Bo Johnels

Long-term efficacy of thalamic deep brain stimulation for tremor: double-blind assessments.

Thalamic deep brain stimulation (DBS) is proven to suppress tremor in Parkinsons disease (PD) and essential tremor (ET). However, there are few reports on its long‐term efficacy. We studied the efficacy of DBS at 2 years and 6–7 years after electrode implantations in the ventrointermediate nucleus of the thalamus in 39 patients (20 PD, 19 ET) with severe tremor. Twenty‐five of the patients completed the study. Evaluations were done in a double‐blind manner with the Unified Parkinsons Disease Rating Scale (UPDRS) and Essential Tremor Rating Scale (ETRS). DBS decreased tremor sum scores in PD (P < 0.025) compared to the preoperative baseline (median, 7; Q25–75, 6–9) both at 2 years (median, 2; Q25–75, 2–3.5; n = 16) and at 6 to 7 years (median, 2.5; Q25–75, 0.5–3; n = 12). Stimulation on improved tremor sum as well as sub scores (P < 0.025) compared to stimulation off conditions. In ET, thalamic stimulation improved (P < 0.025) kinetic and positional tremor at both follow‐up periods (n = 18 and n = 13, respectively) with significant improvements (P < 0.025) in hand‐function tests. PD but not ET patients showed a general disease progression. Stimulation parameters were remarkably stable over time. We conclude that high‐frequency electric thalamic stimulation can efficiently suppress severe tremor in PD and ET more than 6 years after permanent implantation of brain electrodes.

Gender differences in Parkinson's disease symptom profile

Gender symptom differences were studied in 948 subjects with Parkinsons disease (PD) using a questionnaire covering the most common symptoms associated with PD at debut (SP‐1) and at present (SP‐2). The symptoms most frequently reported by both genders were: tremor, fumblingness, writing problems, rigidity and fatigue. At SP‐1 females reported neck‐pain and low back pain more frequently than males. At SP‐2 subjects reported an increased number of symptoms. The following symptoms were more frequent among males than females: writing difficulties, fumblingness, gait problems, speech problems, increased flow of saliva, lack of initiative. Sleep problems were common in both sexes with inability to turn in bed and calf muscle cramps in a high percentage. A majority of female subjects find their symptoms (e.g. depression) constantly distressing. Although depression is not one of primary reported symptoms (36%) attention is called for, due to the problem with compliance to treatment regimes. About 30% do not report having tremor and rigidity. This study indicates the usefulness of a symptom profile instrument capable of capturing the many symptoms involved in PD. Such an instrument could be used to detect apparent mistakes in medication and thereby increase the function and quality of life for the individual.

Cerebrospinal fluid Aβ42 is reduced in multiple system atrophy but normal in Parkinson's disease and progressive supranuclear palsy

The 42‐amino–acid isoform of β‐amyloid Aβ42 in the cerebrospinal fluid (CSF) has recently been proposed as a biochemical marker for Alzheimers disease (AD) and subcortical white‐matter dementia (SWD). In both of these conditions, concentration of CSF‐Aβ42 is reduced. We quantified CSF‐Aβ42 from patients fulfilling strict clinical criteria for multiple system atrophy (MSA; n = 36), Parkinsons disease (PD; n = 48) and progressive supranuclear palsy (PSP; n = 15). The study groups were consecutively recruited among patients referred to a movement disorder unit, and 32 healthy, age‐matched volunteers were used as controls. The CSF concentration of Aβ42 was significantly reduced in the MSA group (P < 0.001), whereas the PD and PSP groups did not differ from controls. On an individual basis, low content of Aβ42 was seen in 9 MSA patients regardless of age and disease duration. Three PD patients with long disease duration also had low concentrations but all PSP patients were normal. We conclude that the reduced CSF‐Aβ42 concentration may be a clue to the pathogenesis of MSA. There is a decreased production, or more possible, an increased consumption of CSF‐Aβ42. The analysis of this protein may also become a supplement to the clinical differentiation of parkinsonian syndromes in a movement disorder unit.

