Journal of Alzheimer's Disease - Volume 54, issue 3

Authors: Santamaría-García, Hernando | Reyes, Pablo | García, Adolfo | Baéz, Sandra | Martinez, Angela | Santacruz, José Manuel | Slachevsky, Andrea | Sigman, Mariano | Matallana, Diana | Ibañez, Agustín

Article Type: Research Article

Abstract: Background: Previous works highlight the neurocognitive differences between apathetic and disinhibited clinical presentations of the behavioral variant frontotemporal dementia (bvFTD). However, little is known regarding how the early presentation (i.e., first symptom) is associated to the neurocognitive correlates of the disease’s clinical presentation at future stages of disease. Objectives: We analyzed the neurocognitive correlates of patients with bvFTD who debuted with apathy or disinhibition as first symptom of disease. Methods: We evaluated the neuropsychological, clinical, and neuroanatomical (3T structural images) correlates in a group of healthy controls (n  = 30) and two groups of bvFTD patients …(presented with apathy [AbvFTD, n  = 18] or disinhibition [DbvFTD, n  = 16]). To differentiate groups according to first symptoms, we used multivariate analyses. Results: The first symptom in patients described the evolution of the disease. AbvFTD and DbvFTD patients showed increased brain atrophy and increased levels of disinhibition and apathy, respectively. Whole brain analyzes in AbvFTD revealed atrophy in the frontal, insular, and temporal areas. DbvFTD, in turn, presented atrophy in the prefrontal regions, temporoparietal junction, insula, and temporoparietal region. Increased atrophy in DbvFTD patients (compared to AbvFTD) was observed in frontotemporal regions. Multivariate analyses confirmed that a set of brain areas including right orbitofrontal, right dorsolateral prefrontal, and left caudate were enough to distinguish the patients’ subgroups.∥Conclusion: First symptom in bvFTD patients described the neurocognitive impairments after around three years of disease, playing an important role in the early detection, disease tracking, and neuroanatomical specification of bvFTD, as well as in future research on potential disease-modifying treatments. Show more

Keywords: Apathy, behavioral variant frontotemporal dementia, apathy, first symptom, voxel-based morphometry

DOI: 10.3233/JAD-160501

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 957-970, 2016

Authors: Tiiman, Ann | Luo, Jinghui | Wallin, Cecilia | Olsson, Lisa | Lindgren, Joel | Jarvet, Jϋri | Per, Roos | Sholts, Sabrina B. | Rahimipour, Shai | Abrahams, Jan Pieter | Karlström, Amelie Eriksson | Gräslund, Astrid | Wärmländer, Sebastian K.T.S.

Article Type: Research Article

Abstract: Aggregation of the amyloid-beta (Aβ) peptide into insoluble plaques is a major factor in Alzheimer’s disease (AD) pathology. Another major factor in AD is arguably metal ions, as metal dyshomeostasis is observed in AD patients, metal ions modulate Aβ aggregation, and AD plaques contain numerous metals including redox-active Cu and Fe ions. In vivo , Aβ is found in various cellular locations including membranes. So far, Cu(II)/Aβ interactions and ROS generation have not been investigated in a membrane environment. Here, we study Cu(II) and Zn(II) interactions with Aβ bound to SDS micelles or to engineered aggregation-inhibiting molecules (the cyclic peptide …CP-2 and the ZAβ3 (12–58)Y18L Affibody molecule). In all studied systems the Aβ N-terminal segment was found to be unbound, unstructured, and free to bind metal ions. In SDS micelles, Aβ was found to bind Cu(II) and Zn(II) with the same ligands and the same KD as in aqueous solution. ROS was generated in all Cu(II)/Aβ complexes. These results indicate that binding of Aβ to membranes, drugs, and other entities that do not interact with the Aβ N-terminal part, appears not to compromise the N-terminal segment’s ability to bind metal ions, nor impede the capacity of N-terminally bound Cu(II) to generate ROS. Show more

Keywords: Alzheimer’s disease, copper-binding protein, hydrogen peroxide, membrane chemistry, neurodegeneration, protein aggregation

