Journal of Alzheimer's Disease - Volume 55, issue 4

Authors: Monacelli, Fiammetta | Cea, Michele | Borghi, Roberta | Odetti, Patrizio | Nencioni, Alessio

Article Type: Review Article

Abstract: In spite of in depth investigations in the field of the amyloid cascade hypothesis, so far, no disease modifying therapy has been developed for Alzheimer’s disease (AD). The pathophysiology provides some evidence of the inverse correlation between cancer and AD. Both AD and cancer are characterized by abnormal cellular behaviors; trigger factors along with a meta synchronously action is expected to drive cancer or neurodegeneration, supporting, respectively, progressive neuronal loss or uncontrolled cell proliferation in cancer cells. So far, cancer and AD are seemingly two opposite ends of the same biological spectrum. Basic science increasingly indicates shared molecular mechanisms between …cancer and AD and gives weight to key relevant biological theories; according to them, the inverse tuning of clustered gene expression, the sharing of mutual independent pathway or the deregulated unfolded proteins system (UPR) may count for this inverse association. Additionally, the common biological background gave credibility to the recent discovery of a repurposing role for cancer drugs in AD. It refers to the development of new uses for existing pharmaceuticals having the same role as the original mechanism or to the discovery of a new drug action with disease modifying effects. The present review summarizes the most important biological theories that link neurodegeneration and cancer and provides an up-to-date revision of the repurposing cancer agents for AD. The review also addresses the gap of knowledge, since drug cancer repositioning holds an important promise but further investigations are warranted to ascertain the clinical relevance of such attractive clinical candidate compounds for AD. Show more

Keywords: Alzheimer’s disease, cancer repurposing drugs

DOI: 10.3233/JAD-160840

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1295-1306, 2017

Authors: Szablewski, Leszek

Article Type: Review Article

Abstract: Neurons need a continuous supply of glucose, the major source of energy for mammalian brain metabolism. The central nervous system is protected by three main physiological cell barriers. Cell membranes are impermeable for glucose, therefore glucose is transferred across the cell membranes by specific transport proteins: sodium-independent glucose transporters (GLUTs), encoded by SLC2 genes, and sodium-dependent glucose transporters (for example SGLTs), encoded by SLC5 genes. Human brain expresses 10 GLUT proteins and 10 proteins encoded by SLC5 genes. In patients with brain diseases, particularly Alzheimer’s (AD) and Huntington’s diseases, abnormalities in neuronal glucose metabolism have been showed. …The levels of GLUT1 and GLUT3, the major brain glucose transporters, are decreased, especially in the cerebral cortex. Therefore, in AD, hypometabolism of glucose and deficits in energy are observed. Production of ATP from glucose metabolism in sporadic AD declines to 50% and the tendency to decline continues throughout the progression of the disease. This decrease is correlated with O -GlcAcetylation and tau hyperphosphorylation, as the compensatory mechanisms in AD are the utilization of endogenous brain substances and drastic increase in GLUT2 levels. The present review focuses on the changes in the expression of glucose transporters due to AD. Show more

Keywords: Alzheimer’s disease, brain, compensatory mechanisms, GLUT proteins, SGLT proteins

DOI: 10.3233/JAD-160841

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1307-1320, 2017

Authors: Fraser, Mariecia D. | Davies, John R.T. | Chang, Xianmin

Article Type: Short Communication

Abstract: Many secondary plant compounds are synthesized in response to stressed growing conditions. We tested the feasibility of exploiting this feature in a novel strategy for the commercial production of the plant alkaloid galanthamine. Experimental lines of Narcissus pseudonarcissus were established under marginal upland permanent pasture at four different sites. Over 80% of bulbs successfully established at each site. There was no effect of altitude or planting density on galanthamine concentrations within vegetative tissues, which were higher than anticipated. The results confirm that planting N. pseudonarcissus under grass competition in upland areas could offer a novel and sustainable source …of plant-derived galanthamine. Show more

Keywords: Alkaloid, daffodil, galantamine, less favored areas, plant stress

DOI: 10.3233/JAD-160791

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1321-1325, 2017

Authors: Gamir-Morralla, Andrea | Belbin, Olivia | Fortea, Juan | Alcolea, Daniel | Ferrer, Isidro | Lleó, Alberto | Iglesias, Teresa

Article Type: Short Communication

Abstract: Identification of neurodegeneration-monitoring biomarkers would be of great clinical value for Alzheimer’s disease (AD) diagnosis. Using N- or C-terminal antibodies, we studied the pro-survival synaptic effector, Kidins220, in the brain and cerebrospinal fluid (CSF) of controls and AD patients. Only the N-terminal antibody showed a positive correlation between Kidins220 and phosphorylated tau in AD brains. Using this antibody, Kidins220 was detected in CSF from AD patients where it positively correlated with CSF phosphorylated tau and tau. This study highlights the potential of Kidins220 as a CSF biomarker in AD.

Keywords: Alzheimer’s disease, amyloid, antibody, ARMS, biomarkers, calpain, cerebrospinal fluid, excitotoxicity, Kidins220, tau protein

DOI: 10.3233/JAD-160639

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1327-1333, 2017

Authors: Bergeron, David | Vermette, Antoine | De La Sablonnière, Justine | Cayer, Anne-Marie | Laforce Jr., Robert | Bouchard, Rémi W.

