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1.  1731, a new retrotransposon with hormone modulated expression. 
Nucleic Acids Research  1986;14(22):9017-9033.
We report here the characterisation of 1731, a new copia-like element of Drosophila melanogaster. 1731 was first isolated in a screening for ecdysterone modulated genes. This element is about 4.6 Kb long and is flanked by two long terminal repeats (LTRs) 336 base pairs in length. The whole 1731 element is transcribed into polyA+ RNAs, and these transcripts decrease rapidly upon hormonal treatment. 1731 is moderately repeated in the fly genome and slightly amplified in Kc/cells where extrachromosomal circular forms are found. The LTRs were sequenced in one cloned copy of 1731 and show a structural organisation similar to that of several other copia-like elements and retroviral proviruses. Small nucleotide stretches, similar to those found in Mouse Mammary Tumor Virus LTRs and known to be important in its regulation by a steroid hormone, occur in 1731 LTRs.
PMCID: PMC311926  PMID: 3024127
2.  Apathy is associated with increased amyloid burden in mild cognitive impairment 
Apathy is the most common neuropsychiatric symptom in mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. We sought to determine whether apathy is associated with cortical amyloid burden measured by Pittsburgh Compound B (PiB) positron emission tomography (PET) and regional hypometabolism measured by 18F-fluorodeoxyglocuse (FDG) PET in MCI. We found a significant association between increased apathy (lower Apathy Evaluation Scale score) and greater cortical PiB retention independent of age (prs=−0.46, p=0.03), but no significant association between apathy and regional FDG metabolism. These results suggest that increased apathy is associated with greater amyloid burden but not regional hypometabolism in MCI.
PMCID: PMC3957217  PMID: 24247857
Alzheimer’s disease; amyloid; apathy; 18F-flourodeoxyglucose; mild cognitive impairment; Pittsburgh Compound B; positron emission tomography
3.  Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene 
Translational Psychiatry  2014;4(2):e358-.
To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundació ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19–1.44); P=9.74 × 10−9).
PMCID: PMC3944635  PMID: 24495969
dementia risk; DNA; GWAS; molecular epidemiology; SNP; thyroid receptor
4.  Cognitive profile of amyloid burden and white matter hyperintensities in cognitively normal older adults 
Amyloid burden and white matter hyperintensities (WMH) are two common markers of neurodegeneration present in advanced aging. Each represents a potential early indicator of an age-related neurological disorder that impacts cognition. The presence of amyloid is observed in a substantial subset of cognitively normal older adults, but the literature remains equivocal regarding whether amyloid in nondemented populations is deleterious to cognition. Similarly, WMH are detected in many nondemented older adults and there is a body of evidence indicating that WMH are associated with decreased executive function and other cognitive domains. The current study investigated amyloid burden and WMH in clinically normal older adult humans aged 65 to 86 (N=168) and examined each biomarker’s relation with cognitive domains of episodic memory, executive function, and speed of processing. Factors for each domain were derived from a neuropsychological battery on a theoretical basis without reference to the relation between cognition and the biomarkers. Amyloid burden and WMH were not correlated with one another. Age was associated with lower performance in all cognitive domains, while higher estimated verbal intelligence was associated with higher performance in all domains. Hypothesis-driven tests revealed that amyloid burden and WMH had distinct cognitive profiles, with amyloid burden having a specific influence on episodic memory and WMH being primarily associated with executive function but having broad (but lesser) effects on the other domains. These findings suggest that even prior to clinical impairment, amyloid burden and WMH likely represent neuropathological cascades with distinct etiologies and dissociable influences on cognition.
PMCID: PMC3523110  PMID: 23152607
5.  Novel Bioimaging Techniques of Metals by Laser Ablation Inductively Coupled Plasma Mass Spectrometry for Diagnosis Of Fibrotic and Cirrhotic Liver Disorders 
PLoS ONE  2013;8(3):e58702.
