Ulrich Dillmann

Methylation Status and Neurodegenerative Markers in Parkinson Disease

BACKGROUNDnIncreased concentrations of plasma total homocysteine (tHcy) have been associated with age-related diseases, including dementia, stroke, and Parkinson disease (PD). Methylation status might link Hcy metabolism to neurodegenerative proteins in patients with PD.nnnMETHODSnWe tested blood samples from 87 patients with PD (median age 68 years; 35 men) for tHcy, methylmalonic acid (MMA), vitamin B(12), vitamin B(6), folate, S-adenosyl methionine (SAM), S-adenosyl homocysteine (SAH), and amyloid-beta(1-42). We collected citrate blood from a subset of 45 patients to prepare platelet-rich plasma, and we used washed platelets to prepare cell extracts for amyloid precursor protein (APP) and alpha-synuclein assays. We used brain parenchyma sonography to estimate the substantia nigra echogenic area in a subset of 59 patients.nnnRESULTSnSerum concentrations of tHcy were increased in PD patients (median 14.8 micromol/L). tHcy (beta coefficient = -0.276) and serum creatinine (beta = -0.422) were significant predictors of the ratio of SAM/SAH in plasma (P < 0.01). The plasma SAM/SAH ratio was a significant determinant for DemTect scores (beta = 0.612, P = 0.004). Significant negative correlations were found between concentrations of SAH in plasma and platelet APP and between SAM and platelet alpha-synuclein. A larger echogenic area of the substantia nigra was related to higher serum concentrations of MMA (P = 0.016).nnnCONCLUSIONSnMarkers of neurodegeneration (APP, alpha-synuclein) are related to markers of methylation (SAM, SAH) in patients with PD. Better cognitive function was related to higher methylation potential (SAM/SAH ratio).

Enlarged hyperechogenic substantia nigra is related to motor performance and olfaction in the elderly

Enlarged substantia nigra hyperechogenicity (SN+) assessed by transcranial sonography (TCS) may be associated with Parkinsons disease (PD) risk markers such as impaired motor performance and hyposmia. The aim of this multicenter cross‐sectional study was to define the association between SN+ and these risk markers in a large population older than 50 years without the diagnosis of PD. In three centers (Tuebingen, Homburg, and Innsbruck), 1,839 individuals were examined. The echostatus of the SN was assessed by TCS, motor performance by the Unified Parkinsons Disease Rating Scale (UPDRS) motor score, and olfactory function with Sniffin Sticks. From the 1,603 subjects included in the analysis, 16.2% were SN+, 23.0% scored above zero in the UPDRS motor section, and 28.0% were hyposmic as defined by less than 75% correctly classified Sniffin Sticks. SN+ was associated with a UPDRS motor score above zero (OR 1.45, 95% CI 1.08–1.96) and with a lower odor identification capability (OR 1.48, 95% CI 1.12–1.96). The combination of these two features (OR 1.98, 95% CI 1.25–3.15) and UPDRS motor scores ≥3 lead to higher OR. It is concluded that SN+, impaired motor performance, and hyposmia are frequently observed in the elderly and in isolation are unspecific and of limited use to predict a subjects risk for PD. Whether the association of SN+ with both impaired motor performance and hyposmia as seen in this study predicts an increased risk for the development of PD needs to be evaluated in the follow‐up investigations.

Pre-motor signs of PD are related to SN hyperechogenicity assessed by TCS in an elderly population.

Much effort has been put in the identification of risk factors and pre-motor markers for Parkinsons disease (PD). In contrast to many of the pre-motor markers, SN hyperechogenicity (SN+) assessed by transcranial sonography (TCS) has been found to be conclusive for vulnerability for PD. In two centers in Germany 1204 individuals ≥50 years without the diagnosis of PD were recruited and the prevalence and relation of SN+ to a range of pre-motor markers was evaluated. SN+ was detected in 193 (16.0%) of 1204 subjects. Hyposmia (25.4%) was the most frequent sign in the cohort, followed by the occurrence of slight motor deficits. Male gender, positive family history of PD as possible risk factors and the pre-motor markers slight parkinsonian signs, one-sided reduced arm swing, and hyposmia were found to be significantly associated with SN+. The number of subjects who had more than one marker was significantly larger in the SN+ subgroup than in the non-hyperechogenic group (9.2% vs. 2.1%). Most of the discussed markers for PD seem to be unspecific with older age, but related to SN+. Co-occurrence of these markers is more probable in SN+ subjects. These findings may have implications for the design of high-risk cohorts for PD.

