Hypothalamic compensatory mechanisms in Parkinson's disease

Parkinson's disease (PD) is associated with loss of dopaminergic neurons of the nigrostriatal bundle and to a lesser extent of the mesolimbic and hypothalamic dopaminergic systems. Frank symptoms of the disease usually emerge when at least 70-80% of striatal dopamine (DA) content have been reduced, raising the possibility that the preclinical phase of the disease might be due to compensatory changes that permit residual dopaminergic neurons to subserve functions previously carried out by the entire projection. These neurochemical compensatory mechanisms are known to occur at a striatal level of the rate limiting enzymes of catecholamine synthesis as well as alterations in the sensitivity of the dopaminergic postsynaptic receptors (Zigmond et al., 1984; Bokobza et al., 1984). Compensatory mechanisms, although generally less well recognized, also occur in the hypothalamus and involve endocrine regulation, abnormal neuropeptide release and the emergence of several autonomic and sensory symptoms manifesting prior to or during the course of the disease. Such neurochemical and clinical adaptation mechanisms of the hypothalamus may help to explain the neurobiological events underlying the preclinical phase of Parkinsonism. Moreover, progressive failure of these hypothalamic adaptive mechanisms may be critical in the transition of the disease into the "malignant phase" (Danielczyk et al., 1980).     

Progressive cerebellar ataxia with diencephalic symptoms (Toyokura)--a case report]

We reported a 16-year-old boy suffering from dwarfism, diabetes insipidus and progressive cerebellar ataxia. The disease entity here reported was originally reported by Toyokura et al. in 1967, under the title of "progressive cerebellar ataxia with diencephalic symptoms". Ten similar cases have been reported in literature so far, all of which were Japanese except for two sibling cases reported by Robinson et al. The topographic distribution of the lesion in this disorder, however, had been conjectured to be at spinocerebellar tract and diencephalon only on a clinical ground. By applying the modern techniques of neuroimaging, electrophysiological and endocrinological test in our patient, the authors were able to demonstrate the lesion of the disorder more precisely. CT and MRI of the head revealed degenerative changes in deeper structures of the bilateral cerebellar hemispheres. ABR abnormality suggested the presence of a wide lesion in the brain stem. Pituitary hormones (GH and ACTH) sufficiently responded to the loading of hypothalamic hormones such as growth hormone releasing factor and corticotropin releasing factor, in spite of poor responses of GH under the insulin stimulation or sleep. These clinical and laboratory findings suggested that the patient has a systemic degenerative disease which preferentially involves hypothalamus, brain stem and cerebellum.     

The neurology clerkship core curriculum

Neurologic symptoms are common in all practice settings, and neurologic diseases comprise a large and increasing proportion of health care expenditures and global disease burden. Consequently, the training of all physicians should prepare them to recognize patients who may have neurologic disease, and to take the initial steps in evaluating and managing those patients. We present a core curriculum outlining the clinical neurology skills and knowledge necessary to achieve that degree of preparation. The curriculum emphasizes general principles and a systematic approach to patients with neurologic symptoms and signs. The ability to perform and interpret the neurologic examination is fundamental to that approach, so the curriculum delineates the essential components of the examination in three different clinical settings. The focus of the curriculum is on symptom-based rather than disease-based learning. The only specific diseases selected for inclusion are conditions that are common or require urgent management. This curriculum has been approved by the national organization of neurology clerkship directors and endorsed by the major national professional organizations of neurologists. It is intended as a template for planning a neurology clerkship and as a benchmark for evaluating existing clerkships. It should be especially helpful to clerkship directors, neurology chairs, deans of medical education, and members of external accreditation groups.     

The history of thought concerning the hypothalamus and its functions

Many initial studies related to identification of the boundaries and structural components, nuclei, tracts and interconnections of the hypothalamus, this continues. Early interest also focused on hypothalamic control of somatic activities and autonomie nervous system functions. During the present century chiefly, interest has developed in the hypothalamus and control of water balance, thirst, water retention and loss (diabetes insipidus and polydipsia). Its role in control of metabolism, body weight (obesity), and the regulation of body temperature has attracted the attention of physiologists for many years. Others have studied hypothalamic regulation of sex and reproductive phenomena. The hypothalamus is now attracting much attention because of its production of neuroendocrine secretions and role in control of the endocrine system. Physiologists realized very early that the hypothalamus is involved in emotional expression, in reaction to stress and adaptive adjustments. Its involvement in disease states and resistance thereto and in determining the nature of behavior has now been recognized as a matter of great importance. The origins of all these interests are reviewed.     

Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities

The adipocyte-derived hormone leptin and the pancreatic beta cell-derived hormone insulin each function as afferent signals to the hypothalamus in an endocrine feedback loop that regulates body adiposity. Although these two hormones, and the receptors on which they act, are unrelated and structurally distinct, they exert overlapping effects in the arcuate nucleus, a key hypothalamic area involved in energy homeostasis. Defects in either insulin or leptin signaling in the brain result in hyperphagia, disordered glucose homeostasis, and reproductive dysfunction. To explain this striking physiological overlap, we hypothesize that hypothalamic insulin and leptin signaling converge upon a single intracellular signal transduction pathway, known as the insulin-receptor-substrate phosphatidylinositol 3-kinase pathway. Here we synthesize data from a variety of model systems in which such "cross-talk" between insulin and leptin signal transduction has either been observed or can be inferred, discuss our own data demonstrating that insulin and leptin both activate hypothalamic phosphatidylinositol 3-kinase signaling, and discuss the significance of such convergence with respect to neuronal function in normal individuals and in pathological states such as obesity. Identification of the key early molecular events mediating the action of both insulin and leptin in hypothalamic neurons promises new insight into the regulation of these neurons in health and disease.     

Functional disturbances of the hypothalamus in patients with anorexia nervosa

Anorexia nervosa is a complex disease characterized by abnormal feeding behaviour, food aversion and acute disturbances in perception of the body shape. Every eating disorder comes about as a consequence of disturbances in synaptic transmission in particular brain regions (hypothalamus, limbic system, cortical centres). The human and animal feeding physiology is precisely regulated by autonomic nuclei of hypothalamus. The perikarya of arcuate nucleus, lateral hypothalamic nuclei and other areas produce and release both the orexigenic (e.g. NPY) and anorexigenic (e.g. a-MSH) signalling substances. The novel hypothalamic and peripheral neurohormones: orexins and ghrelin as well as serotonin and dopamine seem to play a significant role in pathogenesis of eating disorders. In anorexia nervosa simultaneous excess of orexigenic and anorexigenic factors may evoke a "mixed signal" leading to failure of hypothalamic regulatory pathways. Experimental results also suggest that women with anorexia nervosa have disturbances of regional cerebral blood flow.     

Brain mechanism underlying food intake regulation

Food intake is precisely regulated in all normal individuals, with a variation of <1%. The hypothalamus is a critical component of the forebrain pathways that regulate long-term energy homeostasis, and it plays a particularly important role in integrating hormonal, neurotransmitter, and nutrient signals. Obese animals fed with high-fat diets show an increase in the inflammatory signals, endoplasmic reticulum stress, and radical oxygen species in the hypothalamus and impairment in the systems regulating food intake. AMP kinase (AMP-activated protein kinase [AMPK]) is a "metabolic sensor" present in a wide variety of organisms, from yeast to mammals. Recent studies have indicated the role of AMPK in hypothalamic neurons in the integration of hormonal, neurotransmitter, and nutrient signals. Furthermore, analysis of genetically engineered mice has revealed that AMPK alters the fatty acid metabolism in the hypothalamic neurons as well as in peripheral tissues, and thereby regulates feeding behavior. Thus, hypothalamic neurons and intracellular signaling pathway that includes AMPK-fatty acid metabolism appear to be the critical components that regulate food intake and body weight.     

Cluster headache and the hypothalamus: causal relationship or epiphenomenon?