Background and Aims
Hereditary disorders associated with metal overload or unwanted toxic accumulation of heavy metals can lead to morbidity and mortality. Patients with hereditary hemochromatosis or Wilson disease for example may develop severe hepatic pathology including fibrosis, cirrhosis or hepatocellular carcinoma. While relevant disease genes are identified and genetic testing is applicable, liver biopsy in combination with metal detecting techniques such as energy-dispersive X-ray spectroscopy (EDX) is still applied for accurate diagnosis of metals. Vice versa, several metals are needed in trace amounts for carrying out vital functions and their deficiency due to rapid growth, pregnancy, excessive blood loss, and insufficient nutritional or digestive uptake results in organic and systemic shortcomings. Established in situ techniques, such as EDX-ray spectroscopy, are not sensitive enough to analyze trace metal distribution and the quantification of metal images is difficult.
In this study, we developed a quantitative biometal imaging technique of human liver tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) in order to compare the distribution of selected metals in cryo-sections of healthy and fibrotic/cirrhotic livers.
Most of the metals are homogeneous distributed within the normal tissue, while they are redirected within fibrotic livers resulting in significant metal deposits. Moreover, total iron and copper concentrations in diseased liver were found about 3-5 times higher than in normal liver samples.
Biometal imaging via LA-ICP-MS is a sensitive innovative diagnostic tool that will impact clinical practice in identification and evaluation of hepatic metal disorders and to detect subtle metal variations during ongoing hepatic fibrogenesis.
PMCID: PMC3591358  PMID: 23505552
6.  A common variant in Myosin-18B contributes to mathematical abilities in children with dyslexia and intraparietal sulcus variability in adults 
Translational Psychiatry  2013;3(2):e229-.
The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical abilities (Pcomb=7.71 × 10−10, n=699), with an effect size of 4.87%. This association was also found in a sample from the general population (P=0.048, n=1080), albeit with a lower effect size. The identified variant encodes an amino-acid substitution in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between rs133885 and mathematical disability at the level of a specific intermediate phenotype.
PMCID: PMC3591001  PMID: 23423138
dyscalculia; dyslexia; genomic imaging; mathematics; quantitative trait; sulcal morphology
7.  Subjective cognitive complaints and amyloid burden in cognitively normal older individuals 
Neuropsychologia  2012;50(12):2880-2886.
Accumulating evidence suggests that subjective cognitive complaints (SCC) may indicate subtle cognitive decline characteristic of individuals with preclinical Alzheimer’s disease (AD). In this study, we sought to build upon previous studies by associating SCC and amyloid-β deposition using Positron Emission Tomography with Pittsburg Compound B (PiB-PET) in cognitively normal older individuals. One-hundred thirty one subjects (mean age 73.5 ± 6) were administered three subjective cognitive questionnaires and a brief neuropsychological battery. A relationship between a subjective memory complaints composite score and cortical PiB binding was found to be significant, even after controlling for depressive symptoms. By contrast, there were no significant relationships between objective cognitive measures of memory and executive functions and cortical PiB binding. Our study suggests that SCC may be an early indicator of AD pathology detectable prior to significant objective impairment.
PMCID: PMC3473106  PMID: 22940426
preclinical Alzheimer’s disease; early detection; amyloid imaging; subjective cognitive complaints
8.  Correlations between Root-Associated Microorganisms and Peach Replant Disease Symptoms in a California Soil 
PLoS ONE  2012;7(10):e46420.
Replant disease often occurs when certain crops are “replanted” in a soil that had previously supported the same or similar plant species. This disease typically leads to reductions in plant growth, crop yields, and production duration, and its etiology remains ill-defined. The objective of this study was to identify microorganisms associated with peach replant disease symptoms at a field location in California, USA. Soil samples were subjected to treatments to create various levels of replant disease symptoms. Clonal peach seedlings were grown in the treated soils in greenhouse trials. After 6 weeks, plant growth parameters were measured, and both culture and culture-independent analyses were performed to identify root-associated bacteria, fungi and stramenopiles.
