Journal of Alzheimer's Disease - Volume 38, issue 2

Authors: Laurén, Juha

Article Type: Review Article

Abstract: Soluble oligomeric species of amyloid-β (Aβ) peptide are presumed to be drivers of synaptic impairment, and the resulting cognitive dysfunction in Alzheimer's disease. In 2009, cellular prion protein (PrPC ) was identified in a genome-wide screen as a high-affinity receptor for Aβ oligomers, and since then, many studies have explored the role of PrPC in Alzheimer's disease. Herein, I systematically assess the current level of target validation for PrPC in Alzheimer's disease and the merits of the identified approaches to therapeutically affect the PrPC :Aβ oligomer-interaction. The interaction of Aβ oligomers with PrPC in mice impairs hippocampal …long-term potentiation, memory, and learning in a manner that involves Fyn, tau, and glutamate receptors. Furthermore, PrPC acts to catalyze the formation of certain Aβ oligomeric species in the synapse and may mediate the toxic effects of other β-sheet rich oligomers as well. Therapeutic approaches utilizing soluble PrPC ectodomain or monoclonal antibodies targeting PrPC can at least partially prevent the neurotoxic effects of Aβ oligomers in mice. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, c-fyn protein, prion protein

DOI: 10.3233/JAD-130950

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 227-244, 2014

Authors: Wang, Jiajia | Feng, Xuemei | Bai, Zhouxian | Jin, Lee-Way | Duan, Yong | Lei, Hongxing

Article Type: Short Communication

Abstract: Genetic studies have identified several genomic loci including chr19p13.2 relevant to Alzheimer's disease (AD) susceptibility. However, the functional roles of these genomic loci in AD pathogenesis require further clarification. Transcriptome as an endophenotype is critical for the understanding of disease mechanism. Here we demonstrate that chr19p is the most significantly perturbed chromosome region in AD brain transcriptome. With dual evidence from genome and transcriptome, chr19p likely play a special role in AD pathogenesis.

Keywords: Chromosome 19p, complement C3, gene expression, genetic association, KANK2

DOI: 10.3233/JAD-130917

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 245-250, 2014

Authors: Lee, Youngjeon | Kim, Young-Hyun | Park, Sang-Je | Huh, Jae-Won | Kim, Sang-Hyun | Kim, Sun-Uk | Kim, Ji-Su | Jeong, Kang-Jin | Lee, Kyoung-Min | Hong, Yonggeun | Lee, Sang-Rae | Chang, Kyu-Tae

Article Type: Research Article

Abstract: We reported previously that the intracerebroventricular streptozotocin (icv-STZ)-treated cynomolgus monkey showed regionally specific glucose hypometabolism in FDG-PET imaging, similar to that observed in the early stages of sporadic Alzheimer's disease (sAD). However, further pathological analyses of this model at the molecular level are needed to validate it as a feasible model for sAD. Two cynomolgus monkeys were injected with 2 mg/kg STZ into the cerebellomedullary cistern at day 1, 7 and 14. Two control monkeys were given normal saline. At 5 months after injection, the expression levels of genes encoding 9 upstream molecules in insulin/insulin-like growth factor (IGF) signaling and …markers for 4 cell-type populations in the frontal cortex, hippocampus, posterior cingulate, precuneus, and occipital cortex of control and icv-STZ treated cynomolgus monkeys were examined. Real-time quantitative PCR analyses demonstrated that the overall mRNA expression of insulin/IGF signaling-related genes was mainly impaired in the anterior part of the cerebrum, frontal cortex, and hippocampus, similar to the early stage of sAD. The changes were accompanied by the loss of oligodendrocytes and neurons. The posterior part of the cerebrum did not show degenerative alterations. The present study provides important fundamental information on the icv-STZ monkey model for sAD. These results may help guide future studies using this model for the investigation of pathological mechanisms and the development of drugs for sAD. Show more

Keywords: Alzheimer's disease, brain, insulin, monkey, real-time quantitative polymerase chain reaction, streptozotocin

DOI: 10.3233/JAD-130776

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 251-267, 2014

Authors: Zhang, Cong | Cheng, Yufang | Wang, Haitao | Wang, Chuang | Wilson, Steven P. | Xu, Jiangping | Zhang, Han-Ting