Typical clinical features of cluster headache (CH) include circadian/circannual rhythmicity and ipisilateral cranial autonomic features. This presentation has led to the assumption that the hypothalamus plays a pivotal role in this primary headache disorder. Several studies using neuroimaging techniques or measuring hormone levels supported the hypothesis of a hypothalamic involvement in the underlying pathophysiology of CH. Animal studies added further evidence to this hypothesis. Based on previous data, even invasive treatment methods, such as hypothalamic deep brain stimulation, are used for therapy. However, the principal question of whether these alterations are pathognomonic for CH or whether they might be detected in trigeminal pain disorders in general, in terms of an epiphenomenon, is still unsolved. This article summarizes studies on hypothalamic involvement in CH pathophysiology, demonstrates the involvement of the hypothalamus in other diseases and tries to illuminate the role of the hypothalamus based on this synopsis.     

Development of the neuroendocrine hypothalamus

The development of the neuroendocrine hypothalamus has been studied using a variety of neuroanatomical and molecular techniques. Here, the major findings that mold our understanding of hypothalamic development are reviewed. The rat hypothalamus is generated predominantly from the third ventricular neuroepithelium in a "lateral early to medial late" pattern dictated perhaps by the medially receding third ventricle. Neuroendocrine neurons seem to exhibit a delayed migrational strategy, showing relatively early birthdates, although they are located in the latest-generated, periventricular nuclei. Several homeobox genes seem to play a role in hypothalamic development, and gene knockout experiments implicate a number of genes of importance in the generation of the neuroendocrine cell type.     

Current educational issues in the clinical neurosciences.

OBJECTIVE: Canadian training in the clinical neurosciences, neurology and neurosurgery, faces significant challenges. New balances are being set by residents, their associations and the Royal College of Physicians and Surgeons of Canada between clinical service, education and personal time. The nature of hospital-provided medical service has changed significantly over the past decade, impacting importantly on resident training. Finally, future manpower needs are of concern, especially in the field of neurosurgery, where it appears that soon more specialists will be trained than can be absorbed into the Canadian health care system. METHODS: A special symposium on current challenges in clinical neuroscience training was held at the Canadian Congress of Neurological Sciences in June 2000. Representatives from the Canadian Association of Interns and Residents, the Royal College of Physicians and Surgeons of Canada and English and French neurology and neurosurgery training programs made presentations, which are summarized in this report. RESULTS: Residency training has become less service-oriented, and this trend will continue. In order to manage the increasingly sophisticated hospital services of neurology and neurosurgery, resident-alternatives in the form of physician "moonlighters" or more permanent hospital-based clinicians or "hospitalists" will be necessary in order to operate major neuroclinical units. Health authorities and hospitals will need to recognize and assume this responsibility. As clinical experience diminishes during residency training, inevitably so will the concept of the fully competent "generalist" at the end of specialty training. Additional subspecialty training is being increasingly sought by graduates, particularly in neurosurgery. CONCLUSIONS: Training in neurology and neurosurgery, as in all medical specialties, has changed significantly in recent years and continues to change. Programs and hospitals need to adapt to these changes in order to ensure the production of fully qualified specialists in neurology and neurosurgery and the provision of optimal care to patients in clinical teaching units.     

Ethology and pharmacology of hypothalamic aggression in the rat

Stimulation of a restricted area of the rat's hypothalamus elicits unprovoked violent attacks of a species-specific and strain-specific nature. Serotonergic drugs affecting 5HT1 receptors, propranolol, the 5HT re-uptake inhibitor fluvoxamine, and the anxiolytic oxazepam, inhibit hypothalamic attack selectively. However, hypothalamic attack is extremely unsensitive for many drugs that do affect attack provoked by natural stimuli. The pharmacology, the form, the impulsive nature, the absence of preliminaries, the insensitivity for contexts and ultimate aims of aggressive behaviour, suggest that a mechanism with the limited function of damaging adversaries of any kind is activated in the hypothalamus. This hypothalamic attack release mechanism (harm) requires specific sensory input for the expression of specific motor components, such as biting and kicking. The back and dorsal part of the opponent's head are the important attack releasing and directing stimuli. Attacks of this nature are part of the "aggressive" repertoire of the rat in natural settings. "Lateral" or "sideways" postures, specific for intermale fighting cannot be induced by hypothalamic stimulation. Drug, lesion, and stimulation studies suggest that attack and "sideways" postures are under the control of different central mechanisms. These results suggest new ways to describe the patterning of aggressive behaviour. There are interesting ethopharmacological similarities between hypothalamic responses and obsessive compulsive disorders (OCD) in man. It is suggested that further study of the ethopharmacology of hypothalamic responses may shed light on the pathophysiology of impulsive behavioural symptoms which in man seem to be beyond the control of appraisal or context.     

