The use of rhythmic auditory cues to influence gait in patients with Parkinson's disease, the differential effect for freezers and non-freezers, an explorative study.

PURPOSE: To study the effect of rhythmic auditory cues on gait in Parkinson's disease subjects with and without freezing and in controls. METHOD: A volunteer sample of 20 patients (10 freezers, 10 non-freezers) and 10 age-matched controls performed five randomized cued walking conditions in a gait-laboratory. Auditory cues were administered at baseline frequency, at an increased step frequency of 10 and 20% above baseline and at a decreased step frequency of 10 and 20% below baseline. Mean step frequency, walking speed, stride length and double support duration were collected. RESULTS: Rhythmical auditory cueing induced speed changes in all subjects. Stride length was not influenced by rhythmical auditory cues in controls, whereas patients showed a larger stride length in the -10% condition (p < 0.01). Freezers and non-freezers showed the same response to rhythmical auditory cues. Within group analysis for stride length showed different cueing effects. Stride length decreased at the +10% condition for freezers (p < 0.05), whereas it increased for non-freezers. CONCLUSIONS: This study points to fact that physiotherapists might need to carefully adjust the cueing frequency to the needs of patients with and without freezing. On the basis of the present results we recommend to lower the frequency setting for freezers, whereas for non-freezers an increase of up to +10% may have potential therapeutic use.

Dopamine transporter SPECT using fast kinetic ligands: 123I-FP-beta-CIT versus 99mTc-TRODAT-1.

A comparative study was carried out on two promising presynaptic dopamine transporter single-photon emission tomography (SPECT) radioligands with a fast pharmacokinetic profile, 123I-FP-beta-CIT (FP) and 99mTc-TRODAT-1 (TR), in order to assess their differential diagnostic power in early parkinsonism and their sensitivity for detection of disease progression. This cross-sectional study was conducted on 96 patients with early-stage parkinsonism referred in a tertiary clinical setting. Mean disease duration was 2.0+/-1.3 years, and patients had a modified Hoehn and Yahr (H&Y) stage of 1-2 (average 1.2). Forty-seven patients received TR, and 49 received FP. In both groups, ten patients with normal presynaptic function were included as a control population; all other patients were clinically diagnosed as having idiopathic Parkinson's disease. Groups were matched for gender, age, disease duration and modified H&Y stage. Triple-head gamma camera SPECT was analysed using a semiquantitative index of transporter binding (BI). Discriminant analysis with cross-validation resulted in a maximal classification accuracy for FP of 93% (sensitivity 95% and specificity 86%) for the contralateral putamen BI. For TR, the corresponding values were 87% accuracy, 92% sensitivity and 70% specificity. For FP, disease duration was correlated with both the putamen BI (-8.8%/year, rho=-0.41, P=0.025) and the putamen/caudate ratio (-7.4%/year, rho=-0.51, P=0.004), but for TR no significant correlation was found (all P values >0.5). In conclusion, both FP and TR show high sensitivity in a clinically relevant setting, but FP has superior accuracy for early differential diagnosis of idiopathic parkinsonism and non-degenerative extrapyramidal disorders, as well as better sensitivity for disease follow-up.

Predictive testing for Huntington's disease: relationship with partners after testing.

This study focuses on the partner relationship of tested persons, 5 years after their predictive test result for Huntington's disease (HD). We describe changes in marital status, quality of the relationship, and perceived changes in the relationship. Twenty-six carriers, 14 of their partners, 33 non-carriers, and 17 of their partners participated in the study. Qualitative and quantitative methods were used. For the majority of tested persons (about 70%), the marital status was unchanged 5 years post test. Overall, carriers rated the quality of the relationship higher than their partners did and they perceived more positive changes. Qualitative data show that a test result leading to changed roles may induce significant marital distress. Another consequence of the test may be the changes in dynamics in asymptomatic carrier couples. A pre-test discussion of the possible impact of the test result on the relationship should result in a better preparation for and more understanding of the reactions after testing. Counselling after testing should stimulate an open communication between partners with consideration of needs and anxieties of both partners.

Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial.

