Journal of Alzheimer's Disease - Volume 59, issue 1

Authors: De Simone, Maria Stefania | Fadda, Lucia | Perri, Roberta | De Tollis, Massimo | Aloisi, Marta | Caltagirone, Carlo | Carlesimo, Giovanni Augusto

Article Type: Research Article

Abstract: Retrograde amnesia (RA), which includes loss of memory for past personal events (autobiographical RA) and for acquired knowledge (semantic RA), has been largely documented in patients with amnestic mild cognitive impairment (aMCI). However, previous studies have produced controversial results particularly concerning the temporal extent of memory impairment. Here we investigated whether, with the onset of hippocampal pathology, age of memory acquisition and retrieval frequency play different roles in modulating the progressive loss of semantic and episodic contents of retrograde memory respectively. For this purpose, aMCI patients and healthy controls were tested for the ability to recall semantic and autobiographical information …related to famous public events as a function of both age of acquisition and retrieval frequency. In aMCI patients, we found that the impairment in recollecting past personal incidents was modulated by the combined action of memory age and retrieval frequency, because older and more frequently retrieved episodes are less susceptible to loss than more recent and less frequently retrieved ones. On the other side, we found that the loss of semantic information depended only on memory age, because the remoteness of the trace allows for better preservation of the memory. Our results provide evidence that the loss of the two components of retrograde memory is regulated by different mechanisms. This supports the view that diverse neural mechanisms are involved in episodic and semantic memory trace storage and retrieval, as postulated by the Multiple Trace Theory. Show more

Keywords: Cortical reallocation theory, mild cognitive impairment, multiple trace theory, retrieval frequency, retrograde amnesia, temporal gradient

DOI: 10.3233/JAD-170317

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 241-250, 2017

Authors: Tripodis, Yorghos | Alosco, Michael L. | Zirogiannis, Nikolaos | Gavett, Brandon E. | Chaisson, Christine | Martin, Brett | McClean, Michael D. | Mez, Jesse | Kowall, Neil | Stern, Robert A.

Article Type: Research Article

Abstract: Traumatic brain injury (TBI) is thought to be a risk factor for dementia, including dementia due to Alzheimer’s disease (AD). However, the influence of TBI history on the neuropsychological course of AD is unknown and, more broadly, the effect of TBI history on age-related cognitive change is poorly understood. We examined the relationship between history of TBI with loss of consciousness (LOC) history and cognitive change in participants with normal cognition and probable AD, stratified by APOE ɛ 4 allele status. The sample included 706 participants (432 with normal cognition; 274 probable AD) from the National Alzheimer’s Coordinating …Center (NACC) dataset that completed the Uniform Data Set evaluation between 2005 and 2014. Normal and probable AD participants with a history of TBI were matched to an equal number of demographically and clinically similar participants without a TBI history. In this dataset, TBI with LOC was defined as brain trauma with brief or extended unconsciousness. For the normal and probable AD cohorts, there was an average of 3.2±1.9 and 1.8±1.1 years of follow-up, respectively. 30.8% of the normal cohort were APOE ɛ 4 carriers, whereas 70.8% of probable AD participants were carriers. Mixed effects regressions showed TBI with LOC history did not affect rates of cognitive change in APOE ɛ 4 carriers and non-carriers. Findings from this study suggest that TBI with LOC may not alter the course of cognitive function in older adults with and without probable AD. Future studies that better characterize TBI (e.g., severity, number of TBIs, history of subconconcussive exposure) are needed to clarify the association between TBI and long-term neurocognitive outcomes. Show more

Keywords: Alzheimer’s disease, APOE, cognitive decline, dementia, loss of consciousness, normal cognition, risk factor, traumatic brain injury

DOI: 10.3233/JAD-160585

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 251-263, 2017

Authors: Zafar, Saima | Shafiq, Mohsin | Younas, Neelam | Schmitz, Matthias | Ferrer, Isidre | Zerr, Inga

Article Type: Research Article

Abstract: Rapidly progressive Alzheimer’s disease (rpAD) is a variant of AD distinguished by a rapid decline in cognition and short disease duration from onset to death. While attempts to identify rpAD based on biomarker profile classifications have been initiated, the mechanisms which contribute to the rapid decline and prion mimicking heterogeneity in clinical signs are still largely unknown. In this study, we characterized prion protein (PrP) expression, localization, and interactome in rpAD, slow progressive AD, and in non-dementia controls. PrP along with its interacting proteins were affinity purified with magnetic Dynabeads Protein-G, and were identified using Q-TOF-ESI/MS analysis. Our data demonstrated …a significant 1.2-fold decrease in di-glycosylated PrP isoforms specifically in rpAD patients. Fifteen proteins appeared to interact with PrP and only two proteins3/4histone H2B-type1-B and zinc alpha-2 protein3/4were specifically bound with PrP isoform isolated from rpAD cases. Our data suggest distinct PrP involvement in association with the altered PrP interacting protein in rpAD, though the pathophysiological significance of these interactions remains to be established. Show more

