Journal of Alzheimer's Disease - Volume 55, issue 1

Authors: Idland, Ane-Victoria | Wyller, Torgeir Bruun | Støen, Randi | Eri, Lars Magne | Frihagen, Frede | Ræder, Johan | Chaudhry, Farrukh Abbas | Hansson, Oskar | Zetterberg, Henrik | Blennow, Kaj | Bogdanovic, Nenad | Brækhus, Anne | Watne, Leiv Otto

Article Type: Research Article

Abstract: Background: The clinical relevance of brain β-amyloidosis in older adults without dementia is not established. As delirium and dementia are strongly related, studies on patients with delirium may give pathophysiological clues. Objective: To determine whether the Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers amyloid-β 1-42 (Aβ42 ), total tau (T-tau), and phosphorylated tau (P-tau) are associated with delirium in hip fracture patients with and without dementia. Methods: CSF was collected in conjunction to spinal anesthesia in 129 patients. Delirium was assessed using the Confusion Assessment Method once daily in all patients, both pre- and postoperatively. …The diagnosis of dementia at admission was based upon clinical consensus. CSF levels of Aβ42 , T-tau, and P-tau were analyzed. Results: In patients without dementia, we found lower CSF Aβ42 levels (median, 310 ng/L versus 489 ng/L, p  = 0.006), higher T-tau levels (median, 505 ng/L versus 351 ng/L, p  = 0.02), but no change in P-tau in patients who developed delirium (n  = 16) compared to those who remained lucid (n  = 49). Delirious patients also had lower ratios of Aβ42 to T-tau (p  < 0.001) and P-tau (p  = 0.001) relative to those without delirium. CSF Aβ42 and T-tau remained significantly associated with delirium status in adjusted analyses. In patients with dementia, CSF biomarker levels did not differ between those with (n  = 54) and without delirium (n  = 10). Conclusion: The reduction in CSF Aβ42 , indicating β-amyloidosis, and increase in T-tau, indicating neurodegeneration, in hip fracture patients without dementia developing delirium indicates that preclinical AD brain pathology is clinically relevant and possibly plays a role in delirium pathophysiology. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, delirium, dementia, physiopathology

DOI: 10.3233/JAD-160461

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 371-379, 2017

Authors: Kim, Julia | Schweizer, Tom A. | Fischer, Corinne E. | Munoz, David G.

Article Type: Research Article

Abstract: Background: The pathophysiology behind psychosis in patients with Alzheimer’s disease (AD) remains unknown. Recently, vascular risk factors have been recognized as important modifiers of the clinical presentation of AD. Objective: The purpose of our study is to investigate the mechanism through which vascular risk factors mediate psychosis and whether or not it involves cerebrovascular lesions. Methods: Data was provided by the National Alzheimer’s Coordinating Centre. The Uniform Data Set was used to collect information on subject-reported history of vascular risk factors, clinician-reported state of cognitive performance, and presence of psychosis based on the Neuropsychiatric Inventory …Questionnaire (NPI-Q). The Neuropathology Data Set was used to evaluate the presence of vascular lesions and the severity of AD pathology. Subjects with high probability of AD based on the NIA/AA Reagan criteria were included in the analysis. Results: We identified 1,459 patients with high probability of AD and corresponding NPI-Q scores. We confirmed the association between hypertension and diabetes on psychosis, specifically in delusions and the co-occurrence of delusions and hallucinations. Furthermore, the presence of white matter rarefaction based on pathological evaluation was associated with hallucinations. A history of vascular risk factors was positively associated with vascular lesions. However, vascular lesions in the presence of vascular risk factors did not increase the likelihood of psychosis. Furthermore, vascular lesions were not associated with greater cognitive or functional impairments in this group with severe AD pathology. Conclusion: Vascular risk factors and vascular lesions are independently associated with psychosis in patients with severe AD. However, vascular lesions are not the mechanism through which vascular risk factors mediate psychosis. Show more

Keywords: Cerebrovascular diseases, delusions, dementia, hallucinations, infarction, neuropathology, pathology, risk factors, vascular

DOI: 10.3233/JAD-160506

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 381-389, 2017

Authors: Fisher, Carolyn L. | Resnick, Ross J. | De, Soumya | Acevedo, Lucila A. | Lu, Kun Ping | Schroeder, Frank C. | Nicholson, Linda K.

