No abstract

The motor manifestations of Parkinson's disease (PD) have been linked to an abnormal spatial covariance pattern involving basal ganglia thalamocortical pathways. By contrast, little is known about the functional networks that underlie cognitive dysfunction in this disorder. To identify such patterns, we studied 15 non-demented PD patients using FDG PET and a voxel-based network modeling approach. We detected a significant covariance pattern that correlated (p< 0.01) with performance on tests of memory and executive functioning. This PD-related cognitive pattern (PDCP) was characterized by metabolic reductions in frontal and parietal association areas and relative increases in the cerebellar vermis and dentate nuclei. To validate this pattern, we analyzed data from 32 subsequent PD patients of similar age, disease duration and severity. Prospective measurements of PDCP activity predicted memory performance (p<0.005), visuospatial function (p<0.01), and perceptual motor speed (p<0.005) in this validation sample. PDCP scores additionally exhibited an excellent degree of test-retest reliability (intraclass correlation coefficient, ICC=0.89) in patients undergoing repeat FDG PET at an 8-week interval. Unlike the PD-related motor pattern, PDCP expression was not significantly altered by antiparkinsonian treatment with either intravenous levodopa or deep brain stimulation (DBS). These findings substantiate the PDCP as a reproducible imaging marker of cognitive function in PD. Because PDCP expression is not altered by routine antiparkinsonian treatment, this measure of network activity may prove useful in clinical trials targeting the progression of non-motor manifestations of this disorder.

Parkinson's disease (PD) is associated with abnormal activity in spatially distributed neural systems mediating the motor and cognitive manifestations of this disorder. Metabolic PET studies have demonstrated that this illness is characterized by a set of reproducible functional brain networks that correlate with these clinical features. The time at which these abnormalities appear is unknown, as is their relationship to concurrent clinical and dopaminergic indices of disease progression. In this longitudinal study, 15 early stage PD patients (age 58.0 +/- 10.2 years; Hoehn and Yahr Stage 1.2 +/- 0.3) were enrolled within 2 years of diagnosis. The subjects underwent multitracer PET imaging at baseline, 24 and 48 months. At each timepoint they were scanned with [18F]-fluorodeoxyglucose (FDG) to assess longitudinal changes in regional glucose utilization and in the expression of the PD-related motor (PDRP) and cognitive metabolic covariance patterns (PDCP). At each timepoint the subjects also underwent PET imaging with [18F]-fluoropropyl betaCIT (FP-CIT) to quantify longitudinal changes in caudate and putamen dopamine transporter (DAT) binding. Regional metabolic changes across the three timepoints were localized using statistical parametric mapping (SPM). Longitudinal changes in regional metabolism and network activity, caudate/putamen DAT binding, and Unified Parkinson's Disease Rating Scale (UPDRS) motor ratings were assessed using repeated measures analysis of variance (RMANOVA). Relationships between these measures of disease progression were assessed by computing within-subject correlation coefficients. We found that disease progression was associated with increasing metabolism in the subthalamic nucleus (STN) and internal globus pallidus (GPi) (P < 0.001), as well as in the dorsal pons and primary motor cortex (P < 0.0001). Advancing disease was also associated with declining metabolism in the prefrontal and inferior parietal regions (P < 0.001). PDRP expression was elevated at baseline relative to healthy control subjects (P < 0.04), and increased progressively over time (P < 0.0001). PDCP activity also increased with time (P < 0.0001). However, these changes in network activity were slower than for the PDRP (P < 0.04), reaching abnormal levels only at the final timepoint. Changes in PDRP activity, but not PDCP activity, correlated with concurrent declines in striatal DAT binding (P < 0.01) and increases in motor ratings (P < 0.005). Significant within-subject correlations (P < 0.01) were also evident between the latter two progression indices. The early stages of PD are associated with progressive increases and decreases in regional metabolism at key nodes of the motor and cognitive networks that characterize the illness. Potential disease-modifying therapies may alter the time course of one or both of these abnormal networks.

