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1.
Ito M Watanabe H Kawai Y Atsuta N Tanaka F Naganawa S Fukatsu H Sobue G 《Journal of neurology, neurosurgery, and psychiatry》2007,78(7):722-728
Objective
To determine whether apparent diffusion coefficient (ADC) values and fractional anisotropy (FA) values can detect early pathological involvement in multiple system atrophy (MSA), and be used to differentiate MSA‐P (multiple system atrophy if parkinsonian features predominate) from Parkinson''s disease (PD).Methods
We compared ADC and FA values in the pons, cerebellum and putamen of 61 subjects (20 probable MSA patients, 21 age matched PD patients and 20 age matched healthy controls) using a 3.0 T magnetic resonance system.Results
ADC values in the pons, cerebellum and putamen were significantly higher, and FA values lower in MSA than in PD or controls. These differences were prominent in MSA lacking dorsolateral putaminal hyperintensity (DPH) or hot cross bun (HCB) sign. In differentiating MSA‐P from PD using FA and ADC values, we obtained equal sensitivity (70%) and higher specificity (100%) in the pons than in the putamen and cerebellum. In addition, all patients that had both significant low FA and high ADC values in each of these three areas were MSA‐P cases, and those that had both normal FA and ADC values in the pons were all PD cases. Our diagnostic algorithm based on these results accurately diagnosed 90% of patients with MSA‐P.Conclusion
FA and ADC values detected early pathological involvement prior to magnetic resonance signal changes in MSA. In particular, low FA values in the pons showed high specificity in discriminating MSA‐P from PD. In addition, combined analysis of both FA and ADC values in all three areas was more useful than only one.Multiple system atrophy (MSA) is a sporadic adult onset neurodegenerative disease presenting a combination of parkinsonism, cerebellar ataxia and autonomic failure during the course of the illness.1,2,3,4 A consensus statement recommended designating patients as having MSA‐P if parkinsonian features predominated or MSA‐C if cerebellar features predominated.5 Differentiation of Parkinson''s disease (PD) from MSA‐P is particularly important because these disorders differ in progression, prognosis and treatment responses.6 However, a purely clinical differentiation, especially in the early phase of the disease, remains challenging.In advanced MSA, MRI reliably shows characteristic signal changes, such as dorsolateral putaminal hyperintensity (DPH) and the hot cross bun (HCB) sign,7,8,9,10 but these signs are not useful for differentiation between MSA‐P and PD in their early phases.11Apparent diffusion coefficient (ADC) values and fractional anisotropy (FA) values are new parameters on MRI, and these were used to evaluate the degree of tissue degeneration in various disorders. ADC values measure the average water diffusion, and increasing ADC values indicate tissue degeneration. FA values measure the degree of anisotropy of the diffusing water along different axes of the image, and decreasing FA values represent tissue degeneration. Recently, there have been some reports concerning ADC and FA values in MSA‐P and PD patients. ADC values in the striatum were higher in MSA‐P than in PD,12 and those in the basis pontis and cerebellum were higher in MSA‐C than in controls.13 FA values in the middle cerebellar penduncle, basis pontis and internal capsule were lower in MSA‐C than in controls.14 However, these results still do not confirm whether ADC and FA values are really effective at discriminating MSA‐P from PD, particularly in their early phases. To confirm the hypothesis that ADC and FA values can detect abnormalities in patients with MSA, even without DPH and HCB, and discriminate MSA‐P from PD, a direct study of these values at various stages of MSA and PD and in various regions is needed.The aim of the present investigation was to examine the utility of ADC and FA values in the pons, cerebellum and putamen to detect not only the early pathological changes in MSA but also to differentiate MSA‐P from PD. 相似文献2.
Albrecht J Dellani PR Müller MJ Schermuly I Beck M Stoeter P Gerhard A Fellgiebel A 《Journal of neurology, neurosurgery, and psychiatry》2007,78(9):964-969
Background
Fabry disease (FD) is a lysosomal storage disorder associated with marked cerebrovascular disease. Conventional MRI shows an extensive load of white matter lesions (WMLs) which may already be present at an early stage in the disease.Objective
Investigator independent and sensitive quantification of structural changes in the brain in clinically affected men and women with FD.Methods
We performed a voxel based analysis of diffusion tensor images (DTI) in 25 patients with FD and 20 age matched normal controls.Results
DTI revealed significant increases in cerebral white matter mean diffusivity (MD) in patients with FD, which were pronounced in the periventricular white matter. Even the subgroup of patients without significant WMLs load (n = 18) showed increased diffusivity in the cerebral white matter. In gray matter areas, MD elevation was detected only in the posterior part of the thalamus, independent of the visible pulvinar alterations on T1 weighted images. Voxel based fractional anisotropy measurements did not differ significantly between patients and controls.Conclusions
The present study demonstrates the clinical feasibility of voxel based analysis of DTI as a sensitive tool to quantify brain tissue alterations in FD. The pattern of increased brain tissue diffusivity is probably due to microangiopathic alterations, mainly affecting the long perforating arteries.Fabry disease (FD) is a rare X‐linked hereditary lysosomal storage disease.1 Deficiency of α‐galactosidase A activity leads to accumulation of neutral glycosphingolipids, particularly in vascular endothelial and smooth muscle cells of various organs.2 Together with progressive renal and cardiac dysfunction, clinical CNS involvement mainly due to cerebral vasculopathy leading to serious complications such as stroke at an early age has been confirmed in clinical studies3,4 and by neuroimaging.5,6,7,8,9,10 The most prominent brain structural findings in FD are severe progressive white matter lesions (WMLs) that are detectable by T2 and FLAIR weighted images using conventional MRI.5,7,10,11,12Focusing on WMLs and quantifying structural cerebrovascular involvement by visual rating scales on conventional MRI is compromised by limited accuracy.13,14Investigation of the structure of the brain, in particular the detection of typical patterns of brain structural involvement as well as assessment of the natural course of these affections, is important for a better understanding of the pathophysiology of the brain and to study the potential effects of new treatment options, such as enzyme replacement therapy (ERT) in FD.There is evidence that diffusion tensor imaging (DTI) is more accurate and more sensitive in quantifying structural brain alterations than other assessments in conventional magnetic resonance techniques.6,15,16,17 The principal parameters derived from diffusion tensor analysis are fractional anisotropy (FA) and mean diffusivity (MD). Reduced water diffusion parallel to axonal tracts represented by FA is indicative of axonal degeneration.18 Furthermore, MD, which measures randomised mean water diffusion, is a representative DTI parameter for ultrastructural brain tissue alterations.19 Thus DTI provides a promising tool for detection of early ultrastructural cerebral changes in FD.The use of diffusivity measurements in patients with FD has been demonstrated previously. One study showed global elevation of the average diffusion constant in cerebral tissue from men with FD.20 Moreover, analysing DTI with regions of interest (ROI), we previously showed significant elevations in white matter diffusivity (MD), even in those FD patients without significant WMLs.6 However, ROI based analysis is time consuming, investigator dependent and usually does not cover the whole brain.To investigate the feasibility of investigator independent structural data processing procedures which cover the whole brain, we analysed DTI data from patients with FD using a voxel based approach. In this way, structural differences in the brain can be detected by voxel wise comparison of normalised DTI maps between patient and control groups. 相似文献3.
