Verbal memory declines more in female patients with Parkinson's disease: the importance of gender-corrected normative data.

BACKGROUND: Data on gender-specific profiles of cognitive functions in patients with Parkinson's disease (PD) are rare and inconsistent, and possible disease-confounding factors have been insufficiently considered. METHOD: The LANDSCAPE study on cognition in PD enrolled 656 PD patients (267 without cognitive impairment, 66% male; 292 with mild cognitive impairment, 69% male; 97 with PD dementia, 69% male). Raw values and age-, education-, and gender-corrected Z scores of a neuropsychological test battery (CERAD-Plus) were compared between genders. Motor symptoms, disease duration, l-dopa equivalent daily dose, depression - and additionally age and education for the raw value analysis - were taken as covariates. RESULTS: Raw-score analysis replicated results of previous studies in that female PD patients were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.03), while men outperformed women in visuoconstruction (p = 0.002) and figural memory (p = 0.005). In contrast, gender-corrected Z scores showed that men were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.02; recognition, p = 0.04), while no difference was found for visuospatial tests. This picture could be observed both in the overall analysis of PD patients as well as in a differentiated group analysis. CONCLUSIONS: Normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is stronger in women than in men with PD. Future studies are needed to replicate these findings, examine the progression of gender-specific cognitive decline in PD and define different underlying mechanisms of this dysfunction.

White matter damage is related to ataxia severity in SCA3.

Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms.

The tremor network targeted by successful VIM deep brain stimulation in humans.

OBJECTIVE: Deep brain stimulation (DBS) of the ventral intermediate nucleus of thalamus (VIM) is a treatment option in medically intractable tremor, such as essential tremor or tremor-dominant Parkinson disease (PD). Although functional studies demonstrated modulation of remote regions, the structural network supporting this is as yet unknown. In this observational study, we analyzed the network mediating clinical tremor modulation. METHODS: We studied 12 patients undergoing VIM stimulation for debilitating tremor. We initiated noninvasive diffusion tractography from tremor-suppressive VIM electrode contacts. Moreover, we tested for the contribution of primary motor projections in this structural correlate of a functional tremor network, comparing the connectivity of effective DBS contacts with those of adjacent, but clinically ineffective, stimulation sites. RESULTS: VIM stimulation resulted in decrease of tremor and improvement in quality of life. Tractography initiated from the effective stimulation site reconstructed a highly reproducible network of structural connectivity comprising motor cortical, subcortical, and cerebellar sites and the brainstem, forming the anatomic basis for remote effects of VIM stimulation. This network is congruent with functional imaging studies in humans and with thalamic projections found in the animal literature. Connectivity to the primary motor cortex seemed to play a key role in successful stimulation. CONCLUSIONS: Patients undergoing DBS provide a unique opportunity to assess an electrophysiologically defined seed region in human thalamus, a technique that is usually restricted to animal research. In the future, preoperative tractography could aid with stereotactic planning of individual subcortical target points for stimulation in tremor and in other disease entities.

Arm swing asymmetry in Parkinson's disease measured with ultrasound based motion analysis during treadmill gait.

The reduction of arm swing during gait is a frequent phenomenon in patients with early Parkinson's disease (PD). However, the objective quantification of this clinical sign using treadmill-based gait analysis has not been systematically evaluated so far. We simultaneously measured ultrasound based limb kinematics and spatiotemporal gait parameters during treadmill walking at different speeds in 21 early PD patients in Hoehn and Yahr (HY) stage I, 19 patients with bilateral PD in HY stage II and 25 age-matched controls. Both PD groups showed a highly significant reduction of the arm swing amplitude on the more affected body side (MAS). Decomposing total arm swing resulted in a bilateral decrease of arm retroversion in both PD groups, whereas anteversion was normal on the less affected side of the HY I cohort. Early stage patients exhibited a highly significant, almost threefold increase of the arm swing asymmetry index (I(A)) compared with controls. Reduced retroversion on the MAS and increased arm swing I(A) were the independent variables with the closest association to disease status in a multivariate logistic regression analysis. We conclude that ultrasound based motion analysis during treadmill walking allows reliable investigation of asymmetric arm movements in early PD patients which attenuate with ongoing disease. Impaired active arm retroversion seems to be the earliest sign of upper extremity dysfunction in parkinsonian gait. The measurement of limb kinematics during treadmill gait can broaden our methodological line-up for the analysis of complex motor programs in movement disorders.

