Iron deposits in post-mortem brains of patients with neurodegenerative and cerebrovascular diseases: a semi-quantitative 7.0 T magnetic resonance imaging study.

BACKGROUND AND PURPOSE: Accumulation of iron (Fe) is often detected in brains of people suffering from neurodegenerative diseases. However, no studies have compared the Fe load between these disease entities. The present study investigates by T2*-weighted gradient-echo 7.0 T magnetic resonance imaging (MRI) the Fe content in post-mortem brains with different neurodegenerative and cerebrovascular diseases. METHODS: One hundred and fifty-two post-mortem brains, composed of 46 with Alzheimer's disease (AD), 37 with frontotemporal lobar degeneration (FTLD), 11 with amyotrophic lateral sclerosis, 13 with Lewy body disease, 14 with progressive supranuclear palsy, 16 with vascular dementia (VaD) and 15 controls without a brain disease, were examined. The Fe load was determined semi-quantitatively on T2*-weighted MRI serial brain sections in the claustrum, caudate nucleus, putamen, globus pallidus, thalamus, subthalamic nucleus, hippocampus, mamillary body, lateral geniculate body, red nucleus, substantia nigra and dentate nucleus. The disease diagnosis was made on subsequent neuropathological examination. RESULTS: The Fe load was significantly increased in the claustrum, caudate nucleus and putamen of FTLD brains and to a lesser degree in the globus pallidus, thalamus and subthalamic nucleus. In the other neurodegenerative diseases no Fe accumulation was observed, except for a mild increase in the caudate nucleus of AD brains. In VaD brains no Fe increase was detected. CONCLUSIONS: Only FTLD displays a significant Fe load, suggesting that impaired Fe homeostasis plays an important role in the pathogenesis of this heterogeneous disease entity.

Microglial imaging with positron emission tomography and atrophy measurements with magnetic resonance imaging in multiple sclerosis: a correlative study.

OBJECTIVE: The objectives of the present study were to assess brain atrophy in multiple sclerosis (MS) patients during different disease stages and to investigate by PET and [11C]PK11195, a marker of microglial activation, the relationship between inflammation, atrophy and clinically relevant measures. METHODS: Eight healthy subjects and 22 MS patients were included. Semiquantitative [11C]PK11195 uptake values, with normalization on cortical grey matter, were measured for magnetic resonance imaging T2- and T1-lesions and normal appearing white matter (NAWM). As atrophy index we used the ratio of the amount of white and grey matter divided by the ventricular size, using an optimized a priori based segmentation algorithm (SPM99). RESULTS: Atrophy was significantly greater in MS patients compared to age-matched controls. A significant correlation was found between brain atrophy and both disease duration and disability, as measured with the Expanded Disability Status Scale. For NAWM, [11C]PK11195 uptake increased with the amount of atrophy, while T2-lesional [11C]PK11195 uptake values decreased according to increasing brain atrophy. CONCLUSIONS: The present study suggests that brain atrophy, correlating with disease duration and disability, is directly related to NAWM and T2-lesional inflammation as measured by microglial activation.

Pathophysiology of carotid artery disease and related clinical syndromes.

The severity of internal carotid artery lesion per se is a poor indicator of the cerebral haemodynamic status of the brain. Positron emission tomography (PET) of the brain allows to study the different pathophysiological changes related to carotid artery disease. Several stages of impairment of cerebral blood flow and metabolism can be shown such as the compensatory phases by the haemodynamic and the metabolic reserve, the transition to reversible (penumbra) and irreversible ischaemia and the phase of luxury perfusion. Distinct PET patterns correlate with certain clinical outcomes. PET studies found evidence for an embolic origin rather than for a low-flow status as most frequent cause of stroke in severe carotid artery disease. Except for deep borderzone infarcts in the centrum semi-ovale, most cortical borderzone infarcts are not due to chronic misery perfusion. Recent silent and recurrent infarcts can be demonstrated with Cobalt-55 PET, which is of importance for the therapeutical decision. The PET studies argue that carotid endarterectomy is successful probably by removing the source of emboli rather than by restoring the cerebral perfusion in severe carotid artery stenosis.

