The relative and interactive impact of multiple risk factors in schizophrenia spectrum disorders: a combined register-based and clinical twin study.

BACKGROUND: Research has yielded evidence for genetic and environmental factors influencing the risk of schizophrenia. Numerous environmental factors have been identified; however, the individual effects are small. The additive and interactive effects of multiple risk factors are not well elucidated. Twin pairs discordant for schizophrenia offer a unique opportunity to identify factors that differ between patients and unaffected co-twins, who are perfectly matched for age, sex and genetic background. METHODS: Register data were combined with clinical data for 216 twins including monozygotic (MZ) and dizygotic (DZ) proband pairs (one or both twins having a schizophrenia spectrum diagnosis) and MZ/DZ healthy control (HC) pairs. Logistic regression models were applied to predict (1) illness vulnerability (being a proband v. HC pair) and (2) illness status (being the patient v. unaffected co-twin). Risk factors included: A polygenic risk score (PRS) for schizophrenia, birth complications, birth weight, Apgar scores, paternal age, maternal smoking, season of birth, parental socioeconomic status, urbanicity, childhood trauma, estimated premorbid intelligence and cannabis. RESULTS: The PRS [odds ratio (OR) 1.6 (1.1-2.3)], childhood trauma [OR 4.5 (2.3-8.8)], and regular cannabis use [OR 8.3 (2.1-32.7)] independently predicted illness vulnerability as did an interaction between childhood trauma and cannabis use [OR 0.17 (0.03-0.9)]. Only regular cannabis use predicted having a schizophrenia spectrum diagnosis between patients and unaffected co-twins [OR 3.3 (1.1-10.4)]. CONCLUSION: The findings suggest that several risk factors contribute to increasing schizophrenia spectrum vulnerability. Moreover, cannabis, a potentially completely avoidable environmental risk factor, seems to play a substantial role in schizophrenia pathology.

Levodopa/carbidopa intestinal gel (LCIG) infusion as mono- or combination therapy.

Levodopa/carbidopa intestinal gel (LCIG) infusion is an effective escalating therapy in patients with Parkinson disease (PD) suffering from motor fluctuations and dyskinesia. Levodopa/carbidopa given continuously as infusion provides an optimized application of the most effective and best tolerable antiparkinsonian drug. It has been proven to have a superior motor effect compared with oral levodopa and to improve also non-motor symptoms. However, invasiveness, discomfort resulting from carrying an external device, and side effects associated with the way of administration limit its application in PD patients. At present, there are no guidelines that delineate to which patients LCIG should be offered as monotherapy, in combination with oral and/or transdermal medication, or as additional therapy to deep brain stimulation (DBS). Based on clinical studies, we propose an expert consensus for neurologists addressing the question when LCIG therapy should be recommended and in which cases LCIG infusion is suggested in combination with other antiparkinsonian drugs and/or DBS. We describe how LCIG should be initiated and what we consider necessary for clinical follow-up. We suggest an algorithm facilitating decision-making with respect to the currently available invasive PD therapies, namely infusion with subcutaneous apomorphine, LCIG, and DBS.

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.

[Early recognition of Parkinson's disease. Objectifiable non-motor symptoms and biomarkers]. / Früherkennung der Parkinson-Krankheit. Objektivierbare nichtmotorische Symptome und Biomarker.

The clinical diagnosis of Parkinson's disease (PD) according to the UK Brain Bank criteria is based on the presence of motor symptoms and the response to dopaminergic medication. According to these criteria the clinical diagnosis is delineated too late when more than 50 % of the dopaminergic neurons are already degenerated. In recent years interest has shifted increasingly more towards non-motor symptoms (NMS), such as rapid eye movement (REM) sleep behavior disorder (RBD), constipation, hyposmia and neuropsychiatric as well as cognitive symptoms. It was shown that NMS can precede the motor symptoms by some years and may thus possibly enable support of an earlier clinical diagnosis. Furthermore, cerebrospinal fluid or blood biomarkers as well as brain imaging techniques can objectively support an earlier diagnosis of PD. This article reviews important NMSs (e.g. RBD, hyposmia and neuropsychiatric/cognitive symptoms) as well as the current status on biomarkers and brain imaging in early (premotor) phases of PD and their relevance for the early diagnosis.

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.

