Journal of Alzheimer's Disease - Volume 55, issue 3

Authors: Lusardi, Theresa A. | Phillips, Jay I. | Wiedrick, Jack T. | Harrington, Christina A. | Lind, Babett | Lapidus, Jodi A. | Quinn, Joseph F. | Saugstad, Julie A.

Article Type: Research Article

Abstract: Background: Currently available biomarkers of Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) protein analysis and amyloid PET imaging, each of which has limitations. The discovery of extracellular microRNAs (miRNAs) in CSF raises the possibility that miRNA may serve as novel biomarkers of AD. Objective: Investigate miRNAs in CSF obtained from living donors as biomarkers for AD. Methods: We profiled miRNAs in CSF from 50 AD patients and 49 controls using TaqMan® arrays. Replicate studies performed on a subset of 32 of the original CSF samples verified 20 high confidence miRNAs. Stringent data analysis using …a four-step statistical selection process including log-rank and receiver operating characteristic (ROC) tests, followed by random forest tests, identified 16 additional miRNAs that discriminate AD from controls. Multimarker modeling evaluated linear combinations of these miRNAs via best-subsets logistic regression, and computed area under the ROC (AUC) curve ascertained classification performance. The influence of ApoE genotype on miRNA biomarker performance was also evaluated. Results: We discovered 36 miRNAs that discriminate AD from control CSF. 20 of these retested in replicate studies verified differential expression between AD and controls. Stringent statistical analysis also identified these 20 miRNAs, and 16 additional miRNA candidates. Top-performing linear combinations of 3 and 4 miRNAs have AUC of 0.80–0.82. Addition of ApoE genotype to the model improved performance, i.e., AUC of 3 miRNA plus ApoE4 improves to 0.84. Conclusions: CSF miRNAs can discriminate AD from controls. Combining miRNAs improves sensitivity and specificity of biomarker performance, and adding ApoE genotype improves classification. Show more

Keywords: Alzheimer’s disease, ApoE, biomarker, cerebrospinal fluid, microRNA, PCR

DOI: 10.3233/JAD-160835

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1223-1233, 2017

Authors: Iwahara, Naotoshi | Hisahara, Shin | Kawamata, Jun | Matsumura, Akihiro | Yokokawa, Kazuki | Saito, Taro | Fujikura, Mai | Manabe, Tatsuo | Suzuki, Hiromi | Matsushita, Takashi | Suzuki, Syuuichirou | Shimohama, Shun

Article Type: Research Article

Abstract: In response to changes of the central nervous system environment, microglia are capable of acquiring diverse phenotypes for cytotoxic or immune regulation and resolution of injury. Alzheimer’s disease (AD) pathology also induces several microglial activations, resulting in production of pro-inflammatory cytokines and reactive oxygen species or clearance of amyloid-β (Aβ) through phagocytosis. We previously demonstrated that microglial activation and increase in oxidative stress started from the middle age in APPswe/PS1dE9 mice, and hypothesized that M1 activation occurs in middle-aged AD mice by Aβ stimulation. In the present study, we analyzed in vivo expressions of pro-inflammatory cytokines (M1 microglial markers), …M2 microglial markers, and suppressor of cytokine signaling (SOCS) family, and examined the microglial phenotypic profile in APPswe/PS1dE9 mice. Then we compared the in vitro gene expression patterns of Aβ- and lipopolysaccharide (LPS)-stimulated primary-cultured microglia. Microglia in APPswe/PS1dE9 mice exhibited an M1-like phenotype, expressing tumor necrosis factor α (TNFα) but not interleukin 6 (IL6). Aβ-stimulated primary-cultured microglia also expressed TNFα but not IL6, whereas LPS-stimulated primary-cultured microglia expressed both pro-inflammatory cytokines. Furthermore, both microglia in APPswe/PS1dE9 mice and Aβ-stimulated primary-cultured microglia expressed SOCS3. Reduction of SOCS3 expression in Aβ-challenged primary-cultured microglia resulted in upregulation of IL6 expression. Our findings indicate that SOCS3 suppresses complete polarization to M1 phenotype through blocking IL6 production, and Aβ-challenged primary-cultured microglia replicate the in vivo gene expression pattern of microglia in APPswe/PS1dE9 mice. Aβ may induce the M1-like phenotype through blocking of IL6 by SOCS3. Show more