DOI: 10.3233/JAD-160427

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 971-982, 2016

Authors: Chen, Guangyu | Shu, Hao | Chen, Gang | Ward, B. Douglas | Antuono, Piero G. | Zhang, Zhijun | Li, Shi-Jiang | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: This study aims to develop a composite biomarker that can accurately measure the sequential biological stages of Alzheimer’s disease (AD) on an individual level. We selected 144 subjects from the Alzheimer’s Disease Neuroimaging Initiative 2 datasets. Ten biomarkers, from brain function and structure, cerebrospinal fluid, and cognitive performance, were integrated using the event-based probabilistic model to estimate their optimal temporal sequence (Soptimal ). We identified the numerical order of the So ptimal as the characterizing Alzheimer’s disease risk events (CARE) index to measure disease stage. The results show that, in the Soptimal , hippocampal and posterior cingulate cortex network …biomarkers occur first, followed by aberrant cerebrospinal fluid amyloid-β and p-tau levels, then cognitive deficit, and finally regional gray matter loss and fusiform network abnormality. The CARE index significantly correlates with disease severity and exhibits high reliability. Our findings demonstrate that use of the CARE index would advance AD stage measurement across the whole AD continuum and facilitate personalized treatment of AD. Show more

Keywords: Alzheimer’s disease, biomarkers sequence, CARE index, functional connectivity, stage

DOI: 10.3233/JAD-160537

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 983-993, 2016

Authors: Scharre, Douglas W. | Chang, Shu-Ing | Nagaraja, Haikady N. | Park, Ariane | Adeli, Anahita | Agrawal, Punit | Kloos, Anne | Kegelmeyer, Deb | Linder, Shannon | Fritz, Nora | Kostyk, Sandra K. | Kataki, Maria

Article Type: Research Article

Abstract: Limited data compares clinical profiles of Lewy Body Dementia (LBD) with Alzheimer’s disease (AD) and Parkinson’s disease (PD). Twenty-one mildly demented ambulatory LBD subjects were individually matched by MMSE score with 21 AD subjects and by UPDRS motor score with 21 PD subjects. Matched by age, gender, education, and race, pairs were compared using cognitive, functional, behavioral, and motor measures. LBD group performed worse than PD on axial motor, gait, and balance measures. AD had more amnesia and orientation impairments, but less executive and visuospatial deficits than LBD subjects. LBD group had more sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea …than AD or PD. Axial motor, gait, and balance disturbances correlated with executive, visuospatial, and global cognition deficits. LBD is differentiated from AD and PD by retrieval memory, visuospatial, and executive deficits; axial motor, gait and balance impairments; sleepiness, cognitive/behavioral fluctuations, hallucinations, and sleep apnea. Show more

Keywords: Alzheimer’s disease, dementia, Lewy body dementia, Parkinson disease, Parkinsonian disorders

DOI: 10.3233/JAD-160384

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 995-1004, 2016

Authors: Bertoux, Maxime | Ramanan, Siddharth | Slachevsky, Andrea | Wong, Stephanie | Henriquez, Fernando | Musa, Gada | Delgado, Carolina | Flanagan, Emma | Bottlaender, Michel | Sarazin, Marie | Hornberger, Michael | Dubois, Bruno

Article Type: Research Article

Abstract: Background: Memory impairment in behavioral variant frontotemporal dementia (bvFTD) is traditionally considered to be mild and attributed to prefrontal cortex dysfunction. Recent studies, however, indicated that some patients can present with a memory impairment of the hippocampal type, showing storage and consolidation deficits in addition to the more executive/prefrontal related encoding and strategic difficulties. Objective: This study aimed to study the relationship between executive functions (EF) and memory processes in bvFTD via a data-driven approach. Method: Participants consisted of 71 bvFTD (among which 60.6% had a lumbar puncture showing non-Alzheimer biomarker profile) and 60 controls …(among which 45% had amyloid imaging showing a normal profile). EF were assessed by the Frontal Assessment Battery, semantic/lexical verbal fluency tests, and forward/backward digit spans. Patients were split into amnestic (n  = 33) and non-amnestic (n  = 38) subgroups based on normative data (total recall score) from the Free and Cued Selective Reminding Test (FCSRT). Relationships between FCSRT subscores and EF measures were explored through hierarchical clustering analysis, partial correlation analysis with an EF component, and automated linear modeling. Results: Convergent findings across the statistical approaches show that, overall, memory performance was independent from EF in bvFTD whereas the relationship was stronger in controls. Indeed, in bvFTD, memory performance did not cluster with EF, was not correlated with the EF component, and was only partially (4% – 12.7%) predicted by EF. Discussion: These findings show that executive dysfunctions cannot solely explain the memory deficits occurring in bvFTD. Indeed, some patients present with a genuine amnesia affecting storage and consolidation abilities, which are independent from executive dysfunctions. On the clinical level, this study highlights the importance of revising the neuropsychological diagnosis criteria for bvFTD. Show more

Keywords: Consolidation, encoding, episodic amnesia, executive functions, Free and Cued Selective Reminding Test, frontotemporal dementia, memory, retrieval, storage

DOI: 10.3233/JAD-160522

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1005-1014, 2016

Authors: Noh, Young | Seo, Sang Won | Jeon, Seun | Lee, Jong Min | Kim, Jae Seung | Lee, Jae-Hong | Kim, Jung-Hyun | Kim, Geon Ha | Ye, Byoung Seok | Cho, Hanna | Kim, Hee Jin | Yoon, Cindy W | Choe, Yearn Seong | Lee, Kyung-Han | Weiner, Michael W. | Na, Duk L.