Article Type: Research Article

Abstract: Phosphodiesterase-4 (PDE4) inhibitors enhance memory, increase hippocampal neurogenesis, and reverse amyloid-β (Aβ)-induced memory deficits. Here, we examined whether long-form PDE4D knockdown by lentiviral RNA construct containing a specific microRNA/miRNA-mir hairpin structure (4DmiRNA) reversed memory impairment caused by amyloid-β1-42 (Aβ42 ) in mice using the Morris water maze (MWM) and novelty object recognition tests. Western blotting analysis was used to assess protein levels of cAMP response element-binding protein (CREB, unphosphorylated and phosphorylated [pCREB]), brain-derived neurotrophic factor (BDNF), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB) to explore the neurochemical mechanisms. Aggregated Aβ42 (0.5 μg/side) bilaterally infused in …dentate gyrus decreased cAMP levels (p < 0.01) and produced memory deficits in the MWM (p < 0.01) and object recognition tests (p < 0.01). Microinfusions of lentiviruses resulted in downregulated expression of PDE4D4 and 4D5 proteins and reversed Aβ42 -induced cAMP decline (p < 0.05) and memory deficits. Treatment also concomitantly increased pCREB (p < 0.05) and BDNF (p < 0.01) and reduced IL-1β (p < 0.05), TNF-α (p < 0.01), and NF-κB (p65) (p < 0.05) in the hippocampus of Aβ42 -challenged mice. These results suggest that long-form PDE4D knockdown may offer a promising treatment for memory loss associated with Alzheimer's disease. Show more

Keywords: Alzheimer's disease, anti-inflammation, long-form PDE4D, memory, PDE4

DOI: 10.3233/JAD-122236

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 269-280, 2014

Authors: Severini, Cinzia | Passeri, Pamela Petrocchi | Ciotti, MariaTeresa | Florenzano, Fulvio | Possenti, Roberta | Zona, Cristina | Di Matteo, Anna | Guglielmotti, Angelo | Calissano, Pietro | Pachter, Joel | Mercanti, Delio

Article Type: Research Article

Abstract: One of the hallmarks of Alzheimer's disease (AD), the most common age-related neurodegenerative pathology, is the abnormal extracellular deposition of neurotoxic amyloid-β (Aβ) peptides that accumulate in senile plaques. Aβ aggregates are toxic to neurons and are thought to contribute to neuronal loss. Evidence indicates that inflammation is involved in the pathophysiology of AD, and activation of glial cells by a variety of factors, including Aβ, appears to be a central event. Among molecules produced during inflammation associated with neuronal death, CCL2, also known as monocyte chemotactic protein-1 (MCP-1), seems to be particularly important. Indeed, CCL2 levels are higher in …the cerebrospinal fluid of patients with AD than in controls. In the present study, we demonstrated the protective effect of bindarit (which inhibits CCL2 synthesis) against both Aβ25-35 and Aβ1-42 -induced toxicity in primary mixed neural cultures. Bindarit (30–500 μM) reversed cell death induced by Aβ in a dose-dependent manner and reduced the transcription and release of CCL2 by astrocytes after Aβ treatment, as revealed by qRT-PCR, ELISA, and immunofluorescence staining. Astroglial activation and CCL2 release was induced by ATP released by damaged neurons through interaction with P2X7 receptors present on astrocyte surface. CCL2, interacting with its cognate receptor CCR2, present on neuron surface, strongly contributes to the toxic activity of Aβ. Bindarit was able to disconnect this neuro–glial interaction. Our results demonstrate the ability of bindarit to inhibit Aβ-induced neuronal death and suggest the potential role of CCL2 inhibitors in the treatment of neuroinflammatory/neurodegenerative diseases. Show more

Keywords: Alzheimer's disease, amyloid-β toxicity, bindarit, CCL2, neuroinflammation