Deep brain stimulation in trigeminal autonomic cephalalgias

Cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT syndrome) are primary headaches grouped together as trigeminal autonomic cephalalgias (TACs). All are characterized by short-lived unilateral head pain attacks associated with oculofacial autonomic phenomena. Neuroimaging studies have demonstrated that the posterior hypothalamus is activated during attacks, implicating hypothalamic hyperactivity in TAC pathophysiology and suggesting stimulation of the ipsilateral posterior hypothalamus as a means of preventing intractable CH. After almost 10 years of experience, hypothalamic stimulation has proved successful in preventing pain attacks in approximately 60% of the 58 documented chronic drug-resistant CH patients implanted at various centers. Positive results have also been reported in drug-resistant SUNCT and PH. Microrecording studies on hypothalamic neurons are increasingly being performed and promise to make it possible to more precisely identify the target site. The implantation procedure has generally proved safe, although it carries a small risk of brain hemorrhage. Long-term stimulation is proving to be safe: studies on patients under continuous hypothalamic stimulation have identified nonsymptomatic impairment of orthostatic adaptation as the only noteworthy change. Studies on pain threshold in chronically stimulated patients show increased threshold for cold pain in the distribution of the first trigeminal branch ipsilateral to stimulation. When the stimulator is switched off, changes in sensory and pain thresholds do not occur immediately, indicating that long-term hypothalamic stimulation is necessary to produce sensory and nociceptive changes, as also indicated by clinical experience that CH attacks are brought under control only after weeks of stimulation. Infection, transient loss of consciousness, and micturition syncope have been reported, but treatment interruption usually is not required.     

An antiserum to atrial natriuretic factor (ANF) cross-reacts with neurophysins in the hypothalamo-neurohypophysial system of rat brain

The distribution of atrial natriuretic factor (ANF)-like reactivity was examined in rat brain and heart by immunohistochemistry. Immunostaining in heart was confined to atrial myocytes. In the hypothalamus, ANF-absorbable immunoreactivity was observed in magnocellular perikarya of the paraventricular and supraoptic nuclei, and in their projections to the neural lobe of the pituitary gland. No staining was seen in the preoptic or arcuate hypothalamic nuclei or in brain stem nuclei as previously reported by other investigators. The patterns of reactivity for ANF reported here is similar to that observed for neurophysins (NPs). Comparison of sequence data between rat ANF-28 and bovine NPs revealed three regions of 3 amino acid homology between these hypothalamic peptides. Preabsorption of the ANF antiserum with Affigel-coupled bovine NP I also resulted in complete elimination of all "ANF-immunoreactivity" in both atrium and hypothalamus. Cross-reactivity of the ANF antiserum with bovine NP I and II was further confirmed by Western blot analysis. Our findings suggest that ANF antisera can cross-react with NPs if they are directed against the shared antigenic epitopes; complete elimination of staining by preabsorption of the antibody with the immunogen, therefore, does not guarantee authenticity of localization. These observations may have relevance to an earlier study which reported on the existence of ANF-immunoreactivity in oxytocin neurons of the hypothalamus.     

