Journal of Alzheimer's Disease - Volume 50, issue 4

Authors: Siotto, Mariacristina | Simonelli, Ilaria | Pasqualetti, Patrizio | Mariani, Stefania | Caprara, Deborah | Bucossi, Serena | Ventriglia, Mariacarla | Molinario, Rossana | Antenucci, Mirca | Rongioletti, Mauro | Rossini, Paolo Maria | Squitti, Rosanna

Article Type: Research Article

Abstract: Meta-analyses demonstrate copper involvement in Alzheimer’s disease (AD), and the systemic ceruloplasmin status in relation to copper is an emerging issue. To deepen this matter, we evaluated levels of ceruloplasmin concentration, ceruloplasmin activity, ceruloplasmin specific activity (eCp/iCp), copper, non-ceruloplasmin copper iron, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype in a sample of 84 AD patients and 58 healthy volunteers. From the univariate logistic analyses we found that ceruloplasmin concentration, eCp/iCp, copper, transferrin, the ceruloplasmin/transferrin ratio, and the APOE genotype were significantly associated with the probability of AD. In the multivariable logistic regression analysis, we selected the best …subset of biological predictors by the forward stepwise procedure. The analysis showed a decrease of the risk of having AD for eCp/iCp (p  = 0.001) and an increase of this risk for non-ceruloplasmin copper (p  = 0.008), age (p  = 0.001), and APOE -ɛ 4 allele (p  <  0.001). The estimated model showed a good power in discriminating AD patients from healthy controls (area under curve: 88% ; sensitivity: 66% ; specificity 93%). These data strength the breakdown of copper homeostasis and propose eCp/iCp as a reliable marker of ceruloplasmin status . Show more

Keywords: Alzheimer’s disease, ceruloplasmin, ceruloplasmin specific activity, non-ceruloplasmin copper

DOI: 10.3233/JAD-150611

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1181-1189, 2016

Authors: Ashby, Emma L. | Miners, James S. | Kehoe , Patrick G. | Love, Seth

Article Type: Research Article

Abstract: Epidemiological data associate hypertension with a predisposition to Alzheimer’s disease (AD), and a number of postmortem and in vivo studies also demonstrate that hypertension increases amyloid-β (Aβ) pathology. In contrast, anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in postmortem frontal cortex in AD. Aβ load was significantly increased in hypertensive (n  = 20) relative to normotensive cases (n  = 62) and was also significantly higher in treated (n  = 9) than untreated hypertensives …(n  = 11). We then looked into mechanisms by which hypertension and treatment might increase Aβ load, focusing on Aβ-synthesizing enzymes, β- and γ -secretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-degrading enzyme (IDE) and neprilysin. ACE and IDE protein levels were significantly lower in hypertensive (n  = 21) than normotensive cases (n  = 64), perhaps translating to decreased Aβ catabolism in hypertensives. ACE level was significantly higher in treated (n  = 9) than untreated hypertensives (n  = 12), possibly reflecting feedback upregulation of the renin-angiotensin system. Prospective studies in larger cohorts stratified according to anti-hypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments, and Aβ metabolism. Show more

Keywords: Angiotensin-converting enzyme, Alzheimer’s disease, amyloid β protein, anti-hypertensive, β-secretase, BACE, γ-secretase, hypertension, insulin-degrading enzyme

DOI: 10.3233/JAD-150831

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1191-1203, 2016

Authors: Kennedy, Richard E. | Cutter, Gary R. | Wang, Guoqiao | Schneider, Lon S.