Keywords: Aldolase A, Alzheimer’s disease, co-immunofluorescence, co-immunoprecipitation, histone, myelin P2, peroxiredoxin 1, prion, proteomics, synapsin, tubulin, zinc

DOI: 10.3233/JAD-170237

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 265-275, 2017

Authors: Anand, Swati | Barnes, Justin M. | Young, Sydney A. | Garcia, Diana M. | Tolley, H. Dennis | Kauwe, John S.K. | Graves, Steven W.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder lacking early biochemical diagnosis and treatment. Lipids have been implicated in neurodegenerative disorders including AD. A shotgun lipidomic approach was undertaken to determine if lipid biomarkers exist that can discriminate AD cases from controls. The discovery study involved sera from 29 different stage AD cases and 32 controls. Lipid extraction was performed using organic solvent and the samples were directly infused into a time-of-flight mass spectrometer. Differences between AD cases and controls were detected with 87 statistically significant lipid candidate markers found. These potential lipid markers were reevaluated in a second confirmatory study involving …27 cases and 30 controls. Of the 87 candidates from the first study, 35 continued to be statistically significant in the second confirmatory set. Tandem MS studies were performed and almost all confirmed markers were characterized and classified. Using a Bayesian lasso probit regression model on the confirmed markers, a multi-marker set with AUC = 0.886 was developed comparing all stages of AD with controls. Additionally, using confirmed biomarkers, multi-marker sets with AUCs >0.90 were developed for each specific AD Clinical Dementia Rating versus controls, including the earliest stage of AD. More conservative and likely more realistic statistical analyses still found multi-marker sets that appeared useful in diagnosing AD. Finally, using ordinal modeling a set of markers was developed that staged AD accurately 70% of the time, p  = 0.0079. These results suggest that these serum lipidomic biomarkers may help diagnose and perhaps even stage AD. Show more

Keywords: Alzheimer’s disease, biomarkers, diagnosis, disease staging, lipidomics, mass spectrometry

DOI: 10.3233/JAD-170035

Citation: Journal of Alzheimer’s Disease, vol. 59, no. 1, pp. 277-290, 2017

Authors: Wilkins, Heather M. | Mahnken, Jonathan D. | Welch, Paul | Bothwell, Rebecca | Koppel, Scott | Jackson, Richard L. | Burns, Jeffrey M. | Swerdlow, Russell H.

Article Type: Research Article

Abstract: Reductions in bioenergetic fluxes, mitochondrial enzyme activities, and mitochondrial number are observed in Alzheimer’s disease (AD). Preclinical work indicates estrogen pathway signaling by either estrogen or selective β estrogen receptor (ERβ) agonists benefits these parameters. To assess whether an ERβ agonist could improve mitochondrial function in actual AD subjects, we administered S-equol (10 mg twice daily) to 15 women with AD and determined the platelet mitochondria cytochrome oxidase (COX) activity before initiating S-equol (lead-in), after two weeks of S-equol (active treatment), and two weeks after stopping S-equol (wash-out). Because the intra-individual variation of this enzyme across samples taken at different times …was unknown we used a nonparametric, single-arm, dichotomous endpoint that classified subjects whose active treatment COX activity exceeded the average of their lead-in and wash-out measures as positive responders. Eleven positive responses were observed (p  < 0.06). The implications of this finding on our null hypothesis (that S-equol does not influence platelet mitochondria COX activity) are discussed. To our knowledge, this is the first time a direct mitochondrial target engagement biomarker has been utilized in an AD clinical study. Show more

Keywords: Alzheimer’s disease, biomarker, cytochrome oxidase, mitochondria, S-equol

DOI: 10.3233/JAD-170077

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 291-300, 2017

Authors: Cansev, Mehmet | Turkyilmaz, Mesut | Sijben, John W.C. | Sevinc, Cansu | Broersen, Laus M. | van Wijk, Nick