Liang Z Zeng J Liu S Ling X Xu A Yu J Ling L 《Journal of neurology, neurosurgery, and psychiatry》2007,78(6):581-586
Background
Secondary degeneration of the pyramidal tract distal to the primary lesion after a stroke has been detected by some studies using diffusion tensor imaging (DTI) but its potential clinical significance and the degeneration of the fibre tract proximal to the primary lesion have received little attention.Methods
Twelve patients underwent DTI on the 1st, 4th and 12th week following a subcortical infarct involving the posterior limb of the internal capsule, and 12 age and sex matched controls underwent DTI once. The DTI parameters mean diffusivity and fractional anisotropy (FA), and the clinical scores before DTI examination, including the National Institutes of Health Stroke Scale (NIHSS), the Fugl–Meyer (FM) scale and the Barthel index (BI), were assessed. The relations between the per cent changes in DTI parameters and clinical scores were analysed.Results
From the 1st to the 12th week after stroke onset, FA values decreased (p<0.01, respectively) in the fibre tract above and below the internal capsule, and the NIHSS decreased (p<0.01) but the FM scale and BI increased (p<0.01, respectively) progressively. The per cent reductions in FA value in the fibre tract above and below the internal capsule were negatively correlated with the per cent changes in NIHSS and FM scale (p<0.05, respectively).Conclusions
Secondary degeneration of the fibre tract proximal and distal to a primary lesion can be detected by DTI clearly and quantitatively and deteriorates with time progressively, which may hamper functional recovery after a subcortical cerebral infarct.Animal experiments and post‐mortem examinations have demonstrated that a focal cerebral infarct can cause secondary degeneration in fibre pathways remote from the primary lesion. Delayed disintegration of such a fibre tract is considered to be Wallerian degeneration (WD), defined as anterograde degeneration of a nerve tract distal to an injury.1,2,3,4,5 Conventional MRI can detect the ipsilateral cerebral peduncle atrophy during the chronic stage of a focal cortical infarct6,7,8 but cannot reveal the delayed degeneration in the pyramidal tract on other regions clearly or quantitatively. Diffusion tensor imaging (DTI), which uses diffusion sensitive gradients applied in at least six non‐collinear directions, can determine the diffusivity of every voxel and fully depict tissue diffusion characteristics. DTI has been used to detect and quantify the secondary degeneration in the fibre tract in vivo.9,10Thomalla et al11 reported that secondary degeneration revealed by DTI occurred in the pyramidal tract distal to the primary lesion from the acute (5 days from onset) to the chronic (288 days) stage in two patients with ischaemic stroke. In some cross sectional studies, fractional anisotropy (FA) values were found to be generally reduced along the pyramidal tract on the infarct side distal to the primary lesion.9,12,13 After middle cerebral artery territory infarction, lower FA values in the cerebral peduncle were associated with a greater neurological deficit acutely, with worse outcomes 3 months later.13 However, to date, no prospective, controlled, contrast enhanced studies have monitored secondary degeneration, and the potential clinical significance of the degeneration distal to the primary lesion has not been confirmed. In addition, only one case report revealed that a pontine infarct can cause retrograde degeneration in the fibre pathway proximal to the primary lesion.14 However, there has been little research on the retrograde degeneration of the fibre tract after subcortical infarction, and its impact on the patient''s outcome is not well understood.In this study, DTI was used to prospectively quantify and monitor changes in diffusivity in the fibre pathway both proximal and distal to a recent subcortical infarct in 12 patients. The relation between the per cent changes in DTI parameters and clinical scores were analysed. 相似文献4.
Møller M Frandsen J Andersen G Gjedde A Vestergaard-Poulsen P Østergaard L 《Journal of neurology, neurosurgery, and psychiatry》2007,78(6):587-592
Background and aims
The integrity of motor pathways and functional connectivity patterns are important in assessing plastic changes related to successful recovery, to obtain prognostic information and to monitor future therapeutic strategies of stroke patients. We tested the following hypotheses: (1) that changes in axonal integrity along the corticospinal tract after stroke can be detected as a reduction in fractional anisotropy; and (2) that sustained low fractional anisotropy is indicative of axonal loss and therefore is correlated with poor motor outcome, as measured by specific neurological motor scores.Methods
We developed a segmentation tool based on magnetic resonance diffusion tensor imaging in conjunction with three dimensional fibretracking for longitudinal studies of the corticospinal tract, and used specific neurological motor scores to test the hypotheses in five stroke patients within the first week and 30 and 90 days after the stroke.Results
Reduction in fractional anisotropy within the first weeks after stroke reflected a decline in axonal integrity, leading to Wallerian degeneration, and demonstrated a correlation between the temporal evolution of fractional anisotropy and motor function in patients with poor motor outcome.Conclusion
The study demonstrated the feasibility of fibretracking as a segmentation tool for mapping distal parts of the corticospinal motor pathways and showed that fractional anisotropy in the segmented corticospinal tract is a sensitive measure of structural changes after stroke.Studies on the recovery of cerebral grey matter after stroke with positron emission tomography,1,2,3 functional MRI4,5,6 or transcranial magnetic stimulation7,8 demonstrate that the adult brain is capable of regeneration and compensation for motor deficits after ischaemia. However, the integrity of the underlying motor pathways is crucial in understanding the dynamics of cortical activation patterns and qualitatively the substrate of successful recovery in individual patients. The recent introduction of magnetic resonance diffusion tensor imaging (DTI) allows the characterisation of the integrity of the white matter tract by recording the diffusion characteristics of water molecules in the highly organised environment of hydrophobic myelin sheets. White matter fibre orientation can be inferred by measuring the preferred direction of water movements and the course of fibre tracts subsequently visualised by so called “fibretracking”. The extent to which myelin sheets directs water diffusion along a specific direction is parameterised by the fractional anisotropy (FA) index. FA values have been measured in studies of both healthy subjects and chronic stroke patients.9,10,11 In the latter, reduced FA values measured distally to the infarct were low, interpreted as evidence of axonal loss and Wallerian degeneration (WD). In stroke patients,12,13,14 DTI tracks the pyramidal fibres in their craniocaudal course and delineates lesions to motor fibres in relation to existing neurological deficits. A recent study demonstrated a clear prognostic value of the procedure by showing that the degree of corticospinal involvement in the infarcts is related directly to stroke severity, and inversely to functional recovery.15 Furthermore, DTI revealed changes consistent with WD within the first 2 weeks of the insult, thus proving that this technique detects structural changes earlier than conventional T2 and proton density magnetic resonance images.16,17In the present study, we developed a fibretracking based technique to segment the corticospinal tract on initial DTI images and, using this volume as a template and in a longitudinal setting, to monitor FA from the early phase in stroke patients. Using specific neurological scores, we then studied patients, testing the hypothesis that sustained low FA values associate with poor motor outcome. 相似文献5.
Bronnick K Emre M Lane R Tekin S Aarsland D 《Journal of neurology, neurosurgery, and psychiatry》2007,78(10):1064-1068
Objective
To compare the profile of cognitive impairment in Alzheimer''s disease (AD) with dementia associated with Parkinson''s disease (PDD).Methods
Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini‐Mental State Examination (MMSE) and the Alzheimer''s Disease Assessment Scale‐cognitive subscale (ADAS‐cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen''s d).Results
Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS‐cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients.Conclusion
The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.Alzheimer''s disease (AD) and Parkinson''s disease (PD) are the most common neurodegenerative diseases in the elderly. AD is primarily a dementing disease whereas PD is mainly characterised by a movement disorder. However, dementia is common among patients with PD (PDD), with an average point prevalence of 31%1 and a cumulative prevalence close to 80%.2 In PD, dementia is associated with rapid motor3 and functional decline,4 and increased mortality.5Cortical Lewy body pathology correlates best with dementia in PD6,7,8,9; subcortical pathology10 and AD‐type pathology11 have also been found to be associated with PDD. In addition to differences in morphological changes, AD and PDD also differ in the regional pattern of the pathology. In AD the first and most pronounced changes are found in the entorhinal cortex and parahippocampal region,12 subsequently involving neocortical areas, including the posterior association cortices.13 In contrast, in patients with PD without dementia, brainstem nuclei and other subcortical structures are initially affected.14 In PDD, limbic areas, neocortical association cortices, and the motor cortex and primary sensory cortical areas are thought to be successively involved with disease progression.15Given the difference in the distribution and progression of pathology in AD and PDD, it is expected that their cognitive profiles would also differ.16,17 AD is characterised by memory loss emerging in the early stages of the disease,18 primarily involving learning and encoding deficits19 which are associated with medial temporal lobe pathology.20,21,22,23 As the disease progresses, deficits in language, praxis, visuospatial and executive functions gradually develop. In contrast, the cognitive deficits in the early stages of PDD are characterised by executive dysfunction, including impairment in attention24 and working memory,25,26,27 reflecting involvement of brainstem nuclei and frontal–subcortical circuits; deficits in visuoperceptual28,29,30 and visuoconstructional tasks are also frequent.31 Memory impairment is often present26,32,33,34 but whether it is primarily a consequence of frontally mediated executive deficits resulting in poor learning efficacy and retrieval, or whether involvement of limbic areas directly related to memory encoding (such as hippocampal atrophy) also contribute to memory impairment, is debated. Patients with PDD have difficulties in retrieving newly learned material, but perform better in recognition,35 indicating that executive, rather than encoding, deficits, is the underlying mechanism. Conflicting results, however, have been reported recently36,37 which could indicate that the type and mechanisms of memory deficits may vary within the PD group.32Most studies investigating the cognitive profile of PDD patients included small samples which were not community based and thus not necessarily representative of the PD population at large. As there is evidence of interindividual heterogeneity,33 such studies may not adequately reflect the cognitive profile of patients with PDD. In order to assess the profile of cognitive deficits in PDD compared with AD in larger patient populations, we analysed the baseline cognitive data from large clinical trials conducted with the cholinesterase inhibitor rivastigmine.38,39 相似文献6.
