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Biomedical subjects

W Jagust

Publications and source records attributed to W Jagust.

14 recordsLinked to original sources
PubMed2004

Memory impairment, but not cerebrovascular disease, predicts progression of MCI to dementia.

BACKGROUND: Mild cognitive impairment (MCI) is widely viewed as the transition phase between normal aging and Alzheimer disease (AD). Given that MCI can also result from cerebrovascular disease (CVD), the authors used clinical, MRI, and cognitive measures of AD and CVD to test the hypothesis that CVD increases the likelihood of progression from MCI to dementia within 3 years. OBJECTIVE: To examine the impact of CVD on progression of MCI to dementia. METHODS: Fifty-two consecutive patients with MCI (71% men) including many with symptomatic CVD were longitudinally evaluated for 3.1 +/- 1.3 years. MCI was defined as a Clinical Dementia Rating Scale (CDR) score of 0.5. Dementia was defined as progression to a CDR score of > or =1.0. RESULTS: Forty-four percent of the MCI patients had MRI infarcts, 50% of which were symptomatic. Thirty-three percent of patients progressed to dementia, and 37.8% of these had MRI infarcts. Clinically probable or possible AD was diagnosed in approximately 82% of converters. Of the clinical and MRI measures, only hippocampal volume was associated with increased risk to progression (hazard ratio [HR] = 0.31 [95% CI 0.1 to 0.92], p = 0.03). When neuropsychological measures were included in the analysis, memory (HR = 0.90 [95% CI 0.84 to 0.96], p = 0.002) and executive function (HR = 0.96 [95% CI 0.92 to 1.0], p = 0.045) were associated with increased risk of dementia progression, whereas APOE genotype, cerebrovascular risk factors, clinical stroke, presence or absence of lacunes, and extent of white matter hyperintensities did not predict progression. CONCLUSION: Within a heterogenous group of MCI patients, including many with clinically significant CVD, baseline memory and executive performance significantly predicted likelihood to develop dementia.

Aged↗
PubMed2002

Utility of clinical criteria in differentiating frontotemporal lobar degeneration (FTLD) from AD.

OBJECTIVE: To assess the ability of the current diagnostic criteria for frontotemporal lobar degeneration (FTLD) to differentiate FTLD from AD. METHODS: Thirty cases with autopsy-proven FTLD and 30 cases of AD, matched for Mini-Mental State Examination score, were identified from the clinical databases of three dementia subspecialty centers, and their charts were reviewed for the presence of clinical features described in the current criteria for FTLD. The proportion of patients with each clinical feature at the first clinical presentation was compared across groups. RESULTS: A significantly larger proportion of patients with FTLD showed behavioral abnormalities, particularly social and personal conduct disorders and emotional blunting, than patients with AD. Few differences in language features were seen between the groups, and many of the language features detailed in the criteria were found in only a small proportion of patients. In both groups, many patients showed neuropsychological abnormalities, except for perceptual difficulties, which were present in many patients with AD but only in a few patients with FTLD. Extrapyramidal motor symptoms were more likely to be present in FTLD. Logistic regression revealed that five features-social conduct disorders, hyperorality, akinesia, absence of amnesia, and the absence of a perceptual disorder-correctly classified 93% of patients with FTLD and 97% of patients with AD. CONCLUSION: A combination of behavioral, neuropsychological, and physical findings is most useful in distinguishing FTLD from AD. Future studies should be directed at establishing more objective methods of identifying these clinical features.

Aged↗
PubMed2002

Selective reduction of N-acetylaspartate in medial temporal and parietal lobes in AD.

BACKGROUND: Both AD and normal aging cause brain atrophy, limiting the ability of MRI to distinguish between AD and age-related brain tissue loss. MRS imaging (MRSI) measures the neuronal marker N-acetylaspartate (NAA), which could help assess brain change in AD and aging. OBJECTIVES: To determine the effects of AD on concentrations of NAA, and choline- and creatine-containing compounds in different brain regions and to assess the extent NAA in combination with volume measurements by MRI improves discrimination between AD patients and cognitively normal subjects. METHODS: Fifty-six patients with AD (mean age: 75.6 +/- 8.0 years) and 54 cognitively normal subjects (mean age: 74.3 +/- 8.1 years) were studied using MRSI and MRI. RESULTS: NAA concentration was less in patients with AD compared with healthy subjects by 21% (p < 0.0001) in the medial temporal lobe and by 13% to 18% (p < 0.003) in parietal lobe gray matter (GM), but was not changed significantly in white matter and frontal lobe GM. In addition to lower NAA, AD patients had 29% smaller hippocampi and 11% less cortical GM than healthy subjects. Classification of AD and healthy subjects increased significantly from 89% accuracy using hippocampal volume alone to 95% accuracy using hippocampal volume and NAA together. CONCLUSION: In addition to brain atrophy, NAA reductions occur in regions that are predominantly impacted by AD pathology.

