Elio Lugaresi

Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity.

The fundamental event in prion diseases seems to be a conformational change in cellular prion protein (PrPC) whereby it is converted into the pathologic isoform PrPSc. In fatal familial insomnia (FFI), the protease-resistant fragment of PrPSc after deglycosylation has a size of 19 kilodaltons, whereas that from other inherited and sporadic prion diseases is 21 kilodaltons. Extracts from the brains of FFI patients transmitted disease to transgenic mice expressing a chimeric human-mouse PrP gene about 200 days after inoculation and induced formation of the 19-kilodalton PrPSc fragment, whereas extracts from the brains of familial and sporadic Creutzfeldt-Jakob disease patients produced the 21-kilodalton PrPSc fragment in these mice. The results presented indicate that the conformation of PrPSc functions as a template in directing the formation of nascent PrPSc and suggest a mechanism to explain strains of prions where diversity is encrypted in the conformation of PrPSc.

Fatal Familial Insomnia and Dysautonomia with Selective Degeneration of Thalamic Nuclei

The thalamus is affected in diffuse degenerative processes of the nervous system.1 2 3 4 5 However, it has not been established whether a genetically determined degenerative disease may be limited ...

REM sleep behavior disorders in multiple system atrophy

We report the results of clinical and polysomnographic investigations on 39 consecutive multiple system atrophy (MSA) patients. Twenty-seven patients (69%) reported nocturnal motor paroxysmal episodes related to dreams, suggesting the clinical diagnosis of REM sleep behavior disorder (RBD). In 12 of them (44%), RBD preceded the clinical onset of the disease by more than 1 year. In seven (26%), the RBD onset was concomitant with and in eight (30%) was at least 2 years after the appearance of motor or autonomic symptoms. On polysomnographic recordings, 35 of 39 MSA patients (90%) had RBD. Other polysomnographic findings included nonclinical obstructive sleep apnea in 6 patients, laryngeal stridor in 8 patients, and periodic limb movements during sleep in 10 patients. Our data show that RBD represents the most common clinical sleep manifestation and polysomnographic finding in patients with MSA. RBD can frequently herald the appearance of other MSA symptoms by years. Extended polysomnographic montages are recommended in MSA sleep studies.

Arterial pressure changes during spontaneous sleep in man

Abstract The systemic arterial pressure was measured continuously during spontaneous night sleep (using a catheter in the branhial artery) in eight normotensive subjects. The results can be summarized as follows: 1. 1. Arterial pressure decreased rapidly in the first part of the night and increased gradually in the second part. 2. 2. Pressure decreased progressively from when the subject was still awake to successive slow sleep stages: the difference in pressure between one stage and the next is significant. Pressure was slightly higher, but not to a significant degree, in REM stage than in stage 2. 3. 3. Variations of arterial pressure during a particular stage might be present both in stage 2 and in the REM stage. In stage 2, in some subjects, these variations became periodic from time to time, identifiable with the arterial pressure oscillations described by Sigmund Mayer; they were often accompanied by a respiratory periodicity. In the REM stage the increases in arterial pressure were more pronounced but not necessarily in relation to variations of arteriolar tone or of heart rate.

Some periodic phenomena arising during drowsiness and sleep in man.

In the course of numerous polygraphic recordings made on normal subjects and patients with sleep disturbances (Pickwickian syndrome, primary alveolar hypoventilation, restless legs syndrome and nocturnal myoclonus) we observed several vegetative and somatic phenomena which tended to oscillate or repeat themselves periodically every 20–30 sec during sleep, and especially during light sleep. The functional oscillations of this kind could involve the systemic arterial pressure, the pulmonary arterial pressure, cardiac rate, arteriolar tone, breathing, peripheral motoneurone excitability and the level of consciousness, both individually and simultaneously. It has been known for some time that systemic arterial pressure can present periodic oscillations at about every 30 sec (Meyer waves), especially in emergency situations; it has also been demonstrated experimentally that Mayer waves can be associated with periodic breathing and with cyclical oscillations of reticular tone, of pupil diameter and of the excitability of spinal motoneurones. During sleep, the physiological or pathophysiological situations which are the basis of these oscillatory phenomena could be represented by variations in pH, PCO2, and PO2 consequent on arterial hypotension or alveolar hypoventilation.

Nocturnal paroxysmal dystonia.

Sleep-related seizures characterised by choreoathetoid, dystonic and ballic movements occurred in 12 patients, repeatedly each night and over a period of years. The nocturnal attacks were short-lasting, responded well to carbamazepine and were sometimes associated with clearly or possibly epileptic seizures during night- or daytime. They resembled the paroxysmal kinesigenic dystonias of wakefulness. Similar dystonic-dyskinetic attacks, but of long duration and unresponsive to medication, were also observed in two other patients, in one 20 years before the onset of clinically apparent Huntingtons chorea. Nocturnal paroxysmal dystonia represents a syndrome of sleep-related motor attacks which comprises two variants, respectively characterised by short and long-lasting seizures. Its precise nosological definition still awaits elucidation.

