Which cognitive dual-task walking causes most interference on the Timed Up and Go test in Parkinson's disease: a controlled study.

BACKGROUND: There is evidence that cognitive load has a negative effect on the gait of patients with Parkinson's disease (PD). However, it is not clear which type of cognitive activities are more likely to affect dual-task abilities in this patient group. AIMS: To compare the cognitive dual-task abilities in patients with PD and control subjects and to analyze the effect of different cognitive activities on the walking ability of patients with PD. METHODS: The Hoehn and Yahr scale, the Freezing of Gait Questionnaire (FOGQ), Montreal Cognitive Assessment (MoCA), and the Functional Reach Test were used to include and exclude the patients. The Timed Up and Go (TUG) test was applied under single and dual-task conditions. RESULTS: The completion time of TUG was found to be increased in the PD group compared with the healthy controls under single- and dual-task conditions (p < 0.05). The completion time of TUG was significantly increased in dual-task conditions with complex attention activity (serial subtractions test) compared with other dual-task conditions in patients with PD (p < 0.001). DISCUSSION: The gait performance of both healthy subjects and patients with PD was impaired with cognitive activity during walking, and patients with PD showed more impairment under different cognitive dual tasks. Among the other cognitive tasks, the 'serial sevens' test, a measure of complex attention, significantly increased the completion time of TUG. CONCLUSIONS: While assessing the dual-task ability of patients with early-stage PD, tasks that increase the demand for complex attention seem to be more sensitive to showing impaired dual-task ability.

An assessment of Movement Disorder Society Task Force diagnostic criteria for mild cognitive impairment in Parkinson's disease.

BACKGROUND AND PURPOSE: Cognitive impairment is one of the most disabling non-motor symptoms of Parkinson's disease. Mild cognitive impairment constitutes a major risk for the development of Parkinson's disease dementia in the course of the disease. A Movement Disorder Society Task Force proposed diagnostic criteria for mild cognitive impairment in Parkinson's disease (PD-MCI), comprising two operational levels: Level I and Level II. The objective of our study was to test the accuracy of Level I versus Level II diagnostic criteria. METHODS: Eighty-six consecutive patients with Parkinson's disease were screened and 68 patients without dementia or depression were included in the study. We used the Montreal Cognitive Assessment, Mini-Mental State Examination and Addenbrooke's Cognitive Evaluation-R screening tools for Level I and an extensive neuropsychological battery for Level II assessment. We first diagnosed PD-MCI on the basis of Level II assessment and then calculated sensitivity, specificity and area under the receiver-operator characteristics curve, comparing the performance of the three screening batteries. RESULTS: None of the three screening batteries proposed for Level I assessment provided satisfactory combined sensitivity and specificity for detecting PD-MCI, and their performance was similar. Using the Level II criteria, 29 patients (43%) were diagnosed as having PD-MCI. Lowest cut-off levels that provided at least 80% sensitivity were 24 for the Montreal Cognitive Assessment, 29 for the Mini-Mental State Examination and 87 for the Addenbrooke's Cognitive Evaluation-R. However, specificity levels were below 80% at these cut-off levels. CONCLUSIONS: We conclude that Level I assessment alone using screening batteries is not sufficiently sensitive/specific to detect PD-MCI.

SYNE1 related cerebellar ataxia presents with variable phenotypes in a consanguineous family from Turkey.

SYNE1 related autosomal recessive cerebellar ataxia type 1 (ARCA1) is a late-onset cerebellar ataxia with slow progression originally demonstrated in French-Canadian populations of Quebec, Canada. Nevertheless, recent studies on SYNE1 ataxia have conveyed the condition from a geographically limited pure cerebellar recessive ataxia to a complex multisystem phenotype that is relatively common on the global scale. To determine the underlying genetic cause of the ataxia phenotype in a consanguineous family from Turkey presenting with very slow progressive cerebellar symptoms including dysarthria, dysmetria, and gait ataxia, we performed SNP-based linkage analysis in the family along with whole exome sequencing (WES) in two affected siblings. We identified a homozygous variant in SYNE1 (NM_033071.3: c.13086delC; p.His4362GlnfsX2) in all four affected siblings. This variant presented herein has originally been associated with only pure ataxia in a single case. We thus present segregation and phenotypic manifestations of this variant in four affected family members and further extend the pure ataxia phenotype with upper motor neuron involvement and peripheral neuropathy. Our findings in turn established a precise molecular diagnosis in this family, demonstrating the use of WES combined with linkage analysis in families as a powerful tool for establishing a quick and precise genetic diagnosis of complex neurological phenotypes.

Genetic bases and phenotypes of autosomal recessive Parkinson disease in a Turkish population.

