Journal of Alzheimer's Disease - Volume 48, issue 2

Authors: Weise, David | Tiepolt, Solveig | Awissus, Carolin | Hoffmann, Karl-Titus | Lobsien, Donald | Kaiser, Thorsten | Barthel, Henryk | Sabri, Osama | Gertz, Hermann-Josef

Article Type: Research Article

Abstract: Background: Biomarkers of neuronal injury and amyloid pathology play a pivotal role in the diagnosis of Alzheimer’s disease (AD). The degree of AD biomarker congruence is still unclear in clinical practice. Objective: Diagnosis of AD with regard to the congruence of the clinical diagnosis and different biomarkers. Methods: In this prospective cross-sectional observational study, 54 patients with mild cognitive impairment or dementia due to AD or not due to AD were investigated. Biomarkers of neuronal injury were medial temporal lobe atrophy (MTA) on magnetic resonance imaging (MRI) and tau concentration in the cerebrospinal fluid (CSF). …CSF Aβ1-42 and amyloid-targeting positron emission tomography (PET) were considered as biomarkers of amyloid pathology. Results: Forty cases were diagnosed as AD and 14 cases were diagnosed as non-AD based on clinical and routine MRI assessment. AD cases had higher MTA scores, higher levels of CSF tau and lower levels of CSF Aβ1 - 42, and higher amyloid load on PET compared to the non-AD group. In the AD group, completely consistently pathological biomarkers were found in 32.5% , non-pathological in 5% . In 62.5% the findings were inconsistent. Congruence of biomarkers was 67.5% for neuronal injury and for amyloid dysfunction, respectively. In two patients, clinical diagnosis switched to non-AD due to completely consistent non-pathological biomarker findings. The criteria of the international working group were met in 75.0% . Conclusion: Surprisingly, the number of completely congruent biomarkers was relatively low. Interpretation of AD biomarkers is complicated by multiple biomarker constellations. However, the level of biomarker consistency required to reliably diagnose AD remains uncertain. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, dementia, magnetic resonance imaging, positron emission tomography

DOI: 10.3233/JAD-150229

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 425-432, 2015

Authors: Lewczuk, Piotr | Kornhuber, Johannes | on behalf of the German Dementia Competence Network | Toledo, Jon B. | Trojanowski, John Q. | Knapik-Czajka, Malgorzata | Peters, Oliver | Wiltfang, Jens | Shaw, Leslie M. | on behalf of the US-ADNI

Article Type: Research Article

Abstract: Background: In previous studies, a dichotomous stratification of subjects into “cerebrospinal fluid (CSF) normal” and “CSF pathologic” was used to investigate the role of biomarkers in the prediction of progression to dementia in pre-dementia/mild cognitive impairment subjects. With the previously published Erlangen Score Algorithm, we suggested a division of CSF patterns into five groups, covering all possible CSF result combinations based on the presence of pathologic tau and/or amyloid-β CSF values. Objective: This study aimed to validate the Erlangen Score diagnostic algorithm based on the results of biomarkers analyses obtained in different patients cohorts, with …different pre-analytical protocols, and with different laboratory analytical platforms. Methods: We evaluated the algorithm in two cohorts of pre-dementia subjects: the US-Alzheimer’s Disease Neuroimaging Initiative and the German Dementia Competence Network. Results: In both cohorts, the Erlangen scores were strongly associated with progression to Alzheimer’s disease. Neither the scores of the progressors nor the scores of the non-progressors differed significantly between the two projects, in spite of significant differences in the cohorts, laboratory methods, and the samples treatment. Conclusions: Our findings confirm the utility of the Erlangen Score algorithm as a useful tool in the early neurochemical diagnosis of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, clinical neurochemistry, results interpretation, validation