DOI: 10.3233/JAD-131070

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 281-293, 2014

Authors: Cid-Fernández, Susana | Lindín, Mónica | Díaz, Fernando

Article Type: Research Article

Abstract: Although many studies have demonstrated decline in attention and executive function (especially in inhibitory control) in healthy aging and Alzheimer's disease (AD), similar studies concerning mild cognitive impairment (MCI) are scarce. In the present study, we evaluated how the cognitive decline associated with amnestic MCI (aMCI) affects these processes, analyzing the N2 and P3 components of event-related potentials (ERPs) during the response (Go) and inhibition of response (NoGo) to different stimuli. ERPs were analyzed in 63 healthy and 30 aMCI adults (aged 50 to 87 years) during performance of a Go/NoGo auditory-visual attention-distraction task. aMCI adults showed poorer execution (longer …response times and fewer correct responses) and smaller Go-N2 and NoGo-N2 amplitudes than control adults, whereas P3 amplitudes and N2 and P3 latencies did not differ between the groups. These results show that aMCI is associated with decline in executive function and stimuli evaluation in working memory. Show more

Keywords: Alzheimer's disease, amnestic mild cognitive impairment, attention, event-related potentials, inhibition, P300

DOI: 10.3233/JAD-130677

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 295-306, 2014

Authors: Peters, Frédéric | Villeneuve, Sylvia | Belleville, Sylvie

Article Type: Research Article

Abstract: The objective of this work was to assess the predictive accuracy of targeted neuroimaging and neuropsychological measures for the detection of incipient dementia in individuals with mild cognitive impairment (MCI), and to examine the potential benefit of combining both classes of measures. Baseline MRI measures included hippocampal volume, cortical thickness, and white matter hyperintensities. Neuropsychological assessment focused on different aspects of episodic memory (i.e., familiarity, free recall, and associative memory) and executive control functions (i.e., working memory, switching, and planning). Global and regional cortical thinning was observed in MCI patients who progressed to dementia compared to those who remained stable, …whereas no differences were found between groups for baseline hippocampal volume and white matter hyperintensities. The strongest neuroimaging predictors were baseline cortical thickness in the right anterior cingulate and middle frontal gyri. For cognitive predictors, we found that deficits in both free recall and recognition episodic memory tasks were highly suggestive of progression to dementia. Cortical thinning in the right anterior cingulate gyrus, combined to controlled and familiarity-based retrieval deficits, achieved a classification accuracy of 87.5%, a specificity of 90.9%, and a sensitivity of 83.3%. This predictive model including both classes of measures provided more accurate predictions than those based on neuroimaging or cognitive measures alone. Overall, our findings suggest that detecting preclinical Alzheimer's disease is probably best accomplished by combining complementary information from targeted neuroimaging and cognitive classifiers, and highlight the importance of taking into account both structural and functional changes associated with the disease. Show more

Keywords: Alzheimer's disease, cortical thickness, episodic memory, mild cognitive impairment

DOI: 10.3233/JAD-130842

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 307-318, 2014

Authors: Van der Mussele, Stefan | Mariën, Peter | Saerens, Jos | Somers, Nore | Goeman, Johan | De Deyn, Peter P. | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Behavioral disturbances belong to the core symptoms of dementia and are also common in mild cognitive impairment (MCI). The identification of sets of symptoms is clinically interesting, as interventions targeting syndromes may be more effective than the management of individual symptoms. Objective: This study aimed to identify, describe, measure, and compare the fundamental behavioral syndromes that underlie the observed behavioral symptoms in MCI and Alzheimer’s disease (AD). Methods: A cross-sectional analysis of baseline data from a prospective, longitudinal study on behavioral symptoms in MCI and dementia was performed. The study population consisted of 270 MCI …and 402 AD patients. Behavioral assessment was performed by means of Middelheim Frontality Score (MFS), Behave-AD, Cohen-Mansfield Agitation Inventory (CMAI), and Cornell Scale for Depression in Dementia (CSDD). Principal components factor analysis with Direct Oblimin rotation was carried out on the MFS score ≥5, seven cluster scores of the Behave-AD and the total scores of the CMAI and the CSDD. Results: We identified three factors explaining behavior in the MCI group: a depression, a psychosis, and an agitation syndrome. Similar factors were found in AD, but the order: an agitation, a depression, and a psychosis syndrome, respectively, and the structure differed slightly. Diurnal rhythm disturbances and frontal lobe symptoms loaded with the depression syndrome in MCI and in AD they loaded with the agitation syndrome. Behavioral syndromes correlated in AD, but not in MCI, and the prevalence and severity of the behavioral syndromes were higher in AD than in MCI, except for the severity of the depression syndrome. Conclusion: In both MCI and AD, three similar behavioral syndromes exist, but behavior in MCI is more dominated by a depression syndrome, while behavior in AD is more subject to an agitation syndrome. Show more