BACKGROUND AND PURPOSE: To evaluate the phenotype and the frequencies of mutations in PRKN, DJ1 and PINK1 genes in patients with Parkinson disease (PD) in Turkey. METHODS: Eighty-six patients from 77 PD families participated in the study. Seventy-four families were originating from Turkey, two families from Greece and one family from Bulgaria. All patients underwent detailed neurological examination. PRKN, PINK1 and DJ1 genes were sequenced, and dosage analysis was performed by multiplex ligation-dependent probe amplification. RESULTS: Sixteen patients with PD were found to carry homozygous (n = 14) or compound heterozygous (n = 2) PRKN mutations. We identified exon rearrangements, three point mutations and one new point mutation in exon 2 (p.K27del). In two families, two new PINK1 point mutations (L31X and P416L) were identified. No pathogenic mutations were found in DJ1 gene. Clinical phenotypes of PRKN patients were comparable to previously described features, but only in four of 13 families, the pedigree structure was clearly consistent with an autosomal recessive (AR) mode of inheritance in comparison with nine families where also different pattern of transmission could have been possible. CONCLUSIONS: Our data suggest that the PRKN gene mutation is the most frequent form of ARPD in Turkey. The proportion of mutations with regard to the age of onset in our population is in the range of those previously described, but our pedigrees are characterized by high rate of consanguinity, which might explain the high proportion of families with homozygous mutations and of patients in more than one generation. Pathogenic DJ1 mutations do not seem to play a major role in Turkey.

The combinations of TNFalpha-308 and IL-6 -174 or IL-10 -1082 genes polymorphisms suggest an association with susceptibility to sporadic late-onset Alzheimer's disease.

OBJECTIVE: Single nucleotide polymorphisms in the regulatory regions of the cytokine genes for tumor necrosis factor alpha (TNFalpha), interleukin (IL)-6 and IL-10 have been suggested to influence the risk of Alzheimer's disease (AD) with conflicting results. AIM: To investigate the TNFalpha-308, IL-6 -174 and IL-10 -1082 gene polymorphisms as susceptibility factors for AD. METHODS: We analyzed genotype and allele distributions of these polymorphisms in 101 sporadic AD patients and 138 healthy controls. RESULTS: Heterozygotes (AG) or combined genotype (AG+AA) for IL-10 -1082 were associated with approximately two-fold increase in the risk of AD. Carriers of A alleles of both TNFalpha-308 and IL-10 -1082 had 6.5 times higher risk for AD in comparison with non-carriers. Concomitant presence of both mutant TNFalpha-308 A and IL-6 -174 C alleles raised three-fold the AD risk, whereas there was no notable risk for AD afflicted by IL-6 -174 polymorphism alone. CONCLUSION: Our results suggest that TNFalpha and IL-10 promoter polymorphism might be a risk factor for AD. The combined effects of TNFalpha-308, IL-6 -174 and IL-10 -1082 variant alleles may be more decisive to induce functional differences and modify the risk for AD.

Comparison of unilateral pallidotomy and subthalamotomy findings in advanced idiopathic Parkinson's disease.

A prospective, randomized, double-blind pilot study to compare the results of stereotactic unilateral pallidotomy and subthalamotomy in advanced idiopathic Parkinson's disease (PD) refractory to medical treatment was designed. Ten consecutive patients (mean age, 58.4 +/- 6.8 years; 7 men, 3 women) with similar characteristics at the duration of disease (mean disease time, 8.4 +/- 3.5 years), disabling motor fluctuations (Hoehn & Yahr stage 3-5 in off-drug phases) and levodopa-induced dyskinesias were selected. All patients had bilateral symptoms and their levodopa equivalent dosing were analysed. Six patients were operated on in the globus pallidus interna (GPi) and four in the subthalamic nucleus (STN). Clinical evaluation included the use of the Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn&Yahr score and Schwab England activities of daily living (ADL) score in 'on'- and 'off'-drug conditions before surgery and 6 months after surgery. There was statistically significant improvement in all contralateral major parkinsonian motor signs in all patients followed for 6 months. Levodopa equivalent daily intake was significantly reduced in the STN group. Changes in UPDRS, Hoehn & Yahr and Schwab England ADL scores were similar in both groups. Cognitive functions were unchanged in both groups. Complications were observed in two patients: one had a left homonymous hemianopsia after pallidotomy and another one developed left hemiballistic movements 3 days after subthalamotomy which partly improved within 1 month with Valproate 1000 mg/day. The findings of this study suggest that lesions of the unilateral STN and GPi are equally effective treatment for patients with advanced PD refractory to medical treatment.

The prevalence of dementia in an urban Turkish population.