OBJECTIVE: To evaluate the effect of creatine (Cr) supplementation (5 g/day) in Huntington's disease (HD). METHODS: A 1-year double-blind placebo-controlled study was performed in 41 patients with HD (stage I through III). At baseline and after 6 and 12 months, the functional, neuromuscular, and cognitive status of the patients was assessed by a test battery that consisted of 1) the Unified Huntington's Disease Rating Scale (UHDRS), 2) an exercise test on an isokinetic dynamometer to assess strength of the elbow flexor muscles, 3) a maximal exercise test on a bicycle ergometer to evaluate cardiorespiratory fitness, and 4) a test to assess bimanual coordination ability. Following the baseline measurements, the subjects were assigned to either a creatine (n = 26) or a placebo group (n = 15). RESULTS: Scores on the functional checklist of the UHDRS (p < 0.05), maximal static torque (p < 0.05), and peak oxygen uptake (p < 0.05) decreased from the start to the end of the study, independent of the treatment received. Cognitive functioning, bimanual coordination ability, and general motor function (total motor scale, UHDRS) did not change from baseline to 1 year in either group. CONCLUSION: One year of Cr intake, at a rate that can improve muscle functional capacity in healthy subjects and patients with neuromuscular disease (5 g/day), did not improve functional, neuromuscular, and cognitive status in patients with stage I to III HD.

Unimanual and bimanual voluntary movement in Huntington's disease.

Unimanual and bimanual cyclical forearm movements were studied in 15 Huntington's disease (HD) patients and 15 healthy, gender- and age-matched controls. Whereas the unimanual task was only performed at maximal speed, the bimanual movements were performed according to the in-phase and anti-phase mode at different cycling frequencies. The HD patients also performed the tasks after 12 months of follow-up. Findings revealed that maximal cycling frequency during unimanual movement was significantly lower in HD patients as compared with controls. In addition, measures of relative phasing established that bimanual cyclical movements were performed with lower accuracy and higher variability in HD patients. The differential variability between both groups was magnified by increasing the cycling frequency and coordinative complexity whereas only coordinative complexity differentially affected the accuracy of relative phasing. The obtained performance measures were found to be significantly correlated with disease duration (unimanual) and with the score on the total motor scale, the Mini-Mental State Examination and the Stroop Interference Test (uni- and bimanual). After 12 months, maximal cycling frequency of unimanual elbow flexion-extension was significantly decreased in HD patients whereas the quality of the in-phase and anti-phase movement patterns remained stable.

Longitudinal study evaluating neuropsychological changes in so-called asymptomatic carriers of the Huntington's disease mutation after 1 year.

OBJECTIVES: To determine (1) whether the battery of neuropsychological tests was sufficiently sensitive to find differences between symptomatic patients with Huntington's disease (HD) and clinically asymptomatic individuals carrying the HD gene (AGC) and individuals without the HD gene (NGC) and (2) whether increasing cognitive impairment is found in AGC as compared with NGC. METHODS: A case-control, single-blind study comparing subjects with clinically manifest HD (n=21), AGC (n=12) or NGC (n=11) and a 1-year follow-up of AGC and NGC. Genotype for the HD gene was determined by molecular testing. A large battery of neuropsychological tests measuring several cognitive domains was performed. RESULTS: On most neuropsychological tasks, HD patients perform significantly worse than AGC and NGC. At baseline and follow-up examination, compared with NGC, AGC had lower scores on the symbol digit modalities test. Scores on a block span task declined more rapidly among AGC than among NGC. CONCLUSION: Cognitive impairments in HD patients are found when compared with clinically asymptomatic individuals carrying the HD mutation. Furthermore, our results suggest that subtle cognitive deficits are present in asymptomatic persons who have inherited the HD gene.

Abnormalities of the spatiotemporal characteristics of gait at the onset of freezing in Parkinson's disease.

We investigated the spatiotemporal variables of gait leading up to freezing. Gait analysis was carried out on 14 patients with Parkinson's disease in the off phase of the medication cycle. A computerised, three-dimensional gait analysis system was used to measure the walking pattern. After several trials of normal walking with voluntary stopping, distracting manoeuvres and obstacles on the walkway were used to provoke freezing or festination. The gait variables of normal (off phase), festinating, prestop, and prefreezing strides were analysed using analysis of variance for repeated-measures. Cadence was excessively increased (68%) and stride length decreased (69%) during festination compared with normal off walking; a pattern which remained pronounced when comparing prefreezing strides with normal stopping. Analysing in more detail the three steps before a freeze, we found a progressive decrease of stride length and stable cadence rates and proportions of double support phases. The relationship between cadence and stride length exhibited an exponential increase of cadence with a decreasing stride length during festination and freezing. Results suggest that freezing is caused by a combination of an increasing inability to generate stride length superimposed on a dyscontrol of the cadence of walking.

Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation.

The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in > 90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.

The effect of a home physiotherapy program for persons with Parkinson's disease.