A total of 295,785 bacterial operational taxonomic units (OTU) were identified by an Illumina-based, high throughput sequence analysis of rRNA genes. Among the 60 most abundant OTUs, 27 showed significant (P<0.05) negative correlation with peach shoot weights while 10 were positively correlated. Most of these OTUs belonged to the bacterial phylum Proteobacteria (96%), including the classes Gammaproteobacteria (44.4%), Betaproteobacteria (33.3%) and Alphaproteobacteria (22.2%), and the orders Pseudomonadales, Burkholderiales, Chromatiales, Rhodocyclales, and Sphingomonadales. The most abundant fungi were Trichoderma asperellum, Trichoderma virens, Fusarium oxysporum, Ceratocystis fimbriata and Fusarium solani. The most abundant stramenopiles were Pythium vexans, Pythium violae and an unidentified Aplanochytrium species. Validation experiments using sequence-selective quantitative PCR analyses identified negative and positive associations between P. vexans and Trichoderma spp. and peach shoot weights, respectively.
This study identified numerous microorganisms associated with peach replant symptoms, some of which have been previously identified while others represent new candidates. Subsequent Koch's postulates investigations will assess their possible roles in this replant disease.
PMCID: PMC3465339  PMID: 23071565
9.  Population Dynamics of Dactylella oviparasitica and Heterodera schachtii: Toward a Decision Model for Sugar Beet Planting 
Journal of Nematology  2012;44(3):237-244.
A series of experiments were performed to examine the population dynamics of the sugarbeet cyst nematode, Heterodera schachtii, and the nematophagus fungus Dactylella oviparasitica. After two nematode generations, the population densities of H. schachtii were measured in relation to various initial infestation densities of both D. oviparasitica and H. schachtii. In general, higher initial population densities of D. oviparasitica were associated with lower final population densities of H. schachtii. Regression models showed that the initial densities of D. oviparasitica were only significant when predicting the final densities of H. schachtii J2 and eggs as well as fungal egg parasitism, while the initial densities of J2 were significant for all final H. schachtii population density measurements. We also showed that the densities of H. schachtii-associated D. oviparasitica fluctuate greatly, with rRNA gene numbers going from zero in most field-soil-collected cysts to an average of 4.24 x 108 in mature females isolated directly from root surfaces. Finally, phylogenetic analysis of rRNA genes suggested that D. oviparasitica belongs to a clade of nematophagous fungi that includes Arkansas Fungus strain L (ARF-L) and that these fungi are widely distributed. We anticipate that these findings will provide foundational data facilitating the development of more effective decision models for sugar beet planting.
PMCID: PMC3547341  PMID: 23481664
Dactylella oviparasitica; Heterodera schachtii; nematophagous; sugarbeet cyst nematode; suppressive soil; Arkansas Fungus (ARF)
10.  Instrumental Activities of Daily Living Impairment Is Associated with Increased Amyloid Burden 
Instrumental activities of daily living (IADL) impairment in Alzheimer's disease has been associated with global amyloid deposition in postmortem studies. We sought to determine whether IADL impairment is associated with increased cortical Pittsburgh Compound B (PiB) retention.
Fifty-five subjects (19 normal older controls, NC, and 36 with mild cognitive impairment, MCI) underwent clinical assessments and dynamic PiB positron emission tomography imaging.
A linear multiple regression model showed that greater IADL impairment was associated with greater global PiB retention in all subjects (R2 = 0.40; unstandardized partial regression coefficient, β = 5.8; p = 0.0002) and in MCI subjects only (R2 = 0.28; β = 6.1; p = 0.003), but not in NC subjects only.
These results suggest that daily functional impairment is related to greater amyloid burden in MCI.
PMCID: PMC3150869  PMID: 21778725
Alzheimer's disease; Amyloid; Instrumental activities of daily living; Mild cognitive impairment; Pittsburgh compound B; Positron emission tomography
11.  Face-name Associative Memory Performance is Related To Amyloid Burden in Normal Elderly 
Neuropsychologia  2011;49(9):2776-2783.