Article Type: Research Article

Abstract: Background: Many post hoc analyses of clinical trials in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are in small Phase 2 trials. Subject heterogeneity may lead to statistically significant post hoc results that cannot be replicated in larger follow-up studies. Objective: We investigated the extent of this problem using simulation studies mimicking current trial methods with post hoc analyses based on ApoE4 carrier status. Methods: We used a meta-database of 24 studies, including 3,574 subjects with mild AD and 1,171 subjects with MCI/prodromal AD, to simulate clinical trial scenarios. Post hoc …analyses examined if rates of progression on the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) differed between ApoE4 carriers and non-carriers. Results: Across studies, ApoE4 carriers were younger and had lower baseline scores, greater rates of progression, and greater variability on the ADAS-cog. Up to 18% of post hoc analyses for 18-month trials in AD showed greater rates of progression for ApoE4 non-carriers that were statistically significant but unlikely to be confirmed in follow-up studies. The frequency of erroneous conclusions dropped below 3% with trials of 100 subjects per arm. In MCI, rates of statistically significant differences with greater progression in ApoE4 non-carriers remained below 3% unless sample sizes were below 25 subjects per arm. Conclusions: Statistically significant differences for ApoE4 in post hoc analyses often reflect heterogeneity among small samples rather than true differential effect among ApoE4 subtypes. Such analyses must be viewed cautiously. ApoE genotype should be incorporated into the design stage to minimize erroneous conclusions. Show more

Keywords: Alzheimer’s disease, clinical trials, mild cognitive impairment, statistical analysis, trial design

DOI: 10.3233/JAD-150847

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1205-1215, 2016

Authors: Malara, Alba | De Biase, Giuseppe Andrea | Bettarini, Francesco | Ceravolo, Francesco | Di Cello, Serena | Garo, Michele | Praino, Francesco | Settembrini, Vincenzo | Sgrò, Giovanni | Spadea, Fausto | Rispoli, Vincenzo

Article Type: Research Article

Abstract: Background: Pain is under-detected and undertreated in people with dementia. The present study investigates the prevalence of pain in people with dementia hospitalized in nursing homes that are members of National Association of Third Age Residences (ANASTE) Calabria, and evaluates the association among pain, mood, and behavioral and psychological symptoms of dementia (BPSD). Objective: The aim of this study is to define the prevalence of pain in people with dementia in long term care facilities using scales of self-reporting and observational tools and, particularly, to study the relationship between pain and BPSD. Methods: A prospective observational …study was carried out on 233 patients. Pain assessment was performed using self-reporting tools such as the Numeric Rating Scale (NRS) for patients with slight cognitive impairment or no cognitive impairment and observational tools such as Pain Assessment In Advanced Dementia Scale (PAINAD) for patients with moderate or severe cognitive impairment. Mood was evaluated through the Cornell Scale for Depression in Dementia (CSDD) while behavioral problems were assessed through the Cohen-Mansfield Agitation Inventory (CMAI) and Neuropsychiatric Inventory (NPI). Results: Only 42.5% of patients evaluated by NRS provided a reliable answer; of these, 20.4% reported no pain. The percentage of pain evaluated by PAINAD was 51.8% . Analysis of data showed a statistically significant correlation between diagnosis of pain and depressive symptoms, assessed with CSDD (p  = 0.0113), as well as by single items of NPI, such as anxiety (p  = 0.0362) and irritability (p  = 0.0034), and F1 profile (Aggression) of CMAI (p  = 0.01). Conclusion: This study confirms that self-report alone is not sufficient to assess pain in elderly people with dementia; the observational tool is a necessary and suitable way of assessing pain in patients with cognitive impairment. If not adequately treated, chronic pain can cause depression, agitation, and aggression in patients with dementia. Show more

Keywords: Behavior, dementia, nursing home, pain

DOI: 10.3233/JAD-150808

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1217-1225, 2016

Authors: Bourgade, Karine | Le Page, Aurélie | Bocti, Christian | Witkowski, Jacek M. | Dupuis, Gilles | Frost, Eric H. | Fülöp Jr., Tamás

