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Objective Cerebrospinal fluid (CSF) markers of neurodegeneration [neurofilament light chain (NFL), total Tau (T-Tau)], tau pathology [phosphorylated tau (p-Tau)], glial cell damage or activation [glial fibrillary acidic protein (GFAP)], and brain amyloidosis [β-amyloid 1-42 (Aβ42)] are useful for diagnosis and prognosis in several neurodegenerative disorders. In this paper we investigate these markers and their relationship to key clinical milestones in patients with advanced Parkinson´s disease (PD) operated at our center with subthalamic nucleus deep brain stimulation (STN-DBS) for at least 15 years ago. Patients and methods Retrospective analysis of available cerebrospinal fluid and clinical data in PD-patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska University Hospital before January 1, 2001, were regularly assessed until January 10, 2018, or until death, or until lost to follow-up. Results Twenty three PD patients were operated with STN-DBS. Sixteen of these (six females and ten males) underwent at least one lumbar puncture (LP) immediately prior to or after STN-DBS. Their age at the latest available LP was 64 (55–75) years [median (range)], PD duration 20 (11–33) years, and Hoehn & Yahr (H&Y) stage 3 (2–4). Time between DBS operation and the last LP was 4.5 (0.3–10.8) years. Time from the last LP to the last follow up was 6 (0.1–18) years, and for the entire cohort 115 person-years. On January 10, 2018, four PD-patients (25%) were still alive. All preoperative CSF marker levels were normal. Between two days and six months after DBS, NFL and GFAP levels increased sharply but they normalized thereafter in most patients, and were normal up to almost 11 years after neurosurgery. Over time, all patients deteriorated slowly. At the last follow up, H&Y was 5 (3–5) and 12/16 were demented. There was no significant correlation between postoperative (> 6 months) CSF NFL, GFAP, T-Tau, p-Tau, β-amyloid levels and the presence of dementia, psychosis, inability to walk or need for nursing home at the time for LP, nor for presence of dementia at the last follow up or for death as of January 10, 2018. Conclusion CSF protein biomarkers remain normal despite long PD duration, severe disability, and chronic STN-DBS. They cannot be used for PD staging or prognostication but may indicate brain damage caused by other pathological factors.

When we reach for an object, we have to decide which arm to use and the direction in which to move. According to the established view, this is voluntarily controlled and programmed in advance in time-consuming and elaborate computations. Here, we systematically tested the motor strategy used by cats, monkeys, and humans when catching an object moving at high velocity to the left or right. In all species, targets moving to the right selectively initiated movement of the right forelimb and vice versa for targets moving to the left. Movements were from the start directed toward a prospective target position. In humans, the earliest onset of electromyographic activity from start of motion of the target ranged from 90 to 110 ms in different subjects. This indicates that the selection of the arm and specification of movement direction did not result from the subject's voluntary decision, but were determined in a reflex-like manner by the parameters of the target motion. As a whole the data suggest that control of goal-directed arm movement relies largely on an innate neuronal network that, when activated by the visual signal from the target, automatically guides the arm throughout the entire movement toward the target. In the view of the present data, parametric programming of reaching in advance seems to be superfluous.

Constantinescu R, Holmberg B, Rosengren L, Corneliusson O, Johnels B, Zetterberg H. Light subunit of neurofilament triplet protein in the cerebrospinal fluid after subthalamic nucleus stimulation for Parkinson’s disease. Acta Neurol Scand: 2011: 124: 206–210. © 2010 John Wiley & Sons A/S. Objectives – Cerebrospinal fluid (CSF) levels of neurofilament triplet protein (NFL), a non-specific marker of neuronal damage, are normal in Parkinson’s disease (PD) but increased after brain trauma and in several neurological disorders. Using longitudinal CSF-NFL measurements as an indicator of neuronal damage, this study investigated the impact of deep brain stimulation (DBS) of the subthalamic nucleus (STN) on the brain, directly following the surgical intervention and in chronically treated patients with PD. Materials and methods – CSF-NFL levels were measured consecutively in eight patients with PD before and after STN-DBS treatment. Results – CSF-NFL levels were normal prior to STN-DBS and increased sharply during the first 2 weeks post-operatively, but normalized after 12 months or more. Conclusion – The STN-DBS procedure leads to an acute but limited neuronal damage, as expected. However, normal CSF-NFL levels at 12 months post-operatively and beyond suggest the absence of any long-term neuronal damage caused by long-term STN-DBS stimulation.