Article Type: Research Article

Abstract: Background: Some patients clinically diagnosed with subcortical vascular cognitive impairment (SVCI) have co-morbidity with AD pathology. Objective: We investigated topographical differences in amyloid burden between SVCI and Alzheimer’s disease type cognitive impairment (ADCI) using [11 C] Pittsburgh compound B (PiB) positron emission tomography (PET). The purpose of this study was to investigate the role of cerebrovascular disease (CVD) in amyloid deposition. Methods: We recruited 44 patients with SVCI and 44 patients with ADCI (amnestic mild cognitive impairment or Alzheimer’s disease) with absent or minimal white matter hyperintensities, all with PiB-positive PET scans [PiB+]. As controls, …we included 13 participants with normal cognition and PiB-negative scans. We divided the SVCI and ADCI patients into three groups according to global PiB retention ratio of SVCI, and then compared the tertiles in terms of the distribution of PiB retention using statistical parametric mapping analyses. Lobar to global PiB retention ratio and asymmetry indices were also compared between SVCI and ADCI groups Results: Compared to PiB+ ADCI patients, PiB+ SVCI patients exhibited: 1) increased left-right asymmetry, and increased anterior-posterior difference; and 2) increased PiB retention in the parietal cortex, the occipital cortex and the precuneus-posterior cingulate cortex. In contrast, ADCI patients showed increased PiB retention in the striatum. When stratified by level of PiB retention, each group showed different characteristics. Conclusion: Our results showed that the distribution of amyloid deposition differed between patients with PiB+ SVCI and ADCI. These suggest that CVD contribute to and alter the known progression pattern in amyloid deposition in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cerebrovascular disease, magnetic resonance imaging, positron emission tomography, vascular dementia ∥

DOI: 10.3233/JAD-150832

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1015-1026, 2016

Authors: Gertje, Eske Christiane | Pluta, John | Das, Sandhitsu | Mancuso, Lauren | Kliot, Dasha | Yushkevich, Paul | Wolk, David

Article Type: Research Article

Abstract: Background: Volumetry of medial temporal lobe (MTL) structures to diagnose Alzheimer’s disease (AD) in its earliest symptomatic stage could be of great importance for interventions or disease modifying pharmacotherapy. Objective: This study aimed to demonstrate the first application of an automatic segmentation method of MTL subregions in a clinical population. Automatic segmentation of magnetic resonance images (MRIs) in a research population has previously been shown to detect evidence of neurodegeneration in MTL subregions and to help discriminate AD and mild cognitive impairment (MCI) from a healthy comparison group. Methods: Clinical patients were selected and T2-weighted …MRI scan quality was checked. An automatic segmentation method of hippocampal subfields (ASHS) was applied to scans of 67 AD patients, 38 amnestic MCI patients, and 57 healthy controls. Hippocampal subfields, entorhinal cortex (ERC), and perirhinal cortex were automatically labeled and subregion volumes were compared between groups. Results: One fourth of all scans were excluded due to bad scan quality. There were significant volume reductions in all subregions, except BA36, in aMCIs (p  < 0.001), most prominently in Cornu Ammonis 1 (CA1) and ERC, and in all subregions in AD. However, sensitivity of CA1 and ERC hardly differed from sensitivity of WH in aMCI and AD. Conclusion: Applying automatic segmentation of MTL subregions in a clinical setting as a potential biomarker for prodromal AD is feasible, but issues of image quality due to motion remain to be addressed. CA1 and ERC provided strongest group discrimination in differentiating aMCIs from controls, but discriminatory power of different subfields was low overall. Show more

Keywords: Alzheimer’s disease, anatomy, biomarker, Cornu Ammonis, diagnosis, entorhinal cortex, hippocampus, hippocampal subfields, histology, magnetic resonance imaging, medial temporal lobe, mild cognitive impairment

DOI: 10.3233/JAD-160014

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1027-1037, 2016

Authors: Trebbastoni, Alessandro | D’Antonio, Fabrizia | de Lena, Carlo | Onesti, Emanuela | John, Bev | Inghilleri, Maurizio