Cerebral amyloid beta (Aβ) deposition occurs in a substantial fraction of cognitively normal (CN) older individuals. However, it has been difficult to reliably detect evidence of amyloid-related cognitive alterations in CN using standard neuropsychological measures. We sought to determine whether a highly demanding face-name associative memory exam (FNAME) could detect evidence of Aβ-related memory impairment in CN. We studied 45 CN subjects (mean age = 71.7 ± 8.8) with Clinical Dementia Rating (CDR) scores = 0 and MMSE ≥ 28, using Positron Emission Tomography with Pittsburgh Compound B (PiB PET). Memory factor scores were derived from a principal components analysis for FNAME name retrieval (FN-N), FNAME occupation retrieval (FN-O) and the 6-Trial Selective Reminding Test (SRT). Using multiple linear and logistic regression analyses, we related the memory factor scores to PiB distribution volume ratios (DVR, cerebellar reference) as either a continuous or a dichotomous variable in frontal cortex and a posterior cortical region representing the precuneus, posterior cingulate and lateral parietal cortices (PPCLP), co-varying for age and AMNART IQ (a proxy of cognitive reserve (CR)). A significant inverse relationship for FN-N was found with Aβ deposition in frontal (R2 = .29, β = −2.2, p = 0.02) and PPCLP cortices (R2 = .26, β = −2.4, p = 0.05). In contrast, neither FN-O nor the SRT were significantly related to Aβ deposition. Performance on a demanding test of face-name associative memory was related to Aβ burden in brain regions associated with memory systems. Associative memory for faces and names, a common complaint among older adults, may be a sensitive marker of early Aβ-related impairment.
PMCID: PMC3137730  PMID: 21689670
Preclinical Alzheimer’s Disease; Early Detection; Normal Aging; Amyloid Imaging
12.  Evidence for the involvement of ZNF804A in cognitive processes of relevance to reading and spelling 
Translational Psychiatry  2012;2(7):e136-.
Previous studies have shown that individuals with schizophrenia and dyslexia display common neurocognitive abnormalities. The aim of the present study was to determine whether known schizophrenia-risk genes contribute to dyslexia risk or to disease-relevant cognitive functions. For this purpose, we genotyped the schizophrenia-associated risk variants within zinc-finger protein 804A (ZNF804A), transcription-factor 4 and neurogranin in a large dyslexia case–control sample. We tested all variants for association with dyslexia (927 cases, 1096 controls), and with eight language-relevant cognitive processes (1552 individuals). We observed six significant associations between language-relevant traits and the ZNF804A-variant rs1344706. Interestingly, the ZNF804A schizophrenia risk variant was associated with a better cognitive performance in our data set. This finding might be consistent with a previously reported ZNF804A association in schizophrenia, in which patients carrying the schizophrenia-risk allele at rs1344706 showed a better performance in two memory tests. In conclusion, the present study provides evidence that ZNF804A might have a role in cognitive traits of relevance to reading and spelling, and underlines the phenotypic complexity that might be associated with ZNF804A.
PMCID: PMC3410625  PMID: 22781169
cognitive processes; dyslexia; genetic association; reading and spelling; schizophrenia; ZNF804A
13.  Determinants of vascular dementia in the Cardiovascular Health Cognition Study 
Neurology  2005;64(9):1548-1552.
The authors evaluated 3,375 participants without dementia at the time of MRI in 1991 to 1994 over 5.7 years for incident dementia and type of dementia.
Incidence of and risk factors for vascular dementia (VaD) were measured using both pre-MRI and modified State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) post-MRI review and further classified Alzheimer disease (AD) by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDSADRDA) criteria.
Approximately 44% (213) of 480 incident dementia cases were classified as possible or probable VaD by ADDTC. The incidence of VaD increased with age and was greater in blacks than whites. Risk factors for VaD included age, Modified Mini-Mental State Examination, high white matter grade, number of MRI infarcts, ventricular size, and history of stroke.
Vascular disease in the brain is prevalent among incident dementia cases. There is a substantial overlap between cases classified as Alzheimer disease by Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association and vascular dementia (VaD) by modified State of California Alzheimer’s Disease Diagnostic and Treatment Centers criteria. The substantial contribution of vascular disease would be missed without inclusion of MRI. Treatment of risk factors for VaD could have an important impact on incidence of dementia.