Multicentre European study of thalamic stimulation for parkinsonian tremor: a 6 year follow-up

Aim: To evaluate the results of ventral intermediate (Vim) thalamic deep brain stimulation (DBS) in patients with tremor predominant Parkinson’s disease (PD) at 6 years post surgery. Methods: This was a prolonged follow-up study of 38 patients from eight centres who participated in a multicentre study, the 1 year results of which have been published previously. Total scores as well as scores for individual items of the motor part and the disability part of the Unified Parkinson’s Disease Rating Scale were used for evaluation. Results: Tremor was still effectively controlled by DBS and appendicular rigidity and akinesia remained stable compared with baseline. Axial scores (speech, gait and postural instability), however, worsened, and in parallel the initial improvement in activities of daily living scores at the 1 year follow-up had disappeared at 6 years, despite sustained improvement of tremor. Remarkably, neither daily doses of dopaminergic medication nor fluctuations and dyskinesias had changed at 6 years compared with baseline in this particular patient group. Conclusion: This study confirms that patients with tremor dominant PD who do not present with fluctuations and dyskinesias may have a relatively benign progression of the disease. Vim DBS, although having no effect on akinesia and rigidity, is a relatively lenient surgical procedure and may still have a place for long term symptomatic control of PD tremor in selected patients.

Cardiovascular reflex testing contributes to clinical evaluation and differential diagnosis of Parkinsonian syndromes

The differentiation between Parkinsons disease (PD), progressive supranuclear palsy (PSP), and multiple system atrophy (MSA) may be difficult but is important for prognostic and therapeutic purposes. Varying degrees of autonomic failure have been described in PD and MSA, whereas its involvement in PSP remains controversial. The aim of this study was to investigate autonomic function in patients fulfilling strict clinical diagnostic criteria for the disorders above, to evaluate the diagnostic capacity of laboratory autonomic tests. The study group was consecutively recruited among patients referred to a movement disorder unit. Thirty‐four patients with PD, 15 patients with PSP, and 47 patients with MSA were compared with 18 healthy age‐matched controls. Autonomic tests included analysis of heart rate variability (HRV) in temporal domain, at rest and during forced respiration, as well as blood pressure (BP) changes during 75° head‐up tilt.

Interaction of polymorphisms in the genes encoding interleukin-6 and estrogen receptor beta on the susceptibility to Parkinson's disease.

The multifunctional cytokine interleukin‐6 (IL‐6) is involved in inflammatory processes in the central nervous system and increased levels of IL‐6 have been found in patients with Parkinsons disease (PD). It is known that estrogen inhibits the production of IL‐6, via action on estrogen receptors, thereby pointing to an important influence of estrogen on IL‐6. In a previous study, we reported an association between a G/A single nucleotide polymorphism (SNP) at position 1730 in the gene coding for estrogen receptor beta (ERbeta) and age of onset of PD. To investigate the influence of a G/C SNP at position 174 in the promoter of the IL‐6 gene, and the possible interaction of this SNP and the ERbeta G‐1730A SNP on the risk for PD, the G‐174C SNP was genotyped, by pyrosequencing, in 258 patients with PD and 308 controls. A significantly elevated frequency of the GG genotype of the IL‐6 SNP was found in the patient group and this was most obvious among patients with an early age of onset (≤50 years) of PD. When the GG genotypes of the IL‐6 and ERbeta SNPs were combined, the combination was much more robustly associated with PD, and especially with PD with an early age of onset, than respective GG genotype when analyzed separately. Our results indicate that the G‐174C SNP in the IL‐6 promoter may influence the risk for developing PD, particularly regarding early age of onset PD, and that the effect is modified by interaction of the G‐1730A SNP in the ERbeta gene.