Article Type: Research Article

Abstract: Orofacial apraxia (OA) as the main symptom in neurodegenerative disorders has not been yet reported. We present the case of a woman with a 22-month long history of isolated OA, studied with cerebrospinal fluid biomarkers and repeated clinical, neuropsychological, and morpho-functional evaluations. Baseline morpho-functional neuroimages revealed a left frontal operculum hypoperfusion with a widespread fronto-temporal involvement at follow-up. Cerebrospinal fluid concentrations of tau and amyloid-β were normal. The ten-year long clinical observation disclosed progressive OA worsening and the late onset of frontal functions impairment and extrapyramidal signs. The early and late stages of a neurodegenerative syndrome with OA as the …main clinical feature were characterized. Show more

Keywords: Apraxia of speech, cerebrospinal fluid biomarkers, frontotemporal lobar degeneration, orofacial apraxia, primary progressive aphasia, primary progressive apraxia of speech, single-photon emission computed tomography

DOI: 10.3233/JAD-160525

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1039-1045, 2016

Authors: Hara, Hideo | Ono, Fumiko | Nakamura, Shinichiro | Matsumoto, Shin-ei | Jin, Haifeng | Hattori, Nobutaka | Tabira, Takeshi

Article Type: Research Article

Abstract: With the objective to improve the amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an oral vaccine with recombinant adeno-associated virus vector carrying a signal sequence and Aβ1-43 cDNA (rAAV/Aβ) in old non-human primates, 12 African green and 10 cynomolgus monkeys. The enteric-dissolving coated capsules containing rAAV/Aβ were orally administered once or twice, then monkeys’ conditions were carefully observed with complete blood count and laboratory examinations of the sera. General conditions, food intake, water intake, stool conditions, body weight changes, and menstruation cycles were not significantly altered, and laboratory tests and pathological examinations of the systemic …organs were unremarkable. Pathological examinations of the brain showed significant reduction of the amyloid plaque burden and intracellular Aβ without inflammatory or hemorrhagic changes in the brain. However, soluble Aβ and some Aβ oligomers were increased in rAAV-treated monkey brains without changes of the neuronal density and vascular amyloidosis. Thus, this vaccine seems to be safe in general, but we must be cautious about the increase of Aβ oligomers after vaccination. This vaccine may be recommended at a very early stage of Alzheimer’s disease when little amyloid is deposited. Show more

Keywords: Adeno-associated virus vector, Alzheimer’s disease, amyloid-beta, Aβ oligomer, primate, vaccine

DOI: 10.3233/JAD-160514

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1047-1059, 2016

Authors: Taheri, Saeid | Yu, Jin | Zhu, Hong | Kindy, Mark S.

Article Type: Research Article

Abstract: Background: Cerebral ionic homeostasis impairment, especially Ca2+ , has been observed in Alzheimer’s disease (AD) and also with hypertension. Hypertension and AD both have been implicated in impaired cerebral autoregulation. However, the relationship between the ionic homeostasis impairment in AD and hypertension and cerebral blood flow (CBF) autoregulation is not clear. Objective: To test the hypothesis that a high-salt diet regimen influences the accumulation of amyloid-β (Aβand CBF) and CBF, exacerbates cognitive decline, and increases the propensity to AD. Methods: Double transgenic mice harboring the amyloid-β protein precursor (APPswe), and presenilin-1 (PSEN1) along with control …littermates, 2 months of age at initiation of special diet, were divided into 4 groups: Group A, APP/PS1 and Group B, controls fed a high-sodium (4.00%) chow diet for 3 months; Group C, APP/PS1 and Group D, controls fed a low-sodium (0.08%) regular chow diet for 3 months. Mean arterial blood pressure (MAP) and CBF were measured noninvasively using the tail MAP measurement device and magnetic resonance imaging, respectively. Aβ plaques numbers in the cortex and hippocampus of APP/PS1 were quantified. Results: In contrary to controls, APP/PS1 mice fed a high-salt diet did not show markedly elevated mean systolic and diastolic blood pressure (134±4.8 compared with 162±2.8 mmHg, and 114±5.0 compared with 137±20 mmHg, p < 0.0001). However, a high-salt diet increased CBF in both APP/PS1 and controls and did not alter the cerebral tissue integrity. Aβ plaques were significantly reduced in the cortex and hippocampus of mice fed a high-salt diet. Conclusion: These data suggest that a high-salt diet differently affects MAP and CBF in APP/PS1 mice and controls. Show more

Keywords: Alzheimer’s disease, amyloid-β, blood pressure, cerebral blood flow, cerebral blood volume, magnetic resonance imaging

DOI: 10.3233/JAD-160331

Citation: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1061-1072, 2016