PMCID: PMC3378359  PMID: 15883315
14.  Amyloid-β Associated Cortical Thinning in Clinically Normal Elderly 
Annals of neurology  2011;69(6):1032-1042.
Both amyloid-β (Aβ) deposition and brain atrophy are invariably associated with Alzheimer's disease (AD) and the disease process likely begins many years before symptoms appear.
We sought to determine whether clinically normal (CN) older individuals with Aβ deposition revealed by PET imaging using Pittsburgh Compound B (PiB) also have evidence of both cortical thickness and hippocampal volume reductions in a pattern similar to that seen in AD.
One hundred and nineteen older individuals (87 CN subjects and 32 patients with mild AD) underwent PiB PET and high-resolution structural MR. Regression models were used to relate PiB retention to cortical thickness and hippocampal volume.
We found that PiB retention in CN subjects was (1) age-related and (2) associated with cortical thickness reductions particularly in parietal and posterior cingulate regions extending into the precuneus, in a pattern similar to that observed in mild AD. Hippocampal volume reduction was variably related to Aβ deposition.
We conclude that Aβ deposition is associated with a pattern of cortical thickness reduction consistent with AD prior to the development of cognitive impairment.
PMCID: PMC3117980  PMID: 21437929
15.  Biocontrol Efficacy Among Strains of Pochonia chlamydosporia Obtained from a Root-Knot Nematode Suppressive Soil 
Journal of Nematology  2012;44(1):67-71.
Three Pochonia chlamydosporia var. chlamydosporia strains were isolated from a Meloidogyne incognita-suppressive soil, and then genetically characterized with multiple Pochonia-selective typing methods based on analysis of ß-tubulin, rRNA internal transcribed spacer (ITS), rRNA small subunit (SSU), and enterobacterial repetitive intergenic consensus (ERIC) PCR. All strains exhibited different patterns with the ERIC analysis. Strains 1 and 4 were similar with PCR analysis of ß-tubulin and ITS. The strains' potential as biological control agents against root-knot nematodes were examined in greenhouse trials. All three P. chlamydosporia strains significantly reduced the numbers of nematode egg masses. When chlamydospores were used as inoculum, strain 4 reduced egg numbers on tomato roots by almost 50%, and showed effects on the numbers of J2 and on nematode-caused root-galling. A newly developed SSU-based PCR analysis differentiated strain 4 from the others, and could therefore potentially be used as a screening tool for identifying other effective biocontrol strains of P. chlamydosporia var. chlamydosporia.
PMCID: PMC3593255  PMID: 23483846
biological control; Meloidogyne incognita; Pochonia chlamydosporia; Southern root-knot nematode; suppressive soil
16.  Fibronectin 1 protein expression in clear cell renal cell carcinoma 
Oncology Letters  2012;3(4):787-790.
Fibronectin 1 (FN1) is a glycoprotein that is involved in cell adhesion and migration processes including embryogenesis, wound healing, blood coagulation, host defenses and metastasis. The aim of this study was to elucidate the FN1 protein expression in renal cell carcinoma (RCC) and to determine its potential prognostic relevance. A total of 270 clear cell RCC tissue specimens were collected from patients undergoing surgery for renal tumors. Biomarker expression was determined by immunohistochemistry and correlated with clinical variables. Survival analysis was carried out for 153 patients with complete follow-up data and pathologically proven clear cell carcinoma of the kidney. The follow-up group had a mean follow-up period of 83.8 months (IQR 26.2-136.2 months). The calculated median 5-year overall and tumor-specific survival rate of all 153 evaluable patients was 66.6 and 71.0%, respectively. A higher disease-related mortality rate was observed among patients with cytoplasmic FN1 expression (41.3 vs. 24.7%, p=0.039, Fisher's exact test). No significant correlation was found between FN1 staining and patient characteristics such as age, gender, tumor differentiation and visceral metastasis. However, there was a trend for FN1 expression and correlation with tumor stage and lymph node metastasis (p=0.085 and p=0.203; respectively). The Kaplan-Meier analysis revealed significant differences in the 5-year tumor-specific survival for patients with and without cytoplasmic FN1 expression (64.8 vs. 77.7%; p=0.035, log-rank test). However, results of the multivariate Cox regression analysis showed that FN1 expression was not an independent marker of either overall or tumor-specific survival. In conclusion, FN1 protein expression in RCC is associated with a higher disease-related mortality rate, indicating a possible role in RCC progression. Therefore, our data on FN1 encourage further investigations to determine the role of FN1 in RCC.
