Journal of Alzheimer's Disease - Volume 56, issue 2

Authors: Emon, Mohammad Asif Emran Khan | Kodamullil, Alpha Tom | Karki, Reagon | Younesi, Erfan | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Neurodegenerative diseases including Alzheimer’s disease are complex to tackle because of the complexity of the brain, both in structure and function. Such complexity is reflected by the involvement of various brain regions and multiple pathways in the etiology of neurodegenerative diseases that render single drug target approaches ineffective. Particularly in the area of neurodegeneration, attention has been drawn to repurposing existing drugs with proven efficacy and safety profiles. However, there is a lack of systematic analysis of the brain chemical space to predict the feasibility of repurposing strategies. Using a mechanism-based, drug-target interaction modeling approach, we have identified promising drug …candidates for repositioning. Mechanistic cause-and-effect models consolidate relevant prior knowledge on drugs, targets, and pathways from the scientific literature and integrate insights derived from experimental data. We demonstrate the power of this approach by predicting two repositioning candidates for Alzheimer’s disease and one for amyotrophic lateral sclerosis. Show more

Keywords: Alzheimer disease, amyotrophic lateral sclerosis, biological expression language, disease-drug modeling, drug repositioning, neurodegenerative diseases

DOI: 10.3233/JAD-160222

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 677-686, 2017

Authors: Slot, Rosalinde E.R. | Van Harten, Argonde C. | Kester, Maartje I. | Jongbloed, Wesley | Bouwman, Femke H. | Teunissen, Charlotte E. | Scheltens, Philip | Veerhuis, Robert | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Background: HDL-cholesterol transporter Apolipoprotein A1 (ApoA1) holds neuroprotective properties, such as inhibition of amyloid-β aggregation. Low plasma ApoA1 concentrations are associated with Alzheimer’s disease (AD). Little is known about ApoA1 levels in the pre-dementia stages of AD. Objective: To investigate associations between cerebrospinal fluid (CSF) and plasma ApoA1 levels and clinical progression toward AD in non-demented elderly. Methods: From the Amsterdam Dementia Cohort, we included 429 non-demented elderly with subjective cognitive decline (SCD; n  = 206, 61±9 years, Mini-Mental State Exam (MMSE) 28±2) and mild cognitive impairment (MCI; n  = 223, 67±8 years, MMSE 27±2), with a …mean follow-up of 2.5±1.6 years. We used Cox proportional hazard models to investigate relations between CSF and plasma ApoA1 concentrations and clinical progression, defined as progression to MCI or AD for SCD, and progression to AD for MCI. Analyses were adjusted for age, gender, MMSE, and plasma cholesterol levels. Analyses were stratified for diagnosis and APOE ɛ 4 carriership. Results: 117 patients (27%) showed clinical progression. One standard deviation increase of CSF ApoA1 was associated with a 30% increased risk of clinical progression (hazard ratio (HR) (95% CI)  = 1.3(1.0–1.6)). The effect appeared to be attributable to the APOE ɛ 4 carriers with SCD (HR 3.3(1.0–10.9)). Lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOE ɛ 4 carriers with SCD (HR 5.0(1.3–18.9)). Conclusion: Higher CSF and lower plasma ApoA1 levels were associated with an increased risk of clinical progression in APOE ɛ 4 carriers with SCD; suggesting that ApoA1 may be involved in the earliest stages of AD. Show more

Keywords: Alzheimer’s disease, Apolipoprotein-A1, Apolipoprotein E, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-151068

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 687-697, 2017

Authors: Yarchoan, Mark | James, Bryan D. | Shah, Raj C. | Arvanitakis, Zoe | Wilson, Robert S. | Schneider, Julie | Bennett, David A. | Arnold, Steven E.

Article Type: Research Article

Abstract: Background: Cancer and Alzheimer’s disease (AD) are common diseases of aging and share many risk factors. Surprisingly, however, epidemiologic data from several recent independent cohort studies suggest that there may be an inverse association between these diseases. Objective: To determine the relationship between history of cancer and odds of dementia proximate to death and neuropathological indices of AD. Methods: Using data from two separate clinical-pathologic cohort studies of aging and AD, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we compared odds of AD dementia proximate to death among participants …with and without a history of cancer. We then examined the relation of history of cancer with measures of AD pathology at autopsy, i.e., paired helical filament tau (PHFtau) neurofibrillary tangles and amyloid-β load. Results: Participants reporting a history of cancer had significantly lower odds of AD (OR 0.70 [0.55–0.89], p  = 0.0040) proximate to death as compared to participants reporting no prior history of cancer. The results remained significant after adjusting for multiple risk factors including age, sex, race, education, and presence of an APOE ɛ 4 allele. At autopsy, participants with a history of cancer had significantly fewer PHFtau tangles (p  < 0.001) than participants without a history of cancer, but similar levels of amyloid-β. Conclusions: Cancer survivors have reduced odds of developing AD and a lower burden of neurofibrillary tangle deposition. Show more