Article Type: Research Article

Abstract: Senile amyloid plaques are one of the main hallmarks of Alzheimer’s disease (AD). They correspond to insoluble deposits of amyloid-β peptides (Aβ) and are responsible for the inflammatory response and neurodegeneration that lead to loss of memory. Recent data suggest that Aβ possess antimicrobial and anti-viral activity in vitro . Here, we have used cocultures of neuroglioma (H4) and glioblastoma (U118-MG) cells as a minimal in vitro model to investigate whether Aβ is produced by neuroglioma cells and whether this could result in protective anti-viral activity against HSV-1 infection. Results showed that H4 cells secreted Aβ42 in response …to HSV-1 challenge and that U118-MG cells could rapidly internalize Aβ42 . Production of pro-inflammatory cytokines TNFα and IL-1β by H4 and U118-MG cells occurred under basal conditions but infection of the cells with HSV-1 did not significantly upregulate production. Both cell lines produced low levels of IFNα . However, extraneous Aβ42 induced strong production of these cytokines. A combination of Aβ42 and HSV-1 induced production of pro-inflammatory cytokines TNFα and IL-1β, and IFNα in the cell lines. The reported anti-viral protection of Aβ42 was revealed in transfer experiments involving conditioned medium (CM) of HSV-1-infected H4 cells. CM conferred Aβ-dependent protection against HSV-1 replication in de novo cultures of H4 cells challenged with HSV-1. Type 1 interferons did not play a role in these assays. Our data established that H4 neuroglioma cells produced Aβ42 in response to HSV-1 infection thus inhibiting secondary replication. This mechanism may play a role in the etiology of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, cocultures, glial cells, herpes simplex virus-1 (HSV-1), neuronal cells, viral replication inhibition

DOI: 10.3233/JAD-150652

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1227-1241, 2016

Authors: Ni, Ling | Liu, Renyuan | Yin, Zhenyu | Zhao, Hui | Nedelska, Zuzana | Hort, Jakub | Zhou, Fei | Wu, Wenbo | Zhang, Xin | Li, Ming | Yu, Haiping | Zhu, Bin | Xu, Yun | Zhang, Bing

Article Type: Research Article

Abstract: Background: Lacunar infarctions (LI) have been associated with a cognitive decline and an increased risk of dementia. Whether and how the pattern of spontaneous brain activity in patients with mild cognitive impairment (MCI) differs in subjects with and without concomitant LI remains unclear. Objective: To compare the pattern of spontaneous brain activity in MCI patients with versus those without LI using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Forty-eight MCI patients, including 22 with LI [MCI-LI] and 26 without LI [MCI-no LI], and 28 cognitive normal subjects underwent rs-fMRI post-processed using regional homogeneity (ReHo) and the …amplitude of low-frequency fluctuation (ALFF) methods. Results: Compared with cognitively normal subjects, the MCI-LI patients had decreased ReHo in the precuneus/cuneus (Pcu/CU) and insula; decreased ALFF in the Pcu/CU and frontal lobe; and increased ALFF and ReHo in the temporal lobe. While the MCI-no LI group had increased ReHo and ALFF in the bilateral hippocampus and parahippocampal gyrus, frontal lobe, and decreased ALFF and ReHo in the temporal lobe. Compared with the MCI-no LI patients, those with MCI-LI had decreased ALFF in the frontal lobe; decreased ReHo in the Pcu/CU and insula; and increased ALFF and ReHo in the temporal lobe (p  <  0.05, AlphaSim corrected). In MCI-LI patients, the MOCA scores showed a relatively weak correlation with ALFF values in the medial frontal gyrus (r  = 0.432, p  = 0.045) (of borderline significance after Bonferroni correction). Conclusions: The spontaneous brain activities in MCI-LI were distinct from MCI-no LI. The probable compensatory mechanism observed in MCI-no LI might be disrupted in MCI with LI due to vascular damage. Show more

Keywords: Amplitude of low-frequency fluctuation, lacunar infarction, mild cognitive impairment, regional homogeneity

DOI: 10.3233/JAD-150622

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1243-1254, 2016

Authors: Villa, Alessandro

Article Type: Book Review

DOI: 10.3233/JAD-160030

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1255-1256, 2016

Article Type: Other

DOI: 10.3233/JAD-151138

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1257-1261, 2016

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1263-1275, 2016