PMCID: PMC3362387  PMID: 22740994
renal cell carcinoma; fibronectin 1; prognosis
17.  Physical activity predicts gray matter volume in late adulthood 
Neurology  2010;75(16):1415-1422.
Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation.
In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline.
Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold.
Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.
= modified Mini-Mental State Examination;
= Cardiovascular Health Study Cognition Study;
= Digit Symbol Substitution Test;
= gray matter;
= mild cognitive impairment;
= odds ratio;
= physical activity;
= Statistical Parametric Mapping;
= total intracranial volume;
= voxel-based morphometry;
= white matter.
PMCID: PMC3039208  PMID: 20944075
18.  Initial Experience in Using Continuous Arterial Spin-Labeled MR Imaging for Early Detection of Alzheimer Disease 
MR imaging of the brain has significant potential in the early detection of neurodegenerative disorders such as AD. The purpose of this work was to determine if perfusion MR imaging can be used to separate AD from normal cognition in individual subjects. We investigated the diagnostic utility of perfusion MR imaging for early detection of AD compared with structural imaging.
Data were analyzed from 32 participants in the institutional review board–approved CHS-CS: 19 cognitively healthy individuals and 13 with clinically adjudicated AD. All subjects underwent structural T1-weighted SGPR and CASL MR imaging. Four readers with varying experience separately rated each CASL and SPGR scan finding as normal or abnormal on the basis of standardized qualitative diagnostic criteria for observed perfusion abnormalities on CASL or volume loss on SPGR and rated the confidence in their evaluation.
Inter-rater reliability was superior in CASL (κ = 0.7 in experienced readers) compared with SPGR (κ = 0.17). CASL MR imaging had the highest sensitivity (85%) and accuracy (70%). Frontal lobe CASL findings increased sensitivity to 88% and accuracy to 79%. Fifty-seven percent of false-positive readings with CASL were in controls with cognitive decline or instability within 5 years. Three of the 4 readers revealed a statistically significant relationship between confidence and correct classification when using CASL.
Readers were able to separate individuals with mild AD from those with normal cognition with high sensitivity by using CASL but not volumetric MR imaging. This initial experience suggests that CASL MR imaging may be a useful technique for detecting AD.
PMCID: PMC2873119  PMID: 20075093
19.  Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden 
Brain  2011;134(6):1635-1646.
Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.
PMCID: PMC3102239  PMID: 21490054
amyloid; cortical hubs; functional connectivity; metabolism; mild cognitive impairment; positron emission tomography; magnetic resonance imaging
20.  Functional Alterations in Memory Networks in Early Alzheimer’s Disease 
Neuromolecular medicine  2010;12(1):27-43.
The hallmark clinical symptom of early Alzheimer’s disease (AD) is episodic memory impairment. Recent functional imaging studies suggest that memory function is subserved by a set of distributed networks, which include both the medial temporal lobe (MTL) system and the set of cortical regions collectively referred to as the default network. Specific regions of the default network, in particular, the posteromedial cortices, including the precuneus and posterior cingulate, are selectively vulnerable to early amyloid deposition in AD. These regions are also thought to play a key role in both memory encoding and retrieval, and are strongly functionally connected to the MTL. Multiple functional magnetic resonance imaging (fMRI) studies during memory tasks have revealed alterations in these networks in patients with clinical AD. Similar functional abnormalities have been detected in subjects at-risk for AD, including those with genetic risk and older individuals with mild cognitive impairment. Recently, we and other groups have found evidence of functional alterations in these memory networks even among cognitively intact older individuals with occult amyloid pathology, detected by PET amyloid imaging. Taken together, these findings suggest that the pathophysiological process of AD exerts specific deleterious effects on these distributed memory circuits, even prior to clinical manifestations of significant memory impairment. Interestingly, some of the functional alterations seen in prodromal AD subjects have taken the form of increases in activity relative to baseline, rather than a loss of activity. It remains unclear whether these increases in fMRI activity may be compensatory to maintain memory performance in the setting of early AD pathology or instead, represent evidence of excitotoxicity and impending neuronal failure. Recent studies have also revealed disruption of the intrinsic connectivity of these networks observable even during the resting state in early AD and asymptomatic individuals with high amyloid burden. Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD.