Keywords: Alzheimer’s disease, amyloid-β, cancer, cohort study, dementia, malignancy, neurofibrillary tangles, PHFtau

DOI: 10.3233/JAD-160977

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 699-706, 2017

Authors: Nørgaard, Ane | Jensen-Dahm, Christina | Gasse, Christiane | Hansen, Elsebet Steno | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Antipsychotics and other psychotropics are frequently used to treat neuropsychiatric symptoms in patients with dementia, even though the evidence for effect is limited. Concerns have been raised about the safety of antipsychotics, but concomitant use of multiple psychotropic drug classes (psychotropic polypharmacy) may also pose a risk for patients. Objective: To investigate the prevalence and predictors associated with use of psychotropic polypharmacy in patients with dementia. Methods: A population-based study using nationwide registers. Patients with dementia were identified among all Danish residents ≥65 years on January 1, 2012. Data on prescriptions and comorbidity was …included in the analysis. Overlapping prescriptions for different psychotropic drug classes were used to determine psychotropic polypharmacy. A multivariable logistic regression analysis was conducted to evaluate factors independently associated with the prescription of other psychotropic drug classes among patients already using antipsychotics. Results: Among all patients registered with dementia (34,553), 25.3% (8,728) used ≥2 psychotropic drugs. Among patients treated with antipsychotics 75.8% (5,403) used at least one other psychotropic drug during the antipsychotic treatment period. Nursing home residency, number of non-psychotropic medications used in 2011, and prior psychiatric diagnosis were associated with psychotropic polypharmacy among antipsychotic drug users. The most frequent combination of psychotropic drugs was antipsychotics and antidepressants. Conclusion: Concomitant use of psychotropic drugs was frequent in dementia patients. Patients living in nursing homes had the highest risk of receiving a combination of antipsychotics and other psychotropic drugs. Concomitant use of psychotropics may cause adverse events, and potential consequences for patients’ safety call for further investigation. Show more

Keywords: Antidepressant drugs, antipsychotic drugs, dementia, pharmacoepidemiology, polypharmacy, psychotropic drugs

DOI: 10.3233/JAD-160828

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 707-716, 2017

Authors: Gaubert, Malo | Villain, Nicolas | Landeau, Brigitte | Mézenge, Florence | Egret, Stéphanie | Perrotin, Audrey | Belliard, Serge | de La Sayette, Vincent | Eustache, Francis | Desgranges, Béatrice | Chételat, Gaël | Rauchs, Géraldine

Article Type: Research Article

Abstract: Information that is processed with reference to the self (i.e., self-referential processing, SRP) is generally associated with better remembering than information processed in a semantic condition. This benefit of self on memory performance is called self-reference effect (SRE). In the present study, we assessed changes in the SRE and SRP-related brain activity in patients diagnosed with mild cognitive impairment or early Alzheimer’s disease (MCI/AD). Fifteen patients with confirmed amyloid-β deposits (positive florbetapir-PET scan) and 28 healthy controls (negative florbetapir-PET scan) were included. Participants either had to judge personality trait adjectives with reference to themselves (self condition) or to a celebrity …(other condition), or determine whether these adjectives were positive or not (semantic condition). These adjectives were then presented with distractors in a surprise recognition task. Functional MRI data were acquired during both the judgment and recognition tasks. The SRE was observed in controls, but reduced in patients. Both controls and patients activated cortical midline structures when judging items with reference to themselves, but patients exhibited reduced activity in the angular gyrus. In patients, activity at encoding in the angular gyrus positively correlated with subsequent recognition accuracy in the self condition (self accuracy). This region also exhibited significant hypometabolism and Aβ burden, both related to self accuracy. By contrast, there were no differences in brain activity during recognition, either between the self and semantic conditions, or between groups. These results highlight SRE impairment in patients with MCI/AD, despite intact activity in cortical midline structures, and suggest that dysfunction of the angular gyrus is related to this impairment. Show more

