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We evaluated whether patients with young-onset Parkinson's disease (PD) (onset between 21 and 40 years) develop levodopa-induced dyskinesias and motor response fluctuations more frequently and earlier than patients with older- onset PD (onset after 40 years) by determining the period from levodopa introduction to development of dyskinesias or fluctuations in 25 young-onset (mean age at onset, 33.54 years) and in 25 matched older-onset PD patients (mean age at onset, 55.76 years). Young-onset PD patients had significantly higher frequency for both dyskinesias and fluctuations after both 3 and 5 years of levodopa. Young-onset PD patients also developed both levodopa-induced dyskinesias and fluctuations earlier than older-onset PD patients. We suggest that the introduction of levodopa therapy in patients with young-onset PD should be postponed as long as possible.

We examined the status of dopamine (DA) D 1 and D 2 receptors by using [ 3 H]SCH 23390 and [ 3 H]spiperone binding, respectively, and DA uptake sites by using [ 3 H]mazindol binding in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. SHR showed significantly higher [ 3 H]SCH 23390 and [ 3 H]spiperone binding in the caudate-putamen (CPu), the nucleus accumbens (NAc) and the olfactory tubercle (OT) in comparison to the SD rats. There were no significant differences in [ 3 H]mazindol-labeled DA uptake sites between the two strains. Unilateral 6-hydroxydopamine (6-OHDA) injection into the striatum resulted in more than 90% depletion of DA uptake sites in the CPu in both strains. 6-OHDA-induced DA depletion was associated with significant increases in striatal [ 3 H]spiperone binding which were of similar magnitude in the SD rats (+64.1%) and SHR (+51.3%). There were only small decreases (−5.4%) in D 1 receptor binding in the dorsolateral aspect of the CPu in the SHR, whereas there were no changes in striatal D 1 receptors in the SD rats. These results indicate that, although the SHR have higher concentrations of both D 1 and D 2 receptors in the basal ganglia, these receptors are regulated in a fashion similar to DA receptors in SD rats after 6-OHDA-induced striatal DA depletion.

Chronic injections of iminodipropionitrile (IDPN) to rat cause a persistent motor hyperactivity, lateral and vertical sustained twisting movement of the neck, random circling and increased startle response. These abnormalities are similar to those observed after the acute administration of serotonin (5-HT) agonists in rodents. Significant changes in 5-HT concentration and in 5-HT 2 receptor density in several motorrelated brain regions have been observed in IDPN-treated rats. The present quantitative autoradiographic study was undertaken to assess the possibility that IDPN may also affect 5-HT 1 receptors in rat brain. IDPN caused significant increases of 5-[ 3 H]HT binding in the oriens and pyramidal layers of the CA3 field of hippocampus. In contrast, there were significant decreases of 5-[ 3 H]HT binding in the frontal and cingulate cortices, the olfactory tubercle, the ventromedial aspect of the caudate-putamen, the nucleus accumbens, the superior colliculus, and the lateral septal nuclei. These results provide further evidence for the involvement of the 5-HT system in the development of the IDPN-induced dyskinetic syndrome.

Caspases play an important role in neurodegeneration in Huntington's disease (HD). Members of the Bcl-2 family are critical modulators of terminal cell death pathways. However, alterations of Bcl-2 family members and their functional role in an in vivo model of HD have not been documented. With the goal of gaining mechanistic insight, we used a transgenic mouse model of HD (R6/2) to investigate the chronology of caspase activation and functional alterations in members of the Bcl-2 family. In R6/2 mice caspase activation precedes proapoptotic changes in Bcl-2 family members. Of the caspases that we screened, caspase-1-like activation was the first to be detected in the disease process (7 weeks). Proapoptotic changes in members of the Bcl-2 family were first detected at 9 weeks. To demonstrate a potential functional/therapeutic role of Bcl-2 in HD, we crossed R6/2 mice with mice overexpressing Bcl-2 in neurons. Transgenic expression of Bcl-2 in R6/2 mice resulted in slight prolonged survival. Understanding the chronology of apoptotic events provides important information for appropriate therapeutic targeting in this devastating and untreatable disease.

