Intercepting Parkinson disease non-motor subtypes: A proof-of-principle study in a clinical setting.

The construct of non-motor symptoms (NMS) subtyping in Parkinson Disease (PD) is emerging as a line of research in the light of its potential role in etiopathological interpretation of PD heterogeneity. Different approaches of NMS subtyping have been proposed: an anatomical model suggests that NMS aggregate according to the underpinning pathology; other researchers find aggregation of NMS according to the motor phenotype; the contribution of genetic background to NMS has also been assessed, primarily focusing on cognitive impairment. We have analyzed NMS burden assessed through an extensive clinical and neuropsychological battery in 137 consecutive non-demented PD patients genotyped for MAPT haplotypes (H1/H1 vs H2 carriers) in order to explore the applicability of the "anatomo-clinical", "motor" or "genetic" models for subtyping PD in a clinical setting; a subsequent independent analysis was conducted to verify a possible cluster distribution of NMS. No clear-cut NMS profiles according to the previously described models emerged: in our population, the autonomic dysfunctions and depressive symptoms represent the leading determinant of NMS clusters, which seems to better fit with the hypothesis of a "neurotransmitter-based" model. Selective preferential neurotransmitter network dysfunctions may account for heterogeneity of PD and could address translational research.

Dry Eye Syndrome in Non-Exophthalmic Graves' Disease.

BACKGROUND: The present study aims to assess qualitative and quantitative characteristics of tear film and corneal related impairment and to evaluate the quality of life in a cohort of non-exophthalmic Graves' disease (GD) patients. METHODS: The series comprised 50 eyes from 25 newly diagnosed GD patients with no proptosis. As control group, 56 eyes of 28 thyroid disease-free subjects were enrolled. RESULTS: The results of Schirmer I and II, break-up time, and Oxford scheme showed a significant difference between GD and controls. By ocular surface disease index (OSDI) questionnaire, eleven (44%) GD patients had normal ocular surface, while two (8%) had mild, four (16%) had moderate, and eight (32%) had severe dry eye. The mean score of the OSDI in the GD group was significantly (p < 0.001) higher with respect to the control group. CONCLUSIONS: This study shows that the tear film and cornea are damaged in newly non-exophthalmic GD subjects.

Mismatch Negativity in essential tremor: role of age at onset in pre-attentive auditory discrimination.

OBJECTIVE: To investigate whether pre-attentive auditory discrimination is impaired in patients with essential tremor (ET) and to evaluate the role of age at onset in this function. METHODS: Seventeen non-demented patients with ET and seventeen age- and sex-matched healthy controls underwent an EEG recording during a classical auditory MMN paradigm. RESULTS: MMN latency was significantly prolonged in patients with elderly-onset ET (>65 years) (p=0.046), while no differences emerged in either latency or amplitude between young-onset ET patients and controls. CONCLUSIONS: This study represents a tentative indication of a dysfunction of auditory automatic change detection in elderly-onset ET patients, pointing to a selective attentive deficit in this subgroup of ET patients. SIGNIFICANCE: The delay in pre-attentive auditory discrimination, which affects elderly-onset ET patients alone, further supports the hypothesis that ET represents a heterogeneous family of diseases united by tremor; these diseases are characterized by cognitive differences that may range from a disturbance in a selective cognitive function, such as the automatic part of the orienting response, to more widespread and complex cognitive dysfunctions.

Attention in essential tremor: evidence from event-related potentials.

Clinically subtle executive dysfunctions have recently been described in essential tremor (ET), though the presence of attentional deficits is still unclear. We investigated the psychophysiological aspects of attention in ET, using event-related potentials (ERPs). Twenty-one non-demented patients with ET and 21 age- and sex-matched healthy controls underwent a psychophysiological evaluation. P300 components and the Contingent Negative Variation (CNV) were recorded. The latencies and amplitudes of the P3a and P3b subcomponents and CNV areas were evaluated. Possible correlations between clinical parameters and ERP data were investigated. P3a latency was significantly longer in the ET group (p < 0.05), while no differences emerged between patients and controls in P3b latency. No differences were observed between the two groups in the CNV parameters. ET patients display a difficulty in the response to novelty and in the recruitment of prefrontal attentive circuits, while the memory context-updating process appears to be spared. This selective cognitive dysfunction does not appear to interfere with the attentional set linked to the expectancy evaluated during a complex choice-reaction time task, which is preserved in ET. This multitask psychophysiological approach reveals the presence of a peculiar attentional deficit in patients with ET, thus expanding the clinical features of this disease.

