PubMed Health⌕ Search

Biomedical subjects

Chester A Mathis

Publications and source records attributed to Chester A Mathis.

At least 19 recordsLinked to original sources
PubMed2008

Frequent amyloid deposition without significant cognitive impairment among the elderly.

OBJECTIVE: To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests. DESIGN: Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs). SETTING: University medical center. PARTICIPANTS: From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included. MAIN OUTCOME MEASURES: Regional PiB retention and cognitive test performance. RESULTS: Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. CONCLUSIONS: Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.

Aged↗
PubMed2006

Evaluation of voxel-based methods for the statistical analysis of PIB PET amyloid imaging studies in Alzheimer's disease.

Deposition of amyloid plaques is believed to be a central event in the development of Alzheimer's disease (AD). The present study was undertaken to evaluate statistical methods for the assessment of group differences in retention of an amyloid imaging agent, PIB, throughout the brain and to compare these results to FDG studies of glucose metabolism performed in the same subjects on the same day. PET studies were performed in 10 mild to moderate AD and 11 control subjects. Parametric images of PIB retention (over 90 min post-injection) were generated using the Logan graphical analysis with cerebellar (CER, reference region) data as input. FDG parametric images were created by summing the uptake over 40-60 min post-injection and normalizing that to the CER to give a standardized uptake value ratio. Data were compared using parametric (SPM) and non-parametric (SnPM) statistical methods with familywise error (FWE) and false discovery rate (FDR) corrections. PIB results were consistent with previous regional results as AD subjects showed highly significant retention in frontal, parietal, temporal, and posterior cingulate cortices (FDR-corrected p<1.4e-10). FDG results showed regions of marginally significant decreases in uptake in AD subjects (frontal, parietal, temporal, posterior cingulate cortices: FDR-corrected p<0.1) consistent with previous studies. Relative to FDG, the PIB analyses were of greater statistical significance and larger spatial extent. Additionally, the PIB analyses retained significance after both FWE and FDR corrections. These results indicate that voxel-based methods will be useful for future larger longitudinal studies of amyloid deposition that could improve AD diagnosis and anti-amyloid therapy assessment.

Aged↗
PubMed2006

Imaging of CNS myelin by positron-emission tomography.

Promoting myelin repair is one of the most promising therapeutic avenues in the field of myelin disorders. In future clinical trials, evaluation of remyelination will require a reliable and quantifiable myelin marker to be used as a surrogate marker. To date, MRI assessment lacks specificity for evaluating the level of remyelination within the brain. Here, we describe 1,4-bis(p-aminostyryl)-2-methoxy benzene (BMB), a synthesized fluorescent molecule, that binds selectively to myelin both ex vivo and in vivo. The binding of BMB to myelin allows the detection of demyelinating lesions in an experimental autoimmune encephalitis model of demyelination and allows a mean for quantifying myelin loss in dysmyelinating mutants. In multiple sclerosis brain, different levels of BMB binding differentiated remyelination in shadow plaques from either demyelinated lesions or normal-appearing white matter. After systemic injection, BMB crosses the blood-brain barrier and binds to myelin in a dose-dependent and reversible manner. Finally, we provide evidence that (11)C-radiolabeled BMB can be used in vivo to image CNS myelin by positron-emission tomography in baboon. Our results provide a perspective for developing a brain myelin imaging technique by positron-emission tomography.

Animals↗
PubMed2006

Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans.