Valsasina P Agosta F Benedetti B Caputo D Perini M Salvi F Prelle A Filippi M 《Journal of neurology, neurosurgery, and psychiatry》2007,78(5):480-484
Background
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with severe cervical cord damage due to degeneration of the corticospinal tracts and loss of lower motor neurones. Diffusion tensor magnetic resonance imaging (DT MRI) allows the measurement of quantities reflecting the size (such as mean diffusivity) and orientation (such as fractional anisotropy) of water‐filled spaces in biological tissues.Methods
Mean diffusivity and fractional anisotropy histograms from the cervical cord of patients with ALS were obtained to: (1) quantify the extent of tissue damage in this critical central nervous system region; and (2) investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts. Cervical cord and brain DT MRI scans were obtained from 28 patients with ALS and 20 age‐matched and sex‐matched controls. Cord mean diffusivity and fractional anisotropy histograms were produced and the cord cross‐sectional area was measured. Average mean diffusivity and fractional anisotropy along the brain portion of the corticospinal tracts were also measured.Results
Compared with controls, patients with ALS had significantly lower mean fractional anisotropy (p = 0.002) and cord cross‐sectional area (p<0.001). Mean diffusivity histogram‐derived metrics did not differ between the two groups. A strong correlation was found between mean cord fractional anisotropy and the ALS Functional Rating Score (r = 0.74, p<0.001). Mean cord and brain fractional anisotropy values correlated moderately (r = 0.37, p = 0.05).Conclusions
Cervical cord DT MRI in patients with ALS allows the extent of cord damage to be graded. The conventional and DT MRI changes found are compatible with the presence of neuroaxonal loss and reactive gliosis, with a heterogeneous distribution of the pathological process between the brain and the cord. The correlation found between cord fractional anisotropy and disability suggests that DT MRI may be a useful adjunctive tool to monitor the evolution of ALS.Amyotrophic lateral sclerosis (ALS) is the most common adult‐onset motor neurone disease, characterised by a progressive and simultaneous degeneration of upper and lower motor neurones.1,2 In its typical form, the disease begins either in one limb or with a combination of bulbar and corticobulbar symptoms, and continues with progressive weakness of the bulbar, limb, thoracic and abdominal musculature.1,2 By using a variety of conventional magnetic resonance imaging (MRI) sequences, several studies3,4,5,6,7,8,9,10,11,12,13,14,15 have shown changes in signal intensity along the brain portion of the corticospinal tracts, particularly in the posterior limb of the internal capsule and cerebral peduncles, varying between 25% and 80%. Reduced magnetisation transfer ratios in the internal capsule8,11 and N‐acetylaspartate levels in the motor cortex13,16,17 of patients with ALS have also been observed. However, none of these studies has reported a correlation between such magnetic resonance abnormalities and the degree of disability.8,11,13,16,17Diffusion‐tensor magnetic resonance imaging (DT MRI) enables the random diffusional motion of water molecules to be measured and thus provides quantitative indices of the structural and orientational features of the central nervous system (CNS).18 DT MRI has been used to assess quantitatively the tissue damage of the brain portion of the corticospinal tracts in ALS,12,19,20,21,22,23 and all studies have shown increased mean diffusivity (indicating a loss of structural barriers limiting the motion of water molecules) and decreased fractional anisotropy (indicating a loss of tissue organisation). However, brain DT MRI studies also resulted in heterogeneous clinicopathological correlations, as some authors found a moderate correlation between brain DT MRI metrics and the severity of disability,12,21,23 but others did not.19 In the past few years, DT MRI has also been used successfully to grade the extent of cervical cord damage associated with demyelinating conditions.24,25,26Considering that the cervical cord in ALS is one of the most affected portions of the CNS (owing to the combined presence of neuronal loss in the anterior horns of the grey matter and degeneration of the corticospinal tracts), we obtained mean diffusivity and fractional anisotropy histograms of the cervical cord from patients with ALS with the following aims: (1) to quantify the extent of tissue damage in this critical CNS region; and (2) to investigate the magnitude of the correlation of cervical cord DT MRI metrics with patients'' disability and tissue damage along the brain portion of the corticospinal tracts. 相似文献7.
Pritchard AL Harris J Pritchard CW Coates J Haque S Holder R Bentham P Lendon CL 《Journal of neurology, neurosurgery, and psychiatry》2007,78(2):123-126
Background
Patients with Alzheimer''s disease and dementia commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to BPSD development in Alzheimer''s disease has been demonstrated. Several studies have investigated whether the exon 4 ε2/ε3/ε4 haplotype of the apolipoprotein E (APOE) gene is associated with BPSD, with variable results.Objective
We investigated the exon 4 polymorphisms and extended this study to include promoter polymorphisms and the resultant haplotypes across the gene.Methods
Our large independent cohort of 388 patients with longitudinal measures of BPSD assessed by the Neuropsychiatric Inventory was used to analyse whether any of these variants were associated with the presence of BPSD.Results
We revealed several significant relationships before correction for multiple testing. The exon 4 haplotype was associated with hallucinations and anxiety, A‐491T with irritability, T‐427C with agitation/aggression and appetite disturbances, and T‐219C with depression. Haplotype analyses of all variants did not reveal any statistically significant findings.Conclusions
Our data and a review of previous studies showed a diversity of relationships, suggesting that these findings might be due to chance and so collectively do not support a role for the APOE gene in BPSD.Many patients with dementia display behavioural and psychological symptoms of dementia (BPSD). Unlike cognitive decline, BPSD do not continuously exist in a patient once they have occurred. Genetic determinants of BPSD in Alzheimer''s disease have been proposed from studies on families.1,2,3 It has been hypothesised that the genes that increase the risk for Alzheimer''s disease may also determine the presence of BPSD.4 The ε4 allele of the apolipoprotein E (APOE) gene is the only risk factor robustly associated with Alzheimer''s disease. However, previous investigations on APOE have produced inconsistent findings on BPSD, with some researchers reporting associations with a variety of different symptoms and alleles4,5,6,7,8,9,10,11,12,13,14,15,16 (summarised in the table provided online at http://jnnp.bmjjournals.com/supplemental), whereas others find no relevant relationships.17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33 We used a large independent clinical cohort of patients with Alzheimer''s disease, with longitudinal data on BPSD to further extend these studies, and additionally investigated promoter polymorphisms of APOE, which have been shown to independently incur risk of Alzheimer''s disease in some studies.34 相似文献8.