The original article to which this Clarification refers was published in the February 2003 issue of Movement Disorders (Teismann P, Tieu K, Cohen O, Choi DK, Wu dC, Marks D, Vila M, Jackson-Lewis V, Przedborski S. Pathogenic role of glial cells in Parkinson's disease. Mov Disord 2003;18:121–129.). © 2003 Movement Disorder Society

We are grateful to Drs Hirsch and Hunot for their insightful comments on our work1xInducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Liberatore, G.T. et al. Nat. Med. 1999; 5: 1403–1409Crossref | PubMed | Scopus (709)See all References1 and for their thorough review of the potential role of gliosis and inflammatory-related events in the pathogenesis of Parkinson’s disease (PD). We wish to echo Drs Hirsch and Hunot’s view on the importance of this long-neglected aspect of PD neuropathology2xReactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. McGeer, P.L. et al. Neurology. 1988; 38: 1285–1291Crossref | PubMedSee all References, 3xNitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Hunot, S. et al. Neuroscience. 1996; 72: 355–363Crossref | PubMed | Scopus (406)See all References, 4xFcϵRII/CD23 is expressed in Parkinson’s disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-α in glial cells. Hunot, S. et al. J. Neurosci. 1999; 19: 3440–3447PubMedSee all References. Furthermore, we would like to stress a point that can be derived from the work of Hirsch and Hunot as well as from our own, which we believe might have significant therapeutic implications for PD.Almost invariably, the phenotypic expression of neurodegenerative disorders such as PD arises in a specific part of the body (e.g. upper limb, on one side) and then spreads progressively. This fact led us to hypothesize that once the neurodegenerative process has been initiated by the aetiological factor(s), a cascade of secondary deleterious events that is instrumental in the progression and propagation of the disease is set in motion. As we have emphasized1xInducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Liberatore, G.T. et al. Nat. Med. 1999; 5: 1403–1409Crossref | PubMed | Scopus (709)See all References1, our data indicate that the contribution of inducible nitric oxide synthase (iNOS) and gliosis-related deleterious effects to the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD do not initiate the loss of dopamine-containing neurones, but rather amplify the damage in MPTP-intoxicated mice. Dopaminergic fibres and dopamine content in the striatum were not spared from the toxic effects of MPTP in iNOS knockout mice, which differs from that observed in neuronal NOS (nNOS) knockout mice, in which dopamine and its metabolites are spared from the toxic effects of MPTP (Ref. 5xRole of neuronal nitric oxide in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced dopaminergic neurotoxicity. Przedborski, S. et al. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4565–4571Crossref | PubMedSee all ReferencesRef. 5). Thus, MPTP might elicit its toxicity by nNOS-derived nitric oxide (NO) damaging primarily dopaminergic fibres and terminals in the striatum and iNOS-derived NO acting predominately on dopamine-containing neuronal cell bodies in the substantia nigra pars compacta. Injury induced by neuronally derived NO might serve as the catalyst to activate iNOS and gliosis-related deleterious effects. A similar scenario might apply to the demise of dopamine-containing neurones in humans either affected with PD (2xReactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. McGeer, P.L. et al. Neurology. 1988; 38: 1285–1291Crossref | PubMedSee all References, 3xNitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Hunot, S. et al. Neuroscience. 1996; 72: 355–363Crossref | PubMed | Scopus (406)See all References, 4xFcϵRII/CD23 is expressed in Parkinson’s disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-α in glial cells. Hunot, S. et al. J. Neurosci. 1999; 19: 3440–3447PubMedSee all References) or intoxicated by MPTP (Ref. 6xEvidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Langston, J.W. et al. Ann. Neurol. 1999; 46: 598–605Crossref | PubMed | Scopus (567)See all ReferencesRef. 6).Aside from providing insights into the factors that contribute to the progression of the neurodegenerative process in PD, studies on inflammatory-related events shed light on new therapeutic avenues. Thus far, the lion’s share of these avenues has been therapeutic interventions aimed at alleviating symptoms of PD. Unfortunately, the chronic use of potent symptomatic anti-PD drugs is frequently wrought with long-term side-effects, which are as debilitating as the disease itself. Moreover, in the vast majority of cases, PD presents as a sporadic disease. Thus, in the absence of pre-symptomatic markers, PD patients seek medical attention at a time when they are already symptomatic. Consequently, therapeutic interventions that target secondary phenomenon such as iNOS induction and gliosis might represent a promising strategy that could succeed in slowing down or even stopping the progression of PD. Ultimately, the cause of PD must be unravelled and therapeutic strategies aimed at preventing the illness must be developed. But, for now our best therapeutic alternative probably lies in targeting secondary neurodegenerative processes.

