Journal of Alzheimer's Disease - Volume 30, issue 2

Authors: Lindberg, Olof | Walterfang, Mark | Looi, Jeffrey C.L. | Malykhin, Nikolai | Östberg, Per | Zandbelt, Bram | Styner, Martin | Paniagua, Beatriz | Velakoulis, Dennis | Örndahl, Eva | Wahlund, Lars-Olof

Article Type: Research Article

Abstract: Hippocampal pathology is central to Alzheimer's disease (AD) and other forms of dementia such as frontotemporal lobar degeneration (FTLD). Autopsy studies have shown that certain hippocampal subfields are more vulnerable than others to AD and FTLD pathology, in particular the subiculum and cornu ammonis 1 (CA1). We conducted shape analysis of hippocampi segmented from structural T1 MRI images on clinically diagnosed dementia patients and controls. The subjects included 19 AD and 35 FTLD patients [13 frontotemporal dementia (FTD), 13 semantic dementia (SD), and 9 progressive nonfluent aphasia (PNFA)] and 21 controls. Compared to controls, SD displayed severe atrophy of the …whole left hippocampus. PNFA and FTD also displayed atrophy on the left side, restricted to the hippocampal head in FTD. Finally, AD displayed most atrophy in left hippocampal body with relative sparing of the hippocampal head. Consistent with neuropathological studies, most atrophic deformation was found in CA1 and subiculum areas in FTLD and AD. Show more

Keywords: Alzheimer's disease, frontotemporal lobar degeneration, hippocampus, shape analysis

DOI: 10.3233/JAD-2012-112210

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 355-365, 2012

Authors: Zhou, Bin | Nakatani, Eiji | Teramukai, Satoshi | Nagai, Yoji | Fukushima, Masanori | The Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The objective of this study was to develop new risk classifications for conversion to Alzheimer's disease (AD) by comparing the relative reliability of classifiers in patients with mild cognitive impairment (MCI). The 397 MCI subjects and all baseline data, including characteristics, neuropsychological tests, cerebrospinal fluid biomarkers and MRI findings in Alzheimer's Disease Neuroimaging Initiative (ADNI), were used for analysis by Cox proportional hazard regression, bootstrap sampling, and c-index. Multivariate Cox regression analysis revealed the following factors to be associated with increased risk of conversion from MCI to AD during the 53-month follow-up period: AVLT 30-minute delayed recall, AVLT trial 1, …Boston naming, logical delayed recall, trail-making B, CDR-sob, ADAS13, the cortical thickness of the right inferior temporal lobe (st91ta), and the left hippocampus volume. The combinations of ADAS13 at a cutoff point of 15.67 with CDR-sob at 1.5 or with the cortical thickness of the right inferior temporal lobe at 2.56 mm3 produced high conversion rates of 92.7% (82.4%–100.0%) and 88.8% (77.3%–100.0%), respectively, at 48 months. The discriminative ability based on c-index for the proposed combination was 0.68. The sample size was estimated as 504 in the group with a combination of ADAS13 and CDR-sob whose conversion rate is highest. The combination of ADAS13 with CDR-sob at an optimal cutoff point has a high reliability in classifying the MCI patients into high- and low-risk conversion to AD and will be benefit for patients' assessment and potentially facilitate the clinical development of novel therapeutics. Show more

Keywords: Alzheimer's disease, conversion, mild cognitive impairment, risk classification

DOI: 10.3233/JAD-2012-112117

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 367-375, 2012

Authors: Doggui, Sihem | Sahni, Jasjeet Kaur | Arseneault, Madeleine | Dao, Lé | Ramassamy, Charles

Article Type: Research Article

Abstract: Curcumin, a natural polyphenolic pigment present in the spice turmeric (Curcuma longa), is known to possess a pleiotropic activity such as antioxidant, anti-inflammatory, and anti-amyloid-β activities. However, these benefits of curcumin are limited by its poor aqueous solubility and oral bioavailability. In the present study, a polymer-based nanoparticle approach has been utilized to deliver drugs to neuronal cells. Curcumin was encapsulated in biodegradable poly (lactide-co-glycolide) (PLGA) based-nanoparticulate formulation (Nps-Cur). Dynamic laser light scattering and transmission electronic microscopy analysis indicated a particle diameter ranging from 80 to 120 nm. The entrapment efficiency was 31% with 15% drug-loading. In vitro release kinetics …of curcumin from Nps-Cur revealed a biphasic pattern with an initial exponential phase followed by a slow release phase. Cellular internalization of Nps-Cur was confirmed by fluorescence and confocal microscopy with a wide distribution of the fluorescence in the cytoplasm and within the nucleus. The prepared nanoformulation was characterized for cellular toxicity and biological activity. Cytotoxicity assays showed that void PLGA-nanoparticles (Nps) and curcumin-loaded PLGA nanoparticles (Nps-Cur) were nontoxic to human neuroblastoma SK-N-SH cells. Moreover, Nps-Cur was able to protect SK-N-SH cells against H2 O2 and prevent the elevation of reactive oxygen species and the consumption of glutathione induced by H2 O2 . Interestingly, Nps-Cur was also able to prevent the induction of the redox-sensitive transcription factor Nrf2 in the presence of H2 O2 . Taken together, these results suggest that Nps-Cur could be a promising drug delivery strategy to protect neurons against oxidative damage as observed in Alzheimer's disease. Show more

