Journal of Alzheimer's Disease - Volume 57, issue 3

Authors: Hane, Francis T. | Robinson, Morgan | Lee, Brenda Y. | Bai, Owen | Leonenko, Zoya | Albert, Mitchell S.

Article Type: Review Article

Abstract: The field of Alzheimer’s disease (AD) research has grown exponentially over the past few decades, especially since the isolation and identification of amyloid-β from postmortem examination of the brains of AD patients. Recently, the Journal of Alzheimer ’s Disease (JAD) put forth approximately 300 research reports which were deemed to be the most influential research reports in the field of AD since 2010. JAD readers were asked to vote on these most influential reports. In this 3-part review, we review the results of the 300 most influential AD research reports to provide JAD readers with a readily …accessible, yet comprehensive review of the state of contemporary research. Notably, this multi-part review identifies the “hottest” fields of AD research providing guidance for both senior investigators as well as investigators new to the field on what is the most pressing fields within AD research. Part 1 of this review covers pathogenesis, both on a molecular and macro scale. Part 2 review genetics and epidemiology, and part 3 covers diagnosis and treatment. This part of the review, diagnosis and treatment, reviews the latest diagnostic criteria, biomarkers, imaging, and treatments in AD. Show more

Keywords: Alzheimer’s disease, biomarkers, diagnosis, mild cognitive impairment, MRI, PET, treatment

DOI: 10.3233/JAD-160907

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 645-665, 2017

Authors: Mendez, Mario F.

Article Type: Review Article

Abstract: There is a long history linking traumatic brain injury (TBI) with the development of dementia. Despite significant reservations, such as recall bias or concluding causality for TBI, a summary of recent research points to several conclusions on the TBI-dementia relationship. 1) Increasing severity of a single moderate-to-severe TBI increases the risk of subsequent Alzheimer’s disease (AD), the most common type of dementia. 2) Repetitive, often subconcussive, mild TBIs increases the risk for chronic traumatic encephalopathy (CTE), a degenerative neuropathology. 3) TBI may be a risk factor for other neurodegenerative disorders that can be associated with dementia. 4) TBI appears to …lower the age of onset of TBI-related neurocognitive syndromes, potentially adding “TBI cognitive-behavioral features”. The literature further indicates several specific risk factors for TBI-associated dementia: 5) any blast or blunt physical force to the head as long as there is violent head displacement; 6) decreased cognitive and/or neuronal reserve and the related variable of older age at TBI; and 7) the presence of apolipoprotein E ɛ 4 alleles, a genetic risk factor for AD. Finally, there are neuropathological features relating TBI with neurocognitive syndromes: 8) acute TBI results in amyloid pathology and other neurodegenerative proteinopathies; 9) CTE shares features with neurodegenerative dementias; and 10) TBI results in white matter tract and neural network disruptions. Although further research is needed, these ten findings suggest that dose-dependent effects of violent head displacement in vulnerable brains predispose to dementia; among several potential mechanisms is the propagation of abnormal proteins along damaged white matter networks. Show more

Keywords: Alzheimer’s disease chronic traumatic encephalopathy, dementia, traumatic brain injury

DOI: 10.3233/JAD-161002

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 667-681, 2017

Authors: Rüb, Udo | Stratmann, Katharina | Heinsen, Helmut | Seidel, Kay | Bouzrou, Mohamed | Korf, Horst-Werner

