Journal of Alzheimer's Disease - Volume 51, issue 1

Authors: Niemantsverdriet, Ellis | Goossens, Joery | Struyfs, Hanne | Martin, Jean-Jacques | Goeman, Johan | De Deyn, Peter Paul | Vanderstichele, Hugo | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimer’s disease (AD) dementia patients. MCI patients (n  = 85), autopsy-confirmed AD dementia patients (n  = 72), and cognitively healthy controls (n  = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ1-42 <638.5 pg/mL, T-tau>296.5 pg/mL, P-tau181P >56.5 pg/mL. Both increments and decrements (from ± 5% …to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between –20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ±20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria. Show more

Keywords: Alzheimer’s disease, differential dementia diagnosis, cerebrospinal fluid, biomarkers, diagnostic accuracy, (pre-)analytical variability

DOI: 10.3233/JAD-150953

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 97-106, 2016

Authors: Tripathi, Ajai K. | Singh, Neena

Article Type: Research Article

Abstract: Hemin is known to induce endocytosis of prion-protein (PrPC ) from the neuronal plasma membrane, potentially limiting propagation of the disease causing PrP-scrapie (PrPSc ) isoform. Hemin is therefore an attractive disease-modifying option for sporadic Creutzfeldt-Jakob disease (sCJD), a human prion disorder with no effective treatment. The hemin-PrPC interaction is also of interest in cerebral-hemorrhage (CH), a condition where potentially toxic hemin molecules come in contact with neuronal PrPC . Interestingly, PrPC is upregulated in penumbric neurons surrounding CH and is known to confer neuroprotection in a dose-dependent manner. The underlying mechanism, however, is not clear. Here, we …report that hemin binds PrPC on diverse cell lines, resulting in its aggregation or degradation in a cell-type specific manner. Surprisingly, the hemin-PrPC interaction upregulates Hb synthesis in hematopoietic cells, a response reversed by deleting the hemin-binding octa-peptide repeat region of PrPC . A similar response is noted in brain organotypic cultures where exposure to hemin induces significantly more α -globin in wild-type (PrP+/+ ) relative to PrP-knock-out (PrP–/– ) samples. Furthermore, red blood cells and brain tissue from PrP–/– mice show significantly less α -globin relative to PrP+/+ controls, indicating a positive effect of PrPC on Hb synthesis under physiological conditions as well. Surprisingly, levels of α -globin are significantly higher in sCJD brain tissue relative to controls, suggesting compensatory upregulation of Hb synthesis by surviving neurons or misregulation in diseased brains. These observations reveal a unique function of PrPC that is likely to impact the therapeutic management of CH and sCJD. Show more

Keywords: α-Globin, hemin, neuronal hemoglobin, prion protein, sCJD

DOI: 10.3233/JAD-151039

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 107-121, 2016

Authors: Tong, Ming | Deochand, Chetram | Didsbury, John | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: T3D-959, a dual PPAR-δ /PPAR γ nuclear receptor agonist and former diabetes drug candidate, has been repositioned as an Alzheimer’s disease (AD)-modifying therapy. Objective: This study examines the effectiveness and mechanisms of T3D-959’s therapeutic effects using in vivo and ex vivo rat models of sporadic AD. Methods: A sporadic AD model was generated by intracerebral (i.c.) administration of streptozotocin (STZ). Control and i.c. STZ treated rats were gavaged with saline or T3D-959 (0.3 to 3.0 mg/kg/day) for 28 days. Spatial learning and memory were evaluated using the Morris water maze test. Frontal lobe …slice cultures generated 24 hours after i.c. STZ or vehicle were used to study early effects of T3D-959 (0.5–1.0 μM) on viability and molecular markers of AD. Results: T3D-959 significantly improved spatial learning and memory in i.c STZ-treated rats. Mechanistically, T3D-959 significantly improved culture viability and brain morphology, reduced levels of oxidative stress and Aβ, and normalized expression of phospho-tau, choline acetyltransferase, and myelin-associated glycoprotein. Protective effects occurred even at the lowest tested dose of T3D-959. Conclusions: Pre-clinical proof of concept has been demonstrated that T3D-959 can improve multiple pathologies of AD resulting in significant improvements in cognitive function and molecular and biochemical indices of neurodegeneration. These results support the theses that (1) effective disease modification in AD can be achieved by targeting relevant nuclear receptors, and (2) treating AD as a metabolic disease has the potential to be disease remedial. A Phase 2a trial of T3D-959 in mild-to-moderate AD patients has been initiated (ClinicalTrials.gov identifier NCT02560753). Show more

Keywords: Alzheimer’s disease, amyloid, PPAR agonist, slice culture, spatial learning and memory, Streptozotocin, T3D-959, Type 3 diabetes

DOI: 10.3233/JAD-151013

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 123-138, 2016

Authors: Clare, Linda | Quinn, Catherine | Jones, Ian Rees | Woods, Robert T.