PMCID: PMC3036844  PMID: 20069392
Functional magnetic resonance imaging; Amyloid; PiB; Alzheimer’s disease; Aging; Hippocampus; Default network
21.  Age, Alzheimer disease, and brain structure 
Neurology  2009;73(22):1899-1905.
Lack of clear understanding remains on the overlapping atrophy patterns of aging and early Alzheimer disease (AD) pathology in gray matter (GM) of the brain in vivo.
To evaluate the independent and overlapping patterns of GM atrophy in normal aging and AD.
A total of 169 cognitively normal subjects and 33 persons with probable AD enrolled in the longitudinal Cardiovascular Health Study–Cognition Study underwent 3-dimensional volumetric MRI scans. Controls remained cognitively normal for at least 5 years after their MRI scans and the probable AD subjects were relatively early in their clinical course with an average modified Mini-Mental State Examination score of 76/100. The scans were analyzed using voxel-based morphometry adjusting for total intracranial volume, gender, education, and race.
With older age, GM volume was lower in the sensorimotor and heteromodal association areas in frontal, temporal, occipital, and parietal lobes, as well as in the cerebellum (false discovery rate p = 0.05). Additional atrophy was observed in the posterior hippocampus, thalamus, and middle cingulate gyrus. By contrast, atrophy was seen in subjects with AD in the anterior hippocampal/parahippocampal regions and the precuneus. Normal aging and AD overlapped in the hippocampal body and the entorhinal cortex.
Brain atrophy with aging was observed in supratentorial and infratentorial areas, as well in primary motor, sensory, and heteromodal association regions. Age and Alzheimer disease exert independent gray matter atrophy patterns but these effects overlapped substantially in the hippocampus and entorhinal cortex.
= Modified Mini-Mental State Examination;
= Alzheimer disease;
= Cardiovascular Health Study–Cognition Study;
= gray matter;
= spoiled gradient recalled acquisition;
= total intracranial volume;
= voxel-based morphometry;
= white matter.
PMCID: PMC2788799  PMID: 19846828
22.  Vascular risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men 
Neurology  2009;73(16):1292-1299.
The purpose of this study was to evaluate the relationship between cognitive performance, risk factors for cardiovascular and cerebrovascular disease (CVD), and HIV infection in the era of highly active antiretroviral therapy.
We evaluated the cognitive functions of men enrolled in the cardiovascular disease substudy of the Multicenter AIDS Cohort Study who were aged ≥40 years, with no self-reported history of heart disease or cerebrovascular disease. Results from comprehensive neuropsychological evaluations were used to construct composite scores of psychomotor speed and memory performance. Subclinical CVD was assessed by measuring coronary artery calcium and carotid artery intima-media thickness (IMT), as well as laboratory measures, including total cholesterol, fasting glucose, glycosylated hemoglobin, glomerular filtration rate (estimated), and standardized blood pressure and heart rate measures.
After accounting for education, depression, and race, carotid IMT and glomerular filtration rate were significantly associated with psychomotor speed, whereas IMT was associated with memory test performance. HIV serostatus was not significantly associated with poorer cognitive test performance. However, among the HIV-infected individuals, the presence of detectable HIV RNA in plasma was linked to lower memory performance.
These findings suggest that HIV infection may not be the most important predictor of cognitive performance among older gay and bisexual men in the post–highly active antiretroviral therapy era, at least among those with access to medical care and to appropriate medications. Medical factors associated with normal aging are significantly associated with performance on neuropsychological tests, and good clinical management of these factors both in HIV-infected individuals and those at risk for infection may have beneficial effects in the short term and could reduce the risk of subsequent cognitive decline.