Objective-To use 18 F-fluorodeoxyglucose (FDG) and PET to investigate changes in regional metabolism associated with mild cognitive impairment (MCI) in Parkinson disease (PD). Cognitive abnormalities are common in PD. However, little is known about the functional abnormalities that underlie the manifestations of MCI in this disorder.Methods-We used FDG PET to measure regional glucose metabolism in patients with PD with multiple-domain MCI (MD-MCI; n = 18), with single-domain MCI (SD-MCI; n = 15), and without MCI (N-MCI; n = 18). These patients were matched for age, education, disease duration, and motor disability. Maps of regional metabolism in the three groups were compared using statistical parametric mapping (SPM). We also computed the expression of a previously validated cognition-related spatial covariance pattern (PDCP) in the patient groups and in an age-matched healthy control cohort (n = 15). PDCP expression was compared across groups using analysis of variance.Results-SPM revealed decreased prefrontal and parietal metabolism (p < 0.001) in MD-MCI relative to N-MCI, as well as an increase in brainstem/cerebellar metabolism (p < 0.001) in this group. In these regions, SD-MCI occupied an intermediate position between the two other groups. PDCP expression was abnormally elevated in the N-, SD-, and MD-MCI groups (p < 0.05), increasing stepwise with worsening cognitive impairment (p < 0.01).Conclusions-Early cognitive decline in Parkinson disease as defined by mild cognitive impairment is associated with discrete regional changes and abnormal metabolic network activity. The quantification of these alterations with 18 F-fluorodeoxyglucose PET may allow for the objective assessment of the progression and treatment of this disease manifestation.Cognitive decline in Parkinson disease (PD) constitutes a well-defined behavioral syndrome characterized by difficulties in executive and visuospatial functions, as well as deficits in Copyright © 2008 The use of MCI criteria in patients already diagnosed with PD has been shown to have some prognostic value in that 64% of patients with MCI converted to dementia over a 4-year follow-up period as compared with only 20% of those without MCI. 5 Contrary to prodromal Alzheimer disease, PD patients with SD-MCI without memory impairment, as well as those with MD-MCI, appear more likely to progress to dementia. 3 However, the clinical characterization of MCI in PD has not been validated and the underlying pathology is not known.Metabolic imaging with 18 F-fluorodeoxyglucose (FDG) PET, an in vivo assay of synaptic activity in the brain, can potentially be used to identify regional changes in brain function that differentiate PD patients with and without cognitive dysfunction. The presence of specific metabolic abnormalities in patients with PD fulfilling diagnostic criteria for MCI can be used to validate this syndrome as a distinct diagnostic entity. Moreover, these scans can be used to quantify the activity of a distinct spatial covariance pattern associated with co...

IntroductionThe overexpression of human epidermal growth factor receptor (HER)-2 in 20% of human breast cancers and its association with aggressive growth has led to widespread use of HER2-targeted therapies, such as trastuzumab (T) and lapatinib (L). Despite the success of these drugs, their efficacy is limited in patients whose tumors demonstrate de novo or acquired resistance to treatment. The β1 integrin resides on the membrane of the breast cancer cell, activating several elements of breast tumor progression including proliferation and survival.MethodsWe developed a panel of HER2-overexpressing cell lines resistant to L, T, and the potent LT combination through long-term exposure and validated these models in 3D culture. Parental and L/T/LT-resistant cells were subject to HER2 and β1 integrin inhibitors in 3D and monitored for 12 days, followed by quantification of colony number. Parallel experiments were conducted where cells were either stained for Ki-67 and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or harvested for protein and analyzed by immunoblot. Results were subjected to statistical testing using analysis of variance and linear contrasts, followed by adjustment with the Sidak method.ResultsUsing multiple cell lines including BT474 and HCC1954, we reveal that in L and LT resistance, where phosphorylation of EGFR/HER1, HER2, and HER3 are strongly inhibited, kinases downstream of β1 integrin--including focal adhesion kinase (FAK) and Src--are up-regulated. Blockade of β1 by the antibody AIIB2 abrogates this up-regulation and functionally achieves significant growth inhibition of L and LT resistant cells in 3D, without dramatically affecting the parental cells. SiRNA against β1 as well as pharmacologic inhibition of FAK achieve the same growth inhibitory effect. In contrast, trastuzumab-resistant cells, which retain high levels of phosphorylated EGFR/HER1, HER2, and HER3, are only modestly growth-inhibited by AIIB2.ConclusionsOur data suggest that HER2 activity, which is suppressed in resistance involving L but not T alone, dictates whether β1 mediates an alternative pathway driving resistance. Our findings justify clinical studies investigating the inhibition of β1 or its downstream signaling moieties as strategies to overcome acquired L and LT resistance.