Objective – To evaluate whether subjects with palmar hyperhidrosis have functional problems with the handgrip caused by the wet slippery surface of palm and fingertips. We used two different dosages of botulinum toxin to explore its impact on sweating and on muscle strength in the hand. Method – Using an object equipped with force sensors we measured the muscle strength and calculated the coefficients of friction and safety margin (SM) in the precision grip before and 2, 4, 6, 8 10–12 weeks and 6 months after treatment of 13 patients with two different doses of botulinum toxin. Sweat evaporation was measured simultaneously. Results – A significant decrease in evaporation and a parallel reduction of grip force in the dominant hand of the patients were observed. The SM used by the patients was significantly lower after the treatment, and increased gradually when sweating reappeared. Conclusion – These measurements showed, for the first time, that hyperhidrosis of the palms may cause an objective perturbation of the hand function which may be partially corrected by botulinum toxin treatment.

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.

We report a cluster of five cases of Parkinson's disease (PD) among paper mill workers exposed to a fungicide, diphenyl. The cause of PD is still unknown, but epidemiological studies have indicated an elevated risk of developing PD after exposure to pesticides. The five cases of PD were found in a group of 255 diphenyl-exposed workers, and the number of expected cases in the exposed group was estimated to be 0.9, resulting in a relative risk of 5.6 (95% CI 1.8-13). Exposure to diphenyl may have contributed to this PD cluster, but chance is an alternative explanation.

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 Parkinson's 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 (

Objectives – To search for a physiological method for the measurement of upper extremity dexterity during activities of daily life in Parkinson's disease (PD). Materials and methods – We examined load force output during manual transport in seven patients with PD and 10 healthy controls. PD patients were measured in both the non-medicated and medicated states. The test movement included two continuous sub-movements: an upward-forward transport of an object from the table to the stand, and a downward-backward transport of the object from the stand to the table. Hand movements were recorded using an optoelectronic camera, and load force was measured using a force sensor installed in the test object. Results – Compared with the controls, PD patients had a different pattern of load force output characterized by slower force development and release, lower peak force, and less dynamic force generation during movement. After medication, the speed of force development and the level of peak force increased in the patients. Conclusions – These findings suggest that PD impairs the production of preprogrammed movements. The movements observed in the PD patients may result from compensatory strategies relying more on feedback mechanisms.

We analyze hand dexterity in Parkinson's disease patients (PD) and control subjects using a natural manual transport task (moving an object from one place to another). Eight PD patients and 10 control subjects carried out the task repeatedly at maximum speed both in off and on medicated status. The movement parameters and the grip and load forces were recorded. Using the force and velocity signals, 10 subsequent phases of the transport movement were defined and their durations were measured. The difference between the control group and the test group in off and on was established statistically using non-parametric methods. There was slowed reaching and a striking disturbance of establishing the precision grip in PD. The transport capabilities were impaired differentially. Although acceleration and reaching sufficient height of the lift were disturbed in PD subjects, transport of the object toward the target position was almost normal. A partial disturbance was observed when cancelling the grip. Dopaminergic medication improved only specific hand skills, especially establishment of the precision grip and one of the four transport phases. A long movement path was more sensitive for movement disturbance in Parkinson's disease than a short one.

The 42-amino-acid isoform of beta-amyloid Abeta42 in the cerebrospinal fluid (CSF) has recently been proposed as a biochemical marker for Alzheimer's disease (AD) and subcortical white-matter dementia (SWD). In both of these conditions, concentration of CSF-Abeta42 is reduced. We quantified CSF-Abeta42 from patients fulfilling strict clinical criteria for multiple system atrophy (MSA; n = 36), Parkinson's 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 Abeta42 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 Abeta42 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-Abeta42 concentration may be a clue to the pathogenesis of MSA. There is a decreased production, or more possible, an increased consumption of CSF-Abeta42. The analysis of this protein may also become a supplement to the clinical differentiation of parkinsonian syndromes in a movement disorder unit.