PET visualization of microglia in multiple sclerosis patients using [11C]PK11195.

Activated microglia are involved in the immune response of multiple sclerosis (MS). The peripheral benzodiazepine receptor (PBR) is expressed on microglia and up-regulated after neuronal injury. [11C]PK11195 is a positron emission tomography (PET) radioligand for the PBR. The objective of the present study was to investigate [11C]PK11195 imaging in MS patients and its additional value over magnetic resonance imaging (MRI) concerning the immuno-pathophysiological process. Seven healthy and 22 MS subjects were included. Semiquantitative [11C]PK11195 uptake values were assessed with normalization on cortical grey matter. Uptake in Gadolinium-lesions was significantly increased compared with normal white matter. Uptake in T2-lesions was generally decreased, suggesting a PBR down-regulation. However, uptake values increased whenever a clinical or MR-relapse was present, suggestive for a dynamic process with a transient PBR up-regulation. During disease progression, an increase of normal-appearing white matter (NAWM) uptake was found, propagating NAWM as the possible real burden of disease. In conclusion, [11C]PK11195 and PET are able to demonstrate inflammatory processes with microglial involvement in MS.

Evidence for chronic ischaemia in the pathogenesis of vascular dementia: from neuroPATH to neuroPET.

Vascular dementia is actually considered as a ill-defined entity. The clinical and neuropathologic criteria of this multifactorial disorder remain uncertain. Although not widely accepted, the introduction of the concept of incomplete infarction in the brain can help to explain some particular types of vascular dementia. In the hypoxic-hypoperfusion dementia syndromes of cerebral cortex and white matter and in lacunar state dementia, which are the most common types of vascular dementia, areas of incomplete infarction co-exist with regions of complete infarction. Although initially rejected by early positron emission tomographic studies, it can now be demonstrated that these incomplete infarction areas reflect chronic ischaemia of the brain and that they are relevant to the pathogenesis of vascular dementia.

Are Wistar rats not susceptible to organophosphate-induced delayed neurotoxicity?

Male Wistar rats were sacrificed 12 weeks after single exposure to various organophosphate compounds. Peripheral nerves and skeletal muscles were examined light microscopically for the occurrence of a delayed polyneuropathy. Although unequivocal morphological hallmarks of OPIDN had been demonstrated in other rat strains using similar doses of TOCP or mipafox, we were unable to demonstrate any abnormality with these compounds. Normal findings were also obtained with fenthion, the delayed neuropathic potential of which is debated, and with paraoxon or parathion, which are both highly unlikely to cause OPIDN. These data indicate that the Wistar rat strain is highly likely to be resistant to OPIDN.

Variable involvement of rat skeletal muscles in paraoxon-induced necrotizing myopathy.

We studied the incidence of paraoxon-induced myopathy in several rat skeletal muscles in relation to the morphometric properties and oxidative metabolism of their fibers. The necrosis was most pronounced in the predominantly oxidative-rich fiber-composed diaphragm. The purely oxidative-rich masseter and soleus muscles were also severely affected. All 7 mixed muscles with oxidative-poor fiber predominance were far less involved. A high correlation between oxidative capacity and the extent of the muscle fiber necrosis was evidenced in mixed muscles. No relation was found between the muscle fiber diameter and the susceptibility to necrosis. We conclude that muscles predominantly composed of highly oxidative fiber types are more susceptible to organophosphate-induced necrotizing myopathy. Oxidative capacity alone is not the only factor, however, as the mixed diaphragm was more involved than the purely oxidative-rich masseter and soleus. Several features of the distinct fiber types could be responsible for the variable vulnerability.

Neurological aspects of organophosphate poisoning.