Article Type: Research Article

Abstract: The cis /trans isomerization of X-Pro peptide bonds in proteins in some instances acts as a molecular switch in biological pathways. Our prior work suggests that the cis isomer of the phospho-Thr668-Pro669 motif, located in the cytoplasmic domain of the amyloid-β protein precursor (AβPP), is correlated with an increase in amyloidogenic processing of AβPP and production of amyloid-beta (Aβ), the neurotoxic peptide fragment in Alzheimer’s disease (AD). We designed a 100% cis -locked cyclic dipeptide composed of cyclized phospho-Thr-Pro (pCDP) as a mimic for this putative pathological conformation, and three phosphate-blocked derivatives (pCDP-diBzl, pCDP-Bzl, and pCDP-diPOM). Two H4 …neuroglioma cell lines were established as AD cell models for use in testing these compounds: H4-AβPP695 for stable overexpression of wild-type AβPP695, and H4-BACE1 for stable overexpression of β-site AβPP cleaving enzyme-1 (BACE1). The level of the secreted AβPP fragment resulting from BACE1 activity, sAβPPβ, served as a key proxy for amyloidogenic processing, since cleavage of AβPP by BACE1 is a requisite first step in Aβ production. Of the compounds tested, pCDP-diBzl decreased sAβPPβ levels in both cell lines, while pCDP-diPOM decreased sAβPPβ levels in only H4-BACE1 cells, all with similar dose-dependences and patterns of proteolytic AβPP fragments. Enzymatic assays showed that none of the pCDP derivatives directly inhibit BACE1 catalytic activity. These results suggest a model in which pCDP-diBzl and pCDP-diPOM act at a common point to inhibit entry of AβPP into the amyloidogenic AβPP processing pathway but through different targets, and provide important insights for the development of novel AD therapeutics. Show more

Keywords: Alzheimer’s disease, amyloid beta-protein precursor, cyclic dipeptides, diketopiperazine, phosphorylated Thr668

DOI: 10.3233/JAD-160051

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 391-410, 2017

Authors: Banks, William A. | Kovac, Andrej | Majerova, Petra | Bullock, Kristin M. | Shi, Min | Zhang, Jing

Article Type: Research Article

Abstract: Tauopathies are a hallmark of many neurodegenerative diseases, including Alzheimer’s disease and traumatic brain injuries. It has been demonstrated that amyloid-beta peptides, alpha-synuclein, and prion proteins cross the blood-brain barrier (BBB), contributing to their abilities to induce disease. Very little is known about whether tau proteins can cross the BBB. Here we systematically characterized several key forms of tau proteins to cross the BBB, including Tau-441 (2N4R), Tau-410 (2N3R), truncated tau 151–391 (0N4R), and truncated tau 121–227. All of these tau proteins crossed the BBB readily and bidirectonally; however, only Tau-410 had a saturable component to its influx. The tau …proteins also entered the blood after their injection into the brain, with Tau 121–227 having the slowest exit from brain. The tau proteins varied in regards to their enzymatic stability in brain and blood and in their peripheral pharmacokinetics. These results show that blood-borne tau proteins could contribute to brain tauopathies. The result also suggest that the CNS can contribute to blood levels of tau, raising the possibility that, as suggested for other misfolded proteins, blood levels of tau proteins could be used as a biomarker of CNS disease. Show more

Keywords: Alzheimer’s disease, blood-brain barrier, tau protein, tauopathy

DOI: 10.3233/JAD-160542

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 411-419, 2017

Authors: Serra, Laura | Mancini, Matteo | Cercignani, Mara | Di Domenico, Carlotta | Spanò, Barbara | Giulietti, Giovanni | Koch, Giacomo | Marra, Camillo | Bozzali, Marco