[Functional imaging of deep brain stimulation in idiopathic Parkinson's disease]. / Funktionelle Bildgebung der tiefen Hirnstimulation bei idiopathischem Parkinson-Syndrom.

Functional brain imaging allows the effects of deep brain stimulation (DBS) on the living human brain to be investigated. In patients with advanced Parkinson's disease (PD), positron emission tomography (PET) studies were undertaken at rest as well as under motor, cognitive or behavioral activation. DBS leads to a reduction of abnormal PD-related network activity in the motor system, which partly correlates with the improvement of motor symptoms. The local increase of energy consumption within the direct target area suggests a predominant excitatory influence of the stimulation current on neuronal tissue. Remote effects of DBS of the subthalamic nucleus (STN) on frontal association cortices indicate an interference of stimulation energy with associative and limbic basal ganglia loops. Taken together, functional brain imaging provides very valuable data for advancement of the DBS technique in PD therapy.

[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.

Progression of subtle motor signs in PINK1 mutation carriers with mild dopaminergic deficit.

BACKGROUND: While homozygous mutations in the PINK1 gene cause recessively inherited early-onset Parkinson disease (PD), heterozygous mutations have been suggested as a susceptibility factor. METHODS: To evaluate this hypothesis, 4 homozygous PINK1 patients with PD and 10 asymptomatic carriers of a single heterozygous mutation from a large German family (family W) were included in this study. Clinical follow-up of the heterozygous mutation carriers 3 years after the initial visit included a detailed videotaped neurologic examination using the Unified Parkinson's Disease Rating Scale III protocol and smell and color discrimination testing. At follow-up, PET with 18-fluorodopa (FDOPA) of 13 family members was obtained in order to evaluate the clinical phenotype in light of nigostriatal dopaminergic functioning. The clinical and PET data were compared to those of healthy controls. RESULTS: While there was mild worsening of clinical signs in previously affected heterozygous mutation carriers upon follow-up, 3 additional individuals had newly developed signs of possible PD. Hyposmia was found in 7 of the heterozygous mutation carriers, diminished color discrimination in 4. The homozygous mutation carriers who were all definitely affected with PD showed a severe, 60% decrease of caudate and putaminal FDOPA uptake; heterozygous offspring also had a significant 20% putaminal FDOPA uptake reduction compared to controls. CONCLUSIONS: Our findings strengthen the hypothesis that heterozygous PINK1 mutations act as a susceptibility factor to develop at least subtle Parkinson disease motor and nonmotor signs, as supported by the finding of a reduced striatal dopaminergic FDOPA uptake not only in homozygous but also, albeit to a lesser extent, in heterozygous mutation carriers.

[Early deep brain stimulation for Parkinson's disease]. / Brauchen wir die frühzeitige tiefe Hirnstimulation beim Morbus Parkinson?

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment for advanced Parkinson's disease with levodopa-induced motor complications. Randomized controlled studies have shown that motor fluctuations and quality of life are significantly more improved by STN-DBS than by best medical treatment. The main delay before neurosurgery is currently 14 years after diagnosis. Clinical pilot data suggest that neurosurgery performed already with beginning motor fluctuations and an average disease duration of 7 years may lead to earlier improvement of motor deficits and quality of life, thus preventing disease-related psycho-social decline, and extending the period of beneficial effects of STN-DBS. Results of an ongoing multicenter trial (EARLYSTIM) comparing the effects of STN-DBS and best medical treatment on motor symptoms, quality of life, and psycho-social adaptation will be available in 2 years time and will clarify whether or not early STN-DBS is superior to best medical treatment.

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.

[Deep brain stimulation for essential tremor. Consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei essenziellem Tremor. Empfehlungen der Deutschen Arbeitsgemeinschaft Tiefe Hirnstimulation.

In Germany, deep brain stimulation (DBS) of the thalamic ventralis intermedius nucleus (VIM) is licensed for treatment of essential tremor in cases unresponsive to pharmacotherapy. Especially a bothersome hand tremor interfering with activities of daily living will improve, whereas head, tongue or vocal tremor shows less response. DBS was proven to be superior to lesional thalamotomy with better functional outcome and less adverse effects. The consensus statement presented here reflects the current recommendations of the German Deep Brain Stimulation Study Group for inclusion and exclusion criteria as well as for peri-, intra- and postoperative neurological management.