Article Type: Research Article

Abstract: The self-regulatory model proposes that illness representations influence adjustment and coping in chronic conditions. Better understanding of the illness representations held by people with dementia could help with targeting information and support so as to optimize adjustment and coping. In this mixed-methods study of illness representations among people with mild to moderate Alzheimer’s, vascular, or mixed dementia we aimed to clarify the nature of the representations held, to determine whether specific profiles can be identified based on perceptions of the identity and cause of the condition, and to examine associations between these profiles and other participant characteristics. Data were collected …in the second wave of the Memory Impairment and Dementia Awareness Study (MIDAS). Sixty-four people with dementia, who had been told their diagnosis at a memory clinic, completed interviews and responded to questionnaires. In each case a carer was also interviewed. Cluster analysis based on responses about identity and cause identified three profiles. ‘Illness’ cluster participants saw themselves as living with an illness and used diagnostic labels, ‘ageing’ cluster participants did not use diagnostic labels and viewed their difficulties as related to ageing, and ‘no problem’ cluster participants considered that they did not have any difficulties. ‘Illness’ cluster participants had better cognition and better awareness, but lower mood, and perceived more practical consequences, than ‘ageing’ cluster participants. Holding an ‘illness’ model may not be advantageous. Rather than encouraging adoption of such a model, it may be preferable to target information and select interventions in line with the person’s representation profile. Show more

Keywords: Aging, awareness, coping behavior, dementia, diagnosis, psychological adjustment

DOI: 10.3233/JAD-150794

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 139-150, 2016

Authors: Nunez, Kavin | Kay, Jared | Krotow, Alexander | Tong, Ming | Agarwal, Amit R. | Cadenas, Enrique | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: Meta-analysis has shown that smokers have significantly increased risks for Alzheimer’s disease (AD), and neuroimaging studies showed that smoking alters white matter (WM) structural integrity. Objective: Herein, we characterize the effects of cigarette smoke (CS) exposures and withdrawal on WM myelin lipid composition using matrix assisted laser desorption and ionization-imaging mass spectrometry (MALDI-IMS). Methods: Young adult male A/J mice were exposed to air (8 weeks; A8), CS (4 or 8 weeks; CS4, CS8), or CS8 followed by 2 weeks recovery (CS8 + R). Frontal lobe WM was examined for indices of lipid and protein oxidation and lipid …profile alterations by MALDI-IMS. Lipid ions were identified by MS/MS with the LIPID MAPS prediction tools database. Inter-group comparisons were made using principal component analysis and R-generated heatmap. Results: CS increased lipid and protein adducts such that higher levels were present in CS8 compared with CS4 samples. CS8 + R reversed CS8 effects and normalized the levels of oxidative stress. MALDI-IMS demonstrated striking CS-associated alterations in WM lipid profiles characterized by either reductions or increases in phospholipids (phosphatidylinositol, phosphatidylserine, phosphatidylcholine, or phosphatidylethanolamine) and sphingolipids (sulfatides), and partial reversal of CS’s inhibitory effects with recovery. The heatmap hierarchical dendrogram and PCA distinguished CS exposure, duration, and withdrawal effects on WM lipid profiles. Conclusion: CS-mediated WM degeneration is associated with lipid peroxidation, protein oxidative injury, and alterations in myelin lipid composition, including shifts in phospholipids and sphingolipids needed for membrane integrity, plasticity, and intracellular signaling. Future goals are to delineate WM abnormalities in AD using MALDI-IMS, and couple the findings with MRI-mass spectroscopy to improve in vivo diagnostics and early detection of brain biochemical responses to treatment Show more

Keywords: Alzheimer’s disease, cigarette smoke, imaging mass spectrometry, MALDI, mouse model, neurodegeneration, tobacco, white matter