Aged↗
PubMed2002

A videotaped CIBIC for dementia patients: validity and reliability in a simulated clinical trial.

BACKGROUND: The global impression of a clinician is an Food and Drug Administration--mandated primary outcome measure for clinical trials in dementia. Reliability and validity of these measures are not well established. METHODS: A videotaped version of the Clinician's Interview Based Impression of Change (CIBIC) was evaluated. Raters were informed that the videotaped interviews were taken at baseline and 6 to 12 months later, when in fact half of the interviews were shown in reverse order. Ratings on "true order" interviews were compared with ratings on "reverse order" interviews. In addition, ratings by neurologists experienced in dementia were compared with those of less experienced raters. RESULTS: Inter-rater reliability of the neurologists was poor when measured by absolute agreement on a 7-point scale (kappa = 0.18). With a less stringent 3-point scale (better, worse, or unchanged), inter-rater reliability was significantly better for the true order videos (kappa = 0.51) than for the reversed order videos (kappa = 0.12). Validity also was reduced in the reverse order group: neurologists rated 90% of subjects correctly in the "true order" group and 63% correctly in the "reversed order" group. The inter-rater reliability of the neurologists was greater than the less experienced raters, but the validity of the neurologists' ratings was only marginally better. CONCLUSIONS: The reliability and validity of the videotape CIBIC are reasonable when patients follow the expected course of gradual decline, but are poor when patients appear to improve. These findings suggest that global assessments should be modified as outcome measures in clinical trials with patients with dementia.

Aged↗
PubMed2001

SPECT perfusion imaging in the diagnosis of Alzheimer's disease: a clinical-pathologic study.

OBJECTIVE: Numerous studies have suggested that temporoparietal hypoperfusion seen on brain imaging with SPECT may be useful in diagnosing AD during life. However, these studies have often been limited by lack of pathologic validation and unrepresentative samples. The authors performed this study to determine whether SPECT imaging provides diagnostically useful information in addition to that obtained from a clinical examination. METHODS: Clinical data and SPECT images were collected prospectively, and patients were followed to autopsy. Clinical history, pathologic findings, and SPECT images were each evaluated by raters blind to other features, and clinical and SPECT diagnoses were compared with pathologic diagnoses. The study population consisted of 70 patients with dementia, followed to autopsy; 14 controls followed to autopsy; and 71 controls (no autopsy performed). The primary outcome was the likelihood of a pathologic diagnosis of AD given a positive clinical diagnosis, a positive SPECT diagnosis, and both. RESULTS: When all participants (patients and controls) were included in the analysis, the clinical diagnosis of "probable" AD was associated with an 84% likelihood of pathologic AD. A positive SPECT scan raised the likelihood of AD to 92%, whereas a negative SPECT scan lowered the likelihood to 70%. SPECT was more useful when the clinical diagnosis was "possible" AD, with the likelihood of 67% without SPECT, 84% with a positive SPECT, and 52% with a negative SPECT. Similar results were found when only patients with dementia were included in the analysis. CONCLUSIONS: In the evaluation of dementia, SPECT imaging can provide clinically useful information indicating the presence of AD in addition to the information that is obtained from clinical evaluation.

Aged↗
PubMed2000

Method to correlate 1H MRSI and 18FDG-PET.

The in vivo neuronal contribution to human cerebral metabolic rate of glucose (CMRglc), measured by 18FDG-PET, is unknown. Examining the effect of 1H MRSI-derived N-acetyl aspartate (NAA) concentration on positron emission tomography (PET) measures of metabolic activity might indicate the relationship of CMRglc to neuron density. In a population of 19 demented, cognitively impaired, and control subjects, the Miller-Gartner algorithm was applied to whole-brain PET data to isolate the PET signal originating in cortical gray matter alone (GMPET). An analogous procedure applied to multislice proton MRSI data yielded the N-acetyl aspartate concentration in cortical gray matter (GMNAA). In 18 of 19 subjects, a significant linear regression (P < 0.05) resulted when GMPET was plotted against GMNAA, whereby GMPET was higher for higher GMNAA. This suggests that CMRglc rises linearly with increasing neuron density in gray matter. This method may be used to investigate the relationship of CMRglc to neurons in various conditions.