Article Type: Research Article

Abstract: Cognitive reserve (CR) is known to modulate the clinical features of Alzheimer’s disease (AD). This concept may be critical for the development of non-pharmacological interventions able to slow down patients’ cognitive decline in the absence of disease-modifying treatments. We aimed at identifying the neurobiological substrates of CR (i.e., neural reserve) over the transition between normal aging and AD, by assessing the underlying brain networks and their topological properties. A cohort of 154 participants (n  = 68 with AD, n  = 61 with amnestic mild cognitive impairment (aMCI), and 25 healthy subjects) underwent resting-state functional MRI and neuropsychological testing. Within each group, participants …were classified as having high or low CR, and functional connectivity measures were compared, within group, between high and low CR individuals. Network-based statistics and topological network properties derived from graph theory were explored. Connectivity differences between high and low CR were evident only for aMCI patients, with participants with high CR showing a significant increase of connectivity in a network involving mainly fronto-parietal nodes. Conversely, they showed significantly decreased connectivity in a network involving fronto-temporo-cerebellar nodes. Consistently, changes to topological measures were observed in either direction, and were associated with measures of global cognitive function. These findings support the hypothesis that CR impacts on neurodegenerative process in the early phase of AD only. In addition, they fit with the existence of a “neural reserve”, characterized by specific neural networks and their efficiency. It remains to be demonstrated whether interventions later in life can modulate this “neural reserve”. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, brain connectivity, cognitive reserve, compensatory network, neural reserve

DOI: 10.3233/JAD-160735

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 421-430, 2017

Authors: Grau-Rivera, Oriol | Calvo, Anna | Bargalló, Núria | Monté, Gemma C. | Nos, Carlos | Lladó, Albert | Molinuevo, José Luis | Gelpi, Ellen | Sánchez-Valle, Raquel

Article Type: Research Article

Abstract: Background: Quantitative neuroimaging might unveil abnormalities in prion diseases that are not perceivable at visual inspection. On the other hand, scarce studies have quantified volumetric changes in prion diseases. Objectives: We aim to characterize volumetric and diffusion tensor imaging (DTI) changes in patients with prion diseases who presented with either Creutzfeldt-Jakob disease (CJD) or fatal insomnia (FI) phenotype. Methods: Twenty patients with prion diseases— 15 with CJD and 5 with fatal insomnia (FI)— and 40 healthy controls were examined with a 3-Tesla magnetic resonance imaging scanner. Images were segmented and normalized with SPM12. DTI maps …were obtained with FMRIB Software Library. Whole-brain voxel-wise and region-of-interest analyses of volumetric and DTI changes were performed with SPM12. White matter (WM) changes were also analyzed with tract-based spatial statistics. Semiquantitive assessment of neuropathological parameters was compared with DTI metrics in thalamus from 11 patients. Results: Patients with CJD and FI presented significant atrophy in thalamus and cerebellum. In CJD, mean diffusivity (MD) was decreased in striatum and increased in subcortical WM, while both increased and decreased values were observed across different thalamic nuclei. In FI, MD was increased in thalamus and cerebellum. Spongiform change and PrPSc deposition were more intense in thalamus in CJD than in FI, although no significant correlations arose with MD values in the nuclei studied. Conclusion: Volumetric and DTI abnormalities suggest a central common role of the thalamus in prion diseases. We report, for the first time, quantitative MRI changes in FI, and provide further evidence of WM involvement in prion diseases. Show more

Keywords: Creutzfeldt-Jakob syndrome, diffusion tensor imaging, fatal familial insomnia, neuroimaging, prion diseases

DOI: 10.3233/JAD-160750

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 431-443, 2017

Article Type: Retraction

DOI: 10.3233/JAD-179001

Citation: Journal of Alzheimer's Disease, vol. 55, no. 1, pp. 445-445, 2017