[Innovative MRI techniques in Parkinson's disease]. / Innovative MRT-Verfahren bei idiopathischem Parkinson-Syndrom.

Brain imaging enables the investigation of brain morphology and function in patients with Parkinson's disease (PD). Innovative magnetic resonance imaging (MRI) techniques have recently been established as a new research tool in PD. They are based on the investigation of neuronal tissue properties (MR relaxometry, SWI, DWI, DTI, VBM) and of cerebral perfusion and neuronal activity (ASL, fcMRI). Besides a better understanding of the pathophysiology of PD, these innovative MR techniques might be suitable for measuring progression of PD and the effect of therapeutic interventions on brain functioning. In the clinical setting, they could help to advance the differential diagnosis of parkinsonian disorders.

Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo.

OBJECTIVE: Although Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) show a wide clinical and neuropathologic overlap, they are differentiated according to the order and latency of cognitive and motor symptom appearance. Whether both are distinct disease entities is an ongoing controversy. Therefore, we directly compared patients with DLB and PDD with multitracer PET. METHODS: PET with (18)fluorodopa (FDOPA), N-(11)C-methyl-4-piperidyl acetate (MP4A), and (18)fluorodeoxyglucose (FDG) was performed in 8 patients with PDD, 6 patients with DLB, and 9 patients with PD without dementia vs age-matched controls. Data were analyzed with voxel-based statistical parametric mapping and region of interest-based statistics. RESULTS: We found a reduced FDOPA uptake in the striatum and in limbic and associative prefrontal areas in all patient groups. Patients with PDD and patients with DLB showed a severe MP4A and FDG binding reduction in the neocortex with increasing signal diminution from frontal to occipital regions. Significant differences between PDD and DLB were not found in any of the radioligands used. Patients with PD without dementia had a mild cholinergic deficit and no FDG reductions vs controls. CONCLUSIONS: Patients with dementia with Lewy bodies and Parkinson disease dementia share the same dopaminergic and cholinergic deficit profile in the brain and seem to represent 2 sides of the same coin in a continuum of Lewy body diseases. Cholinergic deficits seem to be crucial for the development of dementia in addition to motor symptoms. The spatial congruence of cholinergic deficits and energy hypometabolism argues for cortical deafferentation due to the degeneration of projection fibers from the basal forebrain.

Frontal FDG-PET activity correlates with cognitive outcome after STN-DBS in Parkinson disease.

BACKGROUND: Inconsistent changes of cognitive functioning have been reported in patients with Parkinson disease (PD) with deep brain stimulation (DBS) of the subthalamic nucleus (STN). To investigate the underlying pathomechanisms, we correlated alterations of cognitive test performance and changes of neuronal energy metabolism in frontal basal ganglia projection areas under bilateral STN stimulation. METHODS: We conducted verbal fluency, learning, and memory tests and 18-fluorodeoxyglucose (FDG) PET in nine patients with PD with STN-DBS before and 6 months after surgery. Using coregistered MRI, postoperative changes of the normalized cerebral metabolic rates of glucose (nCMRGlc) in the dorsolateral prefrontal cortex (DLPFC), lateral orbitofrontal cortex (LOFC), ventral and dorsal cingulum (v/dACC), and in Broca area were determined and correlated with alterations of neuropsychological test results. RESULTS: After surgery, highly variable changes of both cognitive test performance and frontal nCMRGlc values were found with significant correlations between verbal fluency and FDG uptake in the left DLPFC (Brodmann area [BA] 9, 46), left Broca area (BA 44/45), and the right dACC (BA 32). A decrease of nCMRGlc in the left OFC (BA 11/47) and dACC (BA 32) correlated with a decline of verbal learning. All patients showed reduced metabolic activity in the right anterior cingulate cortex after DBS. Baseline cognitive abilities did not predict verbal learning or fluency changes after surgery. CONCLUSIONS: These data show a significant linear relationship between changes in frontal 18-fluorodeoxyglucose PET activity and changes in cognitive outcome after deep brain stimulation of the subthalamic nucleus (STN) in advanced Parkinson disease. The best correlations were found in the left frontal lobe (dorsolateral prefrontal cortex and Broca area). Baseline performance on cognitive tests did not predict cognitive or metabolic changes after STN electrode implantation.