Aged↗
PubMed2000

Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach.

Using an approach that combines gene therapy with aromatic l-amino acid decarboxylase (AADC) gene and a pro-drug (l-dopa), dopamine, the neurotransmitter involved in Parkinson's disease, can be synthesized and regulated. Striatal neurons infected with the AADC gene by an adeno-associated viral vector can convert peripheral l-dopa to dopamine and may therefore provide a buffer for unmetabolized l-dopa. This approach to treating Parkinson's disease may reduce the need for l-dopa/carbidopa, thus providing a better clinical response with fewer side effects. In addition, the imbalance in dopamine production between the nigrostriatal and mesolimbic dopaminergic systems can be corrected by using AADC gene delivery to the striatum. We have also demonstrated that a fundamental obstacle in the gene therapy approach to the central nervous system, i.e., the ability to deliver viral vectors in sufficient quantities to the whole brain, can be overcome by using convection-enhanced delivery. Finally, this study demonstrates that positron emission tomography and the AADC tracer, 6-[(18)F]fluoro-l-m-tyrosine, can be used to monitor gene therapy in vivo. Our therapeutic approach has the potential to restore dopamine production, even late in the disease process, at levels that can be maintained during continued nigrostriatal degeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

Subcortical ischemic vascular dementia: assessment with quantitative MR imaging and 1H MR spectroscopy.

BACKGROUND AND PURPOSE: Subcortical ischemic vascular dementia is associated with cortical hypometabolism and hypoperfusion, and this reduced cortical metabolism or blood flow can be detected with functional imaging such as positron emission tomography. The aim of this study was to characterize, by means of MR imaging and 1H MR spectroscopy, the structural and metabolic brain changes that occur among patients with subcortical ischemic vascular dementia compared with those of elderly control volunteers and patients with Alzheimer's disease. METHODS: Patients with dementia and lacunes (n = 11), cognitive impairment and lacunes (n = 14), and dementia without lacunes (n = 18) and healthy age-matched control volunteers (n = 20) underwent MR imaging and 1H MR spectroscopy. 1H MR spectroscopy data were coanalyzed with coregistered segmented MR images to account for atrophy and tissue composition. RESULTS: Compared with healthy control volunteers, patients with dementia and lacunes had 11.74% lower N-acetylaspartate/creatine ratios (NAA/Cr) (P = .007) and 10.25% lower N-acetylaspartate measurements (NAA) in the cerebral cortex (P = .03). In white matter, patients with dementia and lacunes showed a 10.56% NAA/Cr reduction (P = .01) and a 12.64% NAA reduction (P = .04) compared with control subjects. NAA in the frontal cortex was negatively correlated with the volume of white matter signal hyperintensity among patients with cognitive impairment and lacunes (P = .002). Patients with dementia, but not patients with dementia and lacunes, showed a 10.33% NAA/Cr decrease (P = .02) in the hippocampus compared with healthy control volunteers. CONCLUSION: Patients with dementia and lacunes have reduced NAA and NAA/Cr in both cortical and white matter regions. Cortical changes may result from cortical ischemia/infarction, retrograde or trans-synaptic injury (or both) secondary to subcortical neuronal loss, or concurrent Alzheimer's pathologic abnormalities. Cortical derangement may contribute to dementia among patients with subcortical infarction.

Aged↗
PubMed1999

Role of positron emission tomography in determining the extent of CNS ischemia in patients with sickle cell disease.

Nearly 25% of patients with sickle cell disease (SCD) experience central nervous system morbidity involving both large and small vessel disease. Optimal imaging methods for determining the extent of ischemia are not known. Positron emission tomography (PET) has the unique ability to show tissue function as well as structure. Reports concerning patients with non-SCD neurodegenerative disorders suggest PET may be useful in determining prognosis. We compared magnetic resonance imaging, magnetic resonance angiography, and neuropsychological testing with PET prospectively. Six patients with SCD and a history of stroke, aged 10 to 28, were enrolled. PET studies were performed on an ECAT HR 47 scanner (Siemens/CTI, Knoxville, TN) using 18-F-fluorodeoxyglucose as a tracer. PET interpretations were conducted in blinded fashion. MRI studies found two patients with only small vessel disease and four with both large and small vessel disease. In two of four subjects with large vessel disease, PET showed a corresponding metabolic abnormality and also identified an area of hypometabolism extending beyond the anatomical lesion as shown by MRI. PET did not demonstrate an abnormality corresponding with small vessel disease. Detailed neuropsychological testing demonstrated cognitive dysfunction in all cases. For some patients, PET may add sensitivity in detecting impaired metabolism in the area surrounding a major vessel infarct. However, the technique does not appear to be generally useful in characterizing small watershed or deep white matter infarcts. Larger studies, to include control subjects and carefully selected untransfused SCD patients, are needed. A combination of conventional imaging and neuropsychological testing remains the preferred evaluation for most SCD patients with neurologic symptoms.