Effects of selective D1- or D2-like dopamine receptor antagonists with acute "binge" pattern cocaine on corticotropin-releasing hormone and proopiomelanocortin mRNA levels in the hypothalamus

We have previously demonstrated that there are stimulatory effects of acute (1 day) "binge" cocaine on corticotropin-releasing hormone (CRH) gene expression in the rat hypothalamus and on the stress responsive hypothalamic-pituitary-adrenal (HPA) activity. The first aim of the present study was to investigate the possible role of dopamine (DA) D1- or D2-like receptors (D1R or D2R) in modulating these acute effects. Administration of acute "binge" cocaine (3x15 mg/kg, i.p.) was preceded by injections of either the selective D1R antagonist (SCH23390, 2 mg/kg) or D2R antagonist (sulpiride, 50 mg/kg). The D1R or D2R blockade by SCH23390 or sulpiride, respectively, did not alter the mRNA levels of CRH in the hypothalamus, CRH-R1 or proopiomelanocortin (POMC) in the anterior pituitary. However, the acute "binge" cocaine-induced increase in hypothalamic CRH mRNA levels was not found in the rats that received either D1R or D2R antagonist pretreatment. In the anterior pituitary, acute "binge" cocaine or its combinations with either DA antagonist did not alter CRH-R1 receptor or POMC mRNA levels. Both the D1R and D2R antagonists attenuated the elevation of plasma corticosterone levels induced by acute "binge" cocaine. These results suggest that both D1R and D2R mediate acute cocaine's stimulatory effect on HPA axis at the hypothalamic CRH level. Neurobiological evidence has demonstrated functional interactions between dopaminergic and opioidergic systems that regulate preproenkephalin and preprodynorphin gene expression in the striatum. The second aim of our study was to investigate the roles that D1R or D2R could play in regulation of POMC mRNA levels in the hypothalamus in response to acute "binge" cocaine. The D2R blockade by sulpiride increased POMC mRNA levels in the hypothalamus, indicating that D2R exerts a tonic inhibitory effect on hypothalamic POMC gene expression. The POMC mRNA increases induced by the D2R blockade were attenuated by acute "binge" cocaine. Neither the D2R blockade nor acute "binge" cocaine altered POMC mRNA levels in the amygdala, anterior pituitary or neurointermediate lobe of the pituitary. In contrast to the D2R, the D1R blockade by SCH23390, acute "binge" cocaine or their combination had no effect on hypothalamic POMC mRNA levels. These results support a specific role for D2R in acute cocaine's effects on hypothalamic POMC gene expression.     

Surrogate outcomes in neurology, psychiatry, and psychopharmacology

A surrogate outcome can be defined as an outcome that can be observed sooner, at lower cost, or less invasively than the true outcome, and that enables valid inferences about the effect of intervention on the true outcome. There is increasing interest in the use of surrogate outcomes of treatment efficacy measurement in investigational drug trials. However, the significance of surrogate markers of treatment outcome in neurology and psychiatry has not yet been sufficiently demonstrated. Few such markers have been adequately "validated, " that is, shown to predict the effect of the treatment on the clinical outcome of interest. In this article, evidence that would support the validation of such markers is discussed. Biomarkers used during early clinical development programs of new psychotropic compounds are considered in the contexts of Parkinson's disease, affective disorder, and schizophrenia. The particular case of neuroprotective trials is exemplified by Parkinson's disease, where a biomarker substituting for a clinical measure of progression could be considered as a surrogate treatment outcome.     

β-endorphin alters dopamine uptake by the dopamine neurons of the hypothalamus and striatum

The study of hypothalamic dopamine (DA) neurons is complicated by the difficulty in distinguishing DA neurons from norepinephrine (NE) neurons and by the fact that they comprise only a small proportion of the catecholamine neuron population of the hypothalamus. We have studied DA uptake into nerve terminals of hypothalamic DA neurons using a synaptosomal preparation. Desmethylimipramine (DMI) was used to prevent uptake into synaptosomes from NE neurons, thus pharmacologically isolating dopaminergic from noradrenergic nerve terminals. This DMI-insensitive DA uptake in hypothalamus had all the properties of a high affinity uptake process; it was saturable, dependent on incubation time and incubation temperature, increased linearly with increasing amounts of tissue and was completely abolished by excess unlabeled DA. Also, it was completely abolished by benztropine, an inhibitor of amine uptake into DA neurons. We believe that DMI-insensitive DA uptake into hypothalamic synaptosomes represents uptake into DA nerve terminals.The DMI-insensitive DA accumulation in discrete areas of hypothalamus correlated well with the known prevalence of DA neurons relative to NE neurons in these areas: median eminence > median eminence-arcuate nucleus > mediobasal hypothalamus > whole hypothalamus. Comparison of the affinity constants for DA uptake into synaptosomes incubated without DMI revealed a 2-fold higher affinity constant for DA uptake in median eminence compared with striatum, but affinity constants in all the other hypothalamic regions examined (mediobasal hypothalamus, hypothalamus minus median eminence, whole hypothalamus) were identical to that of striatum. In contrast, comparison of the affinity constants for DA uptake in the presence of DMI revealed a 2–3-fold higher affinity constant for DA uptake in all these hypothalamic regions compared with striatum. It appears the tuberoinfundibular DA neurons and the other DA neurons of the hypothalamus have a high affinity uptake system for DA, although affinity for DA in all of these hypothalamic DA neurons appears to be 2–3-fold lower than that in striatal DA neurons. The data also suggest that the much larger mediobasal hypothalamus may serve as a model for studies of DA uptake into tuberoinfundibular DA neurons of the median eminence.     