Keywords: Alzheimer’s disease, functional magnetic resonance imaging, memory, psychology, self

DOI: 10.3233/JAD-160561

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 717-731, 2017

Authors: Matías-Guiu, Jordi A. | Curiel, Rosie E. | Rognoni, Teresa | Valles-Salgado, María | Fernández-Matarrubia, Marta | Hariramani, Roshan | Fernández-Castro, Alejandro | Moreno-Ramos, Teresa | Loewenstein, David A. | Matías-Guiu, Jorge

Article Type: Research Article

Abstract: Background: The Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L) is a novel cognitive test that measures recovery from proactive semantic interference, which may be an early cognitive marker of Alzheimer’s disease (AD). Objective: To generate normative data for a Spaniard population and to validate the LASSI-L for the diagnosis of amnestic mild cognitive impairment (aMCI) and mild AD. Methods: We performed a cross-sectional study in which 97 healthy participants, 34 with aMCI, and 33 with mild AD were studied with LASSI-L and a comprehensive neuropsychological protocol. The overlapping strategy analysis was used to maximize …the sample size and to provide age- and education-adjusted normative data using a logistic regression analysis. Results: Internal consistency was 0.932. Convergent validity with the Free and Cued Selective Reminding Test was moderate. LASSI-L raw scores were correlated with age and years of education, but not gender. The area under the curve for discriminating between healthy controls and aMCI was 0.909, and between healthy controls and mild AD was 0.986. LASSI-L sub-scores representing maximum storage capacity, recovery from proactive interference, and delayed recall yielded the highest diagnostic accuracy. Conclusions: The LASSI-L is a reliable and valid test for the diagnosis of aMCI and mild AD. The age and education influences on the performance of the test and normative data are provided. LASSI-L merits further studies to evaluate its ability to detect preclinical AD and predict progression to aMCI and early dementia. Show more

Keywords: Alzheimer’s disease, LASSI-L, memory, mild cognitive impairment, neuropsychological assessment, proactive interference, validation

DOI: 10.3233/JAD-160866

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 733-742, 2017

Authors: Liu, Peng | Reichl, John H. | Rao, Eshaan R. | McNellis, Brittany M. | Huang, Eric S. | Hemmy, Laura S. | Forster, Colleen L. | Kuskowski, Michael A. | Borchelt, David R. | Vassar, Robert | Ashe, Karen H. | Zahs, Kathleen R.

Article Type: Research Article

Abstract: There exist several dozen lines of transgenic mice that express human amyloid-β protein precursor (AβPP) with Alzheimer’s disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we …provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ∼4.5 times that of 21-month-old Tg2576 mice and ∼15 times that of 21–24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwe PS1Δ E9, and 5XFAD mice eventually far exceeded those measured in the human cohort. Show more

Keywords: Alzheimer’s disease, amyloid plaque, amyloid-β protein precursor, plaque burden, plaque size, Thioflavin S, transgenic mouse

DOI: 10.3233/JAD-161027

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 743-761, 2017

Authors: Borghys, Herman | Van Broeck, Bianca | Dhuyvetter, Deborah | Jacobs, Tom | de Waepenaert, Katja | Erkens, Tim | Brooks, Melissa | Thevarkunnel, Sandy | Araujo, Joseph A.

Article Type: Research Article

Abstract: Understanding differences in Alzheimer’s disease biomarkers before the pathology becomes evident can contribute to an improved understanding of disease pathogenesis and treatment. A decrease in amyloid-β (Aβ)42 in cerebrospinal fluid (CSF) is suggested to be a biomarker for Aβ deposition in brain. However, the relevance of CSF Aβ levels prior to deposition is not entirely known. Dogs are similar to man with respect to amyloid-β protein precursor (AβPP)-processing, age-related amyloid plaque deposition, and cognitive dysfunction. In the current study, we evaluated the relation between CSF Aβ42 levels and cognitive performance in young to middle-aged dogs (1.5–7 years old). …Additionally, CSF sAβPPα and sAβPPβ were measured to evaluate AβPP processing, and CSF cytokines were measured to determine the immune status of the brain. We identified two groups of dogs showing consistently low or high CSF Aβ42 levels. Based on prior studies, it was assumed that at this age no cerebral amyloid plaques were likely to be present. The cognitive performance was evaluated in standard cognition tests. Low or high Aβ concentrations coincided with low or high sAβPPα, sAβPPβ, and CXCL-1 levels, respectively. Dogs with high Aβ concentrations showed significant learning impairments on delayed non-match to position (DNMP), object discrimination, and reversal learning compared to dogs with low Aβ concentrations. Our data support the hypothesis that high levels of CSF Aβ in dogs coincide with lower cognitive performance prior to amyloid deposition. Further experiments are needed to investigate this link, as well as the relevance with respect to Alzheimer’s disease pathology progression. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, biomarker, cognition, dog

