Journal of Alzheimer's Disease - Volume 61, issue 3

Authors: Nielsen, Malene Schjnning | Simonsen, Anja Hviid | Siersma, Volkert | Hasselbalch, Steen Gregers | Hoegh, Peter

Article Type: Research Article

Abstract: Background: Daily living requires the ability to perform dual-tasking. As cognitive skills decrease in dementia, performing a cognitive and motor task simultaneously become increasingly challenging and subtle gait abnormalities may even be present in pre-dementia stages. Therefore, a dual-tasking paradigm, such as the Timed Up and Go-Dual Task (TUG-DT), may be useful in the diagnostic assessment of mild cognitive impairment (MCI). Objective: To investigate the diagnostic and prognostic ability of a dual-tasking paradigm in patients with MCI or mild Alzheimer’s disease (AD) and to evaluate the association between the dual-tasking paradigm and cerebrospinal fluid (CSF) AD biomarkers. …Methods: The study is a prospective cohort study conducted in a clinical setting in two memory clinics. Eighty-six patients were included (28 MCI, 17 AD, 41 healthy controls (HC)). The ability to perform dual-tasking was evaluated by the TUG-DT. Patients underwent a standardized diagnostic assessment and were evaluated to determine progression yearly. Results: ROC curve analysis illustrated a high discriminative ability of the dual-tasking paradigm in separating MCI patients from HC (AUC: 0.78, AUC: 0.82) and a moderate discriminative ability in separating MCI from AD (AUC: 0.73, AUC: 0.55). Performance discriminated clearly between all groups (p  < 0.01). Logistic regression analyses revealed a low prognostic value of the dual-tasking paradigm for progression and rate of cognitive decline. A moderately strong correlation between the dual-tasking paradigm and CSF AD biomarkers was observed. Conclusion: In our study, we found that patients with MCI and mild AD have increasing difficulties in dual-tasking compared to healthy elderly. Hence, the dual-tasking paradigm may be a potential complement in the diagnostic assessment in a typical clinical setting. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, diagnosis, gait, mild cognitive impairment, motor control, prognosis

DOI: 10.3233/JAD-161310

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1189-1199, 2018

Authors: Arner, Andrew | Rockenstein, Edward | Mante, Michael | Florio, Jazmin | Masliah, Deborah | Salehi, Bahar | Adame, Anthony | Overk, Cassia | Masliah, Eliezer | Rissman, Robert A.

Article Type: Research Article

Abstract:  Alzheimer’s disease (AD) is the most common tauopathy, characterized by progressive accumulation of amyloid-β (Aβ) and hyperphosphorylated tau. While pathology associated with the 4-repeat (4R) tau isoform is more abundant in corticobasal degeneration and progressive supranuclear palsy, both 3R and 4R tau isoforms accumulate in AD. Many studies have investigated interactions between Aβ and 4R tau in double transgenic mice, but few, if any, have examined the effects of Aβ with 3R tau. To examine this relationship, we crossed our APP751 mutant line with our recently characterized 3R tau mutant model to create a bigenic line (hAPP-3RTau) to model AD …neuropathology. Mice were analyzed at 3 and 6 months of age for pathological and behavioral endpoints. While both the 3RTau and the hAPP-3RTau mice showed neuronal loss, increased tau aggregation, Aβ plaques and exhibited more behavioral deficits compared to the non-tg control, the bigenic mice often displaying relatively worsening levels. We found that even in young animals we found that the presence of APP/Aβ increased the accumulation of 3R tau in the neocortex and hippocampus. This observation was accompanied by activation of GSK3 and neurodegeneration in the neocortex and CA1 region. These results suggest that in addition to 4R tau, APP/Aβ may also enhance accumulation of 3R tau, a process which may be directly relevant to pathogenic pathways in AD. Our results demonstrate that this bigenic model closely parallels the pathological course of AD and may serve as a valuable model for testing new pharmacological interventions. Show more

Keywords: 3R tau, Alzheimer’s disease, amyloid-β, hippocampus, mouse, Pick’s disease, tau phosphorylation, transgenic

DOI: 10.3233/JAD-170388

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1201-1219, 2018

Authors: Eldholm, Rannveig Sakshaug | Barca, Maria Lage | Persson, Karin | Knapskog, Anne-Brita | Kersten, Hege | Engedal, Knut | Selbæk, Geir | Brækhus, Anne | Skovlund, Eva | Saltvedt, Ingvild