Cluster headache: the history of the Cluster Club and a review of recent clinical research

In September 2003, a scientific meeting was held in Rome to revive the International Cluster Headache Research Group (or "Cluster Club") tradition. This group of specialists was originally formed in the late 1970s by Ottar Sjaastad in order to promote research ideas, and to generate papers and other important information in this field. Its meetings, the last of which had taken place in 1994, had been informal events at which there was ample time for lively discussion. The last decade of the 20th century brought a significant increase in clinical and experimental research into cluster headache (CH), and this review summarizes some of the results of this research. The male preponderance of CH has been shown to be progressively decreasing over the years. Revised clinical criteria and a modern classification have been presented. First-degree relatives of probands with CH have been shown to have an increased risk of suffering from CH compared with the general population. Genetic analysis suggests that an autosomal dominant gene plays a role in some families. Functional neuroimaging has contributed to a better understanding of the pathophysiology of the condition. Positron emission tomography during provoked attacks has shown activation of the ipsilateral inferior posterior hypothalamus and it has been suggested that CH might be a functional neurovascular disorder of pacemaker or circadian regions in the hypothalamic grey matter. Subcutaneously administered sumatriptan has emerged as a highly effective acute treatment, but, in our opinion, the emphasis should be on attack prevention. Deep brain stimulation of the inferior posterior hypothalamic grey matter seems to be very promising as a novel treatment targeting the presumed central origin of pain attacks.     

Evidence of dopamine dysfunction in the hypothalamus of patients with Parkinson's disease: an in vivo 11C-raclopride PET study

A mild to moderate reduction in dopamine, noradrenaline and serotonin levels alongside a progressive loss of hypocretin cells and melanin hormone concentrating cells has been reported in the hypothalamus of PD at postmortem. Hypothalamic uptake of ¹⁸F-dopa PET, an in vivo marker of dysfunction of monoaminergic neurons, is also significantly reduced in these patients. These data indicate a general impairment of hypothalamic function in PD. Dopamine receptors play an important role in the regulation of hypothalamic pathways. To date, possible changes in hypothalamic D₂ receptor availability have not been investigated in PD. The objective in this study was to assess dopamine D₂ receptor availability in hypothalamus of patients with idiopathic Parkinson's disease (PD) using positron emission tomography (PET) with ¹¹C-raclopride (RAC). We evaluated D₂ binding in RAC PET images of 14 PD patients using both region of interest (ROI) analysis and a voxel based approach. ROIs for the hypothalamus were traced on the subject's MRI co-registered to the PET image. ¹¹C-raclopride binding potentials (BP) for hypothalamus were obtained by applying ROIs onto parametric images. Findings were compared with those of 9 normal controls. We found a significant reduction in the mean hypothalamic RAC BP of the PD patients compared with the normal controls (0.2714 ± 0.06 vs. 0.3861 ± 0.04; mean ± SD; p = 0.0005). ROI results were confirmed with statistical parametric mapping (SPM). Individual hypothalamic BP values of PD patients did not correlate with age, disease duration, disease severity and levodopa equivalent dose. It remains to be ascertained whether the reductions in hypothalamic D₂ receptor availability seen in PD are disease related, the results of chronic exposure to levodopa or both. Our results provide further evidence of dopaminergic dysfunction in the hypothalamus in PD, and this may contribute to the development of sleep, endocrine and autonomic disorders.     