Keywords: Alzheimer's disease, antioxidant, glutathione, Nrf2, reactive oxygen species

DOI: 10.3233/JAD-2012-112141

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 377-392, 2012

Authors: Buoso, Erica | Biundo, Fabrizio | Lanni, Cristina | Schettini, Gennaro | Govoni, Stefano | Racchi, Marco

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) can be processed by either the amyloidogenic or the non-amyloidogenic pathway; both pathways lead to release of the AβPP intracellular C-terminal domain (AICD). AICD involvement in signal transduction within Fe65/Tip60 complex is one of the most discussed mechanisms, and different models have been hypothesized to explain the role of AICD within this complex. The analysis of these models in relation to the degradation processes highlights the discrepancy among AICD localization, function, and degradation, leading to the hypothesis that a signaling mechanism may exist which allows AβPP proteolysis to generate either a transcriptionally active fragment or …an inactive one with different involvement of proteasome and IDE (insulin-degrading enzyme). Our work aimed to analyze the functional role of AICD within the Fe65/Tip60 complex considering the AICD degradation processes. Our data suggest a correlation between the role of AICD in gene regulation and its removal operated by proteasome activity. Moreover, treatments with IDE inhibitor underlined the presence of an alternative mechanism involved in AICD removal when the latter is not exerting nuclear activity, thus providing clearer support for the existence of at least two mechanisms as previously suggested. Show more

Keywords: AβPP, AICD, Fe65, IDE, proteasome, Tip60

DOI: 10.3233/JAD-2012-111961

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 393-405, 2012

Authors: Rohrer, Jonathan D. | Clarkson, Matthew J. | Kittus, Raivo | Rossor, Martin N. | Ourselin, Sebastien | Warren, Jason D. | Fox, Nick C.

Article Type: Research Article

Abstract: Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder which presents with either behavioral or language impairment. The two language syndromes are known as progressive nonfluent aphasia (PNFA) and semantic dementia (SEMD). While cross-sectional imaging patterns of brain atrophy are well-described in FTLD, fewer studies have investigated longitudinal imaging changes. We measured longitudinal hemispheric and lobar atrophy rates using serial MRI in a cohort of 18 patients with PNFA and 17 patients with SEMD as well as 14 cognitively-normal control subjects. We subsequently calculated sample size estimates for clinical trials. Rates of left hemisphere atrophy were greater than rates of right …hemisphere atrophy in both PNFA and SEMD with no significant differences between the groups. The disease groups showed asymmetrical atrophy (more severe on the left) at baseline with significantly increasing asymmetry over time. Within a hemisphere, the fastest rate of atrophy varied between lobes: in SEMD temporal > frontal > parietal > occipital, while in PNFA frontal > temporal/parietal > occipital. In SEMD, using temporal lobe measures of atrophy in clinical trials would provide the lowest sample sizes necessary, while in PNFA left hemisphere atrophy measures provided the lowest sample size. These patterns provide information about disease evolution in the FTLD language variants that is of both clinical and neurobiological relevance. Show more

Keywords: Frontotemporal dementia, primary progressive aphasia

DOI: 10.3233/JAD-2012-111556

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 407-411, 2012

Authors: Pearson-Leary, Jiah | McNay, Ewan C.