A cross-sectional, population-based, 2-stage prevalence study was conducted in a sample of 1019 community-dwelling persons over the age of 70 years living in Istanbul. In the first phase, participants were screened with the Mini-Mental State Examination for evidence of cognitive impairment. In the second phase, 79% of those who screened positive (n = 322) and 9% of screen-negatives (n = 63) underwent a standardized diagnostic workup. Diagnosis of dementia and Alzheimer's disease (AD) was made according to established criteria. Ninety-three cases of dementia were identified, 58 of whom were diagnosed with probable AD. Based on these numbers, the prevalence rates of probable AD and dementia were calculated to be 11.0% (95% CI, 7.0% to 15.0%) and 20.0% (95% CI, 14.0% to 26.0%), respectively, in this population. Prevalence rates of dementia and AD in Istanbul, Turkey, are comparable with those seen in the Western world.

The Arg194Trp polymorphism in DNA repair gene XRCC1 and the risk for sporadic late-onset Alzheimer's disease.

Alzheimer's disease (AD) is defined pathologically by the presence of beta-amyloid plaques, neurofibrillary tangles and extensive neuronal loss. Evidence indicates that increased DNA damage may contribute to neuronal loss in AD. Recently, it has been shown that in AD neurons have a reduced capacity for some types of DNA repair. Polymorphisms in DNA repair genes may be associated with differences in repair efficiency of DNA damage. Variants of several DNA repair genes, including the base excision repair gene XRCC1, have been described previously. We hypothesised that Arg194Trp polymorphism of XRCC1 gene may contribute to genetic susceptibility for AD. In order to test this hypothesis, we investigated Arg194Trp polymorphism at the XRCC1 gene in the DNA samples of 98 patients with AD and 95 healthy subjects. The frequency of the Trp allele was more pronounced among cases (11.2%) compared with controls (5.8%). On combining the homozygous and heterozygous variants of each codon, the variants seemed to be at twofold risk of AD, although the risk estimates were not statistically significant (OR=1.95, 95% CI 0.88-4.34, p=0.09). In addition, the 194Trp allele revealed a borderline significance (OR=2.05, 95% CI 0.96-4.37, p=0.056). According to our results, it may be speculated that the polymorphic variants of XRCC1 codon 194 have a role in the development of AD.

Parkin expression in muscle from three patients with autosomal recessive Parkinson's disease carrying parkin mutation.

Absence of parkin has been shown to cause the downturned wing phenotype and severe disruption of myofibrils and mitochondrial abnormalities in parkin null mutant drosophila. The present report refers to studies on 3 patients with autosomal recessive Parkinson's disease with mild histopathological changes in muscle and a 'G' deletion at the exon9/intron9 junction or exon 3 deletion in the parkin gene. Using an antibody against a peptide corresponding to sequence number 305-323 of the human parkin protein it was demonstrated that parkin was expressed in skeletal muscle of these patients and that its distribution was similar to that in normal muscles. The mild nature of the histopathological changes, especially in the young patients, in the presence of parkin mutations may be due to residual E3-ubiquitin ligase activity of the mutant protein, to existence of muscle-specific splice-variants or to the relative functional insignificance of parkin in human muscle fibres. Further investigation of parkin expression in skeletal muscle is warranted.

Parkin expression in human skeletal muscle.

Parkin is known to be present in human neurons and peripheral nerves. Using an antibody against parkin protein we have now demonstrated that parkin is also expressed in the sarcoplasm and sarcolemmal region of human skeletal muscle fibres. We have also found different age-related patterns of expression with increase in intensity and organization of distribution at older ages. These findings suggest a change in the functional role of parkin in skeletal muscle with ageing and may contribute to understanding the mechanisms of muscle aging.

Stiff leg syndrome: case report.

We report on a 28-year-old woman with insulin-resistant diabetes mellitus with a 5-year history of progressive stiffness and painful spasms of the right leg, exaggerated by sudden auditory and tactile stimuli or by emotional stress. There were no signs of truncal rigidity or exaggerated lumbar lordosis. Anti-glutamic acid decarboxylase antibodies were positive in her serum. She improved substantially with clonazepam 4 mg/day. She presented with electrophysiological findings not previously reported in stiff leg syndrome, which may suggest increased inhibition in the uninvolved upper extremities.

Atypical neurological involvement associated with celiac disease.

We report an unusual case of celiac disease in a 31-year-old woman with gait disorder, stimulus-induced myoclonus and abnormalities of eye movement. We suggest that celiac disease can present with a variety of unusual neurological manifestations.

Do unilateral ablative lesions of the subthalamic nucleu in parkinsonian patients lead to hemiballism?

