS) was assessed using structural equation modelling. APOA1 methylation levels were assayed in two cohorts of cognitively normal older individuals. The methylation …status of 12 CpGs in 24 twin pairs from OATS was assayed using the Illumina 450K methylation array. Candidate CpGs were assayed in 454 individuals from Sydney Memory and Ageing Study (Sydney MAS) using pyrosequencing. Regression analyses assessed associations between APOA1 methylation levels, ApoA1 plasma levels, and memory performance. Results: No significant heritability was observed for ApoA1 protein levels. APOA1 candidate-gene analyses revealed CpG sites associated with memory performance in the twin study (p < 0.050). Replication of an association between methylation of a specific CpG (cg03010018) in APOA1 and memory performance was observed in Sydney MAS (β = −0.145, p = 0.010). Methylation of this CpG site was also significantly correlated with ApoA1 protein levels (β = 0.161, p = 0.019). However, no relationship between a composite memory domain score and methylation was observed (p = 0.389). Conclusion: Findings demonstrated that epigenetic control of APOA1 expression and DNA methylation levels are associated with episodic memory performance in older adults. Show more

Keywords: Aging, apolipoprotein A1, DNA methylation, epigenomics, episodic memory

DOI: 10.3233/JAD-141314

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 175-182, 2015

Authors: Suppa, Per | Anker, Ulrich | Spies, Lothar | Bopp, Irene | Rüegger-Frey, Brigitte | Klaghofer, Richard | Gocke, Carola | Hampel, Harald | Beck, Sacha | Buchert, Ralph

Article Type: Research Article

Abstract: Hippocampal volume is a promising biomarker to enhance the accuracy of the diagnosis of dementia due to Alzheimer's disease (AD). However, whereas hippocampal volume is well studied in patient samples from clinical trials, its value in clinical routine patient care is still rather unclear. The aim of the present study, therefore, was to evaluate fully automated atlas-based hippocampal volumetry for detection of AD in the setting of a secondary care expert memory clinic for outpatients. One-hundred consecutive patients with memory complaints were clinically evaluated and categorized into three diagnostic groups: AD, intermediate AD, and non-AD. A software tool based on …open source software (Statistical Parametric Mapping SPM8) was employed for fully automated tissue segmentation and stereotactical normalization of high-resolution three-dimensional T1-weighted magnetic resonance images. Predefined standard masks were used for computation of grey matter volume of the left and right hippocampus which then was scaled to the patient's total grey matter volume. The right hippocampal volume provided an area under the receiver operating characteristic curve of 84% for detection of AD patients in the whole sample. This indicates that fully automated MR-based hippocampal volumetry fulfills the requirements for a relevant core feasible biomarker for detection of AD in everyday patient care in a secondary care memory clinic for outpatients. The software used in the present study has been made freely available as an SPM8 toolbox. It is robust and fast so that it is easily integrated into routine workflow. Show more

Keywords: Alzheimer's disease, atlas-based segmentation, hippocampal volumetry, magnetic resonance imaging, memory clinic, memory impairment

DOI: 10.3233/JAD-141446

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 183-193, 2015

Authors: Yu, Su-Yeon | Lee, Tae-Jin | Jang, Su-Hyun | Han, Ji Won | Kim, Tae Hui | Kim, Ki Woong

Article Type: Research Article

Abstract: Although more demand for screening for dementia is envisaged, the cost-effectiveness of opportunistic population screening for dementia at a nationwide level has never been directly investigated. Since 2010, Korea has implemented “the National Dementia Early Detection Program” (NDEDP) for the aged. This study aims to investigate the cost-effectiveness of the NDEDP of Korea and to explore the requirements for enhancing its cost-effectiveness. A Markov model was developed to simulate the disease progression of dementia patients. Data sources for the model parameters included the NDEDP database for cohort characteristics and other national representative data. The model's estimates of the expected costs …and Quality Adjusted Life Years (QALYs) for each strategy were used to calculate the incremental cost-effectiveness ratio of screening compared to no screening, and sensitivity analysis was performed to assess the effect of key variables on the cost-effectiveness. Screening showed that the cost per QALY gained ranged from $24,150 to $35,661 depending on the age group. The probability of screening being cost-effective was highest in the group over 75 years old in a wide range of willingness to pay (WTP). The implementation of an opportunistic screening program for dementia can be cost-effective depending on disease severity, treatment effect, costs by disease stage, ages of the participants, and the societal WTP. Above all things, improving access to more effective therapies in slowing the course of the disease is essential since the main benefit of earlier diagnosis for dementia is starting early treatment and subsequent savings. Although it is too early to conclude the cost-effectiveness of opportunistic population screening for dementia, this current study may be a meaningful step toward generating practical evidence for implementing an effective and efficient dementia screening program. Show more

Keywords: Cost-effectiveness, dementia, early diagnosis, opportunistic population screening

DOI: 10.3233/JAD-141632

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 195-204, 2015

Authors: Eckerström, Carl | Olsson, Erik | Klasson, Niklas | Berge, Josef | Nordlund, Arto | Bjerke, Maria | Wallin, Anders

Article Type: Research Article

Abstract: Background: Neuropsychological tests, CSF Aβ42 , T-tau, P-tau181, hippocampal volume, and white matter lesions have been shown to predict conversion to dementia in patients with mild cognitive impairment (MCI). Objective: To examine the predictive value of combinations of these markers and to examine if the absence of pathological markers provides a lasting reduction of conversion rates. Methods: The Gothenburg MCI study is a clinically based study. Seventy-three MCI patients were included in the present sub-study and followed for a maximum of ten years. Thirty-four patients converted to dementia (18 to AD) and 39 remained stable. At …inclusion, patients were classified into positive or negative risk groups according to results from neuropsychological testing (Rey auditory verbal learning test, Boston naming test, Trail making test B), CSF biomarkers (amyloid β42 , T-tau, and P-tau181), and MRI scans (hippocampal volume, white matter lesions). Results: Trail making test B (TMT-B) was the best single predictor for the prediction of dementia (AUC 0.89, HR 25), and T-tau was the best predictor of AD (AUC 0.97, HR 41). The combination of hippocampal volume and TMT-B was the best combination for the prediction of dementia (HR 25), and the combination of hippocampal volume and T-tau was the best combination for the prediction of AD (HR 37). Conclusion: Neuropsychological tests, CSF markers, and hippocampal volume predicted conversion from MCI to AD and general dementia. The absence of pathological markers provided a long-time protection from dementia. Show more

Keywords: Cerebrospinal fluid, dementia, magnetic resonance imaging, mild cognitive impairment, neuropsychological test

DOI: 10.3233/JAD-141053

Citation: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 205-214, 2015