Peter Fuhr

Olfactory Impairment Predicts Brain Atrophy in Parkinson's Disease

Olfactory dysfunction is a frequent nonmotor symptom in idiopathic Parkinsons disease (PD) and may be considered as an early clinical feature of the disease preceding motor symptoms by years. According to recent neuropathological staging concepts, impaired olfaction is assumed to indicate an early pathological process and might be associated with structural changes in the brain. A morphometric analysis of magnetic resonance images [voxel-based morphometry (VBM)] was used to investigate gray matter atrophy related to psychophysically measured scores of olfactory function in early PD patients (n = 15, median Hoehn and Yahr stage 1.5), moderately advanced PD patients (n = 12, median Hoehn and Yahr stage 2.5), and age-matched healthy controls (n = 17). In PD patients, but not in controls, cortical atrophy in olfactory-related brain regions correlated specifically with olfactory dysfunction. Positive correlations between olfactory performance and gray matter volume were observed in the right piriform cortex in early PD patients and in the right amygdala in moderately advanced patients. The results provided first evidence that olfactory dysfunction in PD is related to atrophy in olfactory-eloquent regions of the limbic and paralimbic cortex. In addition, olfactory-correlated atrophy in these brain regions is consistent with the assumption that olfactory impairment as an early symptom of PD is likely to be associated with extranigral pathology.

IgM deposits on skin nerves in anti-myelin-associated glycoprotein neuropathy

Anti–myelin‐associated glycoprotein (anti‐MAG) neuropathy is a chronic demyelinating neuropathy with predominant involvement of large sensory fibers and deposits of IgM and complement on sural nerve myelinated fibers. We assessed the presence of IgM deposits on skin myelinated nerve fibers and the involvement of unmyelinated axons in anti‐MAG neuropathy. Skin biopsies were performed in 14 patients with anti‐MAG neuropathy, in 8 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and in 2 patients with IgM paraproteinemic neuropathy. Biopsies were taken at the proximal thigh in 20 patients, at the distal leg in 21 patients, at the proximal arm in 13 patients, and at the hand or fingertip in 10 patients. We found IgM deposits on dermal myelinated fibers in all anti‐MAG neuropathy patients, with a greater prevalence at the distal site of the extremities. Deposits were located throughout the length of the fibers and at the paranodal loops. CIDP and IgM paraproteinemic neuropathies did not show any deposit of IgM. Anti‐MAG neuropathy and CIPD patients showed a decrease in epidermal nerve fiber density reflecting an associated axonal loss. In anti‐MAG neuropathy, both large‐ and small‐diameter nerve fibers are affected, and specific deposits of IgM are found on skin myelinated nerve fibers. Ann Neurol 2005;57:180–187

Functional imaging of the cerebral olfactory system in patients with Parkinson’s disease

Background: Olfactory dysfunction is a frequent non-motor symptom in Parkinson’s disease (PD) and is considered to be an early manifestation of the disease. Objective: To establish the cortical basis of olfactory function in patients with PD. Method: Functional magnetic resonance imaging (fMRI) was used to investigate brain activity related to olfactory processing in patients with hyposmic PD at mild to moderate stages of the disease (nu200a=u200a12, median Hoehn and Yahr stage 2.0) and in healthy, age-matched controls (nu200a=u200a16) while passively perceiving a positively valenced (rose-like) odorant. Results: In both patients with PD and healthy controls, olfactory stimulation activated brain regions relevant for olfactory processing (ie the amygdaloid complex, lateral orbitofrontal cortex, striatum, thalamus, midbrain and the hippocampal formation). In controls, a bilateral activation of the amygdala and hippocampus was observed, whereas patients with PD involved these structures in the left hemisphere only. Group comparison showed that regions of higher activation in patients with PD were located bilaterally in the inferior frontal gyrus (BA 44/45) and anterior cingulate gyrus (BA 24/32), and the left dorsal and right ventral striatum. Conclusions: In patients with PD, results obtained under the specific conditions used suggest that neuronal activity in the amygdala and hippocampus is reduced. Assuming an impact on olfactory-related regions early in PD, our findings support the idea that selective impairment of these brain regions contributes to olfactory dysfunction. Furthermore, neuronal activity in components of the dopaminergic, cortico-striatal loops appears to be upregulated, indicating that compensatory processes are involved. This mechanism has not yet been demonstrated during olfactory processing in PD.