Article Type: Research Article

Abstract: Background: The course of Alzheimer’s disease (AD) varies considerably between individuals. There is limited evidence on factors important for disease progression. Objective: The primary aim was to study the progression of AD, as measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). Secondary aims were to investigate whether baseline characteristics are important for differences in progression, and to examine the correlation between progression assessed using three different instruments: CDR-SB (0–18), the cognitive test Mini-Mental State Examination (MMSE, 0–30), and the functional measure Instrumental Activities of Daily Living (IADL, 0-1). Methods: The Progression of AD …and Resource use (PADR) study is a longitudinal observational study in three Norwegian memory clinics. Results: In total, 282 AD patients (mean age 73.3 years, 54% female) were followed for mean 24 (16–37) months. The mean annual increase in CDR-SB was 1.6 (SD 1.8), the mean decrease in MMSE score 1.9 (SD 2.6), and the mean decrease in IADL score 0.13 (SD 0.14). Of the 282 patients, 132 (46.8%) progressed slowly, with less than 1 point yearly increase in CDR-SB. Cognitive test results at baseline predicted progression rate, and together with age, ApoE, history of hypertension, and drug use could explain 17% of the variance in progression rate. The strongest correlation of change was found between CDR-SB and IADL scores, the weakest between MMSE and IADL scores. Conclusion: Progression rate varied considerably among AD patients; about half of the patients progressed slowly. Cognitive test results at baseline were predictors of progression rate. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia, mild cognitive impairment, prognosis, progression

DOI: 10.3233/JAD-170436

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1221-1232, 2018

Authors: Nikolai, Tomas | Stepankova, Hana | Kopecek, Miloslav | Sulc, Zdenek | Vyhnalek, Martin | Bezdicek, Ondrej

Article Type: Research Article

Abstract: Background: Outside of the United States, international perspectives on normative data for neuropsychological test performance, within diverse populations, have been scarce. The neuropsychological test battery from the Uniform Data Set (UDS) of the Alzheimer’s Disease Centers (ADC) program of the United States National Institute on Aging (NIA) is one of the most sensitive batteries for the evaluation of both normal cognitive aging and pathological cognitive decline. Objective: This study aimed to determine the feasibility of the Czech Neuropsychological Test Battery from the Uniform Data Set (UDS-Cz 2.0), while also evaluating the results obtained from an international perspective. …Methods: This paper describes data from 520 cognitively normal participants. Regression analyses were used to describe the influence of demographic variables on UDS-Cz test performance. Results: Cognitive performance on all measures declined with age, with patient education level serving as a protective factor. Therefore, the present study provides normative data for the UDS-Cz, adjusted for the demographic variables of age and education. Conclusion: The present study determines the psychometric properties of the UDS-Cz and establishes normative values in the aging Czech population, which can be used in clinical settings. Show more

Keywords: Aging, Alzheimer’s disease, healthy subjects, normative

DOI: 10.3233/JAD-170595

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1233-1240, 2018

Authors: Snir, Jonatan A. | Suchy, Mojmir | Bindseil, Geron A. | Kovacs, Michael | Chronik, Blaine A. | Hudson, Robert H.E. | Pasternak, Stephen H. | Bartha, Robert

Article Type: Research Article

Abstract: Background: Early detection of Alzheimer’s disease (AD) pathology is a serious challenge for both diagnosis and clinical trials. The aspartyl protease, Cathepsin D (CatD), is overexpressed in AD and could be a biomarker of disease. We have previously designed a unique contrast agent (CA) for dual-optical and magnetic resonance imaging of the activity of the CatD class of enzymes. Objective: To compare the uptake and retention of a novel, more sensitive, and clinically-translatable 68 Ga PET tracer targeting CatD activity in 5XFAD mice and non-Tg littermates. Methods: The targeted CA consisted of an HIV-1 Tat cell …penetrating peptide (CPP) conjugated to a specialized cleavage sequence targeting aspartyl cathepsins and a DOTA conjugate chelating 68 Ga. PET images were acquired using a Siemens Inveon preclinical microPET in female Tg AD mice and non-Tg age matched female littermates (n  = 5–8) following intravenous CA administration at 2, 6, and 9 months of age. Additionally, 18 F fluorodeoxyglucose (FDG) PET imaging was performed at 10 months to measure glucose uptake. Results: The Tg mice showed significantly higher relative uptake rate of the targeting CA in the forebrain relative to hindbrain at all ages compared to controls, consistent with histology. In contrast, no differences were seen in CA uptake in other organs. Additionally, the Tg mice did not show any differences in relative uptake of FDG at 10 months of age in the forebrain relative to the hindbrain compared to age matched non-Tg controls. Conclusions: Elevated aspartryl cathepsin activity was detected in vivo in the 5XFAD mouse model of AD using a novel targeted PET contrast agent. Show more

Keywords: Alzheimer’s disease, cathepsin D, mice, molecular imaging, radionuclide imaging

DOI: 10.3233/JAD-170115

Citation: Journal of Alzheimer's Disease, vol. 61, no. 3, pp. 1241-1252, 2018