[Deep brain stimulation for dystonia. Consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei Dystonie. Empfehlungen der Deutschen Arbeitsgemeinschaft Tiefe Hirnstimulation.

Medical treatment of dystonia, particularly generalised forms of the disorder, is often not satisfactory or causes intolerable side effects. In focal dystonia, a reasonable treatment option with botulinum toxin exists but some patients either do not respond well or develop neutralising antibodies with secondary therapy failure. Deep brain stimulation (DBS) of the globus pallidus internus has been shown to be effective in both generalised and focal dystonia. This paper gives recommendations regarding the use of DBS in different forms of dystonia based on the currently available scientific data as well as the longstanding personal experience of the authors. The inclusion criteria for DBS candidates as well as the peri- and postoperative patient management are addressed. These recommendations were developed in a consensus procedure in the German Deep Brain Stimulation Association.

[Deep brain stimulation for tremor in multiple sclerosis : consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei Multiple-Sklerose-Tremor : Empfehlungen der Arbeitsgemeinschaft Tiefe Hirnstimulation.

Deep brain stimulation (DBS) in the nucleus ventralis intermedius thalami (VIM) is a common procedure to treat disabling tremor in multiple sclerosis which is refractory to pharmacological treatment. The sparse studies on DBS in multiple sclerosis tremor remain controversial regarding the clinical effect on postural and action tremor of hands, trunk and head. Furthermore, it remains unclear whether DBS in multiple sclerosis tremor is superior to thalamotomy and whether patients show an overall improvement in quality of life and activities of daily living. Therefore, the consensus recommendations of the German Deep Brain Stimulation Study Group rely primarily on expert opinion and include (1) extensive preoperative characterisation of tremor, ataxia with accompanying disabilities, status of the multiple sclerosis, co-morbidities and burden of disease, (2) careful intraoperative testing of effects and side effects and (3) intensive postoperative testing and programming as well as regular re-evaluation of the therapeutic effect.

[Deep brain stimulation for Parkinson's disease. Consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei idiopathischem Parkinson-Syndrom. Empfehlungen der Deutschen Arbeitsgemeinschaft Tiefe Hirnstimulation.

Deep brain stimulation (DBS) has been shown to be effective for levodopa-responsive symptoms and tremor in Parkinson's disease (PD). The subthalamic nucleus (STN) is the preferred target for most patients suffering from late stage motor complications of the disorder. STN DBS is superior to best medical treatment concerning the control of motor fluctuations and the increase of on-time without dyskinesias. In contrast to DBS of the internal pallidum (GPi), STN stimulation also permits a reduction of the dopaminergic medication. Long-term data demonstrated sustained effectiveness of STN DBS despite progressive disease. DBS of the thalamic ventral intermediate nucleus (VIM) is an alternative target in older PD patients with severe PD tremor refractory to medication. In order to minimize potential risks and side effects, the use of DBS needs careful adherence to inclusion and exclusion criteria for eligible PD patients. This paper summarizes the current consensus recommendations of the German Deep Brain Stimulation Association for DBS in PD.

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.

High resolution positron emission tomography demonstrates basal ganglia dysfunction in early Parkinson's disease.

High resolution positron emission tomography (PET) with the newly developed HRRT scanner (Siemens/CTI) permits the reliable quantification of 18-Fluorodeoxyglucose (FDG) uptake as a marker of neuronal activity in small subcortical nuclei which are involved in the pathophysiology of Parkinson's disease (PD). We investigated the normalized cerebral metabolic rates of glucose (nCMRGlc) with HRRT PET in basal ganglia (BG) nuclei of 10 early-stage PD patients and in 9 healthy volunteers. PET data were co-registered to magnetic resonance images and analyzed in a three-dimensional volume-of-interest (VOI) approach. After normalization for global brain activity, PD patients showed a significantly higher nCMRGlc than controls bilaterally in the BG output nuclei (pallidum, substantia nigra) and unilateral in the caudate and putamen. The metabolic activity of the nucleus accumbens, the subthalamic nucleus, the corpus amygdaloideum and the red nucleus was normal. These first HRRT PET data in living parkinsonian humans extend previous brain imaging findings of abnormal network activity in the BG and confirm output nuclei and striatal overactivation also in early stage PD patients.

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.