Twenty-six subjects with idiopathic Parkinson's disease (PD) and normal cognitive status (as measured by the Mini-Mental State Examination) were examined with a battery of tests selected to reveal subtle and/or high-level language impairments. The test battery included 'repetition of long sentences', 'recreating sentences', 'making inferences', 'comprehension of logico-grammatical sentences', 'comprehension of ambiguous sentences' and 'comprehension of metaphors', 'word definitions', 'word fluency', 'naming', 'sentence analysis' and 'morphological completion'. Comparisons were made between the PD subjects and 26 control subjects matched for age, gender and level of education. Significant differences in performance between the PD subjects and the control subjects were found in the ability to make inferences and to analyse sentences (state the correct number of words in a read sentence). An additional four subjects with different degrees of cognitive dysfunction were also investigated and were found to have particular problems in making inferences, recreating sentences and comprehending metaphors and ambiguities. The results suggest that processing implied information might be a specific problem in this group and that the task of making inferences could be a particularly sensitive test of high-level language dysfunction.

Thalamic deep brain stimulation (DBS) is proven to suppress tremor in Parkinson's 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 Parkinson's 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.

During transport of an object using the precision grip with thumb and index finger, a modulation of the grip force is needed in response to the forces evoked by the movement. We measured the grip force (GF) and the load force (LF) in 10 healthy participants moving a 640-g object forward and upward. The task was repeated with various speeds. There were considerable changes with speed of the LF trajectory but not of the GF trajectory. A loss of synergy between GF and LF appeared in fast lifts. This is in contrast to the close coupling between load force and grip force repeatedly demonstrated during simple lifts. We suggest that (a) speed should be considered as an input parameter for movement planning, and (b) regulation of GF and of LF are independent under certain conditions. We discuss whether the grip-load force synergy should be considered a special case rather than a more general principle.

Acommon goal in the rehabilitation of persons with stroke is to improve their abilityto bear weighton the affected lower extremity.With respect to arm positions, rising from a sitting to standing position can be trained in different ways. For example, the hands can be clasped with the arms stretched forward or the arms can be free to move. The purpose of this studywas to examine howthese twodifferent arm positions effect body weight distribution and estimation of perceived exertion when rising from sitting to standing in stroke patients. Ten stroke patients (23-63 years) and ten age and sex-matched controls participated in the study. Two force measuring platforms were used to estimate ground reaction forces and body weight distribution. Perceived exertion was rated on a scale developed by Borg. No differences in body weight distribution or perceived exertion were found between the two ways of rising from sitting to standing in either the patient group or the control group. The results of this studysuggest...

The differentiation between Parkinson's disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is important for prognostic and therapeutic purposes. In order to evaluate the diagnostic capability of two tests reflecting these items, patients fulfilling strict clinical criteria for PD (n=35), MSA (n=36) and PSP (n=14), were consecutively included. An analysis of neurofilament protein (NFL), a marker of axonal degeneration in the cerebrospinal fluid (CSF) and a levodopa test, recorded with optoelectronic technique were performed. Using discriminant analyses, the test's abilities to predict the clinical PD or non-PD (MSA and PSP) diagnoses were compared. Whereas the CSF-NFL and levodopa tests predicted 79 and 85% correct diagnoses respectively, the combined test predicted 90% correct diagnoses. We conclude that the CSF-NFL and levodopa tests provide detailed information of clinical variables on which the clinical diagnostic criteria are based. As they are pathologically unrelated, the diagnostic precision increases compared to clinical diagnoses when they are combined.

Gender symptom differences were studied in 948 subjects with Parkinson's 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.