Psychophysiological aspects of voluntary skilled movement after stroke: a follow-up study.

OBJECTIVES: The aim of the study was to follow the psychophysiological evolution of a self-paced voluntary skilled movement in hemiparetic subjects after ischemic stroke by means of a skilled performance task (SPT). The task consisted in starting a sweep of an oscilloscope trace by pushing one button with the left index finger (trigger point), and in stopping it within a central area on the oscilloscope screen, between 40 and 60 ms (correct performance) after the start of the sweep, by pushing the other button with the right index finger. A SPT yields a considerable amount of information on the electrophysiological components, which reflect pre-programming activity (Bereitschaftspotential--BP), control strategies (Skilled Performance Positivity--SPP) and behavioural response (Correct Performances). The study was also aimed at detecting any longitudinal changes in the psychophysiological pattern, as evaluated by the clinical examination and specific motility scales, that parallel motor recovery. METHODS: Movement related potentials (MRPs) were recorded in 12 control subjects and 9 patients in the acute phase, before the start of neurorehabilitation (time 0), when the patients were able to execute an index finger press with the affected hand. The patients (mean age = 62.33 years, SD = 8.17) presented a mild to moderate central arm paresis caused by a first-ever unilateral supratentorial and subcortical ischemic lesion. The subsequent recordings were carried out respectively 3, 9 and 12 months later. RESULTS: At the first recording, hemiparetic patients achieved a significantly lower percentage of correct performances and had a lower BP amplitude than controls (p < 0.001); SPP was absent. The number of correct performances did not improve significantly during the subsequent recordings. BP amplitude showed a mild increase in the second, third and fourth recordings (p < 0.05), while SPP amplitude revealed a slight improvement at the second and a marked improvement at the third and fourth recordings, when there was no longer a statistically significant difference from controls. CONCLUSIONS: Our findings point to an early recovery of pre-programming activity and a delayed improvement in control activity. The delayed development of control activity in the absence of procedural learning, i.e. skill learning through practice, forces patients to exploit attentional strategies to compensate for their procedural learning impairment. SPT shows that the efficacy of physical therapy aimed at motor ability recovery in hemiparetic patients does not keep up with the slow recovery process of an automatic motor level.

Abnormal head nociceptive withdrawal reaction to facial nociceptive stimuli in Parkinson's disease.

INTRODUCTION: Trigemino-cervical-spinal reflexes (TCSRs) are complex brainstem stereotyped nociceptive responses involved in a defensive withdrawal reaction of the head from facial nociceptive stimuli. OBJECTIVE: The present study was undertaken to collect data on possible TCSR abnormalities in idiopathic Parkinson's disease (PD) and investigate any correlation with motor signs and L-DOPA administration. METHODS: TCSRs were registered from the semispinalis capitis and biceps brachii muscles after electrical stimulation of the supraorbital nerve in 18 patients with PD and 24 controls. The latency (L) and area (A), as well as the sensory (ST), painful (PT) and reflex (RT) thresholds were measured during the 'off' and 'on' state, and possible correlations with the UPDRS III total score, selected subscores (tremor, neck rigidity, upper limb rigidity, akinesia, rising from a chair, posture and posture instability) and duration of illness were investigated. RESULTS: Significant changes between controls and PD patients were found in the L, A, PT and RT of TCSRs. These results were not significantly influenced by L-DOPA treatment. A significant correlation was found between neck rigidity, postural instability scores and duration of illness and the TCSR L and A values in PD patients in the 'off' state. CONCLUSIONS: TCSRs abnormalities, combined with dopamine resistance, are consistent with a primary loss of brainstem neurons mediating a complex sensory-motor integration including neck muscle tone and postural control as well as the head withdrawal reaction to the nociceptive stimuli. SIGNIFICANCE: TCSRs may represent a useful tool for the assessment of brainstem sensory-motor function in PD as well as other movement and degenerative disorders.

Reversible diffusion MRI abnormalities and transient mutism after liver transplantation.

