Journal of Alzheimer's Disease - Volume 20, issue 2

Authors: Godin, Ophélia | Tzourio, Christophe | Rouaud, Olivier | Zhu, Yicheng | Maillard, Pauline | Pasquier, Florence | Crivello, Fabrice | Alpérovitch, Annick | Mazoyer, Bernard | Dufouil, Carole

Article Type: Research Article

Abstract: Several brain magnetic resonance imaging (MRI) changes are observed in older individuals including white matter lesions (WML), silent brain infarcts (SBI), and cerebral atrophy. Few studies, however, have assessed the combined association of these changes on the severity of future cognitive decline. In the prospective population-based 3C-Dijon MRI study, 1701 non-demented participants aged 65 to 80 years at entry had a brain MRI. Information on WML, hippocampal volumes, SBI presence, and brain parenchymal fraction were obtained. At 4-year follow-up, participants were screened for cognitive decline and dementia. Severity of cognitive decline was defined as none, moderate, or severe calculated from …neuropsychological test performance change. The relation between brain MRI markers and longitudinal change in cognition was studied using polytomous logistic regression and multiple linear regression models controlling for potential confounders. Two-by-two interactions were tested including with the apolipoprotein E genotype. At follow-up, 46 participants showed severe cognitive deterioration and 224 participants showed moderate cognitive deterioration. In multivariable analyses, risk of severe cognitive deterioration as well as the cognitive decline rate were significantly increased in participants with higher WML volume (p< 0.01) and smaller hippocampal volume (p< 0.01). The results suggested that WML and hippocampal volumes had a cumulative effect on the future level of cognitive decline. The APOE genotype was found to be an effect modifier of this association. Vascular brain changes and degenerative processes coexist in normal older individuals. The co-occurrence of degenerative and non-degenerative pathologies could strongly affect the course of dementia expression. Show more

Keywords: Alzheimer's disease, cerebrovascular disease, cohort studies, dementia, risk factors in epidemiology, volumetric MRI

DOI: 10.3233/JAD-2010-1389

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 453-463, 2010

Authors: Gahete, Manuel D. | Rubio, Alicia | Durán-Prado, Mario | Avila, Jesús | Luque, Raúl M. | Castaño, Justo P.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive deficit, wherein the impairment of episodic memory is the major hallmark. AD patients exhibit augmented accumulation of amyloid-β (Aβ) and hyperphosphorylated tau protein in specific brain regions. In addition, several neuropeptides/neurotransmitter axes clearly associated with cognitive processes, Aβ turnover, and tau phosphorylation have also been found to be impaired in AD, such as somatostatin (SST)/cortistatin (CST) and dopamine (DA) systems. However, to date there is no precise quantitative data on the expression of these systems in the human brain of AD and normal patients. Here we measured by …quantitative real-time PCR the mRNA levels of SST/CST, their receptors (sst1-5 and DA receptors (drd1-5) in addition to neprilysin (a SST-regulated enzyme involved in Aβ degradation) in three regions of the temporal lobe, one of the cortical regions most severely affected by AD. Our results reveal that some components of SST/CST- and DA-axes are divergently altered in the three areas of AD patients. Despite this region-specific regulation, an overall, common reduction of these systems was observed in the temporal lobe of AD patients. Conversely, neprilysin expression was not altered in AD, suggesting that Aβ accumulation observed in AD is due to a lack of neprilysin activation by SST rather than to a reduction of its expression. Collectively, our results define a comprehensive scenario wherein reduction of ssts, drds, and sst ligands SST and CST, could be involved, at least in part, in some of the more important defects observed in AD. Show more

Keywords: Alzheimer's disease, brain temporal lobe, cortistatin, dopamine, dopamine receptors, neprilysin, somatostatin, somatostatin receptors

DOI: 10.3233/JAD-2010-1385

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 465-475, 2010

Authors: Friese, Uwe | Meindl, Thomas | Herpertz, Sabine C. | Reiser, Maximilian F. | Hampel, >Harald | Teipel, Stefan J.