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) represents the most frequent neurodegenerative disease of the human brain worldwide. Currently practiced treatment strategies for AD only include some less effective symptomatic therapeutic interventions, which unable to counteract the disease course of AD. New therapeutic attempts aimed to prevent, reduce, or remove the extracellular depositions of the amyloid-β protein did not elicit beneficial effects on cognitive deficits or functional decline of AD. In view of the failure of these amyloid-β-based therapeutic trials and the close correlation between the brain pathology of the cytoskeletal tau protein and clinical AD symptoms, therapeutic attention has since shifted to the …tau cytoskeletal protein as a novel drug target. The abnormal hyperphosphorylation and intraneuronal aggregation of this protein are early events in the evolution of the AD-related neurofibrillary pathology, and the brain spread of the AD-related tau aggregation pathology may possibly follow a corruptive protein templating and seeding-like mechanism according to the prion hypothesis. Accordingly, immunotherapeutic targeting of the tau aggregation pathology during the very early pre-tangle phase is currently considered to represent an effective and promising therapeutic approach for AD. Recent studies have shown that the initial immunoreactive tau aggregation pathology already prevails in several subcortical regions in the absence of any cytoskeletal changes in the cerebral cortex. Thus, it may be hypothesized that the subcortical brain regions represent the “port of entry” for the pathogenetic agent from which the disease ascends anterogradely as an “interconnectivity pathology”. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, cytoskeletal pathology, immunotherapy, prion-like diseases, tau protein

DOI: 10.3233/JAD-161102

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 683-696, 2017

Authors: Lombardi, Gemma | Berti, Valentina | Tedde, Andrea | Bagnoli, Silvia | Piaceri, Irene | Polito, Cristina | Lucidi, Giulia | Ferrari, Camilla | Ginestroni, Andrea | Moretti, Marco | Pupi, Alberto | Nacmias, Benedetta | Sorbi, Sandro

Article Type: Short Communication

Abstract: According to the literature, the APP Ala713Thr mutation is associated with Alzheimer’s disease and cerebral amyloid angiopathy. We describe a case of dementia clinically compatible with frontotemporal dementia in an APP Ala713Thr mutation carrier in which both [18 F]Florbetapir PET uptake and Aβ1-42 cerebrospinal fluid levels were normal. Further evidences are required to establish if this association is only incidental.

Keywords: APP Ala713Thr, familial Alzheimer’s disease, florbetapir PET, frontotemporal dementia

DOI: 10.3233/JAD-161170

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 697-703, 2017

Authors: Bouvy, Willem H. | Kuijf, Hugo J. | Zwanenburg, Jaco J.M. | Koek, Huiberdina L. | Kappelle, L. Jaap | Luijten, Peter R. | Ikram, M. Kamran | Biessels, Geert Jan | on behalf of the Utrecht Vascular Cognitive Impairment (VCI) Study group

Article Type: Short Communication

Abstract: Cerebral small vessel disease (SVD) contributes to cognitive impairment and dementia. SVD may affect veins, but veins are difficult to detect with 1.5 and 3T MRI. We compared deep medullary veins (DMVs) visualized on 7T-MRI between patients with early Alzheimer’s disease (eAD; n  = 17) or amnestic MCI (aMCI; n  = 12) and controls (n  = 40). The number and density of DMVs was similar in patients and controls, but tortuosity was higher in eAD (Cohen’s d = 0.7, 95% CI: 0.1–1.2, p  = 0.02) and aMCI (Cohen’s d = 0.8, 95% CI: 0.2–1.5, p  = 0.01), independent of brain atrophy. Venous changes provide a new perspective on vascular …involvement in dementia. Show more

Keywords: Alzheimer’s disease, cerebral small vessel disease, cerebral veins, magnetic resonance imaging

DOI: 10.3233/JAD-160952

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 705-710, 2017

Authors: Kim, Hee Jin | Cho, Hanna | Werring, David J. | Jang, Young Kyoung | Kim, Yeo Jin | Lee, Jin San | Lee, Juyoun | Jun, Soomin | Park, Seongbeom | Ryu, Young Hoon | Choi, Jae Yong | Cho, Young Seok | Moon, Seung Hwan | Na, Duk L. | Lyoo, Chul Hyoung | Seo, Sang Won