Transient mutism was observed in a liver transplant patient under immunosuppressant therapy with cyclosporine A and antifungal prophylaxis with amphotericin B. Fluid-attenuated inversion recovery and diffusion-weighted images revealed reversible bilateral symmetric hyperintensity located in the frontal motor cortex and corticospinal tracts. These MRI abnormalities may be caused by acute edema, possibly a combination of cytotoxic and vasogenic edema, which resolved with a prompt change in therapy.

Psychophysiological approach in Parkinson's disease: L-dopa effects on preprogramming and control activity.

To investigate whether preprogramming (Bereitschaftspotential, BP) and control activity (skilled performance positivity, SPP) in a complex task are sensitive to L-dopa, movement related potentials (MRPs) were recorded in 12 non-demented Parkinson's disease (PD) patients before and after acute L-dopa administration, and in 17 control subjects. After L-dopa administration, the PD patients scored a significantly higher percentage of correct performances ( p<0.05), linked to a decreased BP amplitude ( p<0.001) and an increased SPP amplitude ( p<0.005), than before therapy. Our findings suggest that preprogramming activity is impaired in untreated PD patients. Dopaminergic drug administration seems to restore their ability to use more automatic motor strategies which become more similar to that of normal subjects.

Epidemiology of progressive supranuclear palsy. ESGAP Consortium. European Study Group on Atypical Parkinsonisms.

Progressive supranuclear palsy (PSP) is a rare form of parkinsonism. The incidence rates are about 0.3-1.1 cases per 100,000 persons. The only two case-control studies performed up to now show conflictual results as regards education and residence in rural areas. Recently, a cluster of PSP and atypical parkinsonism has been observed in French Antilles. The hypothesis is that a consumption of both tropical fruit and herbal tea may be associated with PSP onset. Some PSP families with a probably autosomal dominant transmission have been described. A high frequency of a tau haplotype (H1/H1) associated with PSP is reported by some authors. The significance of this association is still not clear. We have performed a case-control study on 58 PSP cases, 116 hospital controls and 58 population controls.

Epidemiology of multiple system atrophy. ESGAP Consortium. European Study Group on Atypical Parkinsonisms.

Multiple system atrophy (MSA) is a form of atypical parkinsonism with unknown etiology. The epidemiological studies conducted up to now on this disease are scarce. The incidence rate is about 0.6 cases per 100,000 persons per year. The prevalence rates show 4-5 cases per 100,000 persons. In Italy, about 4,900 prevalent cases have been estimated. The mean onset age is about 54 years; the median survival is 7-9 years. Only one case-control study has been performed on this disease. This study showed an increased risk of MSA associated with occupational exposure to organic solvents, plastic monomers and additives, pesticides and metals. Smoking habits seem to be less frequent in MSA cases (as in Parkinson's disease cases) than in healthy controls. Quinn's clinical criteria and those of the Consensus Conference promoted by the American Academy of Neurology are in fair agreement. We have performed a case-control study on 73 MSA cases, 146 hospital controls and 73 population controls.

Mitochondrial myopathy, parkinsonism, and multiple mtDNA deletions in a Sephardic Jewish family.

The authors describe a family of Sephardic Jews with progressive external ophthalmoparesis, skeletal muscle weakness, and parkinsonism. Autosomal recessive inheritance was suggested by many consanguineous marriages, although a dominant disorder could not be excluded. No linkage to known progressive external ophthalmoparesis locus was found. The presence of cytochrome c oxidase-negative ragged-red fibers, biochemically reduced respiratory chain complexes, and multiple mitochondrial DNA deletions in muscle biopsies from four patients suggested a new mitochondrial disorder of intergenomic communication.

Heart rate variability in Parkinson's disease patients treated with tolcapone.

Following the introduction of tolcapone, a potent, reversible Catechol-O-methyltransferase (COMT) inhibitor, it has been possible to optimise the management of Parkinson's disease (PD) patients in chronic Levodopa (L-dopa) therapy. The interaction between tolcapone and the endogenous metabolism of catecholamines points to a possible influence on autonomic cardiovascular function.Cardiovascular reflexes have been analysed in a group of seven PD patients (four males, three females; mean age 69.7years, mean disease duration 14.1years) by means of the heart rate variability (HRV) method using a continuous 24-h ECG (ECGD), before and after six months of treatment with tolcapone (in addition to L-dopa).We have observed no statistically significant differences in HRV parameters, nor any changes in the incidence of hyperkinetic and hypokinetic arrhythmias, which suggest that autonomic cardiovascular function in PD patients is not influenced by six months of treatment with tolcapone.