Article Type: Research Article

Abstract: We report evidence that multivariate analyses of deformation-based morphometry and diffusion tensor imaging (DTI) data can be used to discriminate between healthy participants and patients with Alzheimer's disease (AD) with comparable diagnostic accuracy. In contrast to other studies on MRI-based biomarkers which usually only focus on a single modality, we derived deformation maps from high-dimensional normalization of T1-weighted images, as well as mean diffusivity maps and fractional anisotropy maps from DTI of the same group of 21 patients with AD and 20 healthy controls. Using an automated multivariate analysis of the entire brain volume, widespread decreased white matter integrity and …atrophy effects were found in cortical and subcortical regions of AD patients. Mean diffusivity maps and deformation maps were equally effective in discriminating between AD patients and controls (AUC =0.88 vs. AUC=0.85) while fractional anisotropy maps performed slightly inferior. Combining the maps from different modalities in a logistic regression model resulted in a classification accuracy of AUC=0.86 after leave-one-out cross-validation. It remains to be shown if this automated multivariate analysis of DTI-measures can improve early diagnosis of AD in predementia stages. Show more

Keywords: Alzheimer's disease, biomarker, deformation-based morphometry, diagnostic utility, diffusion tensor imaging, MRI

DOI: 10.3233/JAD-2010-1386

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 477-490, 2010

Authors: Li, Jing | Zhang, Meng | Xu, Zhi-Qiang | Gao, Chang-Yue | Fang, Chuan-Qin | Deng, Juan | Yan, Jia-Chuan | Wang, Yan-Jiang | Zhou, Hua-Dong

Article Type: Research Article

Abstract: To investigate whether vascular risk affects the progression of Alzheimer's disease (AD), 415 AD patients aged 65 years old and over without cerebrovascular diseases were enrolled and administered with a structured interview to assess demography, vascular risk factors, and cognitive and functional status at baseline, and 324 AD patients were followed up annually for 5 years. A mixed random effects regression model was used to identify the association between vascular risk, individual vascular risk factors, and the progression of AD. After adjusting for confounding factors, AD patients with vascular risk had faster cognitive and functional decline rates than the subjects …without such risk factors. Individual vascular risk factors including hypertension and diabetes mellitus, transient ischemic attack and cerebrovascular accident during the follow-up were independently associated with the progression of AD. Our findings suggest that vascular risk aggravates the progression of AD and may be involved in the etiologic process of AD. As such, control of vascular risk may slow down the progression of AD. Show more

Keywords: Alzheimer's disease, progression, vascular risk factor

DOI: 10.3233/JAD-2010-1383

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 491-500, 2010

Authors: Cacciari, Claudia | Moraschi, Marta | Di Paola, Margherita | Cherubini, Andrea | Orfei, Maria Donata | Giove, Federico | Maraviglia, Bruno | Caltagirone, Carlo | Spalletta, Gianfranco

Article Type: Research Article

Abstract: In this study, we assess white matter microstructural deficit correlates of apathy level in 20 patients with amnestic mild cognitive impairment by means of diffusion tensor imaging. Mean diffusivity correlated positively with apathy level in the right temporal portion of the uncinate, middle longitudinal and inferior longitudinal fasciculi and in the parathalamic white matter, the fornix and the posterior cingulum of the right hemisphere. Fractional anisotropy results confirmed evidence of disconnection associated with apathy in all white matter areas except the middle longitudinal fasciculus. These results support the view that alterations in the neural mechanisms underlying apathy level occur in …the early phase of degenerative dementias. Show more

Keywords: Apathy, diffusion tensor imaging, microstructure, mild cognitive impairment, MRI, white matter

DOI: 10.3233/JAD-2010-1384

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 501-507, 2010

Authors: Faux, Noel G. | Ritchie, Craig W. | Gunn, Adam | Rembach, Alan | Tsatsanis, Andrew | Bedo, Justin | Harrison, John | Lannfelt, Lars | Blennow, Kaj | Zetterberg, Henrik | Ingelsson, Martin | Masters, Colin L. | Tanzi, Rudolph E. | Cummings, Jeffrey L. | Herd, Caroline M. | Bush, Ashley I.