We report the safety results in nine patients with advanced idiopathic Parkinson's disease (PD) who underwent ablative surgery of unilateral subthalamic nucleus (STN). In eight patients, surgical objectives were attained without induction of abnormal involuntary movements or other adverse effects. One patient developed transient hemiballistic movements which improved within 2 weeks after surgery. Assessment at 2 weeks to 20 months postoperatively revealed no long-term adverse effects. We conclude that hemiballism following unilateral ablation of STN in patients with PD is a rare phenomenon, and unilateral ablative lesions of STN can be performed safely.

Intravenous apomorphine therapy in Parkinson's disease: clinical and pharmacokinetic observations.

Six patients with Parkinson's disease and refractory motor fluctuations, with severe subcutaneous (s.c.) nodule formation as a result of long-term s.c. apomorphine infusions, were switched to intravenous (i.v.) therapy via a long-term in-dwelling venous catheter. Five patients were followed-up for a mean of 7 months (range 0.5-18 months). All patients had plasma apomorphine concentrations measured at baseline during s.c. infusions and three had follow-up measurements when stabilized on i.v. therapy, to test the hypothesis that motor fluctuations in these patients are largely due to impaired absorption of apomorphine. The mean i.v. rate of 9.0 mg/h (range 5-14 mg) and 24-h dose of 256.7 mg (range 90-456 mg) of apomorphine were not significantly reduced compared with the s.c. route (9.24 mg/h and 243.4 mg). However, additional oral anti-parkinsonian medication was reduced by a mean of 59%, and 'off' time was virtually eliminated (mean reduction from 5.4 to 0.5 h per day, P< 0.05). There was also a significant reduction in dyskinesias and markedly improved quality of life. Pharmacokinetic analysis demonstrated more reliable and smoother delivery of apomorphine via the i.v. route, although 'off' periods were not always explained by low plasma apomorphine concentrations. Complication rates were high and included three unforeseen hazardous intravascular thrombotic complications, secondary to apomorphine crystal accumulation, necessitating cardiothoracic surgery. We conclude that i.v. apomorphine therapy holds promise as a more effective way of controlling motor fluctuations than the s.c. route. However, further preclinical research is required before i.v. Britaject apomorphine can be recommended for routine clinical practice. Even when stable plasma apomorphine concentrations were achieved, motor fluctuations could not be totally eradicated, suggesting that postsynaptic receptor changes may also play a role in the refractory 'off' periods in these patients.

Neuronal intranuclear inclusion disease and juvenile parkinsonism.

Juvenile parkinsonism (onset age <20 yrs) is uncommon and few cases with neuropathologic confirmation have been reported. We present the case of a 17-year-old boy who presented with asymmetric arm tremor and bulbar symptoms. His paternal great aunt had parkinsonism with onset at age 22 years. Examination revealed parkinsonism in the absence of additional neurologic signs except for delayed pupillary responses to light. He responded well to levodopa but developed motor fluctuations and disabling dyskinesias after 3 years of treatment. Following attempted withdrawal of levodopa at age 24 years, he developed severe aspiration pneumonia complicated by cardiorepiratory arrests and he died 6 months later. At autopsy, the dominant histologic feature was wide-spread neuronal hyaline intranuclear inclusions. Neuronal depletion was observed in the substantia nigra, locus ceruleus, and, to a lesser extent, in the frontal cortex, and inclusions were particularly prominent in these areas. Inclusions were immunoreactive for ubiquitin and were typical of those seen in neuronal intranuclear inclusion disease (NIID), a rare, multisytem neurodegenerative disease. NIID should be considered in the differential diagnosis of juvenile parkinsonism. A link between NIID and hereditary neurodegenerative disorders characterized by expanded polyglutamine tracts is supported by the similar appearance of intranuclear inclusions in both conditions and by a family history in some cases of NIID.

Evidence-based pharmacological treatment of dementia.

The current literature on the pharmacological treatment of dementia was reviewed and the strength of evidence for the efficacy of each drug was categorized using an evidence-based approach. Acetylcholinesterase-inhibitors represent the only category of drugs with consistently demonstrable efficacy in well-designed studies of Alzheimer's disease, although the effect is not large. There is a lack of prospective, controlled, randomized studies for most of the nootropics. Epidemiological evidence suggests prophylactic effects of oestrogens and anti-inflammatory agents, and a single large-scale trial suggests that long-term administration of vitamin E or selegiline may be associated with improved outcome in patients with Alzheimer's disease. A number of drugs were reported to be effective in the treatment of non-cognitive symptoms of dementia including classical and atypical neuroleptics, antidepressants and anticonvulsants. The evidence for efficacy, however, is not strong for the majority of these compounds.