The purpose of this study was to evaluate the effect of a home physiotherapy program for persons with Parkinson's disease. Thirty-three patients took part in the study using a within-subject controlled design. Functional activities including walking and carrying out transfers were measured at home and in the hospital before and after a 6-week baseline period, after 6 weeks home physiotherapy and after 3 months follow-up. Spatiotemporal and plantar force variables of gait were determined with video and pododynography. Treatment provided by community physiotherapists consisted of teaching cueing and conscious movement control 3 times a week. The study revealed that patients had significantly higher scores on a functional activity scale after treatment in the home setting and to a lesser degree in hospital, a result, which was partly sustained at follow-up. However, duration of the transfer movements, spatiotemporal and plantar force variables were not significantly improved except for stride length. The results support application and development of the treatment concept and highlight that physiotherapy aimed at improving function in Parkinson's disease is best provided in the home situation.

Predicting arm recovery following stroke: value of site of lesion.

OBJECTIVES: The aims of this study were to assess whether the site of lesion is predictive of upper limb recovery after stroke and to determine whether this information adds to the predictive ability of the clinical examination. MATERIAL AND METHODS: Forty-five patients were examined at entry to the study and at 2 and 12 months after stroke. The Brunnström-Fugl-Meyer test was used as outcome measurement. Predictor variables included clinical parameters and classifications of lesion site (obtained by CT/MRI). RESULTS: Correlation analysis revealed small to moderate relationships between lesions of subcortical structures and arm outcome at 2 months. In multiple regression analysis, the best model for predicting recovery at 2 months was found to be a combination of the clinical parameters with a purely subcortical lesion. Motor recovery at 12 months was best predicted by the clinical tests alone. The results further indicated that patients with subcortical damage tended to take longer to recover. CONCLUSIONS: Clinical assessment is most useful for determination of the prognosis of upper limb recovery after stroke. Neuroanatomical parameters measured by CT or MRI can only act as an adjunct.

Development of an activity scale for individuals with advanced Parkinson disease: reliability and "on-off" variability.

BACKGROUND AND PURPOSE: Functional mobility in people with advanced Parkinson disease, some of whom have a variable response to drug treatment, is often difficult to evaluate. The objectives of this study were to investigate the interrater reliability of measurements obtained with a scale designed to measure mobility and to determine the impact of self-rated dyskinesias and fluctuations on the measure. SSUBJECTS: Twenty-nine people with Parkinson disease and with disability and considerable disease duration (mean=11.7 years, SD=4.9, range=6-22) took part in the study. METHODS: The subjects' performance on a 10-item scale was videotaped. The videotapes were then scored by 2 independent raters, and the scores were used to determine interrater reliability. The stability of 6 repeated measurements was examined in the home situation, taking into account self-rated fluctuations of motor performance. RESULTS: Weighted Kappa values of agreement (.86-.98) confirmed the reliability between testers. Measurement during the "on" phase (when medication was working optimally) and the "off" phase (when the action of medication was strongly decreased or absent) led to different measurements. Measuring frequently within "on" and "off" phases gave relatively stable measurements for total function, bed transfers, and gait akinesia, the latter during the "off" phase only (intraclass correlation coefficients [ICCs]=.70-.93). However, more modest repeatability applied to transfers from a chair (ICC=.65-.67). CONCLUSION AND DISCUSSION: To ensure valid results in future effect studies, clinical differentiation between "on" and "off" phase measurements is proposed on the basis of patients' own perception of their medication status.

Lung volume reduction surgery does not improve diaphragmatic contractile properties or atrophy in hamsters with elastase-induced emphysema.

It is claimed that lung volume reduction surgery (LVRS) improves inspiratory muscle function. As diaphragm structure and function are not directly appraisable in patients, we studied the effects of LVRS on the diaphragm in vitro contractile properties and morphology in hamsters with elastase-induced emphysema. Four months after intratracheal instillation of elastase (40 U/100 g), hamsters underwent either bilateral LVRS (LVRS, n = 11) or a sham operation (SHAM, n = 8). Four animals died during the perioperative period in LVRS (n = 7). Hamsters instilled with saline served as control (CTL, n = 8). Animals were studied at the age of 9 mo. LVRS was associated with a significant 25% decrease in functional residual capacity compared to SHAM (p < 0.05). Compared with CTL, LVRS and SHAM showed a significant 18% and 14% reduction in diaphragm mass, respectively (p = 0.02). LVRS had a significantly decreased twitch tension compared to CTL and SHAM (p < 0.01). Both LVRS and SHAM showed increased resistance to muscle fatigue compared with CTL. The histochemical analysis revealed a significant shift from type IIx/b toward type IIa fibers in LVRS and SHAM compared with CTL. In conclusion, emphysema is associated with functional adaptations but LVRS does not appear to beneficially alter the diaphragm contractile and morphological characteristics in hamsters with elastase-induced emphysema.