Article Type: Research Article

Abstract: PBT2 is a copper/zinc ionophore that rapidly restores cognition in mouse models of Alzheimer's disease (AD). A recent Phase IIa double-blind, randomized, placebo-controlled trial found that the 250 mg dose of PBT2 was well-tolerated, significantly lowered cerebrospinal fluid (CSF) levels of amyloid-β42 , and significantly improved executive function on a Neuro-psychological Test Battery (NTB) within 12 weeks of treatment in patients with AD. In the post-hoc analysis reported here, the cognitive, blood marker, and CSF neurochemistry outcomes from the trial were subjected to further analysis. Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg, and PBT2 …250 mg revealed that the proportions of patients showing improvement on NTB Composite or Executive Factor z-scores were significantly greater in the PBT2 250 mg group than in the placebo group. Receiver-operator characteristic analyses revealed that the probability of an improver at any level coming from the PBT2 250 mg group was significantly greater, compared to placebo, for Composite z-scores (Area Under the Curve [AUC] =0.76, p=0.0007), Executive Factor z-scores (AUC =0.93, p=1.3 × 10-9 ), and near-significant for the ADAS-cog (AUC =0.72, p=0.056). There were no correlations between changes in CSF amyloid-β or tau species and cognitive changes. These findings further encourage larger-scale testing of PBT2 for AD. Show more

Keywords: Alzheimer's disease, clinical trials Randomized controlled, cognition, PBT2

DOI: 10.3233/JAD-2010-1390

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 509-516, 2010

Authors: Newberg, Andrew B. | Wintering, Nancy | Khalsa, Dharma S. | Roggenkamp, Hannah | Waldman, Mark R.

Article Type: Research Article

Abstract: This preliminary study determined if subjects with memory loss problems demonstrate changes in memory and cerebral blood flow (CBF) after a simple 8-week meditation program. Fourteen subjects with memory problems had an IV inserted and were injected with 250MBq of Tc-99m ECD while listening to a neutral stimulus CD. They then underwent a pre-program baseline SPECT scan. Then subjects were guided through their first meditation session with a CD, during which they received an injection of 925MBq ECD, and underwent a pre-program meditation scan. Subjects completed an 8-week meditation program and underwent the same scanning protocol resulting in a post-program …baseline and meditation scan. A region of interest (ROI) template obtained counts in each ROI normalized to whole brain to provide a CBF ratio. Baseline and meditation scans and neuropsychological testing were compared before and after the program. The meditation program resulted in significant increases (p< 0.05) in baseline CBF ratios in the prefrontal, superior frontal, and superior parietal cortices. Scores on neuropsychological tests of verbal fluency, Trails B, and logical memory showed improvements after training. This preliminary study evaluated whether an 8-week meditation program resulted in improvements in neuropsychological function and differences in CBF in subjects with memory loss. While the findings are encouraging, there are a number of limitations that can be addressed in future studies with more participants and more detailed analyses. Show more

Keywords: Cerebral blood flow, cognitive impairment, meditation, memory, single photon emission computed tomography

DOI: 10.3233/JAD-2010-1391

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 517-526, 2010

Authors: Capsoni, Simona | Tiveron, Cecilia | Amato, Gianluca | Vignone, Domenico | Cattaneo, Antonino