Mínguez-Castellanos A Escamilla-Sevilla F Hotton GR Toledo-Aral JJ Ortega-Moreno A Méndez-Ferrer S Martín-Linares JM Katati MJ Mir P Villadiego J Meersmans M Pérez-García M Brooks DJ Arjona V López-Barneo J 《Journal of neurology, neurosurgery, and psychiatry》2007,78(8):825-831
Background
Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD).Objective
We conducted a phase I–II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD.Methods
Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1–3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT‐PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson''s Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson''s Disease Rating Scale III score in the off‐medication state. Seven patients had 18F‐dopa positron emission tomography scans before and 1 year after transplantation.Results
Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6–12 months after transplantation (5–74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15–48%). None of the patients developed off‐period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non‐significant 5% increase in mean putaminal 18F‐dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal 18F‐dopa uptake (r = −0.829; p = 0.042).Conclusions
CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.Parkinson disease (PD) is a progressive neurodegenerative disorder of unknown aetiology. Its main pathological hallmark is the degeneration of midbrain dopaminergic neurons projecting to the striatum, although other neuronal systems are also affected.1 Current pharmacological and surgical therapies are symptomatically effective but their long term utility is limited because of disease progression.2,3 Therefore, there is a need for neuroprotective and/or neurorestorative therapies capable of arresting or reversing the neurodegenerative process.Over the past two decades, cell replacement therapies have been tested in PD patients with the objective of restoring the striatal dopaminergic deficit.4 Transplantation of fetal mesencephalic neurons, the most frequently used technique, can increase the striatal dopamine storage, but does not always produce the expected clinical benefit and may induce disabling off‐medication dyskinesias.5,6 Thus it appears that the ectopic placement of dopamine secreting cells in the striatum is not the ideal approach to compensate for progressive nigrostriatal neuronal loss.7 Given this scenario, the clinical applicability of other transplantation procedures based on a similar rationale (eg, intrastriatal grafting of porcine mesencephalic neurons, retinal pigment epithelial cells or stem cell derived dopaminergic neurons) is, for the moment, uncertain.More recently, other strategies aiming to protect or restore the nigrostriatal pathway have emerged. Glial cell line derived neurotrophic factor (GDNF) has been shown to exert neuroprotective and neurorestorative actions in animal models of PD.8,9,10 The clinical efficacy of GDNF has been assayed in clinical trials, but the method of delivery is a critical issue. Whereas intraventricular administration failed to induce clinical benefit,11 intraputaminal infusion showed promising results,12,13 although a placebo controlled trial using this route has been halted because of lack of efficacy and safety concerns about recombinant human GDNF administration.14 Other alternative methods being tested experimentally in parkinsonian animals include in vivo gene therapy using GDNF encoding viral vectors15,16,17 and the intrastriatal grafting of recombinant GDNF producing cell lines.18,19,20,21 Carotid body (CB) glomus cells are neural crest derived dopaminergic cells that express high levels of GDNF. Glomus cell GDNF production is resistant to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine administration, and maintained in aged rodents or after intrastriatal grafting.22,23 The survival rate of these cells after transplantation (>70%) is particularly high as hypoxia stimulates their growth and function. Moreover, CB grafts performed in young rats remain active for the entire animal lifespan.22,23 Transplantation of CB cell aggregates has been shown to induce a neurotrophic mediated recovery in animal models of PD22,23,24,25,26,27 and stroke.28,29We conducted a phase I–II video blinded clinical study to assess the long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with advanced PD. In a pilot report of our first six patients, we showed this procedure to be feasible.30 Here we report the clinical outcomes and prognostic factors in the whole study (n = 13), as well as 18F‐dopa positron emission tomography (PET) outcomes in a subgroup of patients (n = 7). 相似文献9.
Nakayama N Okumura A Shinoda J Yasokawa YT Miwa K Yoshimura SI Iwama T 《Journal of neurology, neurosurgery, and psychiatry》2006,77(7):850-855
Background
Non‐missile traumatic brain injury (nmTBI) without macroscopically detectable lesions often results in cognitive impairments that negatively affect daily life.Aim
To identify abnormal white matter projections in patients with nmTBI with cognitive impairments using diffusion tensor magnetic resonance imaging (DTI).Methods
DTI scans of healthy controls were compared with those of 23 patients with nmTBI who manifested cognitive impairments but no obvious neuroradiological lesions. DTI was comprised of fractional anisotropy analysis, which included voxel‐based analysis and confirmatory study using regions of interest (ROI) techniques, and magnetic resonance tractography of the corpus callosum and fornix.Results
A decline in fractional anisotropy around the genu, stem and splenium of the corpus callosum was shown by voxel‐based analysis. Fractional anisotropy values of the genu (0.47), stem (0.48), and splenium of the corpus callosum (0.52), and the column of the fornix (0.51) were lower in patients with nmTBI than in healthy controls (0.58, 0.61, 0.62 and 0.61, respectively) according to the confirmatory study of ROIs. The white matter architecture in the corpus callosum and fornix of patients with nmTBI were seen to be coarser than in the controls in the individual magnetic resonance tractography.Conclusions
Disruption of the corpus callosum and fornix in patients with nmTBI without macroscopically detectable lesions is shown. DTI is sensitive enough to detect abnormal neural fibres related to cognitive dysfunction after nmTBI.Cognitive and vocational sequelae are common complications after non‐missile traumatic brain injury (nmTBI) without obvious neuroradiological lesions.1,2 They may present as memory disturbance, impairments in multitask execution and loss of self‐awareness.3 These symptoms have been attributed to diffuse brain injury and the diffuse loss of white matter or neural networks in the brain.4,5,6 Currently no accurate method is available for diagnosing and assessing the distribution and severity of diffuse axonal injury. As computed tomography and magnetic resonance imaging (MRI) findings underestimate the extent of diffuse axonal injury and correlate poorly with the final neuropsychological outcome,7,8 this dysfunction tends to be clinically underdiagnosed or overlooked. Indirect evidence for loss of functional connectivity after nmTBI has been provided by both morphometric and functional neuroimaging studies. Morphometric analysis of nmTBI has shown the relationship between atrophy of the corpus callosum and fornix and the neuropsychological outcome.9 Most functional neuroimaging studies conducted after nmTBI have shown that cognitive and behavioural disorders are correlated, with some degree of secondary hypometabolism or hypoperfusion in regions of the cortex.5 To date, however, there has been no direct in vivo demonstration of structural disconnections without macroscopically detectable lesions in patients with nmTBI.Diffusion tensor magnetic resonance imaging (DTI), which measures diffusion anisotropy in vivo, is a promising method for the non‐invasive detection of the degree of fibre damage in various disease processes affecting the white matter.10,11 In biological systems, the diffusional motion of water is impeded by tissue structures, such as cell membranes, myelin sheaths, intracellular microtubules and associated proteins. Motion parallel to axons or myelin sheaths is inhibited to a lesser degree than perpendicular motion, a phenomenon known as diffusion anisotropy.12 Fractional anisotropy was applied to evaluation of post‐traumatic diffuse axonal injury13 and its clinical usefulness described. In a previous study,14 fractional anisotropy score in the acute stage as an index of injury to white matter showed promise in predicting outcome in patients with traumatic brain injury, by using the regions of interest (ROIs) techniques. MRI voxel‐based analysis, a statistical normalising method, has been developed to reduce interindividual variability and to evaluate the whole brain objectively.15,16,17 We investigated the regions in the whole brain that are commonly injured in patients having nmTBI with cognitive impairments but no macroscopic lesions, using voxel‐based analysis of fractional anisotropy, referred to as diffusion anisotropy. The advent of DTI has allowed inter‐regional fibre tracking, called magnetic resonance tractography, which reconstructs the three‐dimensional trajectories of white matter tracts.11,18,19 We also investigated whether magnetic resonance tractography sensitively recognises degeneration of the corpus callosum and fornix in individual patients with nmTBI. 相似文献10.
