Journal of Alzheimer's Disease - Volume 60, issue 1

Authors: Atee, Mustafa | Hoti, Kreshnik | Parsons, Richard | Hughes, Jeffery D.

Article Type: Research Article

Abstract: Pain is common among people with moderate to severe dementia, but inability of patients to self-report means it often goes undetected and untreated. We developed the electronic Pain Assessment Tool (ePAT) to address this issue. A point-of-care App, it utilizes facial recognition technology to detect facial micro-expressions indicative of pain. ePAT also records the presence of pain-related behaviors under five additional domains (Voice, Movement, Behavior, Activity, and Body). In this observational study, we assessed the psychometric properties of ePAT compared to the Abbey Pain Scale (APS). Forty aged care residents (70% females) over the age of 60 years, with moderate …to severe dementia and a history of pain-related condition(s) were recruited into the study. Three hundred and fifty-three paired pain assessments (either at rest or post-movement) were recorded and analyzed. The ePAT demonstrated excellent concurrent validity (r  = 0.882, 95% CI: 0.857–0.903) and good discriminant validity. Inter-rater reliability score was good overall (weighted κ = 0.74, 95% CI: 0.68–0.80) while internal consistency was excellent. ePAT has psychometric properties which make it suitable for use in non-communicative patients with dementia. ePAT also has the advantage of automated facial expression assessment which provides objective and reproducible evidence of the presence of pain. Show more

Keywords: Automated, dementia, ePAT, facial recognition technology, FACS, older people, pain assessment, psychometric evaluation, reliability, validation

DOI: 10.3233/JAD-170375

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 137-150, 2017

Authors: Cavedo, Enrica | Suppa, Per | Lange, Catharina | Opfer, Roland | Lista, Simone | Galluzzi, Samantha | Schwarz, Adam J. | Spies, Lothar | Buchert, Ralph | Hampel, Harald | for the Alzheimer’s Disease Neuroimaging Initiative | for the Alzheimer Precision Medicine Initiative (APMI)

Article Type: Research Article

Abstract: Background: MRI-based hippocampus volume is a core clinical biomarker for identification of Alzheimer’s disease (AD). Objective: To assess robustness of automatic hippocampus volumetry with the freely available FSL-FIRST software with respect to short-term repeat and across field strength imaging. FSL-FIRST hippocampus volume (FIRST-HV) was also evaluated as enrichment biomarker for mild cognitive impairment (MCI) trials. Methods: Robustness of FIRST-HV was assessed in 51 healthy controls (HC), 74 MCI subjects, and 28 patients with AD dementia from ADNI1, each with two pairs of back-to-back scans, one at 1.5T one at 3T. Enrichment performance was tested in a …second sample of 287 ADNI MCI subjects. Results: FSL-FIRST worked properly in all four scans in 147 out of 153 subjects of the first sample (49 HC, 72 MCI, 26 AD). In these subjects, FIRST-HV did not differ between the first and the second scan within an imaging session, neither at 1.5T nor at 3T (p ≥0.302). FIRST-HV was on average 0.78% larger at 3T compared to 1.5T (p  = 0.012). The variance of the FIRST-HV difference was larger in the inter-field strength setting than in the intra-scanner settings (p  < 0.0005). Computer simulations suggested that the additional variability encountered in the inter-field strength scenario does not cause a relevant degradation of FIRST-HV’s prognostic performance in MCI. FIRST-HV based enrichment resulted in considerably increased effect size of the 2-years change of cognitive measures. Conclusion: The impact of intra-scanner test-retest and inter-field strength variability of FIRST-HV on clinical tasks is negligible. In addition, FIRST-HV is useful for enrichment in clinical MCI trials. Show more

Keywords: Alzheimer’s disease, clinical trials, FSL-FIRST, hippocampus, mild cognitive impairment, reproducibility, test/retest