Article Type: Research Article

Abstract: Chronic consumption of a diet enriched with nutritional precursors of phospholipids, including uridine and the polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), was shown previously to enhance levels of brain phospholipids and synaptic proteins in rodents. Vitamin C, vitamin E, and selenium may directly affect the breakdown or synthesis of membrane phospholipids. The present study investigated the necessity of antioxidants for the effectiveness of supplementation with uridine plus DHA and EPA (as fish oil) in rats. Rats were randomized to four treatment groups and received, for 6 weeks, one of four experimental diets, i.e., a diet low …in antioxidants, a diet high in antioxidants, a diet low in antioxidants supplemented with DHA+EPA+uridine, or a diet high in antioxidants supplemented with DHA+EPA+uridine. On completion of dietary treatment, rats were sacrificed, and brain levels of phospholipids, synaptic proteins, and two enzymes involved in phospholipid synthesis (choline-phosphate cytidylyltransferase, PCYT1A, and choline/ethanolamine phosphotransferase, CEPT1) were analyzed. Levels of phospholipids, the pre- and post-synaptic proteins Synapsin-1 and PSD95, and the enzymes PCYT1A and CEPT1 were significantly enhanced by combined supplementation of DHA+EPA+uridine and antioxidants and not enhanced by supplementation of DHA+EPA+uridine with insufficient antioxidant levels. Our data suggest that dietary vitamin C, vitamin E, and selenium are essential for the phospholipid precursors’ effects on increasing levels of membrane phospholipids and synaptic proteins, the indirect indicators of synaptogenesis. Their concomitant supply may be relevant in Alzheimer’s disease patients, because the disease is characterized by synapse loss and lower plasma and brain levels of phospholipid precursors and antioxidants. Show more

Keywords: Alzheimer’s disease, antioxidants, brain, docosahexaenoic acid, membranes, phospholipids, uridine

DOI: 10.3233/JAD-170081

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 301-311, 2017

Authors: Okuda, Michiaki | Fujita, Yuki | Hijikuro, Ichiro | Wada, Mei | Uemura, Takuya | Kobayashi, Yukako | Waku, Tomonori | Tanaka, Naoki | Nishimoto, Takaaki | Izumi, Yasuhiko | Kume, Toshiaki | Akaike, Akinori | Takahashi, Takashi | Sugimoto, Hachiro

Article Type: Research Article

Abstract: Aggregation of amyloid-β (Aβ) and tau plays a crucial role in the onset and progression of Alzheimer’s disease (AD). Therefore, the inhibition of Aβ and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aβ and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on Aβ aggregationin vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aβ and tau aggregation in vivo . PE859 inhibited Aβ aggregation in …vitro and protected cultured cells from Aβ-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aβ and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD. Show more

Keywords: Aggregation inhibitor, Alzheimer’s disease, amyloid-β , tau

DOI: 10.3233/JAD-161017

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 313-328, 2017

Authors: Krasnianski, Anna | Bohling, Geeske T. | Heinemann, Uta | Varges, Daniela | Meissner, Bettina | Schulz-Schaeffer, Walter J. | Reif, Andreas | Zerr, Inga

Article Type: Research Article

Abstract: Background: The polymorphism at codon 129 of the prion protein gene (PRNP) and the PrPSc types 1 and 2 belong to a molecular classification of sporadic Creutzfeldt-Jakob disease (sCJD) that correlates well with the clinical and neuropathological phenotype of sCJD. Objective: The aim of the study was to perform the first detailed evaluation of neuropsychological deficits in a large group of definite sCJD patients with known molecular subtype. Methods: We analyzed neuropsychological symptoms in a cohort of 248 sCJD patients with known M129 V polymorphism of PRNP and prion protein type. Results: Neuropsychological …symptoms were very frequent in our patients (96%) and occurred as early as in the first third of the disease course. Besides amnesia and impaired attention (89% each), frontal lobe syndrome (75%), aphasia (63%), and apraxia (57%) were the most common neuropsychological deficits. There was no statistically significant difference with regard to frequency of neuropsychological symptoms between the subtypes. In MV2 and VV2 patients, the onset of neuropsychological symptoms was significantly later than in all other subtypes. Conclusion: We provide the first detailed analysis of neuropsychological symptoms in a large group of sCJD patients with known M129 V genotype and prion protein type. We suggest that the rate of progression of neuropsychological symptoms is subtype-specific. These data may improve the diagnosis in atypical sCJD subtypes. Show more

Keywords: M129V polymorphism, neuropsychological symptoms, neuropsychology, prion disease, sporadic CJD

