Journal of Alzheimer's Disease - Volume 53, issue 2

Authors: del Valle, Eva | Navarro, Ana | Martínez-Pinilla, Eva | Torices, Silvia | Tolivia, Jorge

Article Type: Research Article

Abstract: Apolipoprotein D (Apo D) and Apolipoprotein J (Apo J) are among the only nine apolipoproteins synthesized in the nervous system. Apart from development, these apolipoproteins are implicated in the normal aging process as well as in different neuropathologies as Alzheimer’s disease (AD), where a neuroprotective role has been postulated. Different authors have proposed that Apo D and Apo J could be biomarkers for AD but as far as we know, there are no studies about the relationship between them as well as their expression pattern along the progression of the disease. In this paper, using double immunohistochemistry techniques, we have …demonstrated that Apo D is mainly located in glial cells while Apo J expression preferentially occurs in neurons; both proteins are also present in AD diffuse and mature senile plaques but without signal overlap. In addition, we have observed that Apo J and Apo D immunostaining shows a positive correlation with the progression of the disease and the Braak’s stages. These results suggest complementary and cell-dependent neuroprotective roles for each apolipoprotein during AD progress. Show more

Keywords: Apolipoproteins, amyloid-β peptide, Braak’s stage, frontal cortex, glia

DOI: 10.3233/JAD-160032

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 639-650, 2016

Authors: Hanseeuw, Bernard | Dricot, Laurence | Lhommel, Renaud | Quenon, Lisa | Ivanoiu, Adrian

Article Type: Research Article

Abstract: Background: Patients with mild cognitive impairment (MCI) are at risk for Alzheimer’s dementia but the presence of amyloid (Aβ) strongly increases this risk. In clinical settings, when Aβ status is not available, different neurodegenerative markers are used to characterize MCI. The accuracy of these markers to discriminate between Aβ–and Aβ+ MCI is not yet determined. Objective: To compare different markers of neurodegeneration in Aβ–and Aβ+ MCI, with an Aβ–elderly control (EC) group. Methods: Patients with MCI (n  = 39) and EC (n  = 28) underwent MRI, 18 F-FDG PET, and Aβ PET (18 F-flutemetamol). We compared FDG …and MRI biomarker values in cortical and hippocampal regions of interest, and using voxel-wise surface maps. We computed ROC curves discriminating between the three groups for each biomarker. Results: All biomarker values were reduced in Aβ+ MCI compared to EC (p  < 0.001). Aβ–MCI had low cortical metabolism (p  = 0.002), but hippocampal volume, cortical thickness, and hippocampal metabolism were not significantly different between Aβ–MCI and EC (p  > 0.40). Cortical metabolism best discriminated between MCI and EC (AUC = 0.92/0.86, Aβ+/Aβ–) while hippocampal volume best discriminated between Aβ–MCI and Aβ+ MCI (AUC = 0.79). Conclusions: Cortical hypometabolism was observed in both Aβ–MCI and Aβ+ MCI whereas hippocampal atrophy was mostly found in Aβ+ MCI. For MCI patients without available Aβ information, hippocampal atrophy is thus more informative about Aβ status than cortical hypometabolism. Show more

Keywords: Alzheimer’s disease, amyloid, 18F-flutemetamol, FDG-PET, hippocampus, magnetic resonance imaging, mild cognitive impairment, neocortex, PALZ score

DOI: 10.3233/JAD-160204

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 651-660, 2016

Authors: Yamasaki, Takao | Horie, Shizuka | Ohyagi, Yasumasa | Tanaka, Eri | Nakamura, Norimichi | Goto, Yoshinobu | Kanba, Shigenobu | Kira, Jun-ichi | Tobimatsu, Shozo