DOI: 10.3233/JAD-160434

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 763-774, 2017

Authors: Brandscheid, Carolin | Schuck, Florian | Reinhardt, Sven | Schäfer, Karl-Herbert | Pietrzik, Claus U. | Grimm, Marcus | Hartmann, Tobias | Schwiertz, Andreas | Endres, Kristina

Article Type: Research Article

Abstract: The regulation of physiological gut functions such as peristalsis or secretion of digestive enzymes by the central nervous system via the Nervus vagus is well known. Recent investigations highlight that pathological conditions of neurological or psychiatric disorders might directly interfere with the autonomous neuronal network of the gut – the enteric nervous system, or even derive from there. By using a murine Alzheimer’s disease model, we investigated a potential influence of disease-associated changes on gastrointestinal properties. 5xFAD mice at three different ages were compared to wild type littermates in regard to metabolic parameters and enzymes of the gut by …fluorimetric enzyme assay and western blotting. Overexpression of human amyloid-β protein precursor (AβPP) within the gut was assessed by qPCR and IHC; fecal microbiome analysis was conducted by 16SrRNA quantitation of selected phyla and species. While general composition of fecal samples, locomotion, and food consumption of male 5xFAD animals were not changed, we observed a reduced body weight occurring at early pathological stages. Human AβPP was not only expressed within the brain of these mice but also in gut tissue. Analysis of fecal proteins revealed a reduced trypsin amount in the 5xFAD model mice as compared to the wild type. In addition, we observed changes in fecal microbiota composition along with age. We therefore suggest that the presence of the mutated transgenes (AβPP and PS1), which are per se the basis for the genetic form of Alzheimer’s disease in humans, directly interferes with gut function as shown here for the disease model mice. Show more

Keywords: Alzheimer’s disease, gut, microbiome, trypsin

DOI: 10.3233/JAD-160926

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 775-788, 2017

Authors: Meijboom, Rozanna | Steketee, Rebecca M.E. | Ham, Leontine S. | van der Lugt, Aad | van Swieten, John C. | Smits, Marion

Article Type: Research Article

Abstract: Semantic dementia (SD) and behavioral variant frontotemporal dementia (bvFTD), subtypes of frontotemporal dementia, are characterized by distinct clinical symptoms and neuroimaging features, with predominant left temporal grey matter (GM) atrophy in SD and bilateral or right frontal GM atrophy in bvFTD. Such differential hemispheric predilection may also be reflected by other neuroimaging features, such as brain connectivity. This study investigated white matter (WM) microstructure and functional connectivity differences between SD and bvFTD, focusing on the hemispheric predilection of these differences. Eight SD and 12 bvFTD patients, and 17 controls underwent diffusion tensor imaging and resting state functional MRI at 3T. …Whole-brain WM microstructure was assessed to determine distinct WM tracts affected in SD and bvFTD. For these tracts, diffusivity measures and lateralization indices were calculated. Functional connectivity was established for GM regions affected in early stage SD or bvFTD. Results of a direct comparison between SD and bvFTD are reported. Whole-brain WM microstructure abnormalities were more pronounced in the left hemisphere in SD and bilaterally— with a slight predilection for the right— in bvFTD. Lateralization of tract-specific abnormalities was seen in SD only, toward the left hemisphere. Functional connectivity of disease-specific regions was mainly decreased bilaterally in SD and in the right hemisphere in bvFTD. SD and bvFTD show WM microstructure and functional connectivity abnormalities in different regions, that are respectively more pronounced in the left hemisphere in SD and in the right hemisphere in bvFTD. This indicates differential hemispheric predilection of brain connectivity abnormalities between SD and bvFTD. Show more

Keywords: Behavioral variant frontotemporal dementia, diffusion tensor imaging, functional connectivity, lateralization, resting state functional MRI, semantic dementia, white matter microstructure

DOI: 10.3233/JAD-160564

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 789-804, 2017