Integrated movement and force analysis of the precision grip-lift sequence (grasping an object between index finger and thumb) is a useful tool in studies on manipulative hand functions. The everyday Manual Transport tasks, moving objects from one place to another, exhibits powerful test possibilities because it includes the precision grip. In this study, as a step towards the exploitation of these possibilities, we created an algorithm that extracts sequence of phases in this task. The mathematical and dynamical properties of the movement and force signals were used to determine the start and the end of each phase. The grip-lift synergy was quantified by the correlation coefficient during each phase. Eight patients with Parkinson's Disease (PD) and 10 healthy persons were studied. The PD patients were tested both in the medicated (ON) and the unmedicated (OFF) state. The object was lifted with the index finger and the thumb, moved a short distance, and put down on a shelf. The preliminary results of these experiments displayed significantly higher coordination between the grip and load forces in the initial phases, before the lift was completely established, than during the transport phases. This was evident both in PD patients and healthy subjects. This method provides an automatic analysis of the motor performance during an arm-hand movement that is important in daily life to aid in clinical diagnosis.

Objective methods for quantifying patients' movement capacity would be valuable for evaluating progression and interventions in neurodegenerative diseases. The Posturo-Locomotor-Manual (PLM) test is a standardized automated movement test developed for the evaluation of hypokinetic symptoms of Parkinsonism. We tested the hypotheses that the PLM movement time correlates with the Unified Parkinson’s Disease Rating scale motor section (UPDRS III) and that the components of the PLM test correlate to constructed corresponding domains of UPDRS III. The coherence between the results of the two assessment methods after a test dose of levodopa (L-DOPA) was also evaluated. Motor function was assessed off medication and after administration of 200 mg L-DOPA in 73 patients with Parkinsonism (47 Parkinson’s disease (PD), 17 Multiple System Atrophy (MSA) and 9 Progressive Supranuclear Palsy (PSP)) using the PLM method and UPDRS III in parallel. We found a fair correlation between the two assessment tools in PD patients but not in the MSA or PSP patients. In the full dataset a fair to good correlation was seen between UPDRS III and PLM movement time. At group level, the PLM L-DOPA test differentiated between PD, MSA and PSP and the UPDRS III L-DOPA test differentiated PD from MSA/PSP. Measurements from the rater independent PLM method showed fair correlations with scorings from the UPDRS III and on group level the PLM method could differentiate between different forms of Parkinsonism in moderate to advanced stages.

Computer-assisted optoelectronic movement analysis using a Posturo-Locomotor-Manual (PLM) test, and assessment with an ADL (Activities of Daily Living) scale were performed in 36 ( 18 women and 18 men) 90-year-old subjects as part of a larger study. In the PLM test, the subjects were asked to pick up an object placed on the floor, and carry it to a shelf at the height of their chin and at a distance of 150 cm from the starting position. In the ADL assessment, the subjects were classified as ADL-dependent or independent in each of 4 instrumental (cleaning, shopping, transport and cooking) and 5 personal activities (bathing, dressing, going to the toilet, transfer and feeding). ADL independence was defined as being able to perform ADL activities without assistance from another person. In this study, ADL-dependent subjects performed the PLM test considerably more slowly than the ADL-independent group. A correlation was found in females between poorer ADL performance and slower and less co-ordinated PLM test results. Particularly, the Postural and Locomotor phases representing lower limb mobility correlated to the ADL steps. In males, no such correlation was found, indicating that factors other than mobility were important for ADL performance in this group, e.g., cooking skills. The relationships between the PLM test and the ADL assessment estimating practical motor function could be an indication that the PLM test is not only a strict laboratory method, but also measures components of everyday motor activities. Combined use of optoelectronic measurements and ADL scales will improve measurements of motor performance in elderly persons. (Aging Clin. Exp. Res. 6: 444-450, 1994)

We present new ideas about motor control in the human central nervous system and about pathophysiological mechanisms of Parkinson's disease, and we describe the Posturo-Locomotion-Manual (PLM) method, which is a new technique utilizing optoelectronic camera recording for objective, fully quantitative, and standardized assessment of human motor performance. In the PLM test, recordings of body movements are made during a simple motor task, where the subject repeatedly moves a small object from its starting position on the floor to a shelf located at chin height a few steps forward. The duration of the postural (raising up), locomotor and the goal-directed manual phase of the forward directed body movement is automatically calculated by a small computer as well as the degree of coordination (simultaneity) of these phases. The technique has high resolution and has been used for clinical assessment of motor performance, drug testing, and so on, in neurological and geriatric practice.