Keywords: Alzheimer's disease, Behave-AD, behavioral symptoms, Cohen-Mansfield agitation inventory, Cornell scale, dementia, factor analysis, mild cognitive impairment, syndromes

DOI: 10.3233/JAD-130596

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 319-329, 2014

Authors: Di Ieva, Antonio | Valli, Mikaeel | Cusimano, Michael D.

Article Type: Research Article

Abstract: Currently, no clinical or neuroradiological techniques have been validated to distinguish Alzheimer's disease (AD) from idiopathic normal pressure hydrocephalus (iNPH). Both share anatomical and clinical similarities: AD is a form of irreversible degenerative dementia, whereas the dementia manifested in iNPH is potentially “reversible” through various neurosurgical procedures. Hence, it is important to find specific imaging biomarkers that distinguish the two conditions. In addition, the ability to predict the response to neurosurgery in iNPH is something that has yet to be accomplished. In this systematic review, we describe and critically analyze the merits and drawbacks of the MR imaging parameters currently …used to distinguish AD from iNPH and assess ways to predict the response after treatment of iNPH. We conclude that the combination of different neuroimaging sequences as well as quantitative and qualitative parameters could provide new insight for better diagnosis and treatment of these two different diseases. Show more

Keywords: Alzheimer's disease, diagnostic imaging, idiopathic normal pressure hydrocephalus, magnetic resonance imaging, neuroimaging

DOI: 10.3233/JAD-130581

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 331-350, 2014

Authors: Anfossi, Maria | Colao, Rosanna | Gallo, Maura | Bernardi, Livia | Conidi, M. Elena | Frangipane, Francesca | Vasso, Franca | Puccio, Gianfranco | Clodomiro, Alessandra | Mirabelli, Maria | Curcio, Sabrina A.M. | Torchia, Giusi | Smirne, Nicoletta | Di Lorenzo, Raffaele | Maletta, Raffaele | Bruni, Amalia C.

Article Type: Research Article

Abstract: Background: LRRK2 mutations are common in familial and sporadic Parkinson’s disease (PD) cases. Objective: We present a screening of the most frequently mutated exons of LRRK2 in Calabrian population. Methods: Eighty-eight PD patients diagnosed according to standard criteria, underwent screening for LRRK2 mutations in exons 19, 21, 24, 25, 27, 29, 31, 32, 33, 35, 38, 40, 41, and 48. Results: Eight LRRK2 variations were identified in nine patients affected by PD, including three novel missense variations (p.Phe1227Leu, p.Gly1520Ala, p.Ile2020Ser) and five previously identified mutations (p.Ala1151Thr, IVS31+3A>G, p.Arg1514Gln, p.Gly2019Ser, p.Thr2356Ile). LRRK2 frequency mutations were …approximately 10.2% in all PD patients, 12% in familial, 8% in sporadic cases. The p.Gly2019Ser mutation was found in 2.3% of the total cohort and in 3.2% of sporadic cases. The clinical features of LRRK2-associated with PD in our patients were similar to those of idiopathic PD although most LRRK2 mutated patients presented with bradykinesia instead of tremor; 33.3% developed dementia. Conclusions: We identified three novel LRRK2 mutations and reported a higher frequency in Calabria compared to previously reported data possibly due to the relative genetic isolation of the Calabrian population. These findings contribute to the understanding of the role of LRKK2 variations in PD and provide additional genetic insight into this disease. Show more

Keywords: Dementia, frequency mutations, genetics association, LRRK2, neurodegenerative disease, Parkinson's disease

DOI: 10.3233/JAD-130689

Citation: Journal of Alzheimer's Disease, vol. 38, no. 2, pp. 351-357, 2014