Veldink JH Kalmijn S Groeneveld GJ Wunderink W Koster A de Vries JH van der Luyt J Wokke JH Van den Berg LH 《Journal of neurology, neurosurgery, and psychiatry》2007,78(4):367-371
Background
To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS).Methods
Patients referred to our clinic during 2001–2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case–control study (132 patients and 220 healthy controls). A food‐frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking).Results
A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B2, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS.Conclusion
A high intake of PUFAs and vitamin E is associated with a 50–60% decreased risk of developing ALS, and these nutrients appear to act synergistically.Sporadic amyotrophic lateral sclerosis (ALS) probably develops through the combined effects of several modifying genes and environmental factors.1 Despite several studies that investigated environmental exposures in relation to ALS, age, gender and smoking are the only established risk factors.2 Several, not mutually exclusive, pathological processes may contribute to motor neurone death in ALS in a so‐called convergence model,3 including oxidative stress, mitochondrial dysfunction, protein misfolding, axonal strangulation, apoptosis, inflammation, glutamate excitotoxicity and defects in neurotrophin biology. Nutrients are factors that could influence these processes and thereby the risk of developing ALS or its clinical expression.ALS was previously found to be positively associated with intake of glutamate,4 fat,4 fish5 and milk,6,7 and inversely associated with intake of lycopene,8 dietary fibre,4 bread and pasta.9 Two other studies, however, failed to establish the relationship with milk.10,11 Several of these studies included only small samples of patients (<25),5,6,9 or investigated nutrition as one of many environmental factors, thus increasing the likelihood of chance findings.5,6,7,9,10,11 Furthermore, most studies did not account for the possible influence of clinical onset preceding the diagnosis5,6,7,8,9,10,11 or adjust for possible confounders including total energy intake, body mass index (BMI), sex, smoking and education.5,6,7,9,10,11One study found an association between intake of total fat and ALS, although this was not hypothesised beforehand.4 This finding is of interest considering the observed associations of intake of saturated and unsaturated fatty acids and cholesterol with other neurodegenerative diseases.12 In this case–control study, therefore, we examined the possible association between premorbid dietary intake of fatty acids, cholesterol, glutamate, phytoestrogens, calcium and anti‐oxidants and the risk of developing ALS, adjusting for confounding factors. 相似文献11.
Hood AJ Amador SC Cain AE Briand KA Al-Refai AH Schiess MC Sereno AB 《Journal of neurology, neurosurgery, and psychiatry》2007,78(6):565-570
Background
The integrity of frontal systems responsible for voluntary control and their interaction with subcortical regions involved in reflexive responses were studied in patients with Parkinson''s disease (PD). Previous studies have shown that patients with PD have impaired executive function, including deficits in attention, motor planning and decision making.Methods
Executive function was measured through eye movements: reflexive (stimulus driven) prosaccades and voluntary (internally guided) antisaccades. Patients with advanced idiopathic PD, off and on their optimal levodopa therapy, were tested on a prosaccade and an antisaccade task and compared with matched controls.Results
Levodopa significantly increased response time for reflexive prosaccades and reduced error rate for voluntary antisaccades.Conclusions
Consistent with our proposed model, patients with PD in the medicated state are better able to plan and execute voluntary eye movements. These findings suggest levodopa improves function of the voluntary frontostriatal system, which is deficient in PD.Parkinson''s disease (PD) is identified by a series of motor abnormalities caused by dopaminergic disruption in the basal ganglia. Also, the basal ganglia have many diverse connections with several brain regions, including frontal cortical areas responsible for executive function and other cognitive processes. Therefore, patients with PD can develop a wide range of cognitive difficulties (eg, dementia, psychosis, depression), and imaging shows that patients with PD tend to have decreased activity in the prefrontal cortex.1,2 The cardinal medicinal treatment of PD, levodopa/carbidopa, helps replenish the lack of dopamine and reduces tremor, rigidity and other common motor symptoms, but what effect does levodopa have on cognition? Recent work has shown that levodopa has both deleterious and beneficial effects on cognition in patients with PD.3,4,5,6,7 Some researchers conclude that dopaminergic medication may improve certain types of neuropsychological performance and hinder others because the brain regions involved are differentially affected by dopamine.3 A reasonable hypothesis is that brain regions have an optimal dopamine level, and shifts from the norm can impair some tasks/measures while benefiting others. Therefore, the present study measured the effect of levodopa on two saccade tasks with dissociable neural substrates.The analysis of saccades is increasingly used for studying cognition and memory.8 Saccade circuitry is clearly understood, and saccades possess dynamic properties that are easily measured non‐invasively.9,10 It is clear from recent imaging studies that the physiological substrates for saccades (overt orienting) and spatial attention (covert orienting) overlap in many brain regions.11 Moreover, recent work has shown a similar pattern of dysfunction across overt and covert orienting in various clinical populations, suggesting saccades may be a useful tool to evaluate higher cognitive functions.12,13Our Tonic Inhibition Model of orienting proposes that there is a voluntary system (prefrontal cortex and basal ganglia) exerting tonic inhibition on a reflexive system (superior colliculus and brainstem); the voluntary system modulates reflexive saccades and attention.14 Typical paradigms that test this model are the prosaccade (reflexively look at the stimulus) and the antisaccade (inhibit the reflexive response and voluntarily look away from the stimulus). In the Tonic Inhibition Model, a deficit in the voluntary system would predict both impaired performance in voluntary saccades and decreased inhibition of reflexive saccades (eg, more direction errors in an antisaccade task and/or shorter latencies for reflexive saccades). Such a baseline pattern has been found in pathologies that involve frontal dysfunction, such as schizophrenia, PD, autism and attention deficit hyperactivity disorder.8,15,16,17,18,19,20Saccades have rarely been used to test the effects of levodopa in PD. Therefore, we tested patients with PD in a moderately advanced stage of the disease on a voluntary antisaccade (AS) task and a reflexive prosaccade (PS) task to measure the effects of levodopa on executive function. Furthermore, each task contained both gap and overlap trials to maximise task sensitivity.12 The present study had two main hypotheses: (1) levodopa would improve performance on the AS task because of improved frontal lobe function; and (2) levodopa would enhance the tonic inhibition of the reflexive system, consequently slowing performance on the reflexive PS task. Finally, a control group was included to evaluate the ability of levodopa to normalise voluntary and reflexive performance. 相似文献12.
Lehmann DJ Refsum H Nurk E Warden DR Tell GS Vollset SE Engedal K Nygaard HA Smith AD 《Journal of neurology, neurosurgery, and psychiatry》2006,77(8):902-908
Background
Among elderly people without dementia, the apolipoprotein E ε4 allele (APOE4) has been associated with cognitive deficit, particularly in episodic memory, but few reports are available on whether this association differs by sex.Methods
In a community‐dwelling Norwegian cohort of 2181 elderly people (55% women), aged 70–74 years, episodic memory was examined in relation to sex and APOE4 zygosity, with the Kendrick Object Learning Test (KOLT).Results
Possession of at least one APOE4 allele had a modest, detrimental effect on episodic memory in women, whereas in men, heterozygotes were unaffected and homozygotes had markedly lower scores across the distribution of KOLT scores. This sex difference was found consistently in all analyses: on comparing means and medians, examining trends across quintiles, and studying the distribution of scores and the risk of cognitive impairment. Results were broadly similar when adjusted for known determinants of cognition and also when severely impaired participants were excluded. The adjusted odds ratio (OR) of cognitive impairment in women was shown to be 1.8 (95% confidence interval (CI): 1.1 to 2.8) for heterozygotes and 1.1 (0.3 to 3.7) for homozygotes; the adjusted OR in men was observed to be 1.1 (0.6 to 2.1) for heterozygotes and 10.7 (4.7 to 24) for homozygotes.Conclusions
Although the harmful effect of APOE4 on episodic memory was modest in women, the risk was found to occur in about 30%. APOE4 was observed to have a dramatic effect on episodic memory in men, but only in homozygotes, who comprised about 3% of men: the whole male homozygous group showed a marked shift to lower memory scores.Age and the apolipoprotein E ε4 allele (APOE4) are the most important known risk factors for sporadic Alzheimer''s disease. The disease is thought to have a long presymptomatic phase,1 which suggests that APOE4 starts exerting its detrimental effects in the preclinical phase. Most studies on elderly people without dementia have found that the APOE4 allele is associated with various cognitive deficits,2,3,4,5,6,7,8,9,10,11,12,13,14 particularly in memory.2,3,4,5,6,7 A recent meta‐analysis of more than 20 000 people concluded that this allele was associated with poorer performance on tests of global cognitive functioning, episodic memory and executive functioning.15The association of APOE4 with Alzheimer''s disease varies with sex.16,17,18,19,20 The meta‐analysis by Farrer et al20 found that APOE4 homozygosity affords a high risk of Alzheimer''s disease for both men and women, but that a single copy of the allele confers a greater risk on women than on men. A similar sex difference related to APOE4 has been found in the degree of hippocampal atrophy in a cohort with mild cognitive impairment.21 We may therefore expect to find an effect related to sex of the APOE4 allele in cognitive tests in elderly people without dementia. Two studies3,22 that have reported an influence of sex on this relationship found a stronger effect of APOE4 in women.3,22In this study, we investigated whether sex influences the relationship between APOE alleles and episodic memory in community‐dwelling elderly people. We selected episodic memory because memory deficit is a hallmark of Alzheimer''s disease. Tests of episodic memory have been found to be particularly effective in identifying people at risk.23,24 We compared the influence of sex in our cohort with that found on the risk of Alzheimer''s disease. We studied a relatively large group of 2181 people from western Norway. 相似文献13.