DOI: 10.3233/JAD-150342

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 433-441, 2015

Authors: Leifert, Wayne R. | Nguyen, Tori | Rembach, Alan | Martins, Ralph | Rainey-Smith, Stephanie | Masters, Colin L. | Ames, David | Rowe, Christopher C. | Macaulay, S. Lance | François, Maxime | Fenech, Michael F. | and the Australian Imaging, Biomarkers and Lifestyle Study Research Group

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) may reflect early stages of neurodegenerative disorders such as Alzheimer’s disease (AD). Our hypothesis was that cytokeratin 14 (CK14) expression could be used with blood-based biomarkers such as homocysteine, vitamin B12, and folate to identify individuals with MCI or AD from the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging. Buccal cells from 54 individuals were analyzed by a newly developed method that is rapid, automated, and quantitative for buccal cell CK14 expression levels. CK14 was negatively correlated with plasma Mg2 + and LDL, while positively correlated with vitamin B12, red cell hematocrit/volume, and …basophils in the MCI group and positively correlated with insulin and vitamin B12 in the AD group. The combined biomarker panel (CK14 expression, plasma vitamin B12, and homocysteine) was significantly lower in the MCI (p  = 0.003) and AD (p  = 0.0001) groups compared with controls. Receiver-operating characteristic curves yielded area under the curve (AUC) values of 0.829 for the MCI (p  = 0.002) group and 0.856 for the AD (p  = 0.0003) group. These complex associations of multiple related parameters highlight the differences between the MCI and AD cohorts and possibly an underlying metabolic pathology associated with the development of early memory impairment. The changes in buccal cell CK14 expression observed in this pilot study supports previous results suggesting the peripheral biomarkers and metabolic changes are not restricted to brain pathology alone in MCI and AD and could prove useful as a potential biomarker in identifying individuals with an increased risk of developing MCI and eventually AD. Show more

Keywords: Alzheimer’s disease, buccal mucosa, cytokeratin, imaging, immunofluorescence, mild cognitive impairment

DOI: 10.3233/JAD-150330

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 443-452, 2015

Authors: Kiosses, Dimitris N. | Rosenberg, Paul B. | McGovern, Amanda | Fonzetti, Pasquale | Zaydens, Hana | Alexopoulos, George S.

Article Type: Research Article

Abstract: Background: Depression is prevalent in dementia and contributes to poor outcomes for patients and their families. Antidepressants have limited efficacy in older adults with major depression and dementia, and psychosocial interventions are under-investigated. Objective: To examine the course, predictors and moderators of depression and suicidal ideation during 12 weeks of home-delivered Problem Adaptation Therapy (PATH) versus Supportive Therapy for Cognitively Impaired Older Adults (ST-CI) in 39 older adults with major depression and dementia. Methods: Thirty-nine older adults with major depression, mild or moderate dementia, and disability participated in a randomized controlled trial …that compared the efficacy of PATH versus ST-CI. Depression and suicidal ideation were assessed with Cornell Scale for Depression in Dementia Total Score and Suicide Item. Results: PATH participants had significantly greater reduction in depression than ST-CI participants over 12 weeks of treatment. PATH participants with high social support had the greatest reduction in depression. Both treatments had comparable reduction in suicidal ideation. Conclusion: PATH is more effective in reducing depression in older adults with major depression and dementia compared to ST-CI. These results are clinically significant as antidepressants have limited efficacy in this population. Home-delivered psychosocial treatments may reduce suicidal ideation in this population. Show more

Keywords: Dementia, depression, psychosocial interventions, social support, suicidal ideation

DOI: 10.3233/JAD-150200

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 453-462, 2015

Authors: Liao, Xiang | Li, Guangming | Wang, Anguo | Liu, Tao | Feng, Shenggang | Guo, Zhiwei | Tang, Qing | Jin, Yu | Xing, Guoqiang | McClure, Morgan A. | Chen, Huaping | He, Bin | Liu, Hua | Mu, Qiwen