Adolescent↗
PubMed1997

Changes of hippocampal N-acetyl aspartate and volume in Alzheimer's disease. A proton MR spectroscopic imaging and MRI study.

Hippocampal atrophy detected by MRI is a prominent feature of early Alzheimer's disease (AD), but it is likely that MRI underestimates the degree of hippocampal neuron loss, because reactive gliosis attenuates atrophy. We tested the hypothesis that hippocampal N-acetyl aspartate (NAA: a neuronal marker) and volume used together provide greater discrimination between AD and normal elderly than does either measure alone. We used proton MR spectroscopic imaging (1H MRSI) and tissue segmented and volumetric MR images to measure atrophy-corrected hippocampal NAA and volumes in 12 AD patients (mild to moderate severity) and 17 control subjects of comparable age. In AD, atrophy-corrected NAA from the hippocampal region was reduced by 15.5% on the right and 16.2% on the left (both p < 0.003), and hippocampal volumes were smaller by 20.1% (p < 0.003) on the right and 21.8% (p < 0.001) on the left when compared with control subjects. The NAA reductions and volume losses made independent contributions to the discrimination of AD patients from control subjects. When used separately, neither hippocampal NAA nor volume achieved to classify correctly AD patients better than 80%. When used together, however, the two measures correctly classified 90% of AD patients and 94% of control subjects. In conclusion, hippocampal NAA measured by 1H MRSI combined with quantitative measurements of hippocampal atrophy by MRI may improve diagnosis of AD.

Aged↗
PubMed1996

Temporal lobe metabolic differences in medication-free outpatients with schizophrenia via the PET-600.

Regional cerebral glucose metabolic rates (rCMRglc) were compared in 18 unmedicated outpatients with schizophrenia and 11 normal controls using high resolution positron emission tomography (PET) and the tracer [F-18]-2-fluoro-2D-deoxyglucose (FDG). From previous work we expected to see abnormal hippocampal rCMRglc in the patients, but no striatal abnormalities. Trial-by-trial Stroop cognitive task, which has been shown to activate the anterior cingulate, was performed within a day of the PET study. As our patients performed abnormally on the Stroop we tested for a correlation between the anterior cingulate rCMRglc and Stroop performance. We found no whole slice cortical average glucose metabolic abnormalities. As, predicted we found abnormally decreased left hippocampal rCMRglc in the patients. No striatal or cingulate rCMRglc abnormalities were noted in patients, but they demonstrated a highly positive correlation between anterior and cingulate rCMRglc and Stroop facilitation. Patients with higher Stroop interference had more prominent hippocampal metabolic decreases. These localized temporal lobe abnormalities could account for some of the patient's positive symptoms and are consistent with recent findings in the literature.

Adult↗
PubMed1992

Criteria for the diagnosis of ischemic vascular dementia proposed by the State of California Alzheimer's Disease Diagnostic and Treatment Centers.

Accurate diagnosis of vascular dementia is important for the recognition of underlying pathophysiology and the institution of appropriate therapy. It is also important for the determination of the incidence and prevalence of not only vascular dementia but also Alzheimer's disease (AD), since differentiating between these two entities is often problematic. The State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) herein propose criteria for the diagnosis of ischemic vascular dementia (IVD). These criteria broaden the conceptualization of vascular dementia, include the results of neuroimaging studies, emphasize the importance of neuropathologic confirmation, refine nosology, and identify areas that require further research. Parallel use of the proposed definitions of "possible" and "mixed" categories in the diagnosis of both AD and IVD would ensure compatibility between the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria for AD and the ADDTC criteria for IVD. Uniform classification of subtypes of IVD will improve the generalizability of individual studies and aid in multicenter collaborations.

Brain Ischemia↗