Article Type: Research Article

Abstract: We previously showed that anti-nerve growth factor (NGF) antibodies expressed in transgenic mice (AD11) elicit a progressive neurodegeneration, comprising the triad of Alzheimer's disease (AD) hallmarks: cholinergic loss, tau hyperphosphorylation, and amyloid-β peptide formation. However, since anti-NGF antibodies are produced both in the brain and in peripheral tissues of AD11 mice, the contribution of peripheral neutralization of NGF to the onset of brain neurodegeneration was still unexplored. To address this question, we characterized a line of transgenic mice (AD10) in which anti-NGF antibodies are obligatorily produced only in lymphocytes, being initially found in blood. In AD10 mice, peripheral NGF neutralization …elicits shrinkage of superior cervical ganglia (immunosympathectomy) and, as a consequence of this, peripheral anti-NGF antibodies cross the blood brain barrier (BBB) and reach the brain, generating an NGF-dependent neurodegeneration, largely superimposable to that observed in AD11 mice. This demonstrates that peripherally originated anti-NGF antibodies can generate a neurodegeneration in the central nervous system of an animal model. Consistently, peripherally-delivered NGF is effective in preventing the onset of the central cholinergic deficit. These findings could have a direct relevance for some human sporadic AD cases, highlighting the role of the BBB disruption and suggesting a causally relevant role of circulating antibodies in AD pathology. Show more

Keywords: Alzheimer's disease, autoantibodies, blood brain barrier deficit, nerve growth factor, peripheral neutralization

DOI: 10.3233/JAD-2010-091357

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 527-546, 2010

Authors: Bastin, Christine | Kerrouche, Nacer | Lekeu, Françoise | Adam, Stéphane | Guillaume, Bénédicte | Lemaire, Christian | Aerts, Joël | d'Ydewalle, Géry | Collette, Fabienne | Salmon, Eric

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by a progressive loss of controlled cognitive processes, and neuroimaging studies at early stages of AD provide an opportunity to tease out the neural correlates of controlled processes. Accordingly, controlled and automatic memory performance was assessed with the Process Dissociation Procedure in 50 patients diagnosed with questionable Alzheimer's disease (QAD). The patients' brain glucose metabolism was measured using FDG-PET. After a follow-up period of 36 months, 27 patients had converted to AD, while 23 remained stable. Both groups showed a similar decrease in controlled memory processes but preserved automatic processes at entry into the study. …Voxel-based cognitive and metabolic correlations showed that a decrease in controlled memory processes was preferentially correlated with lower activity in the dorsomedial prefrontal and posterior cingulate cortices in very early AD patients. In stable QAD patients, reduced controlled performance in verbal memory correlated with impaired activity in the left anterior hippocampal structure. The results demonstrate the central role of a medial frontal-posterior cingulate network for controlled processing of episodic memory in the early stages of AD. Show more

Keywords: Alzheimer's disease, cognitive impairment, controlled processes, FDG, memory, neuroimaging

DOI: 10.3233/JAD-2010-1393

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 547-560, 2010

Authors: Middle, Fiona | Pritchard, Antonia L. | Handoko, Herlina | Haque, Sayeed | Holder, Roger | Bentham, Peter | Lendon, Corinne L.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) patients commonly suffer from behavioral and psychological symptoms of dementia (BPSD). Variants within the neuregulin-1 (NRG1) gene have been investigated both in early onset psychiatric disorders, such as schizophrenia and recently in AD patients with psychosis. In this study, we analyzed NRG1 variants in AD patients with and without psychosis. Our large cohort of 399 probable AD patients had longitudinal information on the BPSD, which was used to dichotomize patients into whether they had ever suffered from psychotic symptoms within the study period. The NRG1 single nucleotide polymorphisms rs3924999, rs35753505 (SNP8NRG221533) and the microsatellites 478B14-848 and 420M9-1395 …were investigated for association with psychosis using genotype, allele, and haplotype analyses. No associations were found between any of these variants or haplotypic combinations with delusions, hallucinations, psychosis, or elation/mania in our cohort. Positive associations with polymorphisms and haplotype combinations of NRG1 have been reported in psychiatric disorders. One previous study found an association with psychosis in AD, with a SNP outside the haplotype block first reported for association with schizophrenia. We found no association with any of these variants in our cohort. Further investigations of this region on chromosome 8 are clearly required, with replication in different large longitudinal cohorts. Show more

Keywords: Alzheimer's disease, BPSD, haplotype, neuregulin 1, psychosis

DOI: 10.3233/JAD-2010-1405

Citation: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 561-567, 2010