Kizawa M Mori K Iijima M Koike H Hattori N Sobue G 《Journal of neurology, neurosurgery, and psychiatry》2006,77(8):967-969
Patients having neuropathy associated with Sjögren''s syndrome may present with pain and superficial sensory involvement in the absence of sensory ataxia. Treatment for this form of associated neuropathy has not been established. The case of a patient with painful sensory neuropathy associated with Sjögren''s syndrome, whose symptoms, particularly pain, responded well to intravenous immunoglobulin both at onset and in a relapse, is reported. Other patients with painful sensory neuropathy associated with Sjögren''s syndrome may also be candidates for intravenous Ig treatment.Ataxic sensory neuropathy associated with Sjögren''s syndrome is well recognised.1,2,3 Pathologically, the underlying lesion is a sensory ganglionopathy affecting predominantly large neurones and their axons.2,4 Intravenous immunoglobulin (Ig) treatment is reported to be effective in sensory ataxic neuropathy occurring in people with Sjögren''s syndrome.5,6,7,8 Recently, another type of neuropathy associated with Sjögren''s syndrome was reported to affect small sensory axons in patients presenting with pain and superficial sensory involvement as opposed to sensory ataxia.1,4,9,10,11 The treatment for this type of neuropathy remains uncertain. We describe a patient with painful sensory neuropathy associated with Sjögren''s syndrome, in whom intravenous Ig treatment dramatically reduced painful symptoms. 相似文献
14.
Kircher TT Weis S Freymann K Erb M Jessen F Grodd W Heun R Leube DT 《Journal of neurology, neurosurgery, and psychiatry》2007,78(8):812-818
Background
Episodic memory enables us to consciously recollect personally experienced past events. Memory performance is reduced in patients with mild cognitive impairment (MCI), an at‐risk condition for Alzheimer''s disease (AD).Patients and methods
We used functional MRI (fMRI) to compare brain activity during memory encoding in 29 healthy elderly subjects (mean age 67.7 (SD 5.4) years) and 21 patients with MCI (mean age 69.7 (SD 7.0) years). Subjects remembered a list of words while fMRI data were acquired. Later, they had to recognise these words among a list of distractor words. The use of an event related paradigm made it possible to selectively analyse successfully encoded items in each individual. We compared activation for successfully encoded words between healthy elderly subjects and patients with MCI.Results
The main intergroup difference was found in the left hippocampus and surrounding medial temporal lobe (MTL) regions for the patients with MCI compared with healthy subjects during successful encoding.Conclusion
These results suggest that in patients with MCI, an increase in MTL activation is necessary for successful memory encoding. Hippocampal activation may help to link newly learned information to items already stored in memory. Increased activation in MTL regions in MCI may reflect a compensatory response to the beginning of AD pathology.Episodic memory, which enables humans to consciously recollect personally experienced past events, is based on at least two fundamental mnemonic operations: memory formation and retrieval. Event related functional MRI (fMRI) provides a unique opportunity to study the neural correlates of these processes and their subcomponents, such as successful and failed encoding.1Studies in young healthy subjects have shown that successful declarative memory formation, measured as the difference in brain activity during encoding between subsequently remembered and forgotten items, is accompanied by increases in activity in medial temporal and inferior prefrontal areas.2,3,4,5,6,7,8,9,10 Structures within the medial temporal lobe (MTL) region, especially hippocampal formation,7,11 are believed to be essential in establishing new memories.Patients with mild cognitive impairment (MCI)12 are characterised by significant memory impairment, which is not severe enough to interfere with usual activities of daily living.13 The majority of patients with MCI go on to develop Alzheimer''s disease (AD).Patients with AD, in comparison with older controls, show consistently decreased MTL activation during encoding of new materials.14,15,16,17 Fewer fMRI studies have investigated MTL encoding activation in patients with MCI,15,16,18 showing inconsistent results. A recent fMRI study showed decreased MTL activation during a memory encoding task.15 However, another study16 found that only a subgroup of subjects with “isolated memory decline” demonstrated decreased hippocampal activation during encoding, whereas still another study19 reported increased MTL activation in cognitively intact individuals genetically at risk for AD. The variability in these fMRI results may be because the groups differed in the degree of impairment and underlying neural pathology.The degree of activation detected by fMRI within MTL regions during encoding strongly correlates with subjects'' subsequent ability to remember the items encoded.2,8 Decreased MTL activation in patients with MCI and AD has been associated with relatively poor performance on post scan memory testing.14,15,17 In contrast, subjects who were genetically at risk for AD, but could successfully perform the fMRI encoding task, showed increased MTL activation. It has been hypothesised that increased MTL activation during successful encoding may represent a compensatory response that allows for relatively normal memory function in the face of developing pathological change19 There is first evidence that elderly subjects with MCI and with a relatively preserved performance in the fMRI memory task show such a compensatory increased hippocampal response in comparison with healthy subjects, while patients with AD who exhibited poorer performance in the task had lower hippocampal activation.20To further examine this question, it is not sufficient to compare general encoding related activation between patients with MCI and healthy subjects as this comparison would be confounded by task performance. Therefore, we used an event related fMRI paradigm, where subjects are instructed to remember visually presented words. According to task performance in subsequent recognition memory tests, all learned items can then be separated into those that are later remembered (subsequent hits) and those that are later forgotten (subsequent misses), individually for each subject. By comparing brain activation between healthy subjects and patients with MCI only for subsequent hits, brain regions can be identified that differ between groups during successful encoding into episodic memory. It has been shown previously that the degree of neural activity increases with the demands of the cognitive task and that the magnitude and spatial extent of brain activation increases with cognitive effort.21,22,23 We hypothesise that successful memory encoding, which should be more demanding for patients with MCI than for healthy elderly subjects, would result in increased MTL activation in patients with MCI. 相似文献15.