To the Editor: We have had a long-standing interest in delayedonset movement disorders after cerebral injury and so we welcomed the paper of Scott and Jankovic, [1] which contributed a substantial number of newly described patients with these disorders. However, some issues related to the neural basis of these disorders were treated only in part by the authors, and we believe that they require further clarification, particularly in relation to effects of hypoxic-ischemic injury on striatal dopamine receptors. In an initial study, performed 7 days after injury, Adair and Filloux [2] confirmed our earlier autoradiographic finding of significant decreases in striatal dopamine D1 receptors in rats after a unilateral perinatal hypoxic/ischemic brain injury. [3] They did not, at this 7-day interval, find a decrease in D2 receptors, which we …

Freezing episodes and related phenomena (as a general term, motor blocks [MBs]) are poorly understood, particularly disabling, and a therapeutically frustrating problem in Parkinson's disease (PD). Epidemiologic and clinical characteristics of MBs, as well as risk factors to develop MBs, have never been fully addressed. Herein, we report our database survey on 990 PD patients, of whom 318 (32%) had MBs. The majority of MBs were linked to gait. Start hesitation occurred in 86%, blocking on turning in 45%, and blocking in narrow spaces in 25% of patients. Initial parkinsonian symptoms in the upper body and tremor as the initial motor symptom were less likely to be associated with the presence of MBs (odds ratios |OR| 0.6 and 0.7, respectively), while initial symptoms affecting gait or trunk had higher association with MBs (OR = 1.58). Longer disease duration, higher Hoehn and Yahr stage, and longer duration of levodopa treatment are all significantly associated with the presence of MBs. We observed significant association between the existence of MBs and levodopa-induced dyskinesias to suggest similar pathophysiology. We propose that MBs in PD are abnormal retrieval or execution of complex motor tasks that can occur as a result of disease progression or as short- or long-term side effects of levodopa treatment.

We evaluated 11 patients with hemiparkinson-hemiatrophy syndrome, 6 with body and contralateral cerebral hemispheric hemiatrophy, 4 with only body hemiatrophy, and 1 with just brain hemiatrophy. The mean age of symptom onset was 38.1 years (range, 18 to 54) with 5.2 ± 3.1 (mean ± SD) years of illness until the last follow-up visit. The presenting symptom was unilateral tremor in 6 patients, hand dystonia in 2, bradykinesia in 2, and abnormal gait in 1 patient. Three patients had a good response to levodopa, 4 had moderate response, and 2 patients had a poor response. During a mean follow-up period of 1.7 years (range, 4 months to 5 years), the Hoehn and Yahr score changed in only 3 patients: 2 gained 1.5 points and 1 gained 3 points over 2.5 years. We discuss the association between hemiparkinsonism-body hemiatrophy and contralateral hemispheric hemiatrophy, and raise the possibility of early childhood brain insult with delayed-onset parkinsonism.

The distribution of cholecystokinin immunoreactive nerve cell bodies and processes is reported in the human striatum and adjacent structures such as the claustrum, the pallidum, the bed nucleus of the stria terminalis and the substantia innominata. Cholecystokinin-positive terminals are present in the striatum where they are arranged in a patchy pattern. Cholecystokinin-positive somata are observed in the claustrum and in the bed nucleus of the stria terminalis but not in the striatum, the pallidum or the substantia innominata. Dense networks of cholecystokinin-positive woolly fibres are present in the bed nucleus of the stria terminalis and the substantia innominata. These results suggested that cholecystokinin is involved in the compartmental organization of the human striatum. This compartmentalization has functional and pathological implications. Involvement of the cholecystokinin system in some basal ganglia diseases is therefore expected. Presence of neuronal cholecystokinin in the accumbens nucleus, bed nucleus of the stria terminalis and substantia innominata also suggests that this peptide may interact at different levels in the human limbic system.