Background: Mild cognitive impairment (MCI) was recently described as a heterogeneous group with a variety of clinical outcomes and high risk to develop Alzheimer's disease (AD). Regional cerebral blood flow (rCBF) as measured by single photon emission computed tomography (SPECT) was used to study the heterogeneity of MCI and to look for predictors of future development of AD.

Aim: We sought to identify markers of motor and nonmotor function in Parkinson's disease (PD) using advanced neuroimaging techniques in subjects with PD. Methods: We enrolled 26 nondemented PD subjects and 12 control subjects. All subjects underwent [¹⁸F]fluorodeoxyglucose positron emission computed tomography (FDG-PET) and magnetic resonance imaging, and a complete neuropsychological battery. Results: FDG-PET of subjects with PD revealed significant metabolic elevations in the bilateral posterior lentiform nucleus, posterior cingulate, and parahippocampus, and metabolic reductions in the bilateral temporoparietal association cortex and occipital lobe versus controls. PD subjects had significant reductions in executive/attention function, memory/verbal learning, and speed of thinking, and significantly increased depression, anxiety and apathy scores compared with controls. Motor dysfunction correlated with increased metabolism in the posterior lentiform nucleus, pons, and cerebellum, and decreased metabolism in the temporoparietal lobe. Cognitive dysfunction correlated with increased posterior cingulate metabolism and decreased temporoparietal lobe metabolism. Depressive symptoms correlated with increased amygdala metabolism; anxiety scores correlated with decreased caudate metabolism, and apathy scores correlated with increased metabolism in the anterior cingulate and orbitofrontal lobe and decreased metabolism in the temporoparietal association cortex. Conclusions: Our findings showed that motor, cognitive, and emotional dysfunction in PD are associated with distinct patterns of cerebral metabolic changes.

Motor sequence learning is abnormal in presymptomatic Huntington's disease (p-HD). The neural substrates underlying this early manifestation of HD are poorly understood. To study the mechanism of this cognitive abnormality in p-HD, we used positron emission tomography to record brain activity during motor sequence learning in these subjects. Eleven p-HD subjects (age, 45.8 ± 11.0 years; CAG repeat length, 41.6 ± 1.8) and 11 age-matched control subjects (age, 45.3 ± 13.4 years) underwent H 2 15 O positron emission tomography while performing a set of kinematically controlled motor sequence learning and execution tasks. Differences in regional brain activation responses between groups and conditions were assessed. In addition, we identified discrete regions in which learning-related activity correlated with performance. We found that sequence learning was impaired in p-HD subjects despite normal motor performance. In p-HD, activation responses during learning were abnormally increased in the left mediodorsal thalamus and orbitofrontal cortex (OFC; BA 11/47). Impaired learning performance in these subjects was associated with increased activation responses in the precuneus (BA 18/31). These data suggest that enhanced activation of thalamocortical pathways during motor learning can compensate for caudate degeneration in p-HD. Nonetheless, this mechanism may not be sufficient to sustain a normal level of task performance, even during the presymptomatic stage of the disease.A clinical triad of movement, behavioral, and cognitive disorders characterizes Huntington's disease (HD). 1-3 However, the neurodegenerative changes of HD precede the onset of clinical signs and may be associated with subclinical alterations in brain physiology. For example, careful neuropsychological testing can detect abnormalities in presymptomatic carriers of the HD gene mutation (p-HD). 4-7 In this study, we applied functional imaging methods with atrophy correction to elucidate the mechanisms that may underlie preclinical cognitive changes in HD gene carriers. In earlier imaging studies conducted in the resting state, we used a network approach to demonstrate that HD is associated with an abnormal spatial covariance pattern in both presymptomatic and symptomatic phases of disease. 8,9 This reproducible regional topography is characterized by caudate/putamen and temporal hypometabolism associated with occipital hypermetabolism. Other investigators have found widespread cortical involvement in the early stages of symptomatic HD, in addition to the well-known subcortical features of the disease. 10-12 Given metabolic abnormalities in brain regions subserving both motor and cognitive functions, we now sought to determine whether p-HD subjects acquire sequential information abnormally. We also sought to understand whether p-HD subjects use the same brain regions as control subjects while performing motor learning tasks, and if not, how the early preclinical pathology of HD alters the neural circuitry of learning-related pathways. Subjects...