Cerebrospinal fluid (CSF) levels of neurofilament light protein (NFL), a marker of neuronal damage, are normal in Parkinson's 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.

We analyze movement in Parkinson’s disease patients (PD) and healthy subjects using a natural manual transport task (moving an object from one place to another). Eight PD patients and ten healthy control subjects performed the transport task repeatedly at maximum speed, the patients in two conditions — without and with medication (OFF and ON).

Accumulating evidence indicate that cyclooxygenase-2 (COX-2) is of pathophysiological importance for the neurodegeneration in Parkinson's disease (PD). For example, in a large epidemiological study, use of NSAIDs was associated with a lower risk of PD. Genetic variants of the COX-2 gene might therefore influence the risk of developing the disease. The genotype distribution of four common single nucleotide polymorphisms (SNPs) in the COX-2 gene (rs689466:A496G, rs20417:G926C, rs5277:G3050C, rs5275:C8473T) was analyzed in PD patients and control subjects in a Swedish population. No differences could be seen between the PD-patient and controls regarding the A496G, G926C, and G3050C SNPs, but the allele frequency of the C8473T SNP was found to differ when male patients were compared to controls (P = 0.007). In females no difference could be seen between PD-patients and controls. In conclusion, the results suggest a possible influence of the COX-2 C8473T SNP in PD, although it only seems to be of importance in men.

Several findings obtained recently indicate that inflammation may contribute to the pathogenesis in Parkinson's 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-gamma (IFN-gamma; T874A in intron 1), interferon-gamma receptor 2 (IFN-gamma 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.

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 Parkinson's 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.

We analyze hand dexterity in Parkinson's disease patients (PD) and control subjects using a natural manual transport task (moving an object from one place to another). Eight PD patients and 10 control subjects carried out the task repeatedly at maximum speed both in off and on medicated status. The movement parameters and the grip and load forces were recorded. Using the force and velocity signals, 10 subsequent phases of the transport movement were defined and their durations were measured. The difference between the control group and the test group in off and on was established statistically using non-parametric methods. There was slowed reaching and a striking disturbance of establishing the precision grip in PD. The transport capabilities were impaired differentially. Although acceleration and reaching sufficient height of the lift were disturbed in PD subjects, transport of the object toward the target position was almost normal. A partial disturbance was observed when cancelling the grip. Dopaminergic medication improved only specific hand skills, especially establishment of the precision grip and one of the four transport phases. A long movement path was more sensitive for movement disturbance in Parkinson's disease than a short one.

Thalamic deep brain stimulation (DBS) is proven to suppress tremor in Parkinson's 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 Parkinson's Disease Rating Scale (UPDRS) and Essential Tremor Rating Scale (ETRS). DBS decreased tremor sum scores in PD (P0.025) 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 (P0.025) compared to stimulation off conditions. In ET, thalamic stimulation improved (P0.025) kinetic and positional tremor at both follow-up periods (n = 18 and n = 13, respectively) with significant improvements (P0.025) 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.

The differentiation between Parkinson's 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 degrees head-up tilt. HRV did not differ between groups during quiet breathing but was significantly reduced during forced respiration in MSA (P < 0.01), while PD and PSP groups did not differ from controls. Hypotensive responses during orthostatic provocation were seen in PD (P < 0.01) and MSA (P < 0.001), whereas BP remained stable in most PSP patients, not differing from the healthy control group. On an individual basis, decreased HRV and severe hypotensive responses were seen in MSA patients regardless of age and disease duration, whereas PD patients showed this combination only at high age and long duration. In PSP, only a few cases with decreased HRV and limited hypotensive responses were found. We conclude that cardiovascular reflex tests can supplement the clinical differentiation of Parkinsonian syndromes.