Keywords: Alzheimer’s disease, amyloid-β, APPswe/PS1dE9 mice, IL6, inflammation, microglia, SOCS3, STAT3

DOI: 10.3233/JAD-160887

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1235-1247, 2017

Authors: Cupidi, Chiara | Frangipane, Francesca | Gallo, Maura | Clodomiro, Alessandra | Colao, Rosanna | Bernardi, Livia | Anfossi, Maria | Conidi, Maria Elena | Vasso, Franca | Curcio, Sabrina Anna Maria | Mirabelli, Maria | Smirne, Nicoletta | Torchia, Giusi | Muraca, Maria Gabriella | Puccio, Gianfranco | Di Lorenzo, Raffaele | Zampieri, Stefania | Romanello, Milena | Dardis, Andrea | Maletta, Raffaele Giovanni | Bruni, Amalia Cecilia

Article Type: Research Article

Abstract: Background: Several neurological and systemic diseases can cause dementia, beyond Alzheimer’s disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. Objective: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. …Methods: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. Results: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. Conclusions: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event. Show more

Keywords: Dementia, heterozygous state, neurodegeneration, Niemann Pick type C, NPC1 gene, NPC2 gene

DOI: 10.3233/JAD-160214

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1249-1259, 2017

Authors: Buongiorno, Mariateresa | Antonelli, Francesca | Compta, Yaroslau | Fernandez, Yolanda | Pavia, Javier | Lomeña, Francisco | Ríos, José | Ramírez, Isabel | García, José Ramón | Soler, Marina | Cámara, Ana | Fernández, Manel | Basora, Misericòrdia | Salazar, Fàtima | Sanchez-Etayo, Gerard | Valldeoriola, Francesc | Barrio, Jorge Raúl | Marti, Maria Jose

Article Type: Research Article

Abstract: Tau and amyloid-β (Aβ) aggregates have been suggested to play a role in the development of dementia in Parkinson’s disease (PD). Positron emission tomography (PET) with [18 F]FDDNP and the determination of cerebrospinal fluid (CSF) levels of these proteins constitute a means to visualize in vivo Aβ and tau brain accumulation. Information about longitudinal changes of these CSF and PET biomarkers in PD with regard to progression to dementia is lacking. We assessed the cross-sectional and longitudinal associations of CSF and PET biomarkers of tau and Aβ with PD-related cognitive dysfunction in 6 healthy-controls (HC), 16 patients with PD …without dementia (PDND), and 8 PD with dementia (PDD). All subjects underwent comprehensive neuropsychological testing, [18 F]FDDNP PET, and CSF Aβ-tau determination. After 18 months, the PDND group was re-assessed clinically and by neuropsychological, PET, and CSF determinations. Cross-sectionally, PDD had higher [18 F]FDDNP binding in lateral temporal regions and lower levels of CSF Aβ levels compared to PDND, with a congruent correlation between the [18 F]FDDNP binding and CSF Aβ levels. Longitudinally, higher baseline lateral temporal [18 F]FDDNP binding was associated to longitudinal worsening in cognitive performances and progression to dementia among subjects classified as PDND at baseline, who additionally disclosed at follow-up an increase in lateral-temporal FDDNP binding, as well as a reduction in CSF Aβ and an increase in CSF tau levels. These results confirm the relevance of these CSF and PET biomarkers to PDD, being specifically the first to show [18 F]FDDNP PET as a dementia risk biomarker in PD, along with longitudinal CSF and PET changes over time. Show more