DOI: 10.3233/JAD-161108

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 151-164, 2017

Authors: Paouri, Evi | Tzara, Ourania | Zenelak, Sofia | Georgopoulos, Spiros

Article Type: Research Article

Abstract: Increasing evidence suggests that neuroinflammation comprises a major characteristic of Alzheimer’s disease (AD). Tumor necrosis factor-α (TNF-α) is a pleiotropic pro-inflammatory cytokine implicated in neurodegenerative diseases including AD, and has been proposed as a potent therapeutic target for AD. Although a number of studies focusing on pharmacological or genetic manipulation of TNF-α and its receptors in AD mice have provided significant knowledge regarding the role of TNF-α signaling pathway in the pathogenesis of AD, the consequences of TNF-α genetic deletion have not been thoroughly examined. Here, we focused on the effect of TNF-α deficiency on the amyloid phenotype of 5XFAD …mice. Our analysis revealed that amyloid deposition, amyloid-β (Aβ) levels, and AβPP-carboxyterminal fragments are significantly reduced in the brains of 5XFAD/TNF-α-/- mice compared to the 5XFAD/TNF-α+/+ . We found decreased protein levels of β- and α-secretases in the 5XFAD/TNF-α-/- brains, suggesting for an effect of TNF-α on AβPP processing and Aβ generation. We also show for the first time that TNF-α affects PS1in vivo, as 5XFAD mice lacking TNF-α expression display reduced PS1-carboxyterminal fragments implying for diminished PS1 activity. Moreover, TNF-α deficiency decreases microglial and astrocytic activation and significantly restricts the phagocytic activity of macrophages against Aβ, supporting for reduced responsiveness of phagocytes toward Aβ. Overall, our results reveal that TNF-α genetic deletion in 5XFAD mice attenuates amyloid plaque formation by lowering Aβ generation through the reduction of functionally active PS1 and β-secretase rather than promoting Aβ clearance by phagocytic cells. Our data further suggest TNF-α inhibition as a therapeutic approach for AD. Show more

Keywords: Alzheimer’s disease, TNF-α, 5XFAD, mouse models, amyloid-β, β-secretase, presenilin-1, neuroinflammation, glia

DOI: 10.3233/JAD-170065

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 165-181, 2017

Authors: Santangelo, Roberto | Cecchetti, Giordano | Bernasconi, Maria Paola | Cardamone, Rosalinda | Barbieri, Alessandra | Pinto, Patrizia | Passerini, Gabriella | Scomazzoni, Francesco | Comi, Giancarlo | Magnani, Giuseppe

Article Type: Research Article

Abstract: Co-existence of Alzheimer’s disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42 ), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and …p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH. Show more

Keywords: Amyloid-β 42, cerebral amyloid burden, glymphatic system, normal pressure hydrocephalus, phosphorylated tau, tau protein

DOI: 10.3233/JAD-170186

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 183-200, 2017

Authors: Miller, Anne-Marie | Balasa, Mircea | Blennow, Kaj | Gardiner, Mary | Rutkowska, Aleksandra | Scheltens, Philip | Teunissen, Charlotte E. | Visser, Pieter Jelle | Winblad, Bengt | Waldemar, Gunhild | Lawlor, Brian

Article Type: Research Article

Abstract: Background: BIOMARKAPD seeks to diminish the barriers associated with the clinical use of cerebrospinal fluid (CSF) biomarker analysis by reducing variation in CSF laboratory methodologies and generating consensus recommendations on their clinical interpretation and application for dementia diagnosis. Objective: To examine the disparity in practitioner attitudes and clinical practice relating to the use of CSF biomarkers for dementia diagnosis across Europe. Methods: Clinical dementia experts were surveyed on the prevalence of national consensus guidelines and analytical reimbursement across Europe, their biomarker platform preferences, lumbar puncture methodologies and application of reference values and cut-offs for CSF analysis. …Results: 74% of respondents (total n  = 51) use CSF biomarkers in clinical practice and 69% perform lumbar punctures on an outpatient basis. Most use CSF biomarkers to diagnose atypical (84%) and early-onset cases of cognitive impairment (71%) and for the differential diagnosis of other dementias (69%). 82% state they are sufficiently informed about CSF biomarkers yet 61% report a lack of national consensus guidelines on their use for dementia diagnosis. 48% of countries represented do not reimburse clinical CSF analysis costs. 43% report using normal reference ranges derived from publications. Conclusion: Variations in attitude and practice relating to CSF biomarkers, widely recognised as barriers to their clinical acceptance, remain evident within and between countries across Europe, even in expert centres. These shortcomings must be addressed by developing consensus guidelines on CSF-related methodologies and their clinical application, to further their use for the diagnostic evaluation of dementia. Show more

Keywords: Alzheimer’s disease, attitudes, biomarkers, cerebrospinal fluid, dementia

DOI: 10.3233/JAD-170502

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 201-210, 2017

Authors: Beagle, Alexander J. | Darwish, Sonja M. | Ranasinghe, Kamalini G. | La, Alice L. | Karageorgiou, Elissaios | Vossel, Keith A.