In a crossover study we compared the single dose effect of 200mg levodopa (plus decarboxylase inhibitor) in the form of Madopar with that of Madopar Dispersible on the motor performance of eight patients with Parkinson's disease, after 12h without their ordinary anti-parkinsonian medication and food intake. Objective recording of their performance was done with an opto-electronic camera and automatic computerised treatment of the movement data and with scoring according to the United Parkinson's Disease Rating Scale. We conclude that Madopar Dispersible has a much faster and more constant onset of action than the standard preparation (25 vs 46min.). The effect duration and the effects on motor performance were otherwise the same.

More reliable tools are needed for the differentiation of Parkinson's disease (PD) from other parkinsonian disorders. The neurofilament protein (NFL) and the glial fibrillary acidic protein (GFAP) are main structural proteins of axons and fibrillary astroglial cells. By using enzyme-linked immunosorbent assays, these proteins were quantified in the cerebrospinal fluid (CSF) of 49 patients referred to the Department of Neurology for diagnostic consideration or treatment of parkinsonism of different etiologies. All patients were first diagnostically evaluated by strict clinical criteria. The procedure included a neurologic and neuro-ophthalmologic examination as well as computed tomography or magnetic resonance imaging. These were performed independently and in advance of the CSF analysis. A total of 19 patients were diagnosed as having PD, 12 had progressive supranuclear palsy (PSP), and 10 had multiple-system atrophy (MSA). Eight were diagnosed as having other diseases, such as arteriosclerotic parkinsonism and undefined parkinsonian syndromes. The content of NFL was significantly higher both in the PSP group (p < 0.001) and in the MSA group (p < 0.0001) compared with the PD group. The high values of NFL indicate an ongoing neuronal degeneration affecting mainly the axonal compartment in the PSP and MSA groups, whereas there was no difference in glial involvement as measured by GFAP in the PD, PSP, and MSA groups. There was a relation between high CSF levels of NFL in the various patient groups and the occurrence of pyramidal symptoms (p < 0.001), possibly reflecting the axonal damage to the corticospinal tract. Furthermore, mortality at 24-month follow up was associated with high NFL levels (p < 0.01). We conclude that analysis of NFL in CSF may become useful in the differential diagnosis of parkinsonian syndromes.

The motor performance of 10 patients with normal pressure hydrocephalus (NPH) was clinically assessed with the aid of a computer assisted optoelectronic movement analysis system (Mac Reflex). We used the Posturo Locomotion Manual (PLM) method that gives a quantitative estimation of the postural, locomotor and manual performance in freely moving humans. Measurements were done before intervention, after CSF tap test and 3 months post installation of a CSF ventriculo peritoneal shunt. Comparison was made to data from 10 matched normal subjects and 10 patients with Parkinson's disease (PD). Shunt operation of the NPH patients and l-dopa treatment of the Parkinson patients improved the motor performance to a comparable degree. However, while the NPH patients improved the speed in the PLM test after the operation, the PD patients also improved the co-ordination after l-dopa treatment. This could indicate a different mechanism behind the improvement of motor performance in NPH and PD after intervention.

Twenty-five patients with suspected Parkinson's disease were submitted to optoelectronic movement analysis with the Posturo- Locomotor-Manual (PLM) test before and 60 min after a single dose of L-Dopa. They were then examined clinically for diagnosis. Two patients were excluded due to L-Dopa intolerance. Seventeen of the remaining patients were classified as having Parkinson's disease. The movement time (MT) in the PLM test was increased for all these patients, and they improved their performance after L-Dopa. The degree of improvement was roughly proportional to the pretreatment augmentation of MT in comparison to healthy subjects of the same age. The PLM phase analysis showed a specific disability profile for each individual. Six patients were given diagnoses other than PD. Some improvement was found in one patient with suspected olivopontocerebellar atrophy and one patient with multiple brain injury. Two patients with progressive supranclear palsy, one with suspected striatonigral degeneration, and one with functional disturbance deteriorated after L-Dopa. In conclusion, truly objective and fully reproducible evaluation of the motor performance before and after a single L-Dopa dose is easily accomplished with computer-assisted modern optoelectronic recording equipment. The technique is a valuable tool for the quantitative measurement of treatment effects and contributes to the differential diagnosis.