Article Type: Short Communication

Abstract: The finger-to-nose test is routinely performed during the clinical assessment of patients with cognitive impairments. Although widely known to screen for cerebellar dysfunction by unmasking appendicular ataxia, we have found that this test could also be interpreted from a cognitive perspective. We describe two typical signs observed at the finger-to-nose test in Alzheimer’s disease (AD) patients: the “second finger syndrome” and the “distal pressure sign”. By retrospectively reviewing the medical records 461 patients followed at our academic memory clinic, we found that these signs are commonplace in AD, but not in vascular dementia or subjective cognitive impairment.

Keywords: Alzheimer’s disease, cerebellum, dementia, diagnosis

DOI: 10.3233/JAD-160941

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1335-1337, 2017

Authors: Chau, Sarah A. | Herrmann, Nathan | Sherman, Chelsea | Chung, Jonathan | Eizenman, Moshe | Kiss, Alex | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with selective attention impairments, which could contribute to cognitive and functional deficits. Using visual scanning parameters, selective attention toward novel stimuli, or novelty preference, can be measured by a non-verbal, non-invasive method that may be of value in predicting disease progression. Objective: In this longitudinal study, we explored whether novelty preference can predict cognitive decline in AD patients. Methods: Mild to moderate AD patients viewed slides containing both novel and repeat images. The number of fixations, the average fixation time, and the relative fixation time on the two types …of images were measured by an eye-tracking system. Novelty preference was estimated by the differences between the visual scanning parameters on novel and repeat images. Cognition and attention were assessed using the Standardized Mini-Mental Status Examination (sMMSE) and the Conners’ Continuous Performance Test (CPT), respectively. Cognition was re-assessed every 6 months for up to 2 years. Results: Multivariate linear regressions of 32 AD patients (14 females, age = 77.9±7.8, baseline sMMSE = 22.2±4.4) indicated that reduced time spent on novel images (t  = 2.78, p  = 0.010) was also associated with greater decline in sMMSE scores (R2  = 0.41, Adjusted R2  = 0.35, F3,28  = 6.51, p  = 0.002), adjusting for attention and baseline sMMSE. Conclusion: These results suggest that novelty preference, measured by visual attention scanning technology, may reflect pathophysiological processes that could predict disease progression in the cognitively-impaired. Show more

Keywords: Alzheimer’s disease, novelty processing, selective attention, visual scanning

DOI: 10.3233/JAD-160641

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1339-1349, 2017

Authors: Gauba, Esha | Guo, Lan | Du, Heng

Article Type: Research Article

Abstract: Brain aging is the known strongest risk factor for Alzheimer’s disease (AD). In recent years, mitochondrial deficits have been proposed to be a common mechanism linking brain aging to AD. Therefore, to elucidate the causative mechanisms of mitochondrial dysfunction in aging brains is of paramount importance for our understanding of the pathogenesis of AD, in particular its sporadic form. Cyclophilin D (CypD) is a specific mitochondrial protein. Recent studies have shown that F1FO ATP synthase oligomycin sensitivity conferring protein (OSCP) is a binding partner of CypD. The interaction of CypD with OSCP modulates F1FO ATP synthase function and mediates mitochondrial permeability transition pore …(mPTP) opening. Here, we have found that increased CypD expression, enhanced CypD/OSCP interaction, and selective loss of OSCP are prominent brain mitochondrial changes in aging mice. Along with these changes, brain mitochondria from the aging mice demonstrated decreased F1FO ATP synthase activity and defective F1FO complex coupling. In contrast, CypD deficient mice exhibited substantially mitigated brain mitochondrial F1FO ATP synthase dysfunction with relatively preserved mitochondrial function during aging. Interestingly, the aging-related OSCP loss was also dramatically attenuated by CypD depletion. Therefore, the simplest interpretation of this study is that CypD promotes F1FO ATP synthase dysfunction and the resultant mitochondrial deficits in aging brains. In addition, in view of CypD and F1FO ATP synthase alterations seen in AD brains, the results further suggest that CypD-mediated F1FO ATP synthase deregulation is a shared mechanism linking mitochondrial deficits in brain aging and AD. Show more

Keywords: Aging brain, Cyclophilin D, F1FO ATP synthase, mitochondria, oligomycin sensitivity conferring protein

DOI: 10.3233/JAD-160822

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1351-1362, 2017

Authors: Reiter, Katherine | Nielson, Kristy A. | Durgerian, Sally | Woodard, John L. | Smith, J. Carson | Seidenberg, Michael | Kelly, Dana A. | Rao, Stephen M.