DOI: 10.3233/JAD-150916

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 151-163, 2016

Authors: Frenkel-Pinter, Moran | Tal, Sharon | Scherzer-Attali, Roni | Abu-Hussien, Malak | Alyagor, Idan | Eisenbaum, Tal | Gazit, Ehud | Segal, Daniel

Article Type: Research Article

Abstract: Tauopathies, such as Alzheimer’s disease (AD), are a group of disorders characterized neuropathologically by intracellular toxic accumulations of abnormal protein aggregates formed by misfolding of the microtubule-associated protein tau. Since protein self-assembly appears to be an initial key step in the pathology of this group of diseases, intervening in this process can be both a prophylactic measure and a means for modifying the course of the disease for therapeutic purposes. We and others have shown that aromatic small molecules can be effective inhibitors of aggregation of various protein assemblies, by binding to the aromatic core in aggregation-prone motifs and preventing …their self-assembly. Specifically, we have designed a series of small aromatic naphthoquinone-tryptophan hybrid molecules as candidate aggregation inhibitors of β -sheet based assembly and demonstrated their efficacy toward inhibiting aggregation of the amyloid-β peptide, another culprit of AD, as well as of various other aggregative proteins involved in other protein misfolding diseases. Here we tested whether a leading naphthoquinone-tryptophan hybrid molecule, namely NQTrp, can be repurposed as an inhibitor of the aggregation of the tau protein in vitro and in vivo . We show that the molecule inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau protein, reduces hyperphosphorylated tau deposits and ameliorates tauopathy-related behavioral defect in an established transgenic Drosophila model expressing human tau. We suggest that NQTrp, or optimized versions of it, could act as novel disease modifying drugs for AD and other tauopathies. Show more

Keywords: AcPHF6 peptide, Drosophila, neurodegeneration, NQTrp compound, protein aggregation, tau protein, tauopathies

DOI: 10.3233/JAD-150927

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 165-178, 2016

Authors: Xu, Zhi-Qiang | Huang, Huang | Chen, Ya-Li | Gao, Yun-Ying | Xu, Jun | Marshall, Charles | Cai, Zhi-You | Xiao, Ming

Article Type: Research Article

Abstract: Extensive loss of hippocampal neurons serves a pathological basis for irreversible cognitive impairment in patients with Alzheimer’s disease (AD). However, this characteristic cannot be replicated by transgenic mouse models, and its underlying mechanisms are unclear. Here, we present evidence that different expression patterns of amyloid-β protein precursor (AβPP) secretases in human and mouse hippocampal neurons are a decisive cause of species difference in the susceptibility to Aβ pathogenesis. Cell bodies of both pyramidal and granular neurons did not appear to undergo Aβ deposits in the 10-month-old transgenic mutant human AβPP/presenilin-1 (PS1) mice. They expressed high levels of non-amyloidogenic α -secretase, …and its neuroprotective products soluble AβPPα , but low levels of amyloidogenic β-secretase and γ -secretase, and a neurotoxic product, Aβ42 peptide. Unlike those found in the mouse, human hippocampal neuronal cell bodies expressed β-secretase and γ -secretase, but not α -secretase, which could increase Aβ generation, thus undergoing death in response to various pathological conditions. Increased hippocampal neuronal apoptosis at 48 h following local microinjection of α -secretase antibody ADAM10 into the hippocampus of AβPP/PS1 mice further suggests that high α -secretase expression in mouse neuronal cell bodies is a factor in the paucity of neuronal loss in AD-like pathology. Therefore, selective down-regulation of brain α -secretase in transgenic AD models will better replicate the disease spectrum, including decreased brain soluble AβPPα levels and massive neuronal loss in AD patients, and be beneficial for preclinical therapeutic evaluation of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β metabolism, AβPP/PS1 mice, hippocampus

DOI: 10.3233/JAD-150634

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 179-195, 2016

Authors: Chang, Lirong | Zhang, Yali | Liu, Jinping | Song, Yizhi | Lv, Angchu | Li, Yan | Zhou, Wei | Yan, Zhen | Almeida, Osborne F.X. | Wu, Yan