OBJECTIVES: Amyloid-beta(42) (Abeta(42)) appears central to Alzheimer's disease (AD) pathogenesis and is a major component of amyloid plaques. Mean cerebrospinal fluid (CSF) Abeta(42) is decreased in dementia of the Alzheimer's type. This decrease may reflect plaques acting as an Abeta(42) "sink," hindering transport of soluble Abeta(42) between brain and CSF. We investigated this hypothesis. METHODS: We compared the in vivo brain amyloid load (via positron emission tomography imaging of the amyloid-binding agent, Pittsburgh Compound-B [PIB]) with CSF Abeta(42) and other measures (via enzyme-linked immunosorbent assay) in clinically characterized research subjects. RESULTS: Subjects fell into two nonoverlapping groups: those with positive PIB binding had the lowest CSF Abeta(42) level, and those with negative PIB binding had the highest CSF Abeta(42) level. No relation was observed between PIB binding and CSF Abeta(40), tau, phospho-tau(181), plasma Abeta(40), or plasma Abeta(42). Importantly, PIB binding and CSF Abeta(42) did not consistently correspond with clinical diagnosis; three cognitively normal subjects were PIB-positive with low CSF Abeta(42), suggesting the presence of amyloid in the absence of cognitive impairment (ie, preclinical AD). INTERPRETATION: These observations suggest that brain amyloid deposition results in low CSF Abeta(42), and that amyloid imaging and CSF Abeta(42) may potentially serve as antecedent biomarkers of (preclinical) AD.

Aged↗
PubMed2006

Molecular targets.

Explore the source record for details and available documents.

Drug Delivery Systems↗
PubMed2006

X-34 labeling of abnormal protein aggregates during the progression of Alzheimer's disease.

Postmortem pathological diagnosis and basic research investigations of neurodegenerative disorders rely on histochemical staining procedures developed specifically to visualize abnormal protein conformation. In Alzheimer's disease (AD), two major pathological hallmarks are required to confirm the clinical diagnosis. Both consist of abnormally aggregated proteins that share the structural and histological properties common to all amyloid deposits. Amyloid-beta peptide (Abeta) of extracellular senile plaques (SP) and hyperphosphorylated tau of intracellular neurofibrillary tangles (NFT) are assembled in the abnormal beta-pleated sheet (amyloid-like) structural conformation that can be visualized with histological staining procedures using Congo red or its derivatives. These histochemical dyes bind amyloid with high affinity and allow easy detection of amyloid structure in postmortem brain samples. This chapter focuses on the development and application of a histological protocol using the compound X-34, a highly fluorescent derivative of Congo red, for sensitive detection of pathological amyloid structures in histopathological investigations of postmortem brain tissue. This procedure provides a simple and effective method for detailed fluorescent visualization of the localization and distribution of the majority of currently known major histopathological structures in AD, including compact cored, neuritic, and diffuse-appearing SP, NFT, dystrophic neurites, neuropil threads, and cerebrovascular amyloidosis.

Alkenes↗
PubMed2006

Positron emission tomography imaging of peripheral benzodiazepine receptor binding in human immunodeficiency virus-infected subjects with and without cognitive impairment.

The pathology associated with late-stage dementia in human immunodeficiency virus (HIV) infection has been studied extensively. Neuropathological examination has demonstrated abundant activation and infection of macrophages/microglia termed HIV encephalitis. For obvious reasons, less is known regarding the neuropathology of minor cognitive impairment seen in earlier stages of HIV infection. The authors examined the utility of the peripheral benzodiazepine receptor ligand PK11195 in positron emission tomography (PET) imaging to assess microglial/macrophage activation in the brains of HIV-infected subjects with minor neurocognitive impairment in a cross-sectional study of 12 HIV infected individuals and 5 age-matched noninfected controls. Subjects were given a battery of neuropsychological tests in addition to assessing CD4 T-cell count and peripheral viremia followed by contrast enhanced magnetic resonance imaging (MRI) and PET with [15O]H2O followed by [11C](R)-PK11195. Two of the six neurocognitively impaired HIV-infected subjects demonstrated plasma viral breakthrough, whereas only one of six nonimpaired individuals demonstrated plasma viral load near the limits of detection. MRI demonstrated no abnormal enhancement and although atrophy was more prominent in impaired subjects, it was also present though to a lesser extent in nonimpaired subjects. None of the 12 HIV-infected subjects demonstrated increased retention of [11C](R)-PK11195 in the brain parenchyma compared to the 5 controls. These results suggest that either [11C](R)-PK11195 PET assessment is insensitive to the degree of macrophage activation in HIV-associated minor neurocognitive impairment or macrophage activation is not the pathological substrate of this neurological condition.

AIDS Dementia Complex↗
PubMed2005

Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain.