Article Type: Research Article

Abstract: Visual dysfunctions are common in Alzheimer’s disease (AD). Our aim was to establish a neurophysiological biomarker for amnestic mild cognitive impairment (aMCI). Visual evoked potentials (VEPs) were recorded in aMCI patients who later developed AD (n  = 15) and in healthy older (n  = 15) and younger controls (n  = 15). Visual stimuli were optimized to separately activate lower and higher levels of the ventral and dorsal streams. We compared VEP parameters across the three groups of participants and conducted a linear correlation analysis between VEPs and data from neuropsychological tests. We then used a receiver operating characteristic (ROC) analysis to discriminate those …with aMCI from those who were healthy older adults. The latency and phase of VEPs to lower-level stimuli (chromatic and achromatic gratings) were significantly affected by age but not by cognitive decline. Conversely, VEP latencies for higher-ventral (faces and kanji-words) and dorsal (kana-words and optic flow motion) stimuli were not affected by age, but they were significantly prolonged in aMCI patients. Interestingly, VEPs for higher-dorsal stimuli were related to outcomes of neuropsychological tests. Furthermore, the ROC analysis showed that the highest areas under the curve were obtained for VEP latencies in response to higher-dorsal stimuli. These results suggest aMCI-related functional impairment specific to higher-level visual processing. Further, dysfunction in the higher-level of the dorsal stream could be an early indicator of cognitive decline. Therefore, we conclude that VEPs associated with higher-level dorsal stream activity can be a sensitive biomarker for early detection of aMCI. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, parallel visual pathways, visual evoked potentials, visual perception

DOI: 10.3233/JAD-150939

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 661-676, 2016

Authors: Merino-Zamorano, Cristina | Fernández-de Retana, Sofía | Montañola, Alex | Batlle, Aina | Saint-Pol, Julien | Mysiorek, Caroline | Gosselet, Fabien | Montaner, Joan | Hernández-Guillamon, Mar

Article Type: Research Article

Abstract: Amyloid-β (Aβ) accumulation in Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) is likely caused by the impairment of its brain clearance that partly occurs through the blood-brain barrier (BBB). In this context, an in vitro BBB model is a valuable tool for studying the molecular mechanisms that regulate this process. This study assessed brain Aβ elimination across the BBB and its modulation by the natural chaperones Apolipoprotein A1 (ApoA1) and Apolipoprotein J/Clusterin (ApoJ). The model was based on primary cerebral endothelial cells that were cultured on Matrigel-coated Transwells and treated with fluorescently labeled-Aβ1-40 to track its efflux …across the BBB, which corresponds to trafficking from the basolateral (brain) to apical (blood) compartments. We observed that the transport of basolateral Aβ1-40 was enhanced when it was complexed to rApoJ, whereas the complex formed with rApoA1 did not influence Aβ1-40 efflux. However, the presence of rApoA1 in the apical compartment was able to mobilize Aβ1-40 from the basolateral side. We also observed that both rApoA1 and rApoJ moderately crossed the monolayer (from blood to brain) through a mechanism involving the LDL receptor-related protein family. In contrast to the increased rApoJ efflux when complexed to Aβ1-40 , rApoA1 trafficking was restricted when it was bound to the Aβ peptide. In summary, the present study highlights the role of ApoJ and ApoA1 in the in vitro modulation of Aβ elimination across the BBB. Show more

Keywords: Amyloid-beta, ApoA1, ApoJ, apolipoprotein, blood-brain barrier, endothelial cells