Characterisation of autoantibodies to peripheral myelin protein 22 in patients with hereditary and acquired neuropathies

To investigate the possibility that an autoimmune mechanism may play a role in the hereditary neuropathy Charcot-Marie-Tooth type 1A (CMT1A), sera were analysed by Western blot for anti-peripheral myelin protein 22 (PMP22) autoantibodies. These sera were compared with sera from patients with CMT type 2 (CMT2), acquired peripheral neuropathies such as chronic inflammatory demyelinating neuropathy (CIDP), anti-MAG IgM neuropathy, Miller-Fisher syndrome (MFS), diabetic neuropathy and with control blood donors. Anti-PMP22 positive sera were detected in 70% of patients with CMT1 and unexpectedly in 60% of patients with CMT2. Interestingly, 44% of the patients with other peripheral neuropathies and 23% of the apparently healthy controls showed also anti-PMP22 antibody reactivity. Immunohistochemical analysis of the human anti-PMP22 antisera on healthy sural nerve sections and on PMP22-expressing COS cells revealed that these sera did not recognise endogenous PMP22. Our results indicate that anti-PMP22 autoantibodies are found in sera of patients with different types of peripheral neuropathies, but their role in the pathogenesis of these diseases remains to be determined.

Autologous peripheral blood stem cell transplantation for chronic acquired demyelinating neuropathy

Six patients with chronic acquired demyelinating neuropathy (CADP) were treated with autologous peripheral blood stem cell transplantation (PBSCT). Two with polyneuropathy, organomegaly, endocrinopathy, M‐protein, and skin changes (POEMS) syndrome improved–improvement was sustained in one but relapsed and required repeat transplant in the other. Two of the three with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and one with an IgM paraprotein and antibodies to nerve improved–of the responders, one relapsed after 18 months and the other was in remission after 6 months. Four developed neutropenic septicemia and pneumonia. The role of PBSCT in CADP refractory to other treatment deserves further investigation but the serious adverse events and lack of sustained response in some patients emphasize the need for caution.

Intramedullary screw fixation in proximal fifth-metatarsal fractures in sports : clinical and biomechanical analysis

Introduction and purposeIntramedullary screw fixation (ISF) of proximal fifth-metatarsal fractures is known as first treatment option in young, sports active patients. No study analyzed functional and biomechanical outcome before. Hypothetically ISF leads to (1) a high bony union rate within 12xa0weeks, (2) normal hindfoot eversion strength, and (3) normal gait and plantar pressure distribution.MethodsFourteen out of 22 patients were available for follow-up with an average follow-up of 42xa0months; clinical and radiological follow-up, and biomechanical evaluation by isometric muscular strength measurement (inversion, eversion strength) and dynamic pedobarography, comparing to the non-affected contralateral foot. Level of significance: 0.05.ResultsSubjective result: Excellent or good result in 14 patients, none fair or poor. AOFAS midfoot score: 100 points in 13 patients and 87 points in 1 patient. The same sports activity level (0–4) was reached in 13 out of 14 patients. Radiologic examination: consolidation after 6xa0weeks in 9 patients and after 12xa0weeks in another 4 patients, one partial union. Average maximal eversion strength 59xa0N (ratio to the contralateral foot: 0.92, not significant). Dynamic pedobarography showed ratios of 0.99–1.01 to the contralateral side for ground reaction force, ground peak time, peak pressure and contact area (not significant).InterpretationA very-high patient-satisfaction, a fast bony healing and complete return to sports were documented. Muscular strength measurement and dynamic pedobarography showed complete functional rehabilitation. Therefore, ISF in proximal fifth-metatarsal fractures can be recommended as a secure procedure.

Gene expression profiling in nerve biopsy of vasculitic neuropathy

To investigate molecular mechanisms of peripheral nerve vasculitis, gene expression patterns in archived frozen sural nerve biopsies from patients with vasculitic neuropathy were compared to control nerves by DNA microarray technology. There was a striking upregulation of mRNA of genes involved in immune system processes. Of special interest was the activation of immunoglobulin genes, such as IGLJ3, IGHG3, IGKC, and IGL, and of several chemokines, such as CXCL9 or CCR2. Genes involved in vascular proliferation or remodelling such as CXC31 and AIF were also upregulated. Among the downregulated genes were the Krüppel-Like Transcription Factors KLF2, KLF4 and the nuclear orphan receptor NR4A1 genes known to be involved in endothelial cell activation. Thus, this gene expression profile analysis revealed that in peripheral nerve vasculitis a prominent activation of immune response related genes as well as genes involved in vascular proliferation is taken place, while genes inhibiting endothelial cell activation are down regulated. These data point to interesting mechanistic clues to the molecular pathogenesis of vasculitic neuropathies.