Article Type: Research Article

Abstract: Background: Patients with Alzheimer’s disease (AD) are more prone to seizures and myoclonus, but relative risk of these symptoms among other dementia types is unknown. Objective: To determine incidence of seizures and myoclonus in the three most common neurodegenerative dementias: AD, dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Methods: Our institution’s medical records were reviewed for new-onset unprovoked seizures and myoclonus in patients meeting criteria for AD (n  = 1,320), DLB (n  = 178), and FTD (n  = 348). Cumulative probabilities of developing seizures and myoclonus were compared between diagnostic groups, whereas age-stratified incidence rates were determined …relative to control populations. Results: The cumulative probability of developing seizures after disease onset was 11.5% overall, highest in AD (13.4%) and DLB (14.7%) and lowest in FTD (3.0%). The cumulative probability of developing myoclonus was 42.1% overall, highest in DLB (58.1%). The seizure incidence rates, relative to control populations, were nearly 10-fold in AD and DLB, and 6-fold in FTD. Relative seizure rates increased with earlier age-at-onset in AD (age <50, 127-fold; 50–69, 21-fold; 70+, 2-fold) and FTD (age <50, 53-fold; 50–69, 9-fold), and relative myoclonus rates increased with earlier age-at-onset in all groups. Seizures began an average of 3.9 years after the onset of cognitive or motor decline, and myoclonus began 5.4 years after onset. Conclusions: Seizures and myoclonus occur with greater incidence in patients with AD, DLB, and FTD than in the general population, but rates vary with diagnosis, suggesting varied pathomechanisms of network hyperexcitability. Patients often experience these symptoms early in disease, suggesting hyperexcitability could be an important target for interventions. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, epilepsy, frontotemporal dementia

DOI: 10.3233/JAD-170031

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 211-223, 2017

Authors: Sugimoto, Taiki | Nakamura, Akinori | Kato, Takashi | Iwata, Kaori | Saji, Naoki | Arahata, Yutaka | Hattori, Hideyuki | Bundo, Masahiko | Ito, Kengo | Niida, Shumpei | Sakurai, Takashi | MULNIAD study group

Article Type: Research Article

Abstract: Background: Weight loss is frequently observed in patients with Alzheimer’s disease (AD); however, the underlying mechanisms are not well understood. Objects: To clarify the associations between nutritional status and AD-related brain changes using Pittsburgh Compound-B (PiB)-PET, fluorodeoxyglucose (FDG)-PET, and structural MRI. Methods: The subjects were 34 amyloid-β (Aβ)-positive individuals with mild cognitive impairment or early AD (prodromal/early AD), and 55 Aβ-negative cognitively normal (CN) subjects who attended the Multimodal Neuroimaging for AD Diagnosis (MULNIAD) study. Nutritional status of the subjects was assessed by body mass index and waist to height ratio (waist circumference/height). The associations between …nutritional status and brain changes were examined by multiple regression analysis using statistical parametric mapping. Results: In the prodromal/early AD group, nutritional status was significantly positively correlated with regional cerebral glucose metabolism (rCGM) in the medial prefrontal cortices, while different topographical associations were seen in the CN group, suggesting these changes were AD-specific. Aβ deposition and gray matter volume were not significantly associated with nutritional status. Sub-analysis in the prodromal/early AD group demonstrated that fat mass index, but not fat-free mass index, was positively correlated with rCGM in the medial prefrontal areas. Conclusion: This present study provides preliminary results suggesting that hypometabolism in the medial prefrontal areas is specifically associated with AD-related weight loss, and decrease in fat mass may have a key role. Show more

Keywords: Alzheimer’s disease, composition, 18F fluorodeoxyglucose, Pittsburgh Compound B, magnetic resonance imaging, nutritional status, positron-emission tomography

DOI: 10.3233/JAD-170257

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 225-233, 2017

Authors: Bertens, Anne Suzanne | Sabayan, Behnam | de Craen, Anton J.M. | Van der Mast, Roos C. | Gussekloo, Jacobijn

Article Type: Research Article

Abstract: Background: Impaired cardiac function has been related to accelerated cognitive decline in late-life. Objective: To investigate whether higher levels of high sensitivity cardiac troponin T (hs-cTnT), a sensitive marker for myocardial injury, are associated with worse cognitive function in the oldest old. Methods: In 455 participants of the population-based Leiden 85-plus Study, hs-cTnT was measured at 86 years. Cognitive function was measured annually during four years with the Mini-Mental State Examination (MMSE). Results: Participants in the highest gender-specific tertile of hs-cTnT had a 2.0-point lower baseline MMSE score than participants in the lowest tertile …(95% confidence interval (CI) (95% CI 0.73–3.3), and had a 0.58-point steeper annual decline in MMSE during follow-up (95% CI 0.06–1.1). The associations remained after adjusting for sociodemographic and cardiovascular risk factors excluding those without a history of overt cardiac disease. Conclusion: In a population-based sample of the oldest old, higher levels of hs-cTnT were associated with worse cognitive function and faster cognitive decline, independently from cardiovascular risk factors and a history of overt cardiac disease. Show more

Keywords: Cardiac disease, cognitive function, high sensitivity cardiac troponin T, oldest old

DOI: 10.3233/JAD-170171

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 235-242, 2017

Authors: Berman, Sara E. | Clark, Lindsay R. | Rivera-Rivera, Leonardo A. | Norton, Derek | Racine, Annie M. | Rowley, Howard A. | Bendlin, Barbara B. | Blennow, Kaj | Zetterberg, Henrik | Carlsson, Cynthia M. | Asthana, Sanjay | Turski, Patrick | Wieben, Oliver | Johnson, Sterling C.