DOI: 10.3233/JAD-150976

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 677-691, 2016

Authors: Yu, Jing | Li, Rui | Jiang, Yang | Broster, Lucas S. | Li, Juan

Article Type: Research Article

Abstract: Older adults with mild cognitive impairment (MCI) manifest impaired explicit memory. However, studies on implicit memory such as repetition effects in persons with MCI have been limited. In the present study, 17 MCI patients and 16 healthy normal controls (NC) completed a modified delayed-match-to-sample task while undergoing functional magnetic resonance imaging. We aim to examine the neural basis of repetition; specifically, to elucidate whether and how repetition-related brain responses are altered in participants with MCI. When repeatedly rejecting distracters, both NC and MCI showed similar behavioral repetition effects; however, in both whole-brain and region-of-interest analyses of functional data, persons with …MCI showed reduced repetition-driven suppression in the middle occipital and middle frontal gyrus. Further, individual difference analysis found that activation in the left middle occipital gyrus was positively correlated with rejecting reaction time and negatively correlated with accuracy rate, suggesting a predictor of repetition behavioral performance. These findings provide new evidence to support the view that neural mechanisms of repetition effect are altered in MCI who manifests compensatory repetition-related brain activities along with their neuropathology. Show more

Keywords: Delayed-match-to-sample task, functional MRI, mild cognitive impairment, repetition, repetition suppression

DOI: 10.3233/JAD-160086

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 693-704, 2016

Authors: Bolívar, Juan Carlos Cejudo | Saladie, Domènec Gil

Article Type: Research Article

Abstract: Background: It has been suggested that mild cognitive impairment (MCI) can be used to identify patients at risk of developing clinical stages of Alzheimer’s disease (AD). Objective: The aim of this study was to describe the characteristics of amnesic syndrome of dementia of the Alzheimer’s type (DAT) as a continuous degenerative process from normality to amnesic syndrome and provide a classification of the degrees of amnesia. Methods: Of 3,800 new incidental cases at the Memory Clinic, 747 were classified as non-demented patients. A 96-month follow-up study was conducted. We described and compared longitudinal outcomes from …normality to amnesic syndrome based on immediate memory, verbal learning, free recall, and recognition using the memory scale from the Basic Neuropsychological Battery, version D (BNB-D) and created a new classification of memory impairment. Results: Based on differences observed in this longitudinal study, we classified patients in four memory stages: M1, Normal episodic memory; M2, mild impairment in learning and/or free recall; M3, clear impairment in learning and/or free recall; and M4, complete amnesic syndrome. With this new amnesia classification, we studied the chronological progression of all patients diagnosed without dementia from baseline to DAT conversion using the Kaplan-Meier estimator of survival probability (Log Rank/Mantel Cox comparison. χ 2  = 171.84, p  = 0.001). Conclusion: This new classification of memory impairment can help increase the prediction certainty of conversion from amnestic MCI to AD and improve research on AD biomarkers and their relationship with memory as the principal manifestation of AD. Show more

Keywords: Alzheimer’s disease, biomarkers in AD, memory in dementia, mild cognitive impairment, neuropsychology, prodromal Alzheimer’s disease

DOI: 10.3233/JAD-160117

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 705-712, 2016

Authors: Hird, Megan A. | Egeto, Peter | Fischer, Corinne E. | Naglie, Gary | Schweizer, Tom A.

Article Type: Research Article

Abstract: Background: Many individuals with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are at an increased risk of driving impairment. There is a need for tools with sufficient validity to help clinicians assess driving ability. Objective: Provide a systematic review and meta-analysis of the primary driving assessment methods (on-road, cognitive, driving simulation assessments) in patients with MCI and AD. Methods: We investigated (1) the predictive utility of cognitive tests and domains, and (2) the areas and degree of driving impairment in patients with MCI and AD. Effect sizes were derived and analyzed in a random …effects model. Results: Thirty-two articles (including 1,293 AD patients, 92 MCI patients, 2,040 healthy older controls) met inclusion criteria. Driving outcomes included: On-road test scores, pass/fail classifications, errors; caregiver reports; real world crash involvement; and driving simulator collisions/risky behavior. Executive function (ES [95% CI]; 0.61 [0.41, 0.81]), attention (0.55 [0.33, 0.77]), visuospatial function (0.50 [0.34, 0.65]), and global cognition (0.61 [0.39, 0.83]) emerged as significant predictors of driving performance. Trail Making Test Part B (TMT-B, 0.61 [0.28, 0.94]), TMT-A (0.65 [0.08, 1.21]), and Maze test (0.88 [0.60, 1.15]) emerged as the best single predictors of driving performance. Patients with very mild AD (CDR = 0.5) mild AD (CDR = 1) were more likely to fail an on-road test than healthy control drivers (CDR = 0), with failure rates of 13.6%, 33.3% and 1.6%, respectively. Conclusion: The driving ability of patients with MCI and AD appears to be related to degree of cognitive impairment. Across studies, there are inconsistent cognitive predictors and reported driving outcomes in MCI and AD patients. Future large-scale studies should investigate the driving performance and associated neural networks of subgroups of AD (very mild, mild, moderate) and MCI (amnestic, non-amnestic, single-domain, multiple-domain). Show more