Besides their well-known anticholinesterase action resulting in a typical acute cholinergic crisis, organophosphorus (OP) agents are capable of producing several subacute or chronic neurological syndromes. The acute over-stimulation at the neuromuscular junction results in muscle fiber necrosis. The significance of this OP-induced myopathy in human intoxication is unknown. Organophosphate-induced delayed neuropathy (OPIDN) arises 1-3 weeks after exposure to some OP compounds all capable of remarkably inhibiting a distinct esterase called neuropathy target esterase (NTE) during a critical time period. An experimental hen model has been designed to screen new OP compounds as to their delayed neurotoxic effects. The recently described intermediate syndrome emerges 1-4 days after an apparently well-treated cholinergic crisis. It main clinical features are sudden respiratory paralysis, cranial motor nerve palsies, and proximal limb muscle and neck flexor weakness. Whether or not this is a separate entity in OP agent toxicology remains to be seen. Further studies are required to further determine its clinical and paraclinical characteristics and the actual type of underlying neuromuscular dysfunction involved.

Acid phosphatase activity of cerebrospinal fluid cells in bacterial and abacterial meningitis.

Acid phosphatase staining is performed on cerebrospinal fluid cells of 365 samples from 105 patients with various types of meningitis. This enzyme activity is strongly positive in the early samples of bacterial meningitis, as far as the patients had not received a pretreatment with antibiotics for more than 24 h. It allows monitoring the response to therapy in subsequent samples. Acid phosphatase activity is positive in 2 cases of cryptococcus meningitis. It is negative in all cases of aseptic and Mycoplasma pneumoniae meningitis. The results in herpes encephalitis are variable, depending on the clinical state and the degree of brain destruction. Acid phosphatase staining is a useful and rapid cytological technique for determination of the nature of the meningitis and for monitoring the therapeutical response.

Long-term study of isoprinosine in a case of subacute sclerosing panencephalitis.

A long-term study of isoprinosine, with temporary discontinuation of the treatment, in a 25-year-old man with subacute sclerosing panencephalitis is presented. Isoprinosine appears to have mainly an effect on the mental disturbances in stage I. EEG and CFS changes correlate well with the clinical course and the influence of isoprinosine.

Cerebral angioarchitecture and perinatal brain lesions in premature and full-term infants.

The present study explains the time sequence and the location of the different ischemic perinatal brain lesions by the changes in the arterial angioarchitecture which take place during the last fetal months. Hemorrhages in the germinal layer and in the subarachnoid space occur at a time when, and in a localization where, the primitive embryonic type of arterial angioarchitecture is in regression, while leukomalacia lesions occur when the periventricular arterial border-zones are already formed.

Wernicke's encephalopathy in patients with tumors of the lymphoid-hemopoietic systems.

In three treated patients with a generalized invasion by a tumor of the lymphoid-hemopoietic systems, the neuropathologic findings were consistent with Wernicke's encephalopathy. The clinical picture was atypical, but thiamine deficiency by severe malabsorption was the probable cause of this neurologic complication. It is postulated that the chronic form of Wernicke's encephalopathy must occur more frequently than previously shown in treated and long-standing cases of such kinds of tumors.

Periventricular leukomalacia in adults. Clinicopathological study of four cases.

The pathological findings in four patients with courses characterized by acute coma and respiratory insufficiency occurring in obscure circumstances are presented. Carbon monoxide intoxication was excluded. After an early partial recovery from coma, the patients remained in a persistent vegetative state, with a tetrapyramidal syndrome. Pathologic changes consisted of infarction and demyelination of periventricular white matter, with associated necrotic foci in the basal ganglia in some cases. We propose that the prolonged hypoxia and ischemia produce a "no reflow" phenomenon causing brain edema (more pronounced in the white matter); this resulted in infarctions of white matter in the periventricular arterial end and border zones.

The arterial angioarchitecture of cerebral infarctions.

The arterial angioarchitecture of twenty post mortem brains, containing thirty infarctions, was examined by means of the translucidation technique after filling the arterial system with a colloïdal barium sulphate solution. Although the large as well as the small arteries and arterioles were filled to a variable degree in the infarcted areas, the angioarchitecture was generally severely affected. Their differences were compared in red and white softenings and in cases of thrombosis, embolism, hemodynamic disturbances and compression of arteries. Also the influence of arterial hypertension and of the age and the location of the infarction was determined.