Article Type: Research Article

Abstract: Synaptic dysfunction during early stages of Alzheimer’s disease (AD) is triggered by soluble amyloid-β (Aβ) oligomers that interact with NMDA receptors (NMDARs). We previously showed that Aβ induces synaptic protein loss through NMDARs, albeit through undefined mechanisms. Accordingly, we here examined the contribution of individual NMDAR subunits to synaptotoxicity and demonstrate that Aβ exerts differential effects on the levels and distribution of GluN2A and GluN2B subunits of NMDAR in dendrites. Treatment of cultured hippocampal neurons with Aβ1-40 (10 μM, 1 h) induced a significant increase of dendritic and synaptic GluN2B puncta densities with parallel decreases in the puncta densities of …denritic and synaptic pTyr1472 -GluN2B. Conversely, Aβ significantly decreased dendritic and synaptic GluN2A and dendritic pTyr1325 -GluN2A puncta densities and increased synaptic pTyr1325 -GluN2A puncta densities. Unexpectedly, Aβ treatment resulted in a significant reduction of GluN2B and pTyr1472 -GluN2B protein levels but did not influence GluN2A and pTyr1325 -GluN2A levels. These results show that Aβ exerts complex and distinct regulatory effects on the trafficking and phosphorylation of GluN2A and GluN2B, as well as on their localization within synaptic and non-synaptic sites. Increased understanding of these early events in Aβ-induced synaptic dysfunction is likely to be important for the development of timely preventive and therapeutic interventions. Show more

Keywords: Alzheimer’s disease, amyloid beta, hippocampus, NMDA receptor subunits, synapse, tyrosine phosphorylation

DOI: 10.3233/JAD-150942

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 197-212, 2016

Authors: Huang, Chunxia | Ng, Olivia Tsz-Wa | Ho, Yuen-Shan | Irwin, Michael Garnet | Chang, Raymond Chuen-Chung | Wong, Gordon Tin-Chun

Article Type: Research Article

Abstract: Several studies suggest a relationship between anesthesia-induced tau hyperphosphorylation and the development of postoperative cognitive dysfunction. This study further characterized the effects of continuous propofol infusion on tau protein phosphorylation in rats, with or without temperature control. Propofol was administered intravenously to 8–10-week-old male Sprague-Dawley rats and infused to the loss of the righting reflex for 2 h continuously. Proteins from cortex and hippocampus were examined by western blot and immunohistochemistry. Rectal temperature was significantly decreased during propofol infusion. Propofol with hypothermia significantly increased phosphorylation of tau at AT8, AT180, Thr205, and Ser199 in cortex and hippocampus except Ser396. With temperature …maintenance, propofol still induced significant elevation of AT8, Thr205, and Ser199 in cortex and hippocampus; however, increase of AT180 and Ser396 was only found in hippocampus and cortex, respectively. Differential effects of propofol with or without hypothermia on multiple tau related kinases, such as Akt/GSK3β, MAPK pathways, or phosphatase (PP2A), were demonstrated in region-specific manner. These findings indicated that propofol increased tau phosphorylation under both normothermic and hypothermic conditions, and temperature control could partially attenuate the hyperphosphorylation of tau. Further studies are warranted to determine the long-term impact of propofol on the tau pathology and cognitive functions. Show more

Keywords: Hypothermia, propofol, protein kinases, tau phosphorylation

DOI: 10.3233/JAD-150645

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 213-226, 2016

Authors: Wang, Hui-Fu | Tan, Lan | Cao, Lei | Zhu, Xi-Chen | Jiang, Teng | Tan, Meng-Shan | Liu, Ying | Wang, Chong | Tsai, Richard M. | Jia, Jian-Ping | Yu, Jin-Tai | and Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The International Working Group (IWG) recently proposed the revised diagnostic criteria for Alzheimer’s disease (AD) to define and refine several types of AD, and to reclassify AD-related biomarkers into diagnostic and progression markers, but its performance is not known. Objective: This study was designed to describe the application of the revised IWG criteria in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset, and to ascertain whether diagnostic and progression markers show significant differences in their relationships to AD severity and progression. Methods: Based on the requirements of the refined criteria, 857 ADNI subjects with memory evaluation …and at least one pathophysiological marker (CSF or amyloid imaging biomarkers) were eligible and reclassified in this study, and we calculated the associations of diagnostic (CSF and amyloid PET) and progression markers (MRI and fluorodeoxyglucose-PET) with AD severity and progression respectively. Results: The majority (84.2% ) of ADNI AD group (n  = 117) and 173 MCI (37.4% ) subjects in ADNI met the definition of typical AD; and 105 cognitively normal (41.0% ) individuals were diagnosed as asymptomatic AD. Furthermore, diagnostic and progression markers showed significant differences when correlated to AD severity and progression. Conclusion: A large proportion of AD dementia subjects were categorized as typical AD, and the revised criteria could identify typical AD from MCI status as well as asymptomatic AD at the asymptomatic stage. Moreover, the significant differences between diagnostic and progression markers further supported the new biomarkers categorization in the refined criteria. Show more