Keywords: KeywordsAlzheimer’s disease, automobile driving, cognition, mild cognitive impairment

DOI: 10.3233/JAD-160276

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 713-729, 2016

Authors: Suh, Seung Wan | Han, Ji Won | Park, Jae Young | Hong, Jong Woo | Kim, Kayoung | Kim, Taehyun | Lee, Kyoung Hwan | Han, Guehee | Jeong, Hyeon | Seo, Jiyeong | Kim, Tae Hui | Lee, Dong Young | Lee, Dong Woo | Ryu, Seung-Ho | Kim, Shin-Gyeom | Youn, Jong Chul | Jhoo, Jin Hyeong | Kim, Jeong Lan | Lee, Seok Bum | Lee, Jung Jae | Kwak, Kyung Phil | Kim, Bong-Jo | Moon, Seok Woo | Park, Joon Hyuk | Kim, Ki Woong

Article Type: Research Article

Abstract: Despite its significance as a contributing factor for late-life dementia risk, illiteracy is frequently underappreciated in the management of dementia. In this study, we estimated the proportion of dementia cases attributable to illiteracy using the population attributable fraction (PAF), and calculated to what extent the monetary cost of dementia could be saved in the future by reducing illiteracy from the South Korean, Latin American, South Asian/Middle Eastern, and African populations. We collected necessary data from the 2011 United Nations Human Development Report and prevalence studies conducted in these regions. Additional variables not included in the above sources were estimated using …a logit model under a “trend scenario”-based assumption. Around 16% of the total number of dementia cases in South Korea in 2015 can be attributed to illiteracy, with this figure predicted to decline to around 2% by 2050. This translates to a saving in dementia care costs of approximately 52 billion USD, providing we are successful in theoretically eradicating illiteracy as of 2015, in the population aged 65 years or under. Likewise, reducing illiteracy to 50% in Latin America, South Asia/The Middle East, and Africa by 2050 could generate further cost savings of between 71 and 244 billion, 13 and 94 billion, and 17 and 78 billion USD, respectively. Even public policies aimed solely at reducing illiteracy in the childhood, adolescent, or middle-aged population could potentially have a role in the primary prevention of dementia. Moving forward, governments will need to address this issue in a purposeful and systematic manner. Show more

Keywords: Africa, cognitive reserve, dementia, dementia care costs, health expenditure, Latin America, literacy, population attributable fraction, Republic of Korea

DOI: 10.3233/JAD-160108

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 731-741, 2016

Authors: Yildiz-Unal, Aysegul | Korulu, Sirin

Article Type: Correction

DOI: 10.3233/JAD-169003

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 743-743, 2016

Authors: Jahng, Geon-Ho | Oh, Janghoon | Lee, Do-Wan | Kim, Hyug-Gi | Rhee, Hak Young | Shin, Wonchul | Paik, Jong-Woo | Lee, Kyung Mi | Park, Soonchan | Choe, Bo-Young | Ryu, Chang-Woo

Article Type: Correction

DOI: 10.3233/JAD-169004

Citation: Journal of Alzheimer's Disease, vol. 53, no. 2, pp. 745-745, 2016