Article Type: Research Article

Abstract: Neuropathological changes associated with Alzheimer’s disease (AD) precede symptom onset by more than a decade. Possession of an apolipoprotein E (APOE ) ɛ 4 allele is the strongest genetic risk factor for late onset AD. Cross-sectional studies of cognitively intact elders have noted smaller hippocampal/medial temporal volumes in ɛ 4 carriers (ɛ 4+) compared to ɛ 4 non-carriers (ɛ 4-). Few studies, however, have examined long-term, longitudinal, anatomical brain changes comparing healthy ɛ 4+ and ɛ 4- individuals. The current five-year study examined global and regional volumes of cortical and subcortical grey and white matter and ventricular size in 42 ɛ …4+ and 30 ɛ 4- individuals. Cognitively intact participants, ages 65–85 at study entry, underwent repeat anatomical MRI scans on three occasions: baseline, 1.5, and 4.75 years. Results indicated no between-group volumetric differences at baseline. Over the follow-up interval, the ɛ 4+ group experienced a greater rate of volume loss in total grey matter, bilateral hippocampi, right hippocampal subfields, bilateral lingual gyri, bilateral parahippocampal gyri, and right lateral orbitofrontal cortex compared to the ɛ 4- group. Greater loss in grey matter volumes in ɛ 4+ participants were accompanied by greater increases in lateral, third, and fourth ventricular volumes. Rate of change in white matter volumes did not differentiate the groups. The current results indicate that longitudinal measurements of brain atrophy can serve as a sensitive biomarker for identifying neuropathological changes in persons at genetic risk for AD and potentially, for assessing the efficacy of treatments designed to slow or prevent disease progression during the preclinical stage of AD. Show more

Keywords: Alzheimer’s disease, ApoE4, longitudinal studies, MRI scans

DOI: 10.3233/JAD-160504

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1363-1377, 2017

Authors: Teipel, Stefan J. | Keller, Felix | Thyrian, Jochen R. | Strohmaier, Urs | Altiner, Attila | Hoffmann, Wolfgang | Kilimann, Ingo

Article Type: Research Article

Abstract: Background: Once a patient or a knowledgeable informant has noticed decline in memory or other cognitive functions, initiation of early dementia assessment is recommended. Hippocampus and cholinergic basal forebrain (BF) volumetry supports the detection of prodromal and early stages of Alzheimer’s disease (AD) dementia in highly selected patient populations. Objective: To compare effect size and diagnostic accuracy of hippocampus and BF volumetry between patients recruited in highly specialized versus primary care and to assess the effect of white matter lesions as a proxy for cerebrovascular comorbidity on diagnostic accuracy. Methods: We determined hippocampus and BF volumes and white …matter lesion load from MRI scans of 71 participants included in a primary care intervention trial (clinicaltrials.gov identifier: NCT01401582) and matched 71 participants stemming from a memory clinic. Samples included healthy controls and people with mild cognitive impairment (MCI), AD dementia, mixed dementia, and non-AD related dementias. Results: Volumetric measures reached similar effect sizes and cross-validated levels of accuracy in the primary care and the memory clinic samples for the discrimination of AD and mixed dementia cases from healthy controls. In the primary care MCI cases, volumetric measures reached only random guessing levels of accuracy. White matter lesions had only a modest effect on effect size and diagnostic accuracy. Conclusions: Hippocampus and BF volumetry may usefully be employed for the identification of AD and mixed dementia, but the detection of MCI does not benefit from the use of these volumetric markers in a primary care setting. Show more

Keywords: Alzheimer’s disease, basal forebrain, hippocampus, magnetic resonance imaging, mild cognitive impairment, primary care

DOI: 10.3233/JAD-160778

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1379-1394, 2017

Authors: Ryu, Hui Jin | Kim, Minyoung | Moon, Yeonsil | Choi, Yeji | Han, Jee-Young | Galvin, James E. | Han, Seol-Heui

Article Type: Research Article

Abstract: The Lewy body composite risk score (LBCRS) is a useful clinical screening tool to help determine whether the dementia is related to Lewy body pathology. The purpose of this study is to verify reliability, validity, and diagnostic usefulness of Korean version of LBCRS (K-LBCRS). CDR-sum of boxes, Mini-Mental State Examination, and standardized scales related to cognition, mood, behavior, and motor function were administered to a total of 107 subjects, including 30 dementia with Lewy bodies (DLB), 54 Alzheimer’s disease (AD), and 23 cognitively normal elderly people and their collateral informants. Internal consistency of the K-LBCRS was good with Cronbach’s alpha of 0.85, …and concurrent validity was also satisfactory, with K-LBCRS correlating highly with CDR-SB and other scales. The test-retest reliability was very high with a Pearson correlation coefficient of 0.97. The mean scores of K-LBCRS were significantly different among three groups, with DLB (6.2±2.4), AD (1.4±1.3), and controls (0.3±0.6). We identified a cut-off score of 3 as best to differentiate between DLB and AD, having AUC of 0.97 (95% CI 0.94–1.00), sensitivity 97%, specificity 83%, positive predictive value 76%, negative predictive value 98%, which is the same score suggested in the original study. This study shows K-LBCRS as a new useful screening tool for Korean DLB patients in clinical settings. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, Korean version of the Lewy body composite risk score (K-LBCRS), Lewy bodies pathology, screening tool

DOI: 10.3233/JAD-160463

Citation: Journal of Alzheimer's Disease, vol. 55, no. 4, pp. 1395-1401, 2017