Keywords: Alzheimer’s disease, Alzheimer’s disease neuroimaging Initiative, diagnostic markers, international working group-2 criteria, progression markers

DOI: 10.3233/JAD-150824

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 227-236, 2016

Authors: Kumfor, Fiona | Teo, Drusilla | Miller, Laurie | Lah, Suncica | Mioshi, Eneida | Hodges, John R. | Piguet, Olivier | Irish, Muireann

Article Type: Research Article

Abstract: Background: Autobiographical memory (ABM) refers to the capacity to remember one’s own past, and is known to be central for supporting one’s identity and sense of self. This capacity is commonly affected in Alzheimer’s disease (AD), as well as semantic dementia (SD) and behavioral-variant frontotemporal dementia (bvFTD). Importantly, ABM plays a critical social function, facilitating relationship intimacy and empathy, and thus loss of ABM may also negatively affect families and carers. Objective: To explore the relationship between ABM disruption and carer burden in AD, SD, and bvFTD, and establish whether characteristic ABM profiles differentially relate to carer burden …across dementia syndromes. Methods: We recruited 12 AD, 10 SD, and 13 bvFTD patients and their primary carer. All participants completed the Autobiographical Interview to assess memory for recent and remote events. Carers completed: the Zarit Burden Interview; Depression, Anxiety and Stress Scale (DASS-21); and the Intimate Bond Measure (IBM). Results: In AD, loss of recent ABM was associated with worse psychological wellbeing of carers on the DASS-21. In contrast in SD, remote ABM dysfunction was associated with SD patients showing greater controlling behavior within their intimate relationships. In bvFTD, surprisingly, despite pervasive ABM impairment, no relationship between extent of ABM loss and carer burden was observed. Conclusion: These preliminary results reveal that ABM impairment impacts on patients’ families and carers and suggest that these influences vary according to the pattern of ABM dysfunction. Disease-specific interventions focusing on preserved aspects of ABM may improve quality of life for both patients and carers. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, quality of life, relationships, semantic dementia, wellbeing

DOI: 10.3233/JAD-150740

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 237-248, 2016

Authors: Premi, Enrico | Cauda, Franco | Costa, Tommaso | Diano, Matteo | Gazzina, Stefano | Gualeni, Vera | Alberici, Antonella | Archetti, Silvana | Magoni, Mauro | Gasparotti, Roberto | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: In light of future pharmacological interventions, neuroimaging markers able to assess the response to treatment would be crucial. In Granulin (GRN ) disease, preclinical data will prompt pharmacological trials in the future. Two main points need to be assessed: 1) to identify target regions in different disease stages and 2) to determine the most accurate functional and structural neuroimaging index to be used. To this aim, we have taken advantage of the multivariate approach of multi-voxel pattern analysis (MVPA) to explore the information of brain activity patterns in a cohort of GRN Thr272fs carriers at different disease stages …(14 frontotemporal dementia (FTD) patients and 17 asymptomatic carriers) and a group of 33 healthy controls. We studied structural changes by voxel-based morphometry (VBM), functional connectivity by assessing salience, default mode, fronto-parietal, dorsal attentional, executive networks, and local connectivity by regional homogeneity, amplitude of low frequency fluctuations (ALFF), fractional ALFF (fALFF), degree centrality, and voxel-mirrored homotopic connectivity. In FTD patients with GRN mutation, the most predictive measure was VBM structural analysis, while in asymptomatic carriers the best predictor marker was the local connectivity measure (fALFF). Altogether, all indexes demonstrated fronto-temporo-parietal damage in GRN pathology, with widespread structural damage of fronto-parietal and temporal regions when disease is overt. MVPA could be of aid in identifying the most accurate neuroimaging marker for clinical trials. This approach was able to identify both the target region and the best neuroimaging approach, which would be specific in the different disease stages. Further studies are needed to simultaneously integrate multimodal indexes in a classifier able to trace the disease progression moving from preclinical to clinical stage of the disease. Show more