Chronic injection of iminodipropionitrile (IDPN) to rats causes a persistent set of abnormalities which includes hyperlocomotion, hyperexcitability, and dyskinetic movements of the neck. These behavioral changes are very similar to those observed after the acute administration of the dopamine (DA) agonist, amphetamine, in rodents. Because of the anatomical and functional evidence that neurotensin (NT) can modulate DA neurotransmission, the present receptor autoradiographic study investigated the binding of [ 3 H]NT in the brains of IDPN-treated rats. There were significant decreases in binding in the frontal and cingulate cortices, the rhinal sulcus, the dorsolateral aspect of the caudate-putamen, and in the ventral tegmental area. These results provide the first evidence for the possible participation of the NT system in the manifestations of the IDPN-induced sydrome.

Chronic injection of iminodipropionitrile (IDPN) to rats causes persistent motor abnormalities such as hyperactivity, lateral and vertical dyskinesia of the neck, and random circling. These behavioral changes are very similar to those observed after the acute administration of serotonin (5-HT) agonists in rodents. Moreover, some aspects of this syndrome are reproduced by stimulation of 5-HT1A receptors. The present quantitative autoradiographic study revealed a number of changes in 8-hydroxy-2-[di-n-propylamino-3H]tetralin (8-OH[3H]DPAT)-labeled 5-HT1A receptors in the brains of IDPN-treated rats. There were significant increases of 8-OH[3H]DPAT binding in the frontal cortex and in the caudate-putamen. In contrast, there were significant decreases in the interpeduncular nucleus, the pyramidal layer of the CA3 field of hippocampus, the superior colliculus and the pars reticulata of the substantia nigra. These results provide further evidence for the involvement of the 5-HT system in the development of the IDPN-induced dyskinetic syndrome.

We measured the human pim-1 protooncogene (PIM) expression during fetal development and in hematopoietic malignancies. Our data indicate that during human fetal hematopoiesis the 33-kDa pim product, p33pim, is highly expressed in the liver and spleen. In contrast, at the adult stage it is only slightly expressed in circulating granulocytes. Out of 70 hematopoietic malignancies analyzed, 51 patients and 19 cell lines, p33pim was overexpressed in approximately 30% of the samples, particularly in myeloid and lymphoid acute leukemias. This overexpression was unrelated to any stage of cellular differentiation and was not due to gene rearrangement or amplification. These results imply a physiological role of the pim-1 protooncogene during hematopoietic development and a deregulation in various leukemias.

Using immunohistochemistry, well-preserved neuronal cell bodies and fibres containing neuropeptide Y, somatostatin, and cholecystokinin immunoreactivity have been identified in all seven supratentorial anaplastic astrocytomas studied. These neurones have been shown not only on the edge but also in the depth of the neoplastic tissue. These neuropeptides were not present in 18 other intracranial tumours (3 astrocytomas, 1 subependymoma, 8 glioblastoma multiformes, 1 meningioma, and 5 metastases). In all 25 intracranial tumours studied, no immunoreactivity was found for vasoactive intestinal polypeptide, substance P, methionine-enkephalin, leucine-enkephalin, synenkephalin, neurophysin I-II, and corticotropin releasing factor.

SummaryMost cases of neurodegenerative diseases are sporadic, hindering the use of genetic mouse models to analyze disease mechanisms. Focusing on the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS), we therefore devised a fully humanized coculture model composed of human adult primary sporadic ALS (sALS) astrocytes and human embryonic stem-cell-derived MNs. The model reproduces the cardinal features of human ALS: sALS astrocytes, but not those from control patients, trigger selective death of MNs. The mechanisms underlying this non-cell-autonomous toxicity were investigated in both astrocytes and MNs. Although causal in familial ALS (fALS), SOD1 does not contribute to the toxicity of sALS astrocytes. Death of MNs triggered by either sALS or fALS astrocytes occurs through necroptosis, a form of programmed necrosis involving receptor-interacting protein 1 and the mixed lineage kinase domain-like protein. The necroptotic pathway therefore constitutes a potential therapeutic target for this incurable disease.

SummaryTo explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations.

Solubilization of rat synaptic membranes by Triton X-100 followed by DEAE-cellulose chromatography allowed the separation of a phosphoramidon-sensitive endopeptidase that cleaved CCK-8. This enzymatic activity revealed similar if not identical to "enkephalinase A." A major cleavage point, at the Trp30-Met31 bond, and a minor one at the Tyr27-Met28 bond were identified in the sequence of CCK-8. Replacements of the Met28 and Met31 residues by Thr and either Leu or Nle respectively, in CCK-9 analogues, did not improve the resistance of these peptides to enzymatic degradation. The regional distribution in rat brain of this CCK-8 cleaving endopeptidase displayed marked variations with the highest activity in striatal membranes; it closely followed that described for "enkephalinase" in mouse brain.

Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells, SCs) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response through actions of heme-regulated inhibitor kinase (HRI), and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines, an intermediate of fatty acid β-oxidation. Importantly, we show that acylcarnitines are released from SCs and induce axonal degeneration. A maladaptive integrated stress response as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies.

Five patients infected with immunodeficiency virus who were suffering from chronic polyradiculoneuropathy were investigated during evolution of the disease. Four of them were immunodeficient. The prominent neurological feature was distal and symmetrical weakness of the legs. After 5 months only one patient had improved. All patients had an increased protein level in the cerebrospinal fluid and pleocytosis. Electrodiagnostic studies and sural nerve biopsies indicated demyelination. Sural nerve viral cultures, including human immunodeficiency virus, were negative. The presence of circulating anti-peripheral nerve antibodies and of immunoglobulin deposits in nerve biopsy specimens was investigated by immunofluorescence techniques but failed to demonstrate any immunoreactivity.

Summary Phenytoin has been proposed in the management of patients with the syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) of neurological origin who fail to respond to water restriction. We have conducted a prospective study in order to evaluate the role of phenytoin in the management of seven consecutive patients with SIADH of neurological origin which could not be controlled by limited water intake. Only one patient was successfully treated with chronic phenytoin regimen. This patient, like one previously reported, had suffered a basal skull fracture. It seems likely that in the majority of cases of SIADH of neurological origin phenytoin is ineffective on a long-term basis.

Ganglionic and aganglionic full-thickness samples, at 4 levels of the colon of 26 infants with Hirschsprung's disease, were studied by immunohistochemistry. In the distal part of the aganglionic bowel, we observe a decrease of substance P and vasoactive intestinal peptide, an absence of methionine-enkephalin and an increase in neuropeptide Y nerve fibres. When detected, substance P and vasointestinal peptide are mainly present in abnormal bundle nerve fibres. In the middle part of the aganglionic bowel, a slight increase in the number of normal nerve fibres containing substance P, methionine-enkephalin and vasoactive intestinal peptide is observed. Some vasoactive intestinal peptide abnormal bundle nerve fibres are detected. They are less numerous than in the distal part. In the proximal ganglionic bowel, the number of vasoactive intestinal peptide, substance P and methionine-enkephalin normal nerve fibres is increased compared to the middle aganglionic segment but is slightly lower than in the normal colon. Again vasoactive intestinal peptide abnormal bundle nerve fibres are present at that level and are also detected in more proximal ganglionic bowel up to the hepatic flexure of the colon. Thus, abnormal distribution of neuropeptides is also found in more proximal ganglionic bowel and not only in the aganglionic segment of bowel usually specific of Hirschsprung's disease.

The levels of homovanillic acid (HVA), 5-hydroxy indoleacetic acid (5HIAA), and 3-methoxy-4-hydroxy phenylglycol (MHPG) were determined in the cerebrospinal fluid (CSF) of 28 patients with cognitive disorders on Day 1 and Days 8 or 15. During that period all patients were kept hospitalized under strict standard conditions, did not develop any acute CNS lesion, had no changes in their treatment and no acute systemic disease. The mean levels found in the first and second determinations were almost identical for the 3 metabolites; respectively 37.8 ng/ml and 36.3 ng/ml for HVA, 27.8 ng/ml and 27.9 ng/ml for 5HIAA, and 12.9 ng/ml and 12.3 ng/ml for MHPG. Thus, the mean values of these metabolites in CSF are reproducible at least during a 15-day hospitalization. However statistically significant individual changes in metabolite levels were found between the two samples in 82% of patients for HVA, 32% for HIAA and 48% for MHPG. The number of patients required to detect a significant change in the mean levels of each monoamine metabolite has been calculated taking into account the extent of intraindividual variations.

The development of new methods for manipulating the animal genome by transgenic and gene-targeting technologies provides a unique means of studying the most intimate aspects of countless human diseases, including Parkinson's disease (PD). In this review, the contribution of such engineered models to our current understanding of the pathophysiology, etiology and pathogenesis of PD will be discussed.