Article Type: Short Communication

Abstract: Cerebrovascular deposition of amyloid-β, known as cerebral amyloid angiopathy (CAA), is associated with MRI findings of lobar hemorrhage, cerebral microbleeds, and cortical superficial siderosis. Although pathological studies suggest that tau may co-localize with vascular amyloid, this has not yet been investigated in CAA in vivo . Three patients with probable CAA underwent 11 C-Pittsburgh Compound B (PiB) PET or 18 F-florbetaben PET to evaluate amyloid burden, and 18 F-AV-1451 PET to evaluate paired helical filament tau burden. Regions that had cerebral microbleeds or cortical superficial siderosis largely overlapped with those showing increased 18 F-AV-1451. Our preliminary study raised the possibility …that lobar cerebral microbleeds, and cortical superficial siderosis, which are characteristic markers of vascular amyloid, may be associated with local production of paired helical filament tau. Show more

Keywords: Cerebral amyloid angiopathy, cortical superficial siderosis, 18F-AV-1451 PET, lobar cerebral microbleeds, tau

DOI: 10.3233/JAD-161139

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 711-716, 2017

Authors: Riancho, Javier | Pozueta, Ana | Santos, Miguel | Lage, Carmen | Carril, José M. | Banzo, Ignacio | Martínez-Rodriguez, Isabel | Gorno-Tempini, Marilu | Sánchez-Juan, Pascual

Article Type: Short Communication

Abstract: Among primary progressive aphasias (PPAs), logopenic variant PPA (lv-PPA) is usually related to Alzheimer’s disease. Although it has been widely clinically and pathologically evaluated, the topography in LPA is still controversial. We report a patient presenting with a logopenic syndrome due to a strategic lesion located in the superior and middle temporal gyrus and compare our findings with those of a PiB-PET positive lv-PPA patient matched by age, gender, and education. We consider that our study provides new anatomical clues to better understand the cognitive mechanisms underlying the logopenic syndrome.

Keywords: Logopenic aphasia, primary progressive aphasia, stroke

DOI: 10.3233/JAD-161267

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 717-721, 2017

Authors: Liu, Lu-Shan | Bai, Xue-Qin | Gao, Ya | Wu, Qi | Ren, Zhong | Li, Qing | Pan, Li-Hong | He, Ni-Ya | Peng, Juan | Tang, Zhi-Han

Article Type: Research Article

Abstract: Background: Hyperlipidemia is a risk factor for neurodegenerative diseases. Proprotein convertase subtilisin / Kexin type 9 (PCSK9) degrades hepatic low-density lipoprotein receptor (LDLR) to regulate lipid metabolism. It is unclear if PCSK9 plays a role in neurodegenerative diseases. Objective: This study was designed to determine whether PCSK9 is crucial between hyperlipidemia and Alzheimer’s disease. The interrelationship between PCSK9 and neuronal apoptosis was explored in PC12 cells in response to treatment with oxidized low-density lipoprotein (oxLDL). Methods: Cultured PC12 cells were serum-starved and incubated with different concentrations of oxLDL for 24 h. Intracytoplasmic lipid droplets were observed …by oil red O staining. Morphological assessment of apoptotic cells was performed using Hoechst 33258 staining and flow cytometry analysis. The expression of mRNA and protein was detected by reverse-transcription polymerase chain reaction (RT-PCR) and western blot analyses, respectively. Transfection of small interfering RNA (siRNA) into PC12 cells was conducted using HiperFect Transfection Reagent. Concentrations of Aβ40 and Aβ42 were detected by enzyme-linked immunosorbent assay (ELISA) kit. Results: Intracellular lipid content, the number of apoptotic cells, and PCSK9 expression were increased in PC12 cells after oxLDL treatment. Transfection with PCSK9 siRNA reduced the oxLDL-induced apoptosis of PC12 cells. We further confirmed the involvement of Bcl-2/Bax-Caspase (9, 3) signaling pathway in the regulation of PC12 cells apoptosis.β-Secretase 1, another target gene of PCSK9, was downregulated in PC12 cells in response to oxLDL treatment. Aβ40 and Aβ42 contents were also decreased. Conclusion: PCSK9 promotes oxLDL-induced PC12 cell apoptosis through the Bcl-2/Bax-Caspase 9/3 signaling pathway. Show more

Keywords: Amyloid β peptide, apoptosis, β-site AβPP cleaving enzyme 1, caspases, oxidized low-density lipoprotein, PC12 cell, proprotein convertase subtilisin/kexin type 9, signal pathway

DOI: 10.3233/JAD-161136

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 723-734, 2017

Authors: Mason, Emily J. | Hussey, Erin P. | Molitor, Robert J. | Ko, Philip C. | Donahue, Manus J. | Ally, Brandon A.