Article Type: Research Article

Abstract: Background: Recent studies have indicated that repetitive transcranial magnetic stimulation (rTMS) could improve cognitive function in people with Alzheimer’s disease (AD). Yet the results are inconclusive. Objective: This meta-analysis aimed to evaluate recent rTMS studies conducted in mild to moderate AD patients. Methods: PubMed, Embase, MEDLINE databases and Science Direct were searched for studies of rTMS treatment on AD patients with cognitive impairment published before February 2015. The relevant primary outcomes of cognition were extracted from those included studies. A crude standardized mean difference (SMD) with 95% confidence interval (CI) was calculated …by using random effect models. Results: Seven studies with a total of 94 mild to moderate AD patients were included in this meta-analysis. A significant overall rTMS treatment effect on cognition was found for all AD patients (p  = 0.0008, SMD = 1.00, 95% CI = 0.41–1.58). Stratification analysis showed that this effect is stimulation frequency- and hemisphere-dependent. High frequency stimulation (>1.0 Hz) (p  <  0.05) but not low frequency stimulation (≤1.0 Hz) (p  >  0.05) was significantly effective in improving the cognition of AD patients. Further, rTMS stimulation on right dorsolateral prefrontal cortex (DLPFC) and bilateral DLPFC (p  <  0.05), but not on the left DLPFC (p  >  0.05) was significantly effective in improving cognitive function of AD patients. A significant effect was observed in the rTMS subgroup (p  <  0.05), rather than in the rTMS+drug subgroup (p  >  0.05). Conclusion: This meta-analysis supports that high frequency rTMS stimulation on right- or bilateral-DLPFC has significant therapeutic effect on cognitive function in patients with mild to moderate AD. Due to small number of studies included, more well-controlled rTMS studies should be evaluated in AD patients in the future. Show more

Keywords: Alzheimer’s disease, meta-analysis, mild to moderate cognitive impairment, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-150346

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 463-472, 2015

Authors: Gauthier, Serge | Rountree, Susan | Finn, Barbara | LaPlante, Barbra | Weber, Eckard | Oltersdorf, Tilman

Article Type: Research Article

Abstract: Background and Objective: ST101, an acetylcholine release agent with efficacy in rodent memory and cognition models, was assessed for clinical safety and efficacy. Methods: A phase 2 double blind, placebo-controlled study enrolled 210 AD patients (MMSE 10–20) on 10 mg donepezil QD. Patients received ST101 (10, 60, or 120 mg QD) or placebo for 12 weeks. The primary endpoint was change in cognitive function measured by ADAS-cog in the modified Intent To Treat (MITT) population and the Per Protocol (PP) population. Results: Mean ADAS-cog change favored ST101 over placebo in the MITT population (p … = 0.0957, one-sided) and in the PP population (p  = 0.0434, one-sided, ∼1.5 point drug-placebo difference) comparing all ST101 dose groups combined to placebo. Among secondary and exploratory outcome measures the ADCS-CGIC also showed a beneficial trend (p  = 0.0294, one-sided). In a post-hoc analysis, the subgroup with more severe disease (MMSE 10–17) showed a dose response in the ADAS-cog with the greatest efficacy at 120 mg (p  = 0.0067, one sided). No significant ST101-related safety concerns were identified. Conclusion: The study supports the possibility that ST101, in patients receiving a stable dose of donepezil, may provide additional symptomatic benefit in moderate AD. Show more

Keywords: Alzheimer’s disease, cholinergic agents, clinical trial, Phase II, donepezil

DOI: 10.3233/JAD-150414

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 473-481, 2015

Authors: Leoutsakos, Jeannie-Marie S. | Forrester, Sarah N. | Lyketsos, Constantine.G. | Smith, Gwenn S.