Microstate connectivity alterations in patients with early Alzheimer’s disease

IntroductionElectroencephalography (EEG) microstates and brain network are altered in patients with Alzheimer’s disease (AD) and discussed as potential biomarkers for AD. Microstates correspond to defined states of brain activity, and their connectivity patterns may change accordingly. Little is known about alteration of connectivity in microstates, especially in patients with amnestic mild cognitive impairment with stable or improving cognition within 30xa0months (aMCI).MethodsThirty-five outpatients with aMCI or mild dementia (mean age 77u2009±u20097xa0years, 47xa0% male, Mini Mental State Examination score ≥24) had comprehensive neuropsychological and clinical examinations. Subjects with cognitive decline over 30xa0months were allocated to the AD group, subjects with stable or improving cognition to the MCI-stable group. Results of neuropsychological testing at baseline were summarized in six domain scores. Resting state EEG was recorded with 256 electrodes and analyzed using TAPEEG. Five microstates were defined and individual data fitted. After phase transformation, the phase lag index (PLI) was calculated for the five microstates in every subject. Networks were reduced to 22 nodes for statistical analysis.ResultsThe domain score for verbal learning and memory and the microstate segmented PLI between the left centro-lateral and parieto-occipital regions in the theta band at baseline differentiated significantly between the groups. In the present sample, they separated in a logistic regression model with a 100xa0% positive predictive value, 60xa0% negative predictive value, 100xa0% specificity and 77xa0% sensitivity between AD and MCI-stable.ConclusionsCombining neuropsychological and quantitative EEG test results allows differentiation between subjects with aMCI remaining stable and subjects with aMCI deteriorating over 30xa0months.

A new role for evoked potentials in MS? Repurposing evoked potentials as biomarkers for clinical trials in MS

Evoked potentials (EP) characterize signal conduction in selected tracts of the central nervous system in a quantifiable way. Since alteration of signal conduction is the main mechanism of symptoms and signs in multiple sclerosis (MS), multimodal EP may serve as a representative measure of the functional impairment in MS. Moreover, EP have been shown to be predictive for disease course, and thus might help to select patient groups at high risk of progression for clinical trials. EP can detect deterioration, as well as improvement of impulse propagation, independently from the mechanism causing the change. Therefore, they are candidates for biomarkers with application in clinical phase-II trials. Applicability of EP in multicenter trials has been limited by different standards of registration and assessment.

Cognitive Behavioral Group Therapy Reduces Stress and Improves the Quality of Life in Patients with Parkinson’s Disease

Objective: The aim of this study is to compare a cognitive behavioral group therapy (CBT) with a health enhancement program (HEP) for stress reduction and the impact on quality of life (QoL) in patients with Parkinson’s disease (PD). Method: Thirty patients with PD participated in the study: 16 received CBT including stress-reducing elements and 14 took part in a HEP. The two groups did not differ significantly in their baseline demographic characteristics. The patients in both groups underwent weekly sessions of 2 h duration for 9 weeks. The Parkinson’s Disease Questionnaire with 39 items (PDQ-39), the Burden Questionnaire for Parkinson’s Disease (translated from the original German: Belastungsfragebogen für Parkinsonpatienten (BELA) and the Disease-Related Questionnaire [Fragebogen zur krankheitsbezogenen Kommunikation (FKK)] were used for assessment. Ratings were completed at baseline and after 9 weeks (immediately after the last treatment session). Results: The patients in the CBT group achieved significantly better BELA, FKK and PDQ-39 scores (p < 0.05). Subscale analysis revealed that the scores on the BELA subscales “emotional well-being” and “somatic motor function” contributed significantly to stress reduction (p < 0.05). The FKK revealed significant improvement in social skills in the CBT group (p < 0.05). Conclusion: Cognitive Behavioral Group Therapy appears to be an effective way for patients with PD to lessen stress and improve their quality of life.