Alcohol dehydrogenases (ADHs) may be involved in the pathogenesis of neurodegenerative disorders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous study, significant association of an ADH class IV allele with Parkinson disease (PD) was found in a Swedish sample.The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls.The previously identified association with an ADH class IV allele remained significant (P.02) in the extended Swedish study. Furthermore, in the international collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). This association was statistically significant (chi(2)(1) = 7.5; 2-sided P = .007; odds ratio, 3.25 [95% confidence interval, 1.31-8.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder.Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.

– A kinesiological analysis of complex movement performance was carried out in patients with Parkinson's disease, and in healthy subjects of different ages, with a computer-assisted optoelectronic camera system. A lifting movement entailing simultaneous coordination of rising, walking some steps and a goal-directed manual movement, the PLM test, was used. Speed reduction through normal aging was greatest at higher ages, where the coordination deficits were also most prominent. The increased movement time in parkinsonian patients was due both to deficient simultaneous coordination of postural, locomotor and manual movement phases, and to varying increases in phase durations. It was possible to determine postural, locomotor and manual disability profiles quantitatively, in terms of the relative phase time values. The presented documentation of parkinsonian disability and single-dose effects of 1-dopa indicates that the technique is applicable in the objective assessment of disability and pharmacotherapeutic efficacy.

A simple mechanographic method for the measurement of muscle tone in awake rats is presented. It utilizes principles corresponding to those in clinical assessment of tone and it has been applied to an animal model of Parkinson's disease: the reserpine-treated rat. The rat was restrained by a plastic cylinder and by metal cuffs at the ankles. The hind feet were repeatedly dorsiflexed by an electromechanical manipulator and the resulting calf muscle tension was indirectly measured with a strain-gauge system. The relative contributions to the stretch response from the different muscle groups acting on the ankle joint in the awake and untreated rat and during reserpine-induced rigidity are described. Very little active tension was found in the untreated rat. After treatment with reserpine, continuous activation of the muscles was found in EMG recordings and there was a sharp increase in the tension recorded during stretch. The static response to the increased isometric stretch was augmented. An additional, tonic response to ramp stretch was elicited at all stretch velocities. There was no evidence for phasic responses to rapid stretch in reserpine-induced rigidity. The amplitude of the myomechanogram was thus found to be independent of the ramp stretch velocity. Subsequent injection of apomorphine abolished the increased stretch response. It is demonstrated that changes in muscle tone could be followed during drug treatment and that the method can be used in investigations of the pathophysiological mechanisms behind the disorders of muscle tone.

A mechanographic method was used to assess the locomotor performance induced by apomorphine or other dopaminergic drugs in reserpine-treated rats. Reserpine was found to induce locomotor hypokinesia. The hypokinesia was dose-dependently reversed by apomorphine (APO), bromocriptine and pergolide. Locomotion was induced by microinjection of APO into the nucleus accumbens. No locomotor effect was found after injection into corpus striatum. Injection into both nuclei was not superior to accumbens only. Intra-striatal or intraaccumbens injections of trifluoperazine blocked the effect on locomotion by systematic apomorphine. The results confirmed that reserpine-induced locomotor hypokinesia is reversed by dopaminergic stimulation in the nucleus accumbens. There were indications that blockade of striatal or accumbens' dopamine receptors counteracts apomorphine-induced locomotion presumably by interaction with postural motor control. Evidence was found for separate dopaminergic control of locomotion and muscletone. This may be of importance for the development of new antiparkinson drugs.