Neural traffic as voxel-based measure of cerebral functional connectivity in fMRI.

To access functional connectivity by in vivo brain imaging voxel-by-voxel, we developed a novel approach named neural traffic (NT). NT depicts the intensity of functional connectivity on a voxel-by-voxel basis in the whole brain. Functional magnetic resonance imaging (fMRI) experiments were carried out on eight individuals during either hearing or viewing words. The blood oxygen level dependant (BOLD) signal was taken as measure of neural activity. For each voxel, functional connectivity with all other brain voxels was determined by calculating Pearson correlation coefficients at two connectivity thresholds (r=0.35 and 0.65). Then, NT images were derived by counting the number of suprathreshold connections for each individual voxel. Calculations based on random networks indicate that statistically reliable NT images can be derived in individuals. With regard to group analysis, at r=0.35 NT images are similar though not identical with the first component of principal component analysis (PCA), displaying a widespread but not ubiquitous pattern of functionally connected cortical areas. At r=0.65, NT group images display functional connectivity confined to circumscribed cortical regions which reach beyond the corresponding primary sensory areas, their known associated areas and the default network. In conclusion, NT goes beyond the approach of correlating the BOLD signal with the external stimulus-presentation time course by computing linear functional connectivity between all brain voxels based on any BOLD time course. First results demonstrate that the NT approach is likely - on an individual base - to reveal novel cortical and subcortical connectivities involved in stimulus processing.

STN-DBS activates the target area in Parkinson disease: an FDG-PET study.

OBJECTIVE: The immediate effects of deep brain stimulation (DBS) on subcortical neurons of its target region are controversial. METHODS: We measured the regional normalized resting cerebral metabolic rate of glucose (nCMRGlc) with 18-fluorodeoxyglucose (FDG) and PET in 12 patients with Parkinson disease (PD) and bilateral DBS of the subthalamic nucleus (STN) compared to 10 age-matched controls. PET was performed before surgery and 6 months after electrode implantation in DBS off- and on-conditions. Stereotactic coordinates of active STN electrode poles were determined with intraoperative skull x-ray and transferred to preoperative MR images. Subsequently, volumes of interest (VOIs) were placed around active electrode contacts, in the STN and in the globus pallidus. DBS induced changes of nCMRGlc values were determined in each VOI after PET and MRI coregistration. RESULTS: Electrode placement without stimulation led to significant FDG uptake reduction in the electrode region and in the STN (microlesional effect). Under active DBS, the local nCMRGlc significantly increased in all VOIs under investigation. CONCLUSIONS: The data demonstrate that deep brain stimulation (DBS) induced metabolic activation of the subthalamic region and the directly connected globus pallidus which is in line with local and remote excitation of neurons by high frequency stimulation. These PET findings most likely reflect tonic driving of the DBS target area and its projection sites via ortho- and antidromic fiber conduction. We conclude that subthalamic nucleus DBS has predominant excitatory properties and does, therefore, fundamentally differ from lesional neurosurgery.

Introduction of helical computed tomography affects patient selection for V/Q lung scan.

AIM: Retrospective analysis for determination of the effect of helical computed tomography (HCT) on utilization of V/Q lung scanning to diagnose pulmonary embolism (PE) in a large general hospital. METHODS: A total number of 2676 V/Q scans of in- and out-patients referred to our department between March 1992 and December 1998 and between April 1997 and December 1998 were analyzed by an identical group of nuclear physicians. RESULTS: Neither the total number of annually performed V/Q scans (446 +/- 135) nor the mean age of patients (56 years +/- 17) changed significantly since the introduction of HCT. However, the referral pattern was different. The percentage of patients with high and intermediate probability for PE decreased significantly from 15.2% to 9.4% (p < 0.01) and from 10.2% to 7.3% (p < 0.05), respectively. Low probability scans significantly increased from 37.8% to 42.7% (p < 0.05). The percentage of normal scans did not change significantly, however, there was a highly significant increase summarizing patients with normal and low probability scans (74.6% to 83.3%; p < 0.01). CONCLUSION: The introduction of HCT affected the selection of patients referred for V/Q lung scanning since V/Q scanning was primarily used to exclude rather to confirm PE.