Julien CL Thompson JC Wild S Yardumian P Snowden JS Turner G Craufurd D 《Journal of neurology, neurosurgery, and psychiatry》2007,78(9):939-943
Background
Psychiatric symptoms are a common feature of Huntington''s disease (HD) and often precede the onset of motor and cognitive impairments. However, it remains unclear whether psychiatric changes in the preclinical period result from structural change, are a reaction to being at risk or simply a coincidental occurrence. Few studies have investigated the temporal course of psychiatric disorder across the preclinical period.Objectives
To compare lifetime and current prevalence of psychiatric disorder in presymptomatic gene carriers and non‐carriers and to examine the relationship of psychiatric prevalence in gene carriers to temporal proximity of clinical onset.Methods
Lifetime and current psychiatric histories of 204 at risk individuals (89 gene carriers and 115 non‐carriers) were obtained using a structured clinical interview, the Composite International Diagnostic Interview. Psychiatric disorders were classified using both standardised diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers (n = 51) enabled analysis of the role of temporal proximity to clinical onset.Results
Gene carriers and non‐carriers did not differ in terms of the lifetime frequency of clinical psychiatric disorders or subclinical symptoms. However, gene carriers reported a significantly higher rate of current depressive symptoms. Moreover, the rate of depression increased as a function of proximity to clinical onset.Conclusions
Affective disorder is an important feature of the prodromal stages of HD. The findings indicate that depression cannot be accounted for by natural concerns of being at risk. There is evidence of a window of several years in which preclinical symptoms are apparent.Huntington''s disease (HD) is an inherited neurodegenerative disorder, characterised by motor dysfunction, cognitive impairment and psychiatric disturbance. HD is associated with a wide range of psychiatric disturbances, including affective disorders,1,2,3 irritability,4,5,6 apathy1,3,6 and psychosis.4,7,8 Both major depression1,2,4,9 and more subtle mood disturbances10 have been reported to predate clinical onset, conventionally defined by onset of motor symptoms. However, the basis for psychiatric symptoms remains unclear. Depression has been observed to occur up to 20 years before the onset of motor symptoms,9,11 raising the possibility that psychiatric symptoms are an early indicator of HD and result from incipient neurodegenerative changes. However, the finding that psychiatric symptoms tend to cluster in certain HD families might indicate that psychiatric changes have a genetic basis and reflect a “switching on” of the HD gene early in life.2,8 High rates of psychiatric disturbance have also been observed in HD family members who do not carry the genetic mutation,9,10 raising the alternative possibility that affective changes arise in response to emotional stressors, such as being at risk, or the burden of growing up in a family with affected members. A more thorough understanding of the underlying basis of psychiatric changes in preclinical gene carriers is crucial, as future therapeutic strategies are most likely to target such individuals.Previous psychiatric studies of at risk individuals have yielded inconsistent results. Earlier studies reported high lifetime rates of psychiatric disorder in preclinical gene carriers (eg, 18% major affective disorder),2 whereas more recent studies indicate little difference between rates for gene carrier and non‐carrier groups.10,12,13,14 A number of factors may account for these discrepancies. The majority of earlier reports were limited to retrospective observation of affected individuals and therefore lacked appropriate controls.4,5 The advent of predictive testing has enabled direct comparison of at risk individuals who have the HD mutation and those who do not, thereby controlling for social and environmental factors.10,12,13,14 Whereas the majority of earlier studies lacked standardised assessment criteria,4,7 more recent studies have utilised operational diagnostic criteria, although these have in turn been criticised for failing to detect the more subtle psychiatric disturbances that can occur in HD.3,15Few studies have taken account of the temporal distance to onset of motor symptoms. It is now well established that the clinical onset of HD is typically preceded by a prodromal period of several months or years during which non‐specific mild neurological signs arise intermittently.16 The difficulty in establishing exact dates of onset for retrospective cases may have led to the inclusion in earlier studies of individuals who were already in the early stages of HD. Studies of presymptomatic individuals have typically recruited participants without motor signs, who may have been further from clinical onset.The present study is a double blind comparison of lifetime and current prevalence of psychiatric disorders in preclinical gene carriers and non‐carriers, using a combination of standardised psychiatric diagnostic criteria and a more subtle symptom based approach. Follow‐up of gene carriers has enabled analysis of the role of temporal proximity to clinical onset. 相似文献16.
Pugdahl K Fuglsang-Frederiksen A de Carvalho M Johnsen B Fawcett PR Labarre-Vila A Liguori R Nix WA Schofield IS 《Journal of neurology, neurosurgery, and psychiatry》2007,78(7):746-749
Background
Amyotrophic lateral sclerosis (ALS) is defined as a disease of the motor neurones, although several studies indicate involvement of the sensory nervous system.Aim
To evaluate the sensory nerve conduction studies (NCS) in 88 patients with ALS as part of a European multicentre study.Methods
Seven European clinical neurophysiologists examined consecutive series of ALS patients. The examinations were peer reviewed, and the diagnosis of ALS was confirmed clinically.Results
20 (22.7%) patients with ALS had sensory NCS abnormalities in at least one nerve. Of those, 11 (12.5% of all patients) obtained an additional peer review diagnosis of electrophysiological polyneuropathy. There was no difference between the subgroups of patients with normal versus abnormal sensory NCS findings with respect to age, duration and region of onset.Conclusion
The findings support previous reports of sensory involvement in ALS, and raise the question of whether patients with ALS with sensory nerve abnormalities represent a variant of ALS. ALS associated with generalised sensory system abnormalities may be consistent with degeneration of motor neurones and dorsal root ganglion cells.Sporadic amyotrophic lateral sclerosis (ALS) is defined as a progressive degeneration of upper motor neurones (UMNs) and lower motor neurones (LMNs). Normal electrophysiological studies on sensory nerves are generally required for the diagnosis of ALS.1 Nevertheless, several neurological, clinical neurophysiological and neuropathological studies have suggested that ALS is a more generalised neurodegenerative disorder.2,3,4,5,6,7,8,9,10,11,12,13,14,15,16The aim of this study was to determine the incidence of patients with ALS with electrophysiological sensory nerve abnormalities and to examine the possible differences between patients with ALS with normal versus abnormal sensory nerve conduction studies (NCS). The study was carried out on the basis of electrodiagnostic examinations of 88 patients with ALS included in the European multicentre project ESTEEM (European Standardised Telematic tool to Evaluate Electrodiagnostic Methods).17 相似文献17.
Haaxma CA Bloem BR Borm GF Oyen WJ Leenders KL Eshuis S Booij J Dluzen DE Horstink MW 《Journal of neurology, neurosurgery, and psychiatry》2007,78(8):819-824
Objective
To investigate gender differences in basic disease characteristics, motor deterioration and nigrostriatal degeneration in Parkinson''s disease (PD).Methods
We studied 253 consecutive PD patients who were not receiving levodopa or dopamine agonists (disease duration ⩽10 years). We investigated the influence of gender and oestrogen status on: (1) age at onset, (2) presenting symptom, (3) severity and progression of motor symptoms (Unified Parkinson''s Disease Rating Scale III (UPDRS‐III) scores) and (4) amount and progression of nigrostriatal degeneration ([123I]FP‐CIT single photon emission computed tomography measurements).Results
Age at onset was 2.1 years later in women (53.4 years) than in men (51.3 years). In women, age at onset correlated positively with parity, age at menopause and fertile life span. Women more often presented with tremor (67%) than men (48%). Overall, patients presenting with tremor had a 3.6 year higher age at onset and a 38% slower UPDRS‐III deterioration. Mean UPDRS‐III scores at disease onset were equal for both genders, as was the rate of deterioration. Women had a 16% higher striatal [123I]FP‐CIT binding than men at symptom onset and throughout the course of PD.Conclusions
Our results suggest that, in women, the development of symptomatic PD may be delayed by higher physiological striatal dopamine levels, possibly due to the activity of oestrogens. This could explain the epidemiological observations of a lower incidence and higher age at onset in women. Women also presented more often with tremor which, in turn, is associated with milder motor deterioration and striatal degeneration. Taken together, these findings suggest a more benign phenotype in women with PD.There are several indications of gender differences in Parkinson''s disease (PD). Epidemiological studies have shown that both incidence and prevalence of PD are 1.5–2 times higher in men than in women.1,2,3,4,5,6 Furthermore, in 6 out of 8 incidence studies mentioning gender specified age at onset, onset in women was slightly later than in men (by a mean of 2.2 years (range 1–4)).7 After progression into the clinical phase of the disease, women had better Unified Parkinson''s Disease Rating Scale (UPDRS) motor scores8 but a greater prevalence of dyskinesias8,9 compared with men (at a disease duration of more than 5 years). Furthermore, men reported several parkinsonian symptoms more frequently than women when asked at a disease duration of 9 years.10 Gender differences in the earlier stage of PD, before initiation of dopamine agonists or levodopa, have not been investigated.The reported gender differences reflecting distinct time periods—before and after symptom onset—could be related to the different levels of circulating oestrogens in men and women. Several findings indicate that oestrogens may play a role in PD. In animal models of PD, oestrogens had a neuroprotective effect when administered prior to or coinciding with a toxic insult.11,12,13 Secondly, the dopaminergic neurons in the substantia nigra and the striatal dopamine content were more vulnerable to chemical lesioning at dioestrus (low oestrogen) than at pro‐oestrus (high oestrogen).14 However, the possibly beneficial effects of oestrogens suggested by these reports could not be confirmed in humans. Postmenopausal oestrogen use in women was associated with both higher, lower and equal risks of PD.15,16,17 Furthermore, trials of postmenopausal oestrogen supplementation, which started after symptom onset, did not affect parkinsonian symptoms.18,19 However, women who had undergone ovariectomy or hysterectomy had an increased risk of PD.20,21 Thus the precise nature and extent of gender differences and the role of oestrogens in PD remain unclear.Here we investigated whether and how gender affects both the preclinical and clinical disease stages, reflected by (1) the age of PD onset, (2) the presenting symptom, (3) the severity and progression of motor symptoms assessed with UPDRS derived variables and (4) the amount and progression of nigrostriatal degeneration assessed using [123I]FP‐CIT single photon emission computed tomography (SPECT). 相似文献18.