Article Type: Research Article

Abstract: Background: A number of studies have linked neuropsychiatric symptoms to increase risk of dementia. Objective: To determine if risk of conversion to mild cognitive impairment or dementia among healthy controls varied as a function of their pattern of neuropsychiatric symptoms. Method: We studied individuals in the National Alzheimer Coordinating Center dataset collected from 34 Alzheimer Disease Centers between 2005 and 2013. The analysis included 4,517 volunteers who were ≥60 years old, cognitively normal, and had complete Neuropsychiatric Inventory data at their baseline visit, and had at least one follow-up. We used latent …class analysis to identify four classes based on patterns of NPI symptoms. We used a Cox proportional hazards model to determine if time to MCI or dementia varied by baseline latent class membership. Results: We identified four latent classes of neuropsychiatric symptoms: irritable, depressed, complex (depression, apathy, irritability, and nighttime behaviors) and asymptomatic. 873 participants converted to MCI or dementia. Hazard ratios for conversion by class were 1.76 (95% CI: 1.34, 2.33) for the irritable class, 3.20 (95% CI: 2.24, 4.58) for the complex class, and 1.90 (95% CI: 1.49, 2.43) for the depressed class, with the asymptomatic class as the reference. Conclusions: Membership in all three symptomatic classes was associated with greater risk of conversion to MCI or dementia; the complex class had the greatest risk. Different patterns of neuropsychiatric symptoms may represent different underlying neuropathological pathways to dementia. Further work imaging and pathology research is necessary to determine if this is the case. Show more

Keywords: Alzheimer’s disease, dementia, depression, latent class analysis, neuropsychiatric symptoms

DOI: 10.3233/JAD-150421

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 483-493, 2015

Authors: Sarlus, Heela | Eyjolfsdottir, Helga | Eriksdotter, Maria | Oprica, Mircea | Schultzberg, Marianne

Article Type: Research Article

Abstract: Background: Peripheral inflammation has been suggested to influence the development of Alzheimer’s disease (AD). Elevated levels of pro-inflammatory markers in the plasma of patients with AD indicate that a systemic pro-inflammatory status occurs concomitantly with inflammatory changes in the brain. Objective: To investigate whether allergy influences the levels of immunoglobulins (Ig) and of pro- and anti-inflammatory cytokines in the serum and cerebrospinal fluid (CSF) from patients with AD, mild cognitive impairment (MCI), and subjective cognitive impairment (SCI). Methods: IgA, IgG, and its subclasses, IgM, and cytokines were analyzed in CSF and serum …from patients with SCI, MCI, and AD, with or without allergy. The relation between allergy and Mini-Mental State Examination (MMSE) scores, and between allergy and CSF biomarkers for AD (phosphorylated (p)-tau, total (t)-tau, amyloid-β 42 (Aβ42 ), were analyzed. Results: In MCI, the CSF levels of IgG2 were lower in allergic patients, and in AD, the levels of IgA and the IgG1/total IgG ratio were lower in allergic patients, compared to patients without allergy. MCI subjects with allergy had higher serum IgM levels compared to those without allergy. CSF levels of Aβ42 were lower and MMSE scores were higher in AD patients with allergy than in those without allergy. Conclusions: The presence of allergy was associated with seemingly beneficial effects on AD as suggested by higher Aβ42 levels in CSF, and higher MMSE scores. Higher IgM levels and lower other Ig classes suggest that allergy may influence senescence of the immune response. Show more

Keywords: Cerebrospinal fluid, cytokines, mild cognitive impairment, Mini-Mental State Examination, serum, subjective cognitive impairment, systemic inflammation, tau

DOI: 10.3233/JAD-143147

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 495-505, 2015

Authors: Sarajärvi, Timo | Marttinen, Mikael | Natunen, Teemu | Kauppinen, Tarja | Mäkinen, Petra | Helisalmi, Seppo | Laitinen, Marjo | Rauramaa, Tuomas | Leinonen, Ville | Petäjä-Repo, Ulla | Soininen, Hilkka | Haapasalo, Annakaisa | Hiltunen, Mikko