Keywords: CSF Aβ, dementia, [18F]FDDNP PET, Parkinson’s disease

DOI: 10.3233/JAD-160698

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1261-1272, 2017

Authors: Mendiola-Precoma, Jesus | Padilla, Karla | Rodríguez-Cruz, Alfredo | Berumen, Laura C. | Miledi, Ricardo | García-Alcocer, Guadalupe

Article Type: Research Article

Abstract: Dementia caused by Alzheimer’s disease (AD) is mainly characterized by accumulation in the brain of extra- and intraneuronal amyloid-β (Aβ) and tau proteins, respectively, which selectively affect specific regions, particularly the neocortex and the hippocampus. Sporadic AD is mainly caused by an increase in apolipoprotein E, a component of chylomicrons, which are cholesterol transporters in the brain. Recent studies have shown that high lipid levels, especially cholesterol, are linked to AD. Adenosine is an atypical neurotransmitter that regulates a wide range of physiological functions by activating four P1 receptors (A1, A2A, A2B, and A3) and P2 purinergic receptors that are …G protein-coupled. A1 receptors are involved in the inhibition of neurotransmitter release, which could be related to AD. The aim of the present work was to study the effects of a lard-enriched diet (LED) on cognitive and memory processes in adult rats (6 months of age) as well as the effect of theobromine on these processes. The results indicated that the fat-enriched diet resulted in a long-term deterioration in cognitive and memory functions. Increased levels of Aβ protein and IL-1β were also observed in the rats fed with a high-cholesterol diet, which were used to validate the AD animal model. In addition, the results of qPCR and immunohistochemistry indicated a decrease in gene expression and distribution of A1 purinegic receptor, respectively, in the hippocampus of LED-fed rats. Interestingly, theobromine, at both concentrations tested, restored A1 receptor levels and improved cognitive functions and Aβ levels for a dose of 30 mg/L drinking water. Show more

Keywords: Adenosine, Alzheimer’s disease, cholesterol, lard, oxidative stress, purinergic receptors, theobromine

DOI: 10.3233/JAD-160569

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1273-1283, 2017

Authors: Moss, Donald E. | Perez, Ruth G. | Kobayashi, Haruo

Article Type: Research Article

Abstract: Irreversible acetylcholinesterase (AChE) inhibition accumulates to high levels in the central nervous system (CNS) because AChE turnover in the brain is much slower than in peripheral tissues. As expected from this CNS selectivity, the irreversible AChE inhibitor methanesulfonyl fluoride (MSF) produces significant cognitive improvement in Alzheimer’s disease patients without the gastrointestinal toxicity that plagues other AChE inhibitors. However, without dose-limiting gastrointestinal toxicity, one shortcoming of the prior human studies of MSF is that the upper limits of CNS AChE inhibition that might be tolerated could not be tested. Therefore, in this study, monkeys were treated with escalating intramuscular (IM) doses …of MSF that culminated with several weeks of 1.5 mg/kg dosing, more than eight times the prior human clinical dose, still without signs of toxicity. Brain biopsies showed that ∼80% AChE inhibition had been produced and that the new synthesis of cortical AChE had a half-time (t1/2 ) of ∼12 days. A single IM dose of 1.5 mg/kg MSF produced ∼59% inhibition in cerebrospinal fluid (CSF) AChE as measured one day later. This corresponds to a peak of ∼80% inhibition in CSF AChE at the time of the injection, recovering with a t1/2 of 2.4 days. Computational analyses suggest that MSF at clinically relevant doses could theoretically produce a steady-state AChE inhibition between 65% and 85% in the CNS. These data suggest that the full therapeutic advantage of AChE inhibition therapy can be realized without interference from dose-limiting gastrointestinal toxicity if an irreversible inhibitor is employed. Show more

Keywords: Acetylcholinesterase (EC 3.1.1.7), Alzheimer’s disease, butyrylcholinesterase (EC 3.1.1.8), central nervous system, Lewy body, methanesulfonyl fluoride (CAS 558-25-8), Parkinson’s disease

DOI: 10.3233/JAD-160733

Citation: Journal of Alzheimer's Disease, vol. 55, no. 3, pp. 1285-1294, 2017