del Mar Matarín M Pueyo R Poca MA Falcón C Mataró M Bargalló N Sahuquillo J Junqué C 《Journal of neurology, neurosurgery, and psychiatry》2007,78(7):760-763
Background
Adult normal pressure hydrocephalus (NPH) is one of the few potentially treatable causes of dementia. Some morphological and functional abnormalities attributed to hydrocephalus improve following treatment.Objectives
We focused on analysis of changes in cerebral metabolites using proton magnetic resonance spectroscopy (1H‐MRS) after NPH treatment, and its clinical and cognitive correlation.Methods
1H‐MRS, neuropsychological and clinical status examinations were performed before and 6 months after shunting in 12 adults with idiopathic NPH. We obtained N‐acetyl‐aspartate (NAA), choline (Cho), myoinositol (MI) and creatine (Cr) values.Results
After surgery, NAA/Cr was significantly increased. Moreover, NAA/Cr values were related to cognitive deterioration.Conclusion
MRS could be a marker of neuronal dysfunction in NPH.Normal pressure hydrocephalus (NPH) is a potentially treatable cause of dementia,1,2 characterised by progressive cognitive dysfunction, gait disturbance and urinary incontinence associated with ventricular enlargement and abnormalities in CSF dynamics. In these patients, some morphological and functional abnormalities attributed to hydrocephalus improve after treatment.3,4,5 Proton magnetic resonance spectroscopy (1H‐MRS) allows non‐invasive in vivo measurement of brain metabolites. Findings from MRS studies reveal that 1H‐MRS is a potentially non‐invasive technique with sufficient sensitivity to detect subtle changes in neuronal function in neurodegenerative diseases, allowing investigation of neuronal injury or dysfunction6,7 and the assessment of treatment efficacy.8,9,101H‐MRS studies in patients with hydrocephalus are scarce.6,7,11,12,13,14,15 Changes in cerebral metabolites after treatment with hydrocephalus using this technique have been analysed in only two studies, which concentrated exclusively on the results of lactate metabolites.11,12The aim of our study was to describe changes in other major metabolites, using 1H‐MRS, before and after treatment in idiopathic NPH patients, and to obtain preliminary data on their clinical and cognitive correlation, which could serve as the basis for larger studies with control subjects. 相似文献19.
Verheyden G Nieuwboer A De Wit L Feys H Schuback B Baert I Jenni W Schupp W Thijs V De Weerdt W 《Journal of neurology, neurosurgery, and psychiatry》2007,78(7):694-698
Background and aim
Trunk performance is an important predictor of functional outcome after stroke. However, the percentage of explained variance varies considerably between studies. This may be explained by the stroke population examined, the different scales used to assess trunk performance and the time points used to measure outcome. The aim of this multicentre study was to examine the predictive validity of the Trunk Impairment Scale (TIS) and its subscales when predicting the Barthel Index score at 6 months after stroke.Methods
A total of 102 subjects were recruited in three European rehabilitation centres. Participants were assessed on admission (median time since stroke onset 20 days) and 6 months after stroke. Correlation analysis and forward stepwise multiple regression analysis were used to model outcome.Results
The best predictors of the Barthel Index scores at 6 months after stroke were total TIS score (partial R2 = 0.52, p<.0001) and static sitting balance subscale score (partial R2 = 0.50, p<.0001) on admission. The TIS score on admission and its static sitting balance subscale were stronger predictors of the Barthel Index score at 6 months than the Barthel Index score itself on admission.Conclusions
This study emphasises the importance of trunk performance, especially static sitting balance, when predicting functional outcome after stroke. The TIS is recommended as a prediction instrument in the rehabilitation setting when considering the prognosis of stroke patients. Future studies should address the evolution of trunk performance over time and the evaluation of treatment interventions to improve trunk performance.Although the age specific incidence of major stroke has fallen over the past few years,1 it is still the main cause of long term disability in adults, with a growing number of survivors being dependent for activities of daily living (ADL).2,3 Frequently identified variables predicting ADL after stroke are age and initial severity of motor and functional deficits.4 Trunk performance has also been identified as an important independent predictor of ADL after stroke.5,6,7,8,9 However, based on multiple regression analyses, the reported variance of functional outcome after stroke explained by trunk performance ranges from 9% to 71%.5,6,7,8,9 Differences in reported variance could be explained by the stroke population included, the various scales used to measure trunk performance and the time points used to measure outcome.Previous studies evaluating the predictive validity of trunk performance after stroke were performed in a single rehabilitation setting, warranting caution when generalising results.5,6,7,8,9,10 Clinical tools used to assess trunk performance are the Trunk Control Test,5,6,10 trunk control items of the Postural Assessment Scale for Stroke patients7,8 and trunk assessment of Fujiwara et al.9 A limitation of the first two tests is that they both have a ceiling effect, which makes their use less suitable in long term outcome studies.5,11,12,13 Furthermore, the trunk control items of the Trunk Control Test and Postural Assessment Scale for Stroke patients are largely comparable with the items of the trunk measure of Fujiwara et al.9 All previously mentioned clinical tools include items in the supine position which involve rolling as well as only basic balance movements in sitting. Finally, with the exception of the trunk control items of the Postural Assessment Scale for Stroke patients,8 no study has evaluated the prognostic value of trunk performance when predicting functional outcome at 6 months after stroke.The Trunk Impairment Scale (TIS) for patients after stroke was designed to measure ADL related selective trunk movements rather than participation of the trunk in gross transfer movements.14 The TIS assesses static and dynamic sitting balance and trunk coordination. Reliability, validity, measurement error, internal consistency and discriminant ability of the TIS have been reported elsewhere.14,15 The TIS has no ceiling effect in subacute and chronic stroke patients and already appeared to be strongly related to measures of gait, balance and functional ability in a cross sectional study.12 To the best of our knowledge, the predictive value of the TIS and its subscales has not been evaluated. Including age and other measures of motor and functional performance could provide a useful combination of variables predicting outcome after stroke. The Barthel Index score is a widely accepted measure in stroke rehabilitation research and assesses functional milestones in stroke recovery. Predicting Barthel Index scores at 6 months after stroke based on measurements taken on admission to a rehabilitation centre would further establish the importance of trunk performance when predicting long term outcome after stroke. Experts in the field of neurological rehabilitation have addressed the trunk as the central key point of the body.16 Proximal stability of the trunk is a prerequisite for distal head and limb movement and therefore expected to be related to functional ADL.In summary, there is still a lack of clarity regarding the importance of trunk performance in functional outcome after stroke. Scales which have been used in previous studies have important statistical limitations and are likely to be a comprehensive measure of motor performance of the trunk. Therefore, the aim of this multicentre study was to examine the predictive validity of the TIS and its subcomponents, together with other known predictors, in predicting functional outcome measured as a Barthel Index score at 6 months after stroke. 相似文献20.
Vucic S Krishnan AV Kiernan MC 《Journal of neurology, neurosurgery, and psychiatry》2007,78(11):1202-1208