Article Type: Research Article

Abstract: It is becoming increasingly recognized that cerebrovascular disease is a contributing factor in the pathogenesis of Alzheimer’s disease (AD). A unique 4D-Flow magnetic resonance imaging (MRI) technique, phase contrast vastly undersampled isotropic projection imaging (PC VIPR), enables examination of angiographic and quantitative metrics of blood flow in the arteries of the Circle of Willis within a single MRI acquisition. Thirty-eight participants with mild cognitive impairment (MCI) underwent a comprehensive neuroimaging protocol (including 4D-Flow imaging) and a standard neuropsychological battery. A subset of participants (n  = 22) also underwent lumbar puncture and had cerebrospinal fluid (CSF) assayed for AD biomarkers. Cut-offs for …biomarker positivity in CSF resulting from a receiver operating characteristic curve analysis of AD cases and controls from the larger Wisconsin Alzheimer’s Disease Research Center cohort were used to classify MCI participants as biomarker positive or negative on amyloid-β (Aβ42 ), total-tau and total-tau/Aβ42 ratio. Internal carotid artery (ICA) and middle cerebral artery (MCA) mean flow were associated with executive functioning performance, with lower mean flow corresponding to worse performance. MCI participants who were biomarker positive for Aβ42 had lower ICA mean flow than did those who were Aβ42 negative. In sum, mean ICA and MCA arterial flow was associated with cognitive performance in participants with MCI and lower flow in the ICA was associated with amyloid positivity. This provides further evidence for vascular health as a contributing factor in the etiopathogenesis of AD, and could represent a point to intervene in the disease process. Show more

Keywords: Aging, Alzheimer’s disease, cerebrovascular disease, mild cognitive impairment

DOI: 10.3233/JAD-170402

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 243-252, 2017

Authors: Basselerie, Hubert | Bracoud, Luc | Zeestraten, Eva | Bouguen, Eva | Kiyasova, Vera | Pueyo, Maria | Cognard, Christophe | Dumas, Hervé | Gramada, Raluca | Ousset, Pierre Jean | Vellas, Bruno | Bonneville, Fabrice

Article Type: Research Article

Abstract: Background: The relationship between cerebral microbleeds (CMB) and Alzheimer’s disease (AD) has not yet been clearly determined, particularly with susceptibility weight-imaging (SWI). Objective: To evaluate the SWI sequence using 3T MRI for the detection of CMB, and its ability to differentiate elderly control subjects (CS), stable mild cognitive impairment patients (MCI-s), MCI patients progressing to AD (MCI-p), and AD patients. Methods: It was a prospective, monocentric, observational study that took place in Toulouse, France. Participants were 65 years and older, enrolled in three groups: CS, MCI, and AD. Based on the longitudinal analysis of cognitive decline, …MCI subjects were retrospectively classified as MCI-s or MCI-p. Each patient had a 4-year follow-up with MRI at baseline (MRI#1) and during the fourth year (MRI#3). CMB were counted on native SWI images juxtaposed to minIP reformatted images. Results: 150 patients were enrolled: 48 CS, 25 MCI-s, 18 MCI-p, 59 AD. At MRI#1 and at MRI#3, there was no significant difference in the prevalence of CMB between groups (p  = 0.75 and p  = 0.87). In the MCI-p + AD group, significantly more subjects had≥4 incident CMB compared to the CS + MCI-s group (p  = 0.016). In the MCI-p + AD group, the prevalence of patients with >4 CMB was significantly higher at MRI#3 than at MRI#1 (p  = 0.008). Conclusion: Using SWI, AD and MCI-p patients had developed significantly more new CMB than CS and MCI-s patients during the follow-up. Incident CMB might be suggested as a potential imaging marker of AD progression. Show more

Keywords: Alzheimer’s disease, disease progression, imaging biomarker, incident cerebral microbleeds, longitudinal MRI, mild cognitive impairment, susceptibility weight imaging

DOI: 10.3233/JAD-170470

Citation: Journal of Alzheimer's Disease, vol. 60, no. 1, pp. 253-262, 2017