The tau gene in progressive supranuclear palsy: exclusion of mutations in coding exons and exon 10 splice sites, and identification of a new intronic variant of the disease-associated H1 haplotype in Italian cases.

Mutations in coding exons or exon 10 5'-splice-site of the gene for microtubule-associated protein tau can cause chromosome 17-linked frontotemporal dementia and parkinsonism (FTDP-17). We sequenced the 11 coding exons plus exon-intron boundaries of the tau gene in 15 cases of progressive supranuclear palsy (PSP), and found no mutations in coding exons or exon ten 5'-splice sites. These data indicate that typical PSP is not associated with tau gene mutations similar to those causing FTDP-17. We also observed a +39deltaG base change in the intron following exon 4 in three out of 69 PSP cases (all three Italians), whereas it was not found in 150 Dutch controls and once in 112 Italian controls. The +39deltaG variant arose in the context of the PSP-associated tau H1 haplotype. Although a pathogenic role cannot be entirely excluded, +39deltaG is likely to be a rare polymorphism that may be in linkage disequilibrium with a biologically relevant locus inside or near to the tau gene.

The circulating insulin-like growth factor system in children with coeliac disease: an additional marker for disease activity.

BACKGROUND: Chronic undernutrition resulting from coeliac disease (CD) could be associated with changes in the circulating insulin-like growth factor (IGF) system, which may participate in the pathogenesis of growth retardation occurring in these patients. METHODS: We performed a cross-sectional study in CD subjects attempting to (1) document the pattern of serum IGF-I and IGF binding protein (IGFBP) 1 and 3 at diagnosis and (2) assess the response of circulating IGF system to dietary treatments, in comparison with the response of clinical and laboratory findings utilized for the diagnosis of CD. Thirty-two prepubertal CD children were divided into three groups based on the dietetic treatment: at diagnosis (D, n=18); on gluten-free diet for at least 6 months (GFD, n=7); and on gluten challenge for at least 3 months (CH, n=7). Six postpubertal CD patients were also studied at diagnosis. RESULTS: In prepubertal children IGF-I levels were significantly reduced (by 29%) in D vs sex- and age-matched normal control (NC) subjects, with reductions being more pronounced before 3 years of age. Likewise, serum IGFBP-3 concentrations were decreased by 22%, whereas circulating IGFBP-1 levels were increased by 60%, compared with NC, with more marked IGFBP changes in older children. Similar alterations were observed in postpubertal patients. Changes in the circulating IGF system disappeared in GFD subjects and reappeared in CH children, as positivity of disease-specific antibodies. Body mass index (BMI) also improved in GFD subjects, but did not decrease in CH children. Changes in IGF-I and IGFBPs did not correlate with each other. Levels of IGF-I, but not of IGFBPs, maintained the relation with age and correlated significantly with BMI and positivity of antibodies. CONCLUSIONS: These results demonstrate that CD patients show significant changes in serum IGF-I, in younger children, and IGFBPs (particularly IGFBP-1), in older children and adolescents, correlating with clinical course and response to dietary treatments. The alteration in the circulating IGF system could be implicated in the pathogenesis of growth retardation occurring in CD and may provide an additional tool in monitoring of the disease.

Twenty-four-hour heart rate variability to assess autonomic function in Parkinson's disease.

OBJECTIVES: To evaluate the autonomic dysfunction in Parkinson's disease patients by means of a 24-h heart rate variability (HRV) method. MATERIAL AND METHODS: Thirteen patients with a diagnosis of Parkinson's disease were compared with 13 age-matched healthy persons (control group). The 13 patients had a mean age of 70.5 years, and mean disease duration of 10.9 years. The autonomic function was evaluated by HRV analysis using a continuous 24-h ECG. The parameters of SDNN (standard deviation of the normal-to-normal intervals between adjacent QRS complexes), of LF (power in low frequency) and of HF (power in high frequency) were studied during the following 3 periods: 24 h, night and day. RESULTS: The data show a statistically significant difference between groups for SDNN and LF in all the periods, while for HF parameters the difference is statistically significant only in the night period. CONCLUSION: The use of the 24-h HRV method can provide more accurate and reproducible data than other conventional cardiovascular tests.

Increased activity of the insulin-like growth factor system in mesangial cells cultured in high glucose conditions. Relation to glucose-enhanced extracellular matrix production.