Familial Creutzfeldt-Jakob disease in a patient carrying both a presenilin 1 missense substitution and a prion protein gene insertion.

We describe a patient who was clinically diagnosed with familial early-onset Alzheimer disease (AD) carrying both the E318G substitution in presenilin 1 (PSEN1) and an insertion of 7 octapeptide coding repeats in the prion protein gene (PRNP). Neuropathological examination revealed elongated cerebellar prion protein deposits in the absence of AD pathology. Further analysis of other family members showed that the Creutzfeldt-Jakob disease phenotype in this family was caused solely by the PRNP insertion. This observation is consistent with our previous finding that PSEN1 E318G is not causally related to AD.

Retrospective study of Creutzfeldt-Jakob disease in Belgium: neuropathological findings.

Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy that affects about 1 in 10(6) inhabitants in most countries. Recently, a new variant of CJD has been linked to the epidemic of bovine spongiform encephalopathy. Therefore, vigilance concerning the disease's incidence has been increased. We conducted a comprehensive, nation-wide and retrospective study. In 79 Belgian autopsies, we found the characteristic triad of spongiosis, neuronal loss and reactive gliosis. The occipital cortex was most affected, while the cerebellum was mostly spared. Immunohistochemistry was performed using hydrated autoclave pretreatment and several monoclonal antibodies directed against the prion protein. We identified prion-immunoreactive patterns and locations reflecting the important heterogeneity, independently of the antibody that was used. Granular prion immunoreactivity was observed in astrocytes. We studied the regional intensity of the prion immunostaining and determined that the frontal cortex with 95% positive immunoreactivity was best suited for a biopsy. We studied the disease duration in sporadic CJD patients who showed neuropathological lesions of other neurodegenerative disorders (such as Alzheimer's disease). The study shapes the framework in which a prospective neuropathological registry will be able to function.

Torque variations during repeated passive isokinetic movements of the knee in subjects with Parkinson's disease and healthy control subjects.

The purpose of this study was to quantify response variations during isokinetic passive movements of the knee in subjects with Parkinson's disease. Parkinsonian patients demonstrated a greater decrease of resistive torque compared to healthy control subjects, particularly in tests at higher velocities and during knee flexion movements. Responses were influenced by electromyographic activity in stretched and shortened muscle groups and also by mechanical factors. The results indicate that repetition of movements needs to be taken into account when measuring hypertonia in parkinsonian subjects.

Psychological functioning before predictive testing for Huntington's disease: the role of the parental disease, risk perception, and subjective proximity of the disease.

BACKGROUND: Psychometric testing of participants in predictive DNA testing for Huntington's disease (HD) has shown that 15% of the subjects at risk for HD had at least mild depression or a high score for general anxiety or both in the pre-test period. The main aim of the study was the delineation of variables associated with pre-test distress of applicants for predictive testing for HD. Based on theoretical considerations, four specific hypotheses were tested regarding the role of (1) the test participant's age at the (perceived) parental onset of HD, (2) the affected parent's sex, (3) the perception of the risk for HD, and (4) the subjective proximity of the disease. Secondly, these four variables were used in multiple regression analyses to select the best predictors of pre- and post-test psychological functioning (one year after the test). Increasing the understanding of pre- and post-test distress is important for developing better counselling and support strategies for test applicants. METHODS: Data were collected by means of clinical interviews and psychometric questionnaires during the pre- and post-test (one year after the test) counselling sessions for predictive testing for HD. RESULTS: We found significant associations of the participant's age at the parental onset, the subjective proximity of the disease onset, and the perceived risk with pre-test psychometric measures of psychological functioning. Multiple regression analyses showed that the best predictors of pre-test functioning were the perceived proximity of the disease onset and its interaction with risk perception. Regarding post-test functioning, none of the proposed variables had a unique contribution beyond that accounted for by pre-test psychological functioning. CONCLUSIONS: Test participants who are close to the perceived age of onset of HD and who have a pessimistic risk perception should be given special attention during pre-test counselling because of their possible negative affective condition at that time. Pre-test psychological measures were the best predictors of post-test distress, irrespective of the test result. Suggestions for future longitudinal research are formulated. This kind of research should enable clinical geneticists and mental health professionals to refine the pre- and post-test counselling strategies for predictive DNA testing, not only for HD, but also for other incurable late onset disorders.