Keywords: Degree centrality, fractional amplitude of low frequency fluctuation, frontotemporal dementia, granulin, multivoxel pattern analysis, regional homogeneity, resting state fMRI, support vector machine learning, voxel-mirrored homotopic connectivity

DOI: 10.3233/JAD-150340

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 249-262, 2016

Authors: Haworth, Judy | Phillips, Michelle | Newson, Margaret | Rogers, Peter J. | Torrens-Burton, Anna | Tales, Andrea

Article Type: Research Article

Abstract: A substantial body of research evidence is indicative of disproportionately slowed information processing speed in a wide range of multi-trial, computer-based, neuroimaging- and electroencephalography-based reaction time (RT) tests in Alzheimer’s disease and mild cognitive impairment (MCI). However, in what is arguably a dichotomy between research evidence and clinical practice, RT associated with different brain functions is rarely assessed as part of their diagnosis. Indeed, often only the time taken to perform a single, specific task, commonly the Trail making test (TMT), is measured. In clinical practice therefore, there can be a failure to assess adequately the integrity of the rapid, …serial information processing and response, necessary for efficient, appropriate, and safe interaction with the environment. We examined whether a typical research-based RT task could at least match the TMT in differentiating amnestic MCI (aMCI) from cognitively healthy aging at group level. As aMCI is a heterogeneous group, typically containing only a proportion of individuals for whom aMCI represents the early stages of dementia, we examined the ability of each test to provide intra-group performance variation. The results indicate that as well as significant slowing in performance of the operations involved in TMT part B (but not part A), individuals with aMCI also experience significant slowing in RT compared to controls. The results also suggest that research-typical RT tests may be superior to the TMT in differentiating between cognitively healthy aging and aMCI at group level and in revealing the performance variability one would expect from an etiologically heterogeneous disorder such as aMCI. Show more

Keywords: Dementia, information processing speed, mild cognitive impairment, reaction time

DOI: 10.3233/JAD-150791

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 263-275, 2016

Authors: Bocchetta, Martina | Mega, Anna | Bernardi, Livia | Di Maria, Emilio | Benussi, Luisa | Binetti, Giuliano | Borroni, Barbara | Colao, Rosanna | Di Fede, Giuseppe | Fostinelli, Silvia | Galimberti, Daniela | Gennarelli, Massimo | Ghidoni, Roberta | Piaceri, Irene | Pievani, Michela | Porteri, Corinna | Redaelli, Veronica | Rossi, Giacomina | Suardi, Silvia | Babiloni, Claudio | Scarpini, Elio | Tagliavini, Fabrizio | Padovani, Alessandro | Nacmias, Benedetta | Sorbi, Sandro | Frisoni, Giovanni B. | Bruni, Amalia C. | SINdem

Collaborators: Bozzali, Marco | Parnetti, Lucilla | Ferrarese, Carlo | Cappa, Stefano F. | Marra, Camillo | Masullo, Carlo | Rainero, Innocenzo | Silani, Vincenzo | Sorrentino, Giuseppe | Bruno, Giuseppe | Cagnin, Annachiara

Article Type: Research Article

Abstract: Background: Genetic testing of familial Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) is attracting interest thanks to innovative primary prevention clinical trials and increased request for information by at-risk individuals. However, ethical, social, and psychological implications are paramount and genetic testing must be supported by structured genetic counseling. In Italy, practice parameters and guidelines for genetic counseling in dementia are not available. Objective: To develop a nationally harmonized protocol for genetic counseling and testing of familial AD and FTLD. Methods: Activities were carried out in the context of the Italian Dominantly Inherited Alzheimer’s and …Frontotemporal Network (IT-DIAfN) project, a national network of centers of excellence with expertise in managing patients with familial AD and FTLD. A survey of the literature on genetic counseling protocols and guidelines was conducted. Local protocols for genetic counseling were surveyed. Differences and commonalities among protocols were identified and discussed among project partners. Consensus was reached following implicit aggregation methods. Results: Consensus was reached on a protocol for patients with clinically diagnosed familial AD or FTLD and a distinct protocol for their at-risk relatives. Genetic counseling should be provided by a multidisciplinary team including a geneticist, a neurologist/geriatrician, and a psychologist/psychiatrist, according to the following schedule: (i) initial consultation with tailored information on the genetics of the dementias; (ii) clinical, psychological, and cognitive assessment; if deemed appropriate (iii) genetic testing following a structured decision tree for gene mutation search; (iv) genetic testing result disclosure; (v) psychological support follow-up. Conclusion: This genetic counseling protocol provides Italian centers with a line of shared practice for dealing with the requests for genetic testing for familial AD and FTLD from patients and at-risk relatives, who may also be eligible participants for novel prevention clinical trials. Show more