A study of the pathophysiological mechanisms of reserpine rigidity with the aid of a mechanographic method for the quantification of muscle tone. Apomorphine was used as a test substance to reduce reserpine rigidity by stimulation of dopamine receptors. Some experiments were made with additional drug treatment in an attempt to ascertain the dopaminergic specificity of the test. Apomorphine injected bilaterally to the corpus striatum has been shown to counteract the rigidity [6]. Microinjections of reserpine to corpus striatum induced rigidity with dominance in the hindleg ipsilateral to the side of injection. This rigidity was reduced by subcotaneous apomorphine. The effect of subcutaneous apomorphine on the rigity was blocked by prior microinjection of trifluoperazine to the corpus striatum. Injections to nucleus accumbens were ineffective in all these respects. It is concluded that reserpine induces rigidity mainly by interference with the dopamine transmission in the corpus striatum.

A simple treadmill arrangement has been developed to quantify the quadruped or hindleg locomotor activity in rats. The method provides information on the accumulated distance passed by the rat in the treadmill but also on the temporal distribution of locomotion and the stepping cycle. It can be used with intact rats but also during stereotaxically guided electric stimulation of the brain. The accumulated locomotion produced by apomorphine showed a partly linear relation to the dose and the results were comparable to those found with other methods. The locomotor effect of brainstem stimulation was enhanced by apomorphine. This method combines the advantages of several other methods and is well suited as a tool for the analysis of nervous regulation of locomotor activity.

Publisher Summary This chapter describes motor functions of the striatum. Parkinson's disease presents at least three major symptoms of disturbed motor control, namely hypokinesia, augmented muscle tone, and a characteristic alternating tremor of the limbs and the trunk. In Parkinson's disease, it is often possible to reverse the hypokinetic–hypertonic syndrome into a hyperkinetic–hypotonic counterpart by giving an overdose of levodopa or dopamine agonists such as apomorphine. With levodopa, it is possible to modulate these motor functions between the two extremes by dose adjustments. Parkinsonian tremor is thought to be a centrally induced phenomenon relying upon the integrity of certain loops in the brain including the efferent pathways of the striatum and the cortex cerebri as it can be relieved after lesions in the ventrolateral thalamic nuclei and as it is absent after removal of the motor cortex in man. Clinical data indicate that the augmented muscle tone in Parkinson's disease depends on striatal dysfunction and that there is no primary malfunction at spinal or peripheral levels.

One purpose of this paper is to show that the concepts of locomotor physiology as they have been expressed in this symposium are useful for the analysis of motor disorders of basal ganglia diseases such as Parkinson’s disease.

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 Parkinson's 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 l-dopa treatment were quantified in each patient.

By using stereotaxic surgical techniques, ventral mesencephalic tissues from aborted human fetuses of 8 to 10 weeks' gestational age were implanted unilaterally into the striata in two patients with advanced Parkinson's disease. The patients were treated with a cyclosporine, azathioprine, and steroid regimen to minimize the risk for graft rejection. They were examined for 6 months preoperatively and 6 months postoperatively and continued to receive the same doses of antiparkinsonian medication. There were no significant postoperative complications. No major therapeutic effect from the operation was observed. However, in the clinical tests, both patients showed small but significant increases of movement speed for repeated pronation-supination, fist clenching, and foot lifting. The rate of walking also increased in the one patient tested. For both patients, there was an initial worsening postoperatively, followed by improvement vs preoperative performance at 1 to 3 months. Both patients also showed significant improvement in the magnitude of response to a single dose of levodopa (L-dopa), but there was no increase in the duration of drug action. The motor readiness potential increased in both patients postoperatively, primarily over the operated hemisphere. Neurophysiological measurements also showed a more rapid performance of simple and complex arm and hand movements on the side contralateral to transplantation in one patient at 5 months postoperatively. Positron emission tomography demonstrated no increased uptake of 6-L-(18F)-fluorodopa in the transplanted striatum at 5 and 6 months. Taken together, these results suggest that the fetal nigral implants may have provided a modest improvement in motor function, consistent with the presence of small surviving grafts. Although our results support further scientific experimentation with transplantation in Parkinson's disease, widespread clinical trials with this procedure are probably not warranted at this time.