Amine accumulation: a possible precursor of Lewy body formation in Parkinson's disease.

It is now well recognized that the hypothalamus is an important site of neuropathology in Parkinson's disease (PD). Lewy bodies, a marker of nerve cell degeneration and a pathological hallmark of PD, have been observed frequently in the hypothalamus of PD patients by Lewy (1923) and other investigators and confirmed by more recent systematic studies by Langston & Forno (1978). Both Lewy and Langston & Forno found a predilection of Lewy body formation in specific hypothalamic nuclei with the tuberomammillary, lateral, and posterior areas containing by far the highest average counts per nucleus. Selective vulnerability of the tuberomammillary, lateral, and posterior hypothalamic cell groups to degeneration has been observed also in aging, postencephalitic Parkinsonism, Alzheimer's disease, and schizophrenia. The susceptibility of these particular nuclei to degenerative changes including Lewy body formation is not presently understood nor are the mechanisms by which Lewy bodies are formed in PD and other CNS disorders. Accumulation of amines, a pathological process which follows degeneration of catecholamine-containing neurons in experimental animals, also occurs most frequently in the lateral and posterior hypothalamic areas. In the present communication we propose that in PD, amine accumulation may be a precursor to Lewy body formation and that the susceptibility of certain hypothalamic areas to Lewy body formation may be related to their propensity to accumulate amines. Furthermore, the frequent co-existence of Lewy bodies and Alzheimer's neurofibrillary tangles in the lateral and posterior hypothalamic nuclei suggest that they may share a common pathogenetic etiology. If confirmed, this hypothesis may provide an experimental model by which the formation of Lewy bodies and neurofibrillary tangles may be investigated.     

The most probable clinical diagnosis to the applicants for the intractable disease registration of Parkinson's disease, spinocerebellar degeneration and amyotrophic lateral sclerosis]

Amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and spinocerebellar degeneration (SCD) are included in the 45 intractable diseases" acknowledged by the Ministry of Health, Labour and Welfare of Japan. The registration of applicants is based on the attending doctors' diagnosis, and medical costs of registered patients are covered by the government. However, the accuracy of the diagnoses has not been investigated previously. The aim of the present study is to investigate the accuracy of the diagnoses of patients registered as PD, SCD and ALS in Mie prefecture of Japan. The study design was cross-sectional and the survey was carried out using an anonymous questionnaire. We asked the attending doctors the most probable clinical diagnosis in each applicant for PD, SCD or ALS at the annual renewal of application form of the specified diseases by the Ministry. The questionnaires were sent to the 57 neurologists in 20 general hospitals and 2 neurology clinics in Mie prefecture, Japan. The survey was carried out from July to September, 2003. For each disorder (PD, ALS, SCD), the accuracy rates were calculated as the ratio of the number of patients with the most probable diagnosis of the consistent disease to the number of all patients registered each disease. Questionnaires on 678 patients replied from 31 neurologists, 27 of whom were the neurology specialists approved by the Japanese Society of Neurology, were retrieved and analyzed. They covered 41.1% of the total registered PD cases, 45.4% of total SCD cases, and 54.0% of total ALS cases in Mie prefecture. The final clinical diagnosis were made by such specialists in 641 cases (94.5%). The accuracy rate of PD was 97.3% for all degenerative parkinsonisms and 90.2% for idiopathic PD, 96.0% for SCD, and 77.8% for typical ALS and 81.5% for ALS and Kennedy-Alter-Sung syndrome. Although the most probable diagnoses were performed by the attending physicians without verification by other raters, the accuracy rates were excellently high in these diseases, partly because most of the attending physicians were neurology specialists. The relatively low accuracy rate in ALS may be caused partly by the difficulty in differentiating it from spine diseases, neuropathies or myopathies at the early stage of the disease when the patients had been registered, or by inclusion of other motor neuron diseases such as Kennedy-Alter-Sung syndrome.