During the development of in vivo amyloid imaging agents, an effort was made to use micro-positron emission tomography (PET) imaging in the presenilin-1 (PS1)/amyloid precursor protein (APP) transgenic mouse model of CNS amyloid deposition to screen new compounds and further study Pittsburgh Compound-B (PIB), a PET tracer that has been shown to be retained well in amyloid-containing areas of Alzheimer's disease (AD) brain. Unexpectedly, we saw no significant retention of PIB in this model even at 12 months of age when amyloid deposition in the PS1/APP mouse typically exceeds that seen in AD. This study describes a series of ex vivo and postmortem in vitro studies designed to explain this low retention. Ex vivo brain pharmacokinetic studies confirmed the low in vivo PIB retention observed in micro-PET experiments. In vitro binding studies showed that PS1/APP brain tissue contained less than one high-affinity (K(d) = 1-2 nm) PIB binding site per 1000 molecules of amyloid-beta (Abeta), whereas AD brain contained >500 PIB binding sites per 1000 molecules of Abeta. Synthetic Abeta closely resembled PS1/APP brain in having less than one high-affinity PIB binding site per 1000 molecules of Abeta, although the characteristics of the few high-affinity PIB binding sites found on synthetic Abeta were very similar to those found in AD brain. We hypothesize that differences in the time course of deposition or tissue factors present during deposition lead to differences in secondary structure between Abeta deposited in AD brain and either synthetic Abeta or Abeta deposited in PS1/APP brain.

Alzheimer Disease↗
PubMed2005

Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory.

Alzheimer's disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.

Adolescent↗
PubMed2005

Increased dopamine D2/D3 receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [11c]raclopride.

BACKGROUND: Several lines of evidence support the possibility that disturbances of dopamine (DA) function could contribute to alterations of weight, feeding, motor activity, and reward in anorexia nervosa (AN). METHODS: To assess possibly trait-related disturbances but avoid confounding effects of malnutrition, 10 women who were recovered from AN (REC AN) were compared with 12 healthy control women (CW). Positron emission tomography with [(11)C]raclopride was used to assess DA D2/D3 receptor binding. RESULTS: The women who were recovered from AN had significantly higher [(11)C]raclopride binding potential in the antero-ventral striatum than CW. For REC AN, [(11)C]raclopride binding potential was positively related to harm avoidance in the dorsal caudate and dorsal putamen. CONCLUSIONS: These data lend support for the possibility that decreased intrasynaptic DA concentration or increased D2/D3 receptor density or affinity is associated with AN and might contribute to the characteristic harm avoidance or increased physical activity found in AN. Most intriguing is the possibility that individuals with AN might have a DA related disturbance of reward mechanisms contributing to altered hedonics of feeding behavior and their ascetic, anhedonic temperament.

Adult↗
PubMed2005

Serotonin alterations in anorexia and bulimia nervosa: new insights from imaging studies.

Anorexia nervosa (AN) and bulimia nervosa (BN) are related disorders with relatively homogenous presentations such as age of onset and gender distribution. In addition, they share symptoms, such as extremes of food consumption, body image distortion, anxiety and obsessions, and ego-syntonic neglect, raises the possibility that these symptoms reflect disturbed brain function that contributes to the pathophysiology of this illness. Recent brain imaging studies have identified altered activity in frontal, cingulate, temporal, and parietal cortical regions in AN and BN. Importantly, such disturbances are present when subjects are ill and persist after recovery, suggesting that these may be traits that are independent of the state of the illness. Emerging data point to a dysregulation of serotonin pathways in cortical and limbic structures that may be related to anxiety, behavioral inhibition, and body image distortions. In specific, recent studies using PET with serotonin specific radioligands implicate alterations of 5-HT1A and 5-HT2A receptors and the 5-HT transporter. Alterations of these circuits may affect mood and impulse control as well as the motivating and hedonic aspects of feeding behavior. Such imaging studies may offer insights into new pharmacology and psychotherapy approaches.

Animals↗
PubMed2005

Cognitive correlates of alterations in acetylcholinesterase in Alzheimer's disease.