We estimated regional and global metabolic rates for glucose using 18F-fluorodeoxyglucose (FDG) and PET in six patients with hemiparkinsonism-hemiatrophy syndrome (HPHA; mean age, 41.0 +/- 12.4 years). We used 18F-fluorodopa (FDOPA) and PET in two patients to quantify presynaptic nigrostriatal dopaminergic function. We compared measures of brain glucose metabolism and striatal FDOPA uptake with those calculated for 10 age-matched normal volunteers (mean age, 35.1 +/- 8.0 years) and 10 patients with typical unilateral Parkinson's disease (unilat-PD; mean age, 58.2 +/- 13.8 years). All six HPHA patients demonstrated significant metabolic reductions (3 SD) in the contralateral basal ganglia or frontal cortex as compared with normal control values. Mean normalized glucose metabolism was reduced in the contralateral caudate and lentiform nuclei (p0.005) as compared with that in unilat-PD and normal controls. In both patients studied with FDOPA, contralateral striatal uptake was significantly reduced (3 SD) as compared with normal control values. These results suggest that the clinical manifestations of HPHA arise through a combination of pre- and postsynaptic nigrostriatal dopaminergic dysfunction. FDG and PET may be useful in differentiating this disorder from typical unilat-PD.

Huntington’s disease (HD) is caused by an expanded CAG repeat in exon 1 of the gene coding for the huntingtin protein. The cellular pathway by which this mutation induces HD remains unknown, although alterations in protein degradation are involved. To study intrinsic cellular mechanisms linked to the mutation, we examined dissociated postnatally derived cultures of striatal neurons from transgenic mice expressing exon 1 of the human HD gene carrying a CAG repeat expansion. While there was no difference in cell death between wild-type and mutant littermate-derived cultures, the mutant striatal neurons exhibited elevated cell death following a single exposure to a neurotoxic concentration of dopamine. The mutant neurons exposed to dopamine also exhibited lysosome-associated responses including induction of autophagic granules and electron-dense lysosomes. The autophagic/lysosomal compartments co-localized with high levels of oxygen radicals in living neurons, and ubiquitin. The results suggest that the combination of mutant huntingtin and a source of oxyradical stress (provided in this case by dopamine) induces autophagy and may underlie the selective cell death characteristic of HD.

Three sibs, a boy and two girls, born to Moroccan consanguineous parents, were affected with a syndrome characterized by brittle hair, mental retardation, short stature, ataxia, and gonadal dysfunction. The hair in these three patients displayed the morphological and biochemical hallmarks of trichothiodystrophy (TTD). Gonadal function tests showed abnormal gonadotropic responses to LHRH, consistent with delayed puberty in the male and ovarian failure in both females. Comparison with previously reported cases of TTD associated with mental retardation suggests genetic heterogeneity, although specific biochemical markers are needed in order to answer this question.

Parkinson's disease (PD) is a disease of an aging population and its etiology is still unknown. In vivo models are attempts to capture as many of the hallmarks of PD as possible. To this end, a number of animal models are in use. These models parallel our thinking about the etiology of PD. Thus, herein, we discuss the most popular neurotoxin animal models, 6-hydroxydopamine and MPTP as one school of thought believes that PD is the result of a toxic insult. Since several researchers think that pesticide and herbicide use can increase the risk of developing PD, we review some of the aspects of rotenone and paraquat in rodents. Furthermore, now that we know that 10% of all PD cases are genetic in nature, we discuss some of the more common genetic rodent models of PD. None of the above models captures all of the hallmarks of PD. Thus, a given model should never be used indiscriminately to investigate every question, but should instead be carefully selected on the basis of being the most suitable model for the question being asked.

We studied a 62-year-old man with Creutzfeldt-Jakob disease (CJD), using positron emission tomography (PET) and (18F)-2-fluoro-2-deoxy-D-glucose (FDG). Glucose metabolism was heterogeneously decreased throughout the brain. At autopsy, regional distributions of spongiosis, astrogliosis, and neuronal loss correlated with premortem regional metabolic deficits. These results suggest that PET with FDG may provide metabolic regional markers for CJD neuropathology.

We recorded the EMG of parasternal intercostal muscles in 25 patients with flaccid hemiplegia during quiet spontaneous breathing, voluntary hyperventilation, and CO2-induced hyperventilation. The respiratory drive was abnormal on the hemiplegic side and the function of the intercostal muscles was affected specifically during voluntary hyperventilation.