Fatal familial insomnia: Clinical and pathologic study of five new cases

In 1986, we reported two anatomoclinical observations of a familial condition that we called “fatal familial insomnia” (FFI). We now present the pedigree as well as the clinical and neuropathologic findings in five new subjects. The pedigree includes 288 members from six generations. Men and women are affected in a pattern consistent with an autosomal dominant inheritance. The age of onset of the disease varies between 37 and 61 years; the course averages 13 months with a range of 7 to 25 months. Progressive insomnia (polygraphically proven in two cases); autonomic disturbances including hyperhidrosis, hyperthermia, tachycardia, and hypertension; and motor abnormalities including ataxia, myoclonus, and pyramidal dysfunction, were present in every case, but with variable severity and time of presentation. Sleep and autonomic disorders were the earliest signs in two subjects, motor abnormalities were dominant in one, and others had intermediate clinical patterns. Pathologically, all the cases had severe atrophy of the anterior ventral and mediodorsal thalamic nuclei. Other thalamic nuclei were less severely and inconsistently affected. In addition, most of the cases had gliosis of the cerebral cortex, a moderate degree of cerebellar atrophy with “torpedoes,” and severe atrophy of the inferior olivary nuclei. One case also showed spongy degeneration of the cerebral cortex. We conclude that all the lesions were primary, and that FFI is a multisystem disease in which the different structures are primarily affected with different severity. The insomnia appears to correlate best with the major thalamic pathology. The possibility that FFI belongs to the group identified as prion diseases or diseases transmitted by unconventional agents is examined.

Fatal Familial Insomnia and Familial Creutzfeldt‐Jakob Disease: Clinical, Pathological and Molecular Features

Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt‐Jakob disease (CJD178) are two prion diseases that have different clinical and pathological features, the same aspartic acid to asparagine mutation (D178N) at codon 178 of the prion protein (PrP) gene, but distinct genotypes generated by the methionine‐valine polymorphism at codon 129 (129M or 129V) in the mutant allele of the PrP gene. The D178N, 129M allele segregates with FFI while the D178N, 129V allele segregates with CJD178. The proteinase K resistant PrP (PrPres) isoforms present in FFI and CJD178 differ in degree of glycosylation and size. Thus, the amino acid, methionine or valine, at position 129 of the mutant allele, in conjunction with D178N mutation results in significant alterations of PrPres in FFI and CJD178. The 129 polymorphic site also exerts influence through the normal allele: the course of the disease is shorter in the patients homozygous at codon 129 and other minor but consistent phenotypic differences occur between homozygous and heterozygous FFI patients. The comparative study of PrPres distribution in FFI homozygotes and heterozygotes at codon 129 has lead to the conclusion that the phenotypic differences observed between these two FFI patient populations may be the result of different rates of conversion of normal PrP into PrPres, at least in some brain regions.

Abnormal brain and muscle energy metabolism shown by 31P magnetic resonance spectroscopy in patients affected by migraine with aura

We studied brain and muscle energy metabolism by phosphorus 31 magnetic resonance spectroscopy (31P-MRS) in 12 patients affected by migraine with aura (classic migraine) in interictal periods. Brain 31P-MRS disclosed a low phosphocreatine content in all patients, accompanied by high adenosine diphosphate concentration, a high percentage of V/Vmax (adenosine triphosphate), and a low phosphorylation potential—features showing an unstable state of metabolism in classic migraine. Abnormal muscle mitochondrial function, in the absence of clinical signs of muscle impairment, was present in nine of the 12 patients examined.

Undiagnosed sleep-disordered breathing among male nondippers with essential hypertension.

Objective A blunting of the nocturnal fall in arterial blood pressure is found in a minority of patients (nondippers) with essential hypertension. We tested whether sleep-disordered breathing (snoring and apnea or hypopnea) might explain such a finding for male patients, among whom its prevalence is much higher. Setting and patients We studied 100 new cases of hypertension in men, observed consecutively by a local group of general practitioners and diagnosed essential hypertensives in a referral clinic. By using 24 h ambulatory blood pressure monitoring with a SpaceLabs 90207 device, 15 patients were classified initially nondippers (daytime ambulatory blood pressure ≥ 136/87 mmHg; night-time decrease by < 10% of the daytime mean), but only 11 were confirmed to be nondippers by continuous blood pressure monitoring with a Finapres device. Ten dippers matched by age, body mass index and mean 24 h blood pressure were used as controls. Main outcome measures Parameters of nocturnal polysomnography. Results During polysomnography, the nondippers exhibited a blunting of the sleep-related fall in blood pressure and an increased variability in blood pressure associated with sleep-disordered breathing (heavy snoring for all, with an apnea or hypopnea index > 10 in 10 cases). Six of the control patients breathed normally and four snored nonapneically. There was a normal fall in nocturnal blood pressure in all 10 cases. Conclusions The nondipper condition appears to be associated with undiagnosed apneic snoring for an unselected population of previously untreated male subjects with a diagnosis of essential hypertension. Ambulatory blood pressure monitoring of such patients is of limited diagnostic value.