= blood pressure;
= California Computerized Assessment Package;
= Center for Epidemiologic Studies–Depression scale;
= cardiovascular and cerebrovascular disease;
= glomerular filtration rate;
= highly active antiretroviral therapy;
= high-density lipoprotein;
= HIV-associated neurocognitive disorder;
= hemoglobin;
= intima-media thickness;
= low-density lipoprotein;
= Multicenter AIDS Cohort Study;
= odds ratio;
= Rey Auditory Verbal Learning Test.
PMCID: PMC2764414  PMID: 19841381
23.  Amyloid deposition is associated with impaired default network function in older persons without dementia 
Neuron  2009;63(2):178-188.
Alzheimer's disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid β-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pathology may be in early stages of AD.
PMCID: PMC2738994  PMID: 19640477
24.  Acceleration of cerebral ventricular expansion in the Cardiovascular Health Study 
Neurobiology of aging  2006;28(9):1316-1321.
Interactions between prevalent late-life medical conditions and expansion of the cerebral ventricles are not well understood. Thirty elderly subjects received three magnetic resonance (MR) scans each, in 1997–1999, 2002–2004, and 2003–2005. A linear expansion model of MR-measured lateral ventricle volume was estimated for each subject by fitting a line to a plot of their 1997–1999 and 2002–2004 volumes as a function of time. Acceleration in ventricular expansion was defined as the deviation between the 2003–2005 volumes measured from MR and the 2003–2005 volumes predicted by the linear expansion model. Ventricular acceleration was analyzed in a multivariate model with age, race, history of heart disease, diabetes, and hypertension as fixed effects. Ventricular acceleration was significantly higher in non-whites, diabetics, and those without heart disease (p < 0.05). Ventricular acceleration was higher in subjects with a history of hypertension, but the difference was not statistically significant (p = 0.08). Acceleration of ventricular expansion in the elderly may be related to demographic and cardiovascular factors.
PMCID: PMC2877585  PMID: 16875759
Magnetic resonance imaging; Lateral ventricles; Aging; Diabetes; Heart disease
25.  The progress of early phase bone healing using porous granules produced from calcium phosphate cement 
Bone grafting is a vital component in many surgical procedures to facilitate the repair of bone defects or fusions. Autologous bone has been the gold standard to date in spite of associated donor-site morbidity and the limited amount of available donor bone. The aim of this study was to investigate the progress of bone regeneration and material degradation of calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder compared to the use of autologous bone grafting in the treatment of "critical size defects" on load-bearing long bones of minipigs.
A critical size defect in the tibial metaphysis of 16 mini-pigs was filled either with autologous cancellous graft or with micro- and macroporous carbonated, apatic calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder. After 6 weeks, the specimens were assessed by X-ray and histological evaluation. The amount of new bone formation was analysed histomorphometrically.
The semi-quantitative analysis of the radiological results showed a complete osseous bridging of the defect in three cases for the autograft group. In the same group five animals showed a beginning, but still incomplete bridging of the defect, whereas in the CPG group just two animals developed this. All other animals of the CPG group showed only a still discontinuous new bone formation. Altogether, radiologically a better osseous bridging was observed in the autograft group compared to the CPG group.
Histomorphometrical analysis after six weeks of healing revealed that the area of new bone was significantly greater in the autograft group concerning the central area of the defect zone (p < 0.001) as well as the cortical defect zone (p < 0.002). All defects showed new bone formation, but only in the autograft group defects regenerated entirely
Within the limits of the present study it could be demonstrated that autologous cancellous grafts lead to a significantly better bone regeneration compared to the application of calcium phosphate granules (CPG) produced from a calcium phosphate self-setting cement powder after 6 weeks. In the early phase of bone-healing, the sole application of CPG appears to be inferior to the autologous cancellous grafts in an in vivo critical size defect on load-bearing long bones of mini-pigs.
PMCID: PMC3352008  PMID: 20562058
Calcium phosphate granules; Calcium phosphate cement; Bone healing; Bone defect; Animal model; Mini-pig

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