Article Type: Research Article

Abstract: Increasing evidence suggests that abnormal brain accumulation of amyloid-β1-42 (Aβ1-42 ) oligomers plays a causal role in Alzheimer's disease (AD), and in particular may cause the cognitive deficits that are the hallmark of AD. In vitro, Aβ1-42 oligomers impair insulin signaling and suppress neural functioning. We previously showed that endogenous insulin signaling is an obligatory component of normal hippocampal function, and that disrupting this signaling led to a rapid impairment of spatial working memory, while delivery of exogenous insulin to the hippocampus enhanced both memory and metabolism; diet-induced insulin resistance both impaired spatial memory and prevented insulin from …increasing metabolism or cognitive function. Hence, we tested the hypothesis that Aβ1-42 oligomers could acutely impair hippocampal metabolic and cognitive processes in vivo in the rat. Our findings support this hypothesis: Aβ1-42 oligomers impaired spontaneous alternation behavior while preventing the task-associated dip in hippocampal ECF glucose observed in control animals. In addition, Aβ1-42 oligomers decreased plasma membrane translocation of the insulin-sensitive glucose transporter 4 (GluT4), and impaired insulin signaling as measured by phosphorylation of Akt. These data show in vivo that Aβ1-42 oligomers can rapidly impair hippocampal cognitive and metabolic processes, and provide support for the hypothesis that elevated Aβ1-42 leads to cognitive impairment via interference with hippocampal insulin signaling. Show more

Keywords: Amyloid, glucose, glucose transporter type 4, hippocampal, insulin, memory

DOI: 10.3233/JAD-2012-112192

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 413-422, 2012

Authors: Wang, Pei-Ning | Chou, Kun-Hsien | Lirng, Jiing-Feng | Lin, Ker-Neng | Chen, Wei-Ta | Lin, Ching-Po

Article Type: Research Article

Abstract: Different diffusivity measurements in diffusion-tensor imaging (DTI) could be helpful for detecting the distinct mechanisms of white matter degeneration in Alzheimer's disease (AD). However, few studies have explored the changes of white matter in amnestic mild cognitive impairment (aMCI) and AD by whole-brain voxel-wise analyses of all diffusivity indices. The association between grey matter atrophy and white matter damage measured by distinct diffusivities is still uncertain. Structural magnetic resonance imaging and DTI with four diffusivity indices, comprising fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, were performed in 30 normal controls, 26 mild AD patients, and 40 aMCI patients …with isolated memory impairment. T1 voxel-based morphometry and DTI tract-based spatial statistics were applied to compare the grey and white matter changes in the 3 groups. In contrast to the lack of significant white matter change presenting in aMCI patients, extended white matter degeneration over entire cerebral networks was exhibited in mild AD patients. Both axonal degradation and demyelination contributed to the white matter degeneration in AD; nevertheless, demyelination essentially involved the frontal portion of cerebral networks. Axonal degradation and demyelination over the temporal region were associated with the contiguous grey matter atrophy. However, only the severity of demyelination over the frontal region was correlated with the degree of atrophy over adjacent frontal grey matter. Our results suggest that different mechanisms of white matter damage demonstrate discrete regional distribution in AD. Demyelination may independently correlate with contiguous grey matter over the frontal region. Show more

Keywords: Alzheimer's disease, diffusion tensor imaging, grey matter, mild cognitive impairment, MRI, white matter

DOI: 10.3233/JAD-2012-111304

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 423-437, 2012

Authors: Aso, Ester | Palomer, Ernest | Juvés, Salvador | Maldonado, Rafael | Muñoz, Francisco J. | Ferrer, Isidro

Article Type: Research Article

Abstract: The present study shows that chronic administration of the Cannabinoid receptor type 1 (CB1 ) receptor agonist arachidonyl-2-chloroethylamide (ACEA) at pre-symptomatic or at early symptomatic stages, at a non-amnesic dose, reduces the cognitive impairment observed in double AβPP(swe)/PS1(1dE9) transgenic mice from 6 months of age onwards. ACEA has no effect on amyloid-β (Aβ) production, aggregation, or clearance. However, ACEA reduces the cytotoxic effect of Aβ42 oligomers in primary cultures of cortical neurons, and reverses Aβ-induced dephosphorylation of glycogen synthase kinase-3β (GSK3β) in vitro and in vivo. Reduced activity of GSK3β in ACEA-treated mice is further supported by the reduced …amount of phospho-tau (Thr181) in neuritic processes around Aβ plaques. In addition, ACEA-treated mice show decreased astroglial response in the vicinity of Aβ plaques and decreased expression of the pro-inflammatory cytokine interferon-γ in astrocytes when compared with age-matched vehicle-treated transgenic mice. Our present results show a beneficial effect of ACEA at both the neuronal, mediated at least in part by GSK3β inhibition, and glial levels, resulting in a reduction of reactive astrocytes and lower expression of interferon-γ. As a consequence, targeting the CB1 receptor could offer a versatile approach for the treatment of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, astrogliosis, cannabinoid receptor, CB1 cognition, GSK3β, neuroprotection, transgenic mice

DOI: 10.3233/JAD-2012-111862

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 439-459, 2012

Article Type: Correction

DOI: 10.3233/JAD-2012-128000

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 461-461, 2012

Article Type: Other

DOI: 10.3233/JAD-2012-111863

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 463-465, 2012