Article Type: Research Article

Abstract: The agonist-induced activation of human δ -opioid receptor (δ OR) has been shown to increase β- (BACE1) and γ -secretase activities leading to increased production of amyloid-β (Aβ) peptide. We have recently shown that phenylalanine to cysteine substitution at amino acid 27 in δ OR (δ OR-Phe27Cys) increases amyloid-β protein precursor processing through altered endocytic trafficking. Also, a genetic meta-analysis of the δ OR-Phe27Cys variation (rs1042114) in two independent Alzheimer’s disease (AD) patient cohorts indicated that the heterozygosity of δ OR-Phe27Cys increases the risk of AD. Here, we investigated α -, β-, and γ -secretase activities in human brain with …respect to δ OR-Phe27Cys variation in the temporal cortex of 71 subjects with varying degree of AD-related neurofibrillary pathology (Braak stages I-VI). As a result, a significant increase in β- (p  = 0.03) and γ - (p  = 0.01), but not α -secretase, activities was observed in late stage AD samples (Braak stages V-VI), which were heterozygous for δ OR-Phe27Cys as compared to the δ OR-Phe27 and δ OR-Cys27 homozygotes. The augmented β-secretase activity was not associated with increased mRNA expression or protein levels of BACE1 in the late stage AD patients, who were heterozygous for the δ OR-Phe27Cys variation. These findings suggest that δ OR-Phe27Cys variation modulates β- and γ -secretase activity in the late stages of AD likely via post-translational mechanisms other than alterations in the mRNA or protein levels of BACE1, or, in the expression of γ -secretase complex components. Show more

Keywords: Alzheimer disease, amyloid-β, amyloid-β protein precursor, β-secretase, γ-secretase, δ-opioid receptor

DOI: 10.3233/JAD-150221

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 507-516, 2015

Authors: Samuraki, Miharu | Matsunari, Ichiro | Yoshita, Mitsuhiro | Shima, Keisuke | Noguchi-Shinohara, Moeko | Hamaguchi, Tsuyoshi | Ono, Kenjiro | Yamada, Masahito

Article Type: Research Article

Abstract: Background: Microbleeds (MBs) are frequently observed in Alzheimer’s disease (AD); however, the relevance to AD pathophysiology has not been elucidated. Objectives: We investigated correlation of MBs, especially cerebral amyloid angiopathy (CAA)-related MBs with cognitive function, gray matter volume, and glucose metabolism in AD. Methods: We performed magnetic resonance imaging including T2* -weighted imaging sequence for 206 patients with AD. Among them, 158 AD patients with no focal brain lesions except for MBs were investigated with cognitive tests, voxel-based morphometry, and 18 F-fluorodeoxyglucose positron emission tomography in a cross-sectional observational study. …Results: Of the 158 patients with no hemorrhagic and/or ischemic stroke lesions except for MBs, 27 patients had MBs, in which 17 patients showed CAA-related MBs that located only in cortex/subcortex (CAA-related MBs), and 10 patients showed CAA-unrelated MBs that located in deep regions regardless of the presence of MBs in cortical/subcortical regions. There were slightly but significant differences in cognitive functions between the patients without MBs, those with CAA-related MBs, and those with CAA-unrelated MBs. MBs were recognized frequently in the occipital lobe in the patients with CAA-related MBs. The patients with CAA-related MBs showed gray matter atrophy in the temporal lobe and cerebellum, and glucose hypometabolism in the temporal lobe compared with those without MBs. Conclusions: Our results indicate that MBs, particularly CAA-related MBs would cause gray matter atrophy and glucose hypometabolism in AD. Show more

Keywords: Alzheimer’s disease, brain microbleeds, cerebral amyloid angiopathy, 18F-FDG PET, voxel-based morphometry

DOI: 10.3233/JAD-150274

Citation: Journal of Alzheimer's Disease, vol. 48, no. 2, pp. 517-528, 2015