Keywords: Alzheimer’s disease, frontotemporal degeneration, genetic counseling, genetic testing

DOI: 10.3233/JAD-150849

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 277-291, 2016

Authors: Kim, Yong Hwan | Beak, Seung Han | Charidimou, Andreas | Song, Min

Article Type: Research Article

Abstract: Late onset Alzheimer’s disease (AD) and Parkinson’s disease (PD) are mostly “sporadic” age-related neurodegenerative disorders, but with a clear genetic component. However, their genetic architecture is complex and heterogeneous, largely remaining a conundrum, with only a handful of well-established genetic risk factors consistently associated with these diseases. It is possible that numerous, yet undiscovered, AD and PD related genes might exist. We focused on the ‘gene’ as a mediator to find new potential genes that might have a relationship with both disorders using bio-literature mining techniques. Based on Entrez Gene, we extracted the genes and directional gene-gene relation in the …entire MEDLINE records and then constructed a directional gene-gene network. We identified common genes associated with two different but related diseases by performing shortest path analysis on the network. With our approach, we were able to identify and map already known genes that have a direct relationship with PD and AD. In addition, we identified 7 genes previously unknown to be a bridge between these two disorders. We confirmed 4 genes, ROS1, FMN1, ATP8A2, and SNORD12C, by biomedical literature and further checked 3 genes, ERVK-10, PRS, and C7orf49, that might have a high possibility to be related with both diseases. Additional experiments were performed to demonstrate the effectiveness of our proposed method. Comparing to the co-occurrence approach, our approach detected 25% more candidate genes and verified 10% more genes that have the relationship between both diseases than the co-occurrence approach did. Show more

Keywords: Alzheimer’s disease, bio-textmining, literature-based discovery, Parkinson’s disease

DOI: 10.3233/JAD-150769

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 293-312, 2016

Authors: Pasquini, Lorenzo | Scherr, Martin | Tahmasian, Masoud | Myers, Nicholas E. | Ortner, Marion | Kurz, Alexander | Förstl, Hans | Zimmer, Claus | Grimmer, Timo | Akhrif, Atae | Wohlschläger, Afra M. | Riedl, Valentin | Sorg, Christian

Article Type: Research Article

Abstract: In Alzheimer’s disease (AD), disrupted connectivity between medial-parietal cortices and medial-temporal lobes (MTL) is linked with increased MTL local functional connectivity, and parietal atrophy is associated with increased MTL memory activation. We hypothesized that intrinsic activity in MTL subregions is increased and associated with medial-parietal degeneration and impaired memory in AD. To test this hypothesis, resting-state-functional and structural-MRI was assessed in 22 healthy controls, 22 mild cognitive impairment patients, and 21 AD-dementia patients. Intrinsic activity was measured by power-spectrum density of blood-oxygenation-level-dependent signal, medial-parietal degeneration by cortical thinning. In AD-dementia patients, intrinsic activity was increased for several right MTL subregions. …Raised intrinsic activity in dentate gyrus and cornu ammonis 1 was associated with cortical thinning in posterior cingulate cortices, and at-trend with impaired delayed recall. Critically, increased intrinsic activity in the right entorhinal cortex was associated with ipsilateral posterior cingulate degeneration. Our results provide evidence that in AD, intrinsic activity in MTL subregions is increased and associated with medial-parietal atrophy. Results fit a model in which medial-parietal degeneration contributes to MTL dysconnectivity from medial-parietal cortices, potentially underpinning disinhibition-like changes in MTL activity. Show more

Keywords: Alzheimer’s disease, atrophy, functional magnetic resonance imaging, hippocampus, medial-parietal cortex, medial-temporal lobe, neurodegeneration, neuroimaging, physiopathology, resting-state activity

DOI: 10.3233/JAD-150823

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 313-326, 2016

Article Type: Other

DOI: 10.3233/JAD-151171

Citation: Journal of Alzheimer's Disease, vol. 51, no. 1, pp. 327-331, 2016