Frequency and treatment of depressive symptoms in a Parkinson's disease registry

Purpose of this cross-sectional study was to estimate the occurrence of depressive symptoms, as related to other clinical data, in a sample of Parkinsons disease (PD) patients (n=226). Furthermore, we examined the medical care of depressive symptoms in this sample. H&Y stages, cognitive status, sleeping disorders, and dysphagia resulted as significant predictors for depression. Prevalence of depressive symptoms was 35.4%. Only 25.0% of patients suffering from moderate to severe depressive symptoms were prescribed antidepressants. This study supports the view that depression may be underrecognized and undertreated in PD patients. A significant proportion of patients continues to experience depressive symptoms despite antidepressive medication. Recognition and treatment of depression remains a challenge for management of PD. Possible coexisting depressive symptoms should be revealed and assessed by standardized interviews in everyday clinical routine. Large scale randomized controlled trials examining efficacy and safety of antidepressants in PD patients are urgently required.

Width of the third ventricle assessed by transcranial sonography can monitor brain atrophy in a time- and cost-effective manner - Results from a longitudinal study on 500 subjects

Ventricular width and its enlargement over time are discussed as promising markers for preclinical brain atrophy. The aim of our study was to define whether brain atrophy can reliably be monitored by transcranial ultrasound (TCS). In a prospective longitudinal trial over 5years, 500 healthy persons were examined by a standardized protocol with TCS in addition to an extensive cognitive testing using the Consortium to Establish a Registry of Alzheimers Disease - Neuropsychological Testing (CERAD-NP). TCS displayed the third ventricle in 96% of all cases at the follow-up with a high intra-individual reproducibility and excellent inter-rater coefficient (0.992). The mean diameter of the third ventricle in subjects with a cognitive decline was significantly wider (6mm±2) than in subjects with normal cognitive testing results (4.6mm±1.8). We demonstrated that the width of the third ventricle, as a marker of brain atrophy can reliably be monitored by using TCS as a non-invasive, time- and cost-effective method. We provide evidence that the assessed width of the third ventricle can differentiate between subjects with a normal cognitive performance and subjects with a cognitive decline. TCS may be a useful screening tool in the early diagnosis of cognitive decline.

Cerebral and Extracranial Neurodegeneration are Strongly Coupled in Parkinson's Disease.

In idiopathic Parkinson’s disease (PD), a generalized Lewy body type-degeneration in the brain as well as extracranial organs was identified. It is unclear, whether cerebral and extracranial Lewy body type-degeneration in PD are coupled or not. To address this question, cerebral [123I]FP-CIT SPECT – to quantify cerebral nigrostriatal dopaminergic degeneration – and myocardial [123I]MIBG scintigraphy – to quantify extracranial myocardial sympathetic degeneration – were performed in 95 PD patients and 20 healthy controls. At each Hoehn and Yahr stage separately, myocardial MIBG uptake correlated significantly with striatal FP-CIT uptake. No such correlation was found in the controls. Cerebral and extracranial Lewy body type-degeneration in PD do not develop independently from each other but develop in a strongly coupled manner. Obviously cerebral and extracranial changes are driven by at least similar pathomechanisms. Our findings in controls contradict a physiological correlation between nigrostriatal dopaminergic and myocardial sympathetic function.