We recently reported findings of modest loss of cortical acetylcholinesterase (AChE) activity in patients with overall mild Alzheimer's disease (AD) using N-[11C]methyl-pi-peridin-4-yl propionate ([11C]PMP) AChE positron emission tomography (PET). To determine cognitive correlates of in vivo cortical AChE activity in patients with mild to moderate AD (n=15), and in normal controls (NC, n=12) using [11C]PMP AChE PET imaging. Mean cortical AChE activity in the AD subjects was mildly reduced (-11.1%) compared to the control subjects (P<0.05). Analysis of the cognitive data showed that mean cortical AChE activity was significantly associated with performance on a test of attention and working memory (WAIS-III Digit Span, R=0.46, P=0.01) but not with tests of delayed short or long-term memory functions. Similar findings were present when the analysis was limited to the temporal cortex. Cortical AChE activity is more robustly associated with functions of attention and working memory compared to performance on primary memory tests in AD.

Acetylcholinesterase↗
PubMed2005

Imaging technology for neurodegenerative diseases: progress toward detection of specific pathologies.

Advances in neuroimaging over the past 2 decades are products of breakthroughs in imaging technology, developments of more powerful computers and image-processing software, and expanding knowledge in basic and clinical neuroscience. In addition to the insights into normal brain structure and function that such methods provide and the information that can be gained from disease-related changes in structure and function, the promise of achieving diagnostic specificity through neuroimaging lies with the potential identification of pathognomonic proteins. Recent advances in imaging beta-amyloid plaques, one of the hallmarks of Alzheimer disease, offer such a technological breakthrough and the possibility for more efficient assessment of antiamyloid interventions as well as specific noninvasive diagnostic capabilities.

Amyloid↗
PubMed2005

Altered brain serotonin 5-HT1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [carbonyl11C]WAY-100635.

CONTEXT: Previous studies have shown that women with anorexia nervosa (AN), when ill and after recovery, have alterations of serotonin (5-HT) neuronal activity and core eating disorder symptoms, such as anxiety. OBJECTIVE: To further characterize the 5-HT system in AN, we investigated 5-HT1A receptor activity using positron emission tomography imaging because this receptor is implicated in anxiety and feeding behavior. DESIGN, SETTING, AND PARTICIPANTS: To avoid the confounding effects of malnutrition, we studied 13 women who had recovered from restricting-type AN (mean age, 23.3 +/- 5.2 years) and 12 women who had recovered from bulimia-type AN (mean age, 28.6 +/- 7.3 years) (>1 year normal weight, regular menstrual cycles, no bingeing or purging). These subjects were compared with 18 healthy control women (mean age, 25.1 +/- 5.8 years). Intervention The 5-HT1A receptor binding was measured using positron emission tomography imaging and a specific 5-HT1A receptor antagonist, [carbonyl-11C]WAY-100635. MAIN OUTCOME MEASURE: Specific 5-HT1A receptor binding was assessed using the binding potential measure. Binding potential values were derived using both the Logan graphical method and compartmental modeling. The binding potential in a region of interest was calculated with the formula: binding potential = distribution volume of the region of interest minus distribution volume of the cerebellum. RESULTS: Women recovered from bulimia-type AN had significantly (P<.05) increased [11C]WAY-100635 binding potential in cingulate, lateral and mesial temporal, lateral and medial orbital frontal, parietal, and prefrontal cortical regions and in the dorsal raphe compared with control women. No differences were found for women recovered from restricting-type AN relative to controls. For women recovered from restricting-type AN, the 5-HT1A postsynaptic receptor binding in mesial temporal and subgenual cingulate regions was positively correlated with harm avoidance. CONCLUSIONS: We observed increased 5-HT1A receptor binding in women who had recovered from bulimia-type AN but not restricting-type AN. However, 5-HT1A receptor binding was associated with a measure of anxiety in women recovered from restricting-type AN. These data add to a growing body of evidence showing that altered serotonergic function and anxiety symptoms persist after recovery from AN. These psychobiological alterations may be trait related and may contribute to the pathogenesis of AN.

Adult↗