Article Type: Research Article

Abstract: Early detection may be the key to developing therapies that will combat Alzheimer’s disease (AD). It has been consistently demonstrated that one of the main pathologies of AD, tau, is present in the brain decades before a clinical diagnosis. Tau pathology follows a stereotypical route through the medial temporal lobe beginning in the entorhinal and perirhinal cortices. If early pathology leads to very subtle changes in behavior, it may be possible to detect these changes in subjects years before a clinical diagnosis can currently be made. We aimed to discover if cognitively normal middle-aged adults (40–60 years old) at increased …risk for AD due to family history would have impaired performance on a cognitive task known to challenge the perirhinal cortex. Using an oddity detection task, we found that subjects with a family history of AD had lowered accuracy without demonstrating differences in rate of acquisition. There were no differences between subjects’ medial temporal lobe volume or cortical thickness, indicating that the changes in behavior were not due to significant atrophy. These results demonstrate that subtle changes in perceptual processing are detectable years before a typical diagnosis even when there are no differences detectable in structural imaging data. Anatomically-targeted cognitive testing may be useful in identifying subjects in the earliest stages of AD. Show more

Keywords: Alzheimer’s disease, cognition, early diagnosis, neuroimaging, risk, visual perception

DOI: 10.3233/JAD-160772

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 735-745, 2017

Authors: Gregory, Michael A. | Boa Sorte Silva, Narlon C. | Gill, Dawn P. | McGowan, Cheri L. | Liu-Ambrose, Teresa | Shoemaker, J. Kevin | Hachinski, Vladimir | Holmes, Jeff | Petrella, Robert J.

Article Type: Research Article

Abstract: This 6-month experimental case series study investigated the effects of a dual-task gait training and aerobic exercise intervention on cognition, mobility, and cardiovascular health in community-dwelling older adults without dementia. Participants exercised 40 min/day, 3 days/week for 26 weeks on a Biodex GaitTrainer2 treadmill. Participants were assessed at baseline (V0), interim (V1: 12-weeks), intervention endpoint (V2: 26-weeks), and study endpoint (V3: 52-weeks). The study outcomes included: cognition [executive function (EF), processing speed, verbal fluency, and memory]; mobility: usual & dual-task gait (speed, step length, and stride time variability); and vascular health: ambulatory blood pressure, carotid arterial compliance, and intima-media thickness (cIMT). …Fifty-six participants [age: 70(6) years; 61% female] were included in this study. Significant improvements following the exercise program (V2) were observed in cognition: EF (p  = 0.002), processing speed (p  < 0.001), verbal fluency [digit symbol coding (p  < 0.001), phonemic verbal fluency (p  < 0.001)], and memory [immediate recall (p  < 0.001) and delayed recall (p  < 0.001)]; mobility: usual & dual-task gait speed (p  = 0.002 and p  < 0.001, respectively) and step length (p  = 0.001 and p  = 0.003, respectively); and vascular health: cIMT (p  = 0.002). No changes were seen in the remaining outcomes. In conclusion, 26 weeks of dual-task gait training and aerobic exercise improved performance on a number of cognitive outcomes, while increasing usual & dual-task gait speed and step length in a sample of older adults without dementia. Show more

Keywords: Aging, dual-task exercise, executive function, laboratory-based, prevention

DOI: 10.3233/JAD-161240

Citation: Journal of Alzheimer's Disease, vol. 57, no. 3, pp. 747-763, 2017