Improvement of upper limb ataxia and intention tremor allowing cessation of thalamic electrostimulation after four years

A 34-year-old female patient suffering from multiple sclerosis was treated with thalamic electrostimulation for right dominant brachial ataxia and intention tremor. At the end of the fourth year, the energy of the battery of the impulse generator was depleted. However, the patient was able to use her hands without major impairment with the stimulator OFF, due to a stable reduction of the degree of ataxia and intention tremor. The opposite thalamus received an electrode that was never activated because of a permanent thalamotomy effect. Thus, it can be concluded that restoration of function by means of deep brain stimulation might have been beneficial towards achieving a reorganization and stabilization of subcortico-cortical and cerebellar circuitry, supporting the process of self-repair in this patient with a less aggressive course of multiple sclerosis. However, scientific proof has yet to be found. This exceptional observation emphasizes the need for longterm studies.

FP-CIT SPECT Does Not Predict the Progression of Motor Symptoms in Parkinson’s Disease

Background/Aims: FP-CIT (fluoropropyl-2β-carbomethoxy-3β-4-iodophenyl-nortroptane) SPECT is a well-established nuclear medicine method to support the clinical diagnosis of Parkinson’s disease (PD). In this study, we examined the prognostic value of FP-CIT SPECT concerning the PD motor symptoms. Methods: All 38 PD patients (age 57 ± 7 years, Hoehn & Yahr stage 1.6 ± 0.8, mean ± SD) underwent a baseline visit and a follow-up visit 3–7 years (5.2 ± 1.3 years) after the baseline visit. Cerebral [123I]FP-CIT SPECT was performed only once at the baseline visit. At both visits the motor symptoms bradykinesia, rigidity, resting tremor, postural tremor and axial symptoms were quantified by means of the UPDRS motor scale. Results: There was no significant correlation between the initial striatal FP-CIT uptake and the annual progress of any motor symptom (= difference [(motor symptom at follow-up visit) – (motor symptom at baseline visit)]/time (in years) between assessments). Conclusion: The initial striatal FP-CIT SPECT does not predict the velocity of progress of PD motor symptoms within an interval of 3–7 years.

[Early deep brain stimulation for Parkinson's disease].

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment for advanced Parkinsons 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.

Auswirkungen der Elektrostimulation subkortikaler Hirnstrukturen auf das glottale Schwingungsverhalten bei Patienten mit Morbus Parkinson und multipler Sklerose

Die vorliegenden Studie hat die Auswirkungen neurostimulatorischer Eingriffe auf die glottale Phonation bei 3 Patienten mit Morbus Parkinson und 3 Patienten mit multipler Sklerose zum Gegenstand. Unter Verwendung zweier Stimmanalyseprogramme (MDVP von Kay Elemetrics und EGG-Programm von Marasek) mit akustischer bzw. elektrophysiologischer Untersuchungsausrichtung wurden Vokalproduktionen der Patienten analysiert, die unter Stimulation bzw. Nichtstimulation aufgezeichnet wurden. In einem ersten Schritt können durch signifikant unterschiedliche Mittelwerte der Analyseparameter die intrasubjektiven Stimulationsauswirkungen nachgewiesen werden. Sie sind in verschiedener Ausprägung vor allem bei den Patienten mit M. Parkinson vorhanden. In einem zweiten Schritt erfolgt der geschlechtsgebundene Vergleich der individuellen Patientendaten unter den Bedingungen der Stimulation bzw. Nichtstimulation mit den Referenzdaten einer umfangreichen Kontrollgruppe stimmgesunder erwachsener Personen (150 männliche und 150 weibliche). Diese intersubjektiv referentielle Bewertung erweist sich im Vergleich zur intrasubjektiven Betrachtung auf Grund unterschiedlicher Ergebnisse bei den meisten Patienten als sinnvoll. Die pathologiebezogenen Tendenzen unter Stimulationseinwirkung bestehen bei den Personen mit M. Parkinson in einer relativen Verschlechterung des glottalen Schwingungsablaufs, während bei den Personen mit multipler Sklerose eine hyperfunktionelle Komponente bei der Phonation deutlich wird, auf Grund derer eine longitudinale Betrachtung des Phonationsverhaltens nach Elektrodenimplantation unter chronischer Stimulation für notwendig erachtet werden kann.