Disability profiles and objective quantitative assessment in Parkinson's disease

ABSTRACT— A new technique for quick objective and quantitative determination of important aspects of the motor handicap in movement disorders is presented. A compound, but natural, test movement was used to find out if the degree of dysfunction in postural, locomotor and manual motor functions differed among the patients and if medication influenced these functions differently. After 12 h without medication, 16 patients with Parkinsons disease showed a movement time between 1.5 and 13.6 times that of an age‐matched normal subject and a greater performance variability on repeated examination. In some patients the increase of test movement time was caused mainly by the locomotion component while in others the time for the postural or manual part of the movement was more markedly augmented. Thus, a specific motor disability profile was found for each patient and expressed in quantitative terms. The effects of 1‐dopa treatment were quantified in each patient.

Consecutive analyses of cerebrospinal fluid axonal and glial markers in Parkinson's disease and atypical parkinsonian disorders

Cerebrospinal fluid (CSF) levels of neurofilament light protein (NFL), a marker of neuronal damage, are normal in Parkinsons disease (PD) but elevated in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Therefore, CSF NFL can help differentiate between PD on one hand and MSA/PSP on the other. In the present study of 10 patients with PD, 21 with MSA, 14 with PSP, 11 with corticobasal degeneration (CBD), and 59 healthy controls, this previous observation is confirmed and also extended to include CBD by showing that similarly high CSF NFL levels are seen not only in MSA and PSP but also in CBD. CSF levels of glial fibrillary acidic protein (GFAP), a protein expressed mainly in fibrillary astrocytes, were similar in all investigated groups. In addition, consecutive analyses of CSF NFL and CSF GFAP levels showed relatively stable levels over time in all the investigated parkinsonian disorders, suggesting that the rate of neuronal degeneration is rather constant over time. Our results suggest that measurements of CSF NFL but not GFAP can be useful in the differential diagnosis of PD versus atypical parkinsonian disorders (APD). However they do not help differentiate between the different APD.

Lack of association between the BDNF Val66Met polymorphism and Parkinson's disease in a Swedish population.

Polymorphism and Parkinson’s Disease in a Swedish Population Anna Håkansson, MS, Jonas Melke, MS, Lars Westberg, BS, Haydeh Niazi Shahabi, MS, Silva Buervenich, PhD, Andrea Carmine, MS, Kjell Klingborg, MD, Maj-Britt Grundell, MD, Barbara Schulhof, MD, Björn Holmberg, MD, PhD, Jarl Ahlberg, MD, Elias Eriksson, PhD, Olof Sydow, MD, PhD, Lars Olson, PhD, Bo Johnels, MD, PhD, and Hans Nissbrandt, MD, PhD

Investigation of genes coding for inflammatory components in Parkinson's disease

Several findings obtained recently indicate that inflammation may contribute to the pathogenesis in Parkinsons disease (PD). Genetic variants of genes coding for components involved in immune reactions in the brain might therefore influence the risk of developing PD or the age of disease onset. Five single nucleotide polymorphisms (SNPs) in the genes coding for interferon‐γ (IFN‐γ; T874A in intron 1), interferon‐γ receptor 2 (IFN‐γ R2; Gln64Arg), interleukin‐10 (IL‐10; G1082A in the promoter region), platelet‐activating factor acetylhydrolase (PAF‐AH; Val379Ala), and intercellular adhesion molecule 1 (ICAM‐1; Lys469Glu) were genotyped, using pyrosequencing, in 265 patients with PD and 308 controls. None of the investigated SNPs was found to be associated with PD; however, the G1082A polymorphism in the IL‐10 gene promoter was found to be related to the age of disease onset. Linear regression showed a significantly earlier onset with more A‐alleles (P = 0.0095; after Bonferroni correction, P = 0.048), resulting in a 5‐year delayed age of onset of the disease for individuals having two G‐alleles compared with individuals having two A‐alleles. The results indicate that the IL‐10 G1082A SNP could possibly be related to the age of onset of PD.