Recent evidence suggests that several growth factors participate in diabetic glomerular disease by mediating increased extracellular matrix accumulation and altered cell growth and turnover leading to mesangial expansion. Transforming growth factor (TGF)-beta has been demonstrated to be upregulated both in vivo and in vitro, whereas studies on the activity of the renal insulin-like growth factor (IGF) system in experimental diabetes have provided conflicting results. We investigated the effects of prolonged exposure (4 weeks) of cultured human and rat mesangial cells to high (30 mmol/l) glucose vs iso-osmolar mannitol or normal (5.5 mmol/l) glucose levels on: 1) the autocrine/paracrine activity of the IGF system (as assessed by measuring IGF-I and II, IGF-I and II receptors, and IGF binding proteins); and, in parallel, on 2) TGF-beta 1 gene expression; 3) matrix production; and 4) cell proliferation. High glucose levels progressively increased the medium content of IGF-I and the mRNA levels for IGF-I and IGF-II, increased IGF-I and IGF-II binding and IGF-I receptor gene expression, and reduced IGF binding protein production. TGF-beta 1 transcripts and matrix accumulation and gene expression were increased in parallel, whereas cell proliferation was reduced. Iso-osmolar mannitol did not affect any of the above parameters. These experiments demonstrated that high glucose levels induce enhanced mesangial IGF activity, together with enhanced TGF-beta 1 gene expression, increased matrix production, and reduced cell proliferation. It is possible that IGFs participate in mediating diabetes-induced changes in matrix turnover leading to mesangial expansion, by acting in a paracrine/autocrine fashion within the glomerulus.

Insulin-like growth factors I and II stimulate extracellular matrix production in human glomerular mesangial cells. Comparison with transforming growth factor-beta.

An enhanced paracrine/autocrine activity of the insulin-like growth factor (IGF) system within the glomerulus has been implicated together with up-regulation of transforming growth factor-beta (TGFbeta) in the pathogenesis of diabetic glomerular disease. This would imply their ability to modulate extracellular matrix (ECM) and cell turnover at the mesangial level, but the direct effects of IGFs on ECM production have not been demonstrated to date. These experiments in cultured human mesangial cells were aimed at assessing the effects of IGF-I and IGF-II, compared with those of TGFbeta, on 1) ECM medium accumulation and gene expression, and 2) total protein synthesis and cell proliferation. Human mesangial cells were grown to subconfluence, growth arrested for 48 h, and then exposed for 4-24 h to serum-free medium containing IGF-I (10(-7) - 10(-11) M), IGF-II (10(-7) - 10(-11) M), TGFbeta (10(-9) - 10(-11) M), or various combinations of two of these growth factors (10(-9)M). All three growth factors dose dependently increased ECM protein and messenger RNA levels. The combination of either IGF-I or IGF-II with TGFbeta, but not the two IGFs together, produced additive effects on matrix production. Total protein synthesis was also increased by IGF-I, IGF-II, and TGFbeta, although to a lesser extent than ECM production, whereas cell proliferation was enhanced by IGFs but not by TGFbeta. These results demonstrate that IGF-I and IGF-II are effective, although less potent than TGFbeta, in stimulating the production of the ECM components that accumulate in the mesangial region during the course of diabetic glomerular disease.

Changes in central and peripheral nervous system function during hypoglycemia in man: an electro-physiological quantification.

We measured somatosensory evoked potentials (SEP) in normal subjects during acute (group A) and moderately prolonged (group B) hypoglycemia. We considered the following parameters: peripheral conduction velocity (wrist-Erb CV), conduction time (CT) between brachial plexus and the cervical cord (Erb-N13) and central CT from the cervical cord/lower brainstem lemniscal pathway to the cortex (N13-N20). In group A, the electrophysiological parameters did not change significantly throughout the study. In group B, mean N13-N20 CT increased from a basal values of 5.82 +/- 0.11 to 6.22 +/- 0.11 msec at 105 min (p less than 0.02) and 6.33 +/- 0.11 msec at 120 min (p less than 0.05). This study indicates that neither acute nor moderately prolonged hypoglycemia influence the peripheral nerve function in normal subjects and provides evidence that hypoglycemia as low as 2.4 mmol/L, lasting more than 60 min, can significantly increase the conduction time of central somatosensory pathways.