99mTc-MAMA-chrysamine G, a probe for beta-amyloid protein of Alzheimer's disease.

Chrysamine G (CG), an analogue of Congo red, is known to bind in vitro to the beta-amyloid protein (Abeta 10-43) and to homogenates of several regions of the brain of Alzheimer's disease (AD) patients. We synthesised a conjugate of 2-(acetamido)-CG with a bis-S-trityl protected monoamide-monoaminedithiol (MAMA-Tr(2)) tetraligand, which was efficiently deprotected and labelled with a 75% yield with technetium-99m, to obtain (99m)Tc-MAMA-CG. In mice, (99m)Tc-MAMA-CG was cleared mainly by the hepatobiliary system, resulting in a fast blood clearance. Brain uptake of (99m)Tc-MAMA-CG was low. Co-injection with the blood pool tracer iodine-125 human serum albumin ((125)I-HSA) demonstrated a brain/blood activity ratio for (99m)Tc-MAMA-CG that was significantly higher than that for (125)I-HSA (t test for dependent samples, P<0.02), indicating the ability of (99m)Tc-MAMA-CG to cross the blood-brain barrier. In vitro autoradiography demonstrated pronounced binding of (99m)Tc-MAMA-CG to beta-amyloid deposits in autopsy sections of the parietal and occipital cortex of an AD patient as compared with controls. Adding 10 microM Congo red during incubation displaced the binding of (99m)Tc-MAMA-CG. Congo red staining and autoradiography identified the same lesions. (99m)Tc-MAMA-CG seems to bind selectively to beta-amyloid deposition in human brain parenchyma and blood vessels in vitro and thus might be a lead compound for further development of a useful tracer agent for the in vivo diagnosis of Alzheimer's disease.

Methodological issues in a cost-of-dementia study in Belgium: the NAtional Dementia Economic Study (NADES).

The NAtional Dementia Economic Study (NADES) is an on-going prospective, one-year cohort study developed in Belgium to assess the socio-economic consequences of dementia in a group of patients and their caregivers (n = 400). Comparison is made with a group of subjects with cognitive impairment and no dementia (n = 100) and a group of subjects without any cognitive impairment (n = 100). Recruitment of subjects is based on screening of warning signs of dementia by general practitioners, followed by a Cambridge Mental Disorders of the Elderly Examination (CAMDEX) performed at home. This paper presents an overview of the study protocol and the rationale for basic design options, such as the choice of study population, screening strategy, and methods used for the case validation. It also presents preliminary results on the prevalence of dementia in general practice, the sensitivity and specificity of the warning signs as a screening test of dementia, and the validity of a computerised case ascertainment algorithm based on DSM-III-R criteria.

NADPH-diaphorase-containing neurons in cortex, subcortical white matter and neostriatum are selectively spared in Alzheimer's disease.

To investigate the involvement of NADPH-diaphorase (NADPH-d)-containing neurons in Alzheimer's disease (AD), NADPH-d enzyme histochemistry in vibratome sections was applied to the superior frontal and superior temporal cortex and the neostriatum in 5 AD and 6 aged control brains. Overall there was a neuronal loss and atrophy in the cortex of AD. Despite slight morphological neuronal changes in the cortex of AD, we found no significant difference in the number of NADPH-d-positive neurons in both cortex and neostriatum between control and AD cases. These results provide further evidence for a selective preservation of NADPH-d neurons in AD. In order to check whether nNOS-immunoreactive neurons are identical to NADPH-d-positive neurons in the human brain, we examined the frontal and temporal cortex and neostriatum of normal human brains in serial cryostat sections. We found that nNOS-containing neurons paralleled NADPH-d-positive neurons in these brain regions. Copyrightz1999S.KargerAG,Basel

A retrospective study of Creutzfeldt-Jakob disease in Belgium.

Using data from Belgian neuropathological archives, completed with the results of a comprehensive study of available medical records, we found 100 patients who fulfilled diagnostic criteria for probable or definite Creutzfeldt-Jakob d1551isease (CJD). Mean age at death was 63 years. The median disease duration was 9 months. Progressive mental deterioration was present in all cases, whereas signs of cerebellar dysfunction and myoclonus were found in approximately 80% of the patients. In 50% of the population, the EEG revealed characteristic abnormalities. Ninety-six patients suffered from the sporadic type of CJD, while 4 suffered from a hereditary form. In our series, we could find no evidence for the new variant, neither for an iatrogenic cause.