Matti Haltia

Atypical and anaplastic meningiomas: Radiology, surgery, radiotherapy, and outcome ☆

Out of 936 primary intracranial meningiomas, 94.3% were histologically benign (grade I), 4.7% atypical (grade II), and 1.0% anaplastic (grade III); one recurrence was sarcomatous (grade IV). Meningiomas with histologic anaplasia (grades II-IV) occurred in 12% of the men, but only 4% of the women. Only 26% of atypical or anaplastic meningiomas appeared completely innocent on a computed tomography scan. Angiograms, usually showing a meningeal feeding artery, suggested meningioma when computed tomography scans did not. At 5 years after complete removal, the recurrence rate was only 3% (21% at 25 years) for benign meningiomas, but 38% for atypical ones, and 78% for anaplastic ones. The median times to recurrence were 7.5, 2.4, and 3.5 years, respectively. In spite of postoperative radiotherapy, four of five anaplastic meningiomas recurred.

A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration

The neuronal ceroid lipofuscinoses (NCLs) constitute a group of neurodegenerative storage diseases characterized by progressive psychomotor retardation, blindness and premature death. Pathologically, there is accumulation of autofluorescent material in lysosome‐derived organelles in a variety of cell types, but neurons in the central nervous system appear to be selectively affected and undergo progressive death. In this report we show that a novel form of NCL, congenital ovine NCL, is caused by a deficiency in the lysosomal aspartyl proteinase cathepsin D. A single nucleotide mutation in the cathepsin D gene results in conversion of an active site aspartate to asparagine, leading to production of an enzymatically inactive but stable protein. This results in severe cerebrocortical atrophy and early death, providing strong evidence for an important role of cathepsin D in neuronal development and/or homeostasis.

The growth rate of intracranial meningiomas and its relation to histology. An analysis of 43 patients

The growth rate of intracranial meningiomas was studied in 43 patients against a histologic grading based on the degree of anaplasia. The mean time for doubling of the tumor volume was 415 days (138-1045) in grade I (benign), 178 days (34-551) in grade II (atypical), and 205 days (30-472) in grade III (anaplastic). The difference between grade I and the combined grades II-III was highly significant. Both the mitotic index and the absence of calcification on the computed tomography scan correlated strongly with the doubling time. The growth rate should be carefully considered in planning therapy and timing computed tomography studies for patients with meningioma.

Intracranial hemangiopericytoma: Radiology, surgery, radiotherapy, and outcome in 21 patients

At operation, 21 meningeal intracranial hemangiopericytomas resembled meningiomas, but differed histologically. They were frequently attached to sinuses, occipitally located, bled profusely at operation, and had a higher risk of recurrence and metastasis. Specific preoperative diagnosis is possible: computed tomography scan showed a meningiomalike tumor, which on the angiogram looked malignant and highly vascular. Two tumors showed a malignant growth pattern on computed tomography scan, mushrooming. After a radical removal, three patients have lived for more than 10 years without recurrence; two of them were irradiated postoperatively. Three recurrent tumors were treated with radiotherapy only; one responded favorably.

Prevalence of Alzheimer’s disease in very elderly people: A prospective neuropathological study

Background: No previous autopsy-controlled, prospective, and population-based studies are available on the prevalence of AD in very elderly people. Objective: To study the point prevalence of neuropathologically defined AD in a population of people at least 85 years of age, stratified according to their APOE genotype. Methods: A population-based sample of 532 (of a total population of 601) elderly Finnish individuals, aged 85 years or more, were clinically tested for dementia in 1991 (with follow-up studies of the survivors in 1994, 1996, and 1999) and genotyped for APOE. An autopsy involving neuropathologic diagnosis of AD according to modified consensus criteria was performed in 118 of 198 deceased subjects who had been demented on April 1, 1991, and in 62 of 201 nondemented individuals. Results: The prevalence of neuropathologically defined AD was 33%, whereas the prevalence of clinically diagnosed AD was 16%. There was a highly significant (p < 0.001) association between the APOE ε4 allele and AD: Sixty-three percent of APOE ε4 carriers and 20% of noncarriers had neuropathologic AD. The respective figures in subjects aged 90 years or more were 71 and 22%. Conclusions: The prevalence of neuropathologically defined AD is higher than that reported in most previous studies based on clinical diagnosis. The discrepancy between the neuropathologic and clinical diagnoses of AD in very elderly subjects may affect the results of population-based studies. The APOE genotype has a strong effect on the prevalence of neuropathologically defined AD, even after 90 years of age.

Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by ps-1 mutations that lead to exceptionally high amyloid-β concentrations

We describe 3 new families affected by Alzheimers disease with spastic paraparesis. In affected individuals, including the earliest known patient with this clinical syndrome, neuropathological examination revealed large “cotton wool” plaques similar to those we have previously described in a Finnish family. In the families in which DNA was available, presenilin‐1 mutations were observed. Transfection of cells with these mutant genes caused exceptionally large increases in secreted Aβ42 levels. Furthermore, brain tissue from individuals with this syndrome had very high amyloid‐β concentrations. These findings define the molecular pathogenesis of an important subgroup of Alzheimers disease and have implications for the pathogenesis of the disease in general. Ann Neurol 2000;48:806–808

Northern Epilepsy: A Novel Form of Neuronal Ceroid‐Lipofuscinosis

Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic‐clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid‐Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane‐bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N‐terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid‐lipofuscinosis with an exceptionally protracted course.

Genetic association of α2-macroglobulin with Alzheimer's disease in a Finnish elderly population

Recently, two studies have reported an association between the α2‐macroglobulin gene on chromosome 12 and late‐onset Alzheimers disease, whereas others have not been able to replicate these findings. By using a prospective population‐based study, we have investigated the relation between two polymorphisms in this gene with the presence of the disease and also with the extent of pathological changes in the cerebral cortex. The Vantaa 85+ Study includes all 601 persons, at least 85 years of age, who were living in Vantaa, Finland, on April 1, 1991. The neocortical β‐amyloid protein load and the number of neurofibrillary tangles were determined on tissue sections by using methenamine silver staining and a modified Bielschowsky staining, respectively. The A/A genotype in exon 24 of the α2‐macroglobulin gene was associated with neuropathologically defined diagnosis of Alzheimers disease according to the CERAD (Consortium to Establish a Registry for Alzheimers Disease) criteria and with an increase in the neocortical β‐amyloid protein load. The effect of this association was stronger in the apolipoprotein E ε4–negative group. Therefore, genetic variability in the α2‐macroglobulin gene is a risk factor associated with neuropathologically defined Alzheimers disease in our population, as well as with the extent of neocortical β‐amyloid protein deposition.

Cathepsin D-deficient Drosophila recapitulate the key features of neuronal ceroid lipofuscinoses.

Neuronal ceroid lipofuscinoses (NCLs) are a group of lysosomal storage disorders characterized pathologically by neuronal accumulation of autofluorescent storage material and neurodegeneration. An ovine NCL form is caused by a recessive point mutation in the cathepsin D gene, which encodes a lysosomal aspartyl protease. This mutation results in typical NCL pathology with neurodegeneration and characteristic neuronal storage material. We have generated a Drosophila NCL model by inactivating the conserved Drosophila cathepsin D homolog. We report here that cathepsin D mutant flies exhibit the key features of NCLs. They show progressive neuronal accumulation of autofluorescent storage inclusions, which are also positive for periodic acid Schiff and luxol fast blue stains. Ultrastructurally, the storage material is composed of membrane-bound granular electron-dense material, similar to the granular osmiophilic deposits found in the human infantile and ovine congenital NCL forms. In addition, cathepsin D mutant flies show modest age-dependent neurodegeneration. Our results suggest that the metabolic pathway leading to NCL pathology is highly conserved during evolution, and that cathepsin D mutant flies can be used to study the pathogenesis of NCLs.

Amyloidosis Due to a Mutation of the Gelsolin Gene in an American Family with Lattice Corneal Dystrophy Type II

AMYLOID is a homogeneous, largely extracellular, proteinaceous material with a fibrillar ultrastructure and the property of green birefringence when stained with Congo red and viewed by polarizatio...