DOI: 10.3233/JAD-161129

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 329-337, 2017

Authors: Babiloni, Claudio | Del Percio, Claudio | Lizio, Roberta | Noce, Giuseppe | Cordone, Susanna | Lopez, Susanna | Soricelli, Andrea | Ferri, Raffaele | Pascarelli, Maria Teresa | Nobili, Flavio | Arnaldi, Dario | Famà, Francesco | Aarsland, Dag | Orzi, Francesco | Buttinelli, Carla | Giubilei, Franco | Onofrj, Marco | Stocchi, Fabrizio | Stirpe, Paola | Fuhr, Peter | Gschwandtner, Ute | Ransmayr, Gerhard | Caravias, Georg | Garn, Heinrich | Sorpresi, Fabiola | Pievani, Michela | D’Antonio, Fabrizia | De Lena, Carlo | Güntekin, Bahar | Hanoğlu, Lutfu | Başar, Erol | Yener, Görsev | Emek-Savaş, Derya Durusu | Triggiani, Antonio Ivano | Franciotti, Raffaella | Frisoni, Giovanni B. | Bonanni, Laura | De Pandis, Maria Francesca

Article Type: Research Article

Abstract: The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI) and Parkinson’s disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak …(IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77–0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery. Show more

Keywords: Exact low resolution brain electromagnetic source tomography, mild cognitive impairment due to Alzheimer’s disease, mild cognitive impairment due to Parkinson’s disease, receiver operating characteristic curve, resting state electroencephalographic rhythms

DOI: 10.3233/JAD-160883

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 339-358, 2017

Authors: Vasavada, Megha M. | Martinez, Brittany | Wang, Jianli | Eslinger, Paul J. | Gill, David J. | Sun, Xiaoyu | Karunanayaka, Prasanna | Yang, Qing X.

Article Type: Research Article

Abstract: Background: Olfactory deficits are present in early Alzheimer’s disease (AD) and mild cognitively impaired (MCI) patients. However, whether these deficits are due to dysfunction of the central or peripheral olfactory nervous system remains uncertain. This question is fundamentally important for developing imaging biomarkers for AD using olfactory testing. Objective: This study sought to use olfactory functional magnetic resonance imaging (fMRI) to further demonstrate the involvement of the central olfactory system in olfactory deficits in MCI and AD. Methods: We investigated the central olfactory system in 27 cognitively normal controls (CN), 21 MCI, and 15 AD …subjects using olfactory fMRI with an odor-visual association paradigm during which a visual cue was paired with lavender odorant (odor condition) or odorless air (no-odor condition). Results: The CN subjects had significantly greater activated volume in the primary olfactory cortex during both the odor and no-odor conditions compared to either the MCI or AD groups (p  < 0.05). No significant differences were observed between the odor and no-odor conditions within each group. No-odor condition activation in AD and MCI correlated with the cognitive and olfactory assessments. Conclusion: The no-odor condition, allowing investigation of activation patterns when the peripheral olfactory system was not directly involved, elicited the same functional response as the odor condition for each of the three groups. Thus, the olfactory activation deficits present in AD and MCI patients are most likely caused by degeneration of the central olfactory nervous system. Show more

Keywords: Alzheimer’s disease, functional magnetic resonance imaging, mild cognitive impairment, olfaction

DOI: 10.3233/JAD-170310

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 359-368, 2017

Authors: Beishon, Lucy | Haunton, Victoria J. | Panerai, Ronney B. | Robinson, Thompson G.

Article Type: Research Article

Abstract: Background: The incidence of dementia is projected to rise over the coming decades, but with no sensitive diagnostic tests available. Vascular pathology precedes the deposition of amyloid and is an attractive early target. Objective: The aim of this review was to investigate the use of cerebral hemodynamics and oxygenation as a novel biomarker for mild cognitive impairment (MCI), focusing on transcranial Doppler ultrasonography (TCD) and near-infrared spectroscopy (NIRS). Methods: 2,698 articles were identified from Medline, Embase, PsychINFO, and Web of Science databases. 306 articles were screened and quality assessed independently by two reviewers; 26 met …the inclusion criteria. Meta-analyses were performed for each marker with two or more studies and limited heterogeneity. Results: Eleven studies were TCD, 8 NIRS, 5 magnetic resonance imaging, and 2 positron/single photon emission tomography. Meta-analyses showed reduced tissue oxygenation index, cerebral blood flow and velocity, with higher pulsatility index, phase and cerebrovascular resistance in MCI compared to controls. The majority of studies found reduced CO2 reactivity in MCI, with mixed findings in neuroactivation studies. Conclusion: Despite small sample sizes and heterogeneity, meta-analyses demonstrate clear abnormalities in cerebral hemodynamic and oxygenation parameters, even at an early stage of cognitive decline. Further work is required to investigate the use of cerebral hemodynamic and oxygenation parameters as a sensitive biomarker for dementia. Show more

Keywords: Cognitive dysfunction, functional neuroimaging, near-infrared spectroscopy, neurovascular coupling, transcranial Doppler ultrasonography

DOI: 10.3233/JAD-170181

Citation: Journal of Alzheimer's Disease, vol. 59, no. 1, pp. 369-385, 2017