CAIDE Dementia Risk Score, Alzheimer and cerebrovascular pathology: a population-based autopsy study.

BACKGROUND: CAIDE Dementia Risk Score is a tool for estimating dementia risk in the general population. Its longitudinal associations with Alzheimer or vascular neuropathology in the oldest old are not known. AIM: To explore the relationship between CAIDE Dementia Risk Score at baseline and neuritic plaques, neurofibrillary tangles, cerebral infarcts and cerebral amyloid angiopathy (CAA) after up to 10-year follow-up in the Vantaa 85 +  population. METHODS: Study population included 149 participants aged ≥85 years, without dementia at baseline, and with available clinical and autopsy data. Methenamine silver staining was used for ß-amyloid and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, CAA and α-synuclein pathologies. The CAIDE Dementia Risk Score was calculated based on scores for age, sex, BMI, total cholesterol, systolic blood pressure, physical activity and APOEε4 carrier status (range 0-18 points). RESULTS: A CAIDE Dementia Risk Score above 11 points was associated with more cerebral infarctions up to 10 years later: OR (95% CI) was 2.10 (1.06-4.16). No associations were found with other neuropathologies. CONCLUSION: In a population of elderly aged ≥85 years, higher CAIDE Dementia Risk Score was associated with increased risk of cerebral infarcts.

Prevalence and severity of cerebral amyloid angiopathy: a population-based study on very elderly Finns (Vantaa 85+).

BACKGROUND: Cerebral amyloid angiopathy (CAA) is frequent in patients with Alzheimer's disease while its prevalence in different populations is variable. We investigated the prevalence and severity of CAA in a very elderly Finnish population. METHODS: Neuropathological investigation was performed on 306 subjects from the population-based Vantaa 85+ Study (253 women, 53 men, mean age at death 92.3 years). The presence of CAA was analysed in six brain regions by using Congo red and immunohistochemistry with an antibody against amyloid beta peptide. The severity of CAA was assessed by counting the percentage of the CAA-positive blood vessels. RESULTS: In total, 69.6% of the participants (170 women, 43 men) had CAA, with median severity of 1.0%, inter-quartile range (IQR) 0-5.4% and range 0-72.7%. CAA was more prevalent (81.1% vs. 67.2%; P = 0.046) and severe (median 2.7%, IQR 0.4-7.5%, range 0-72.7%) in the men than in the women (median 1.0%, IQR 0-4.6%, range 0-52.8%; P = 0.004). Parietal lobe showed the highest prevalence (57.8%) whereas the severity was highest (median 1.0%, IQR 0-6.0%, range 0-77%) in the frontal lobe. Prevalence of CAA in the six regions was variable, but the severity indices between those regions correlated highly (P < 0.001 for all regions). Meningeal CAA was more prevalent (69.5%) than cortical (59.3%; P < 0.001). CONCLUSION: CAA was highly prevalent, albeit mild, in the very old. The prevalence and severity of CAA were found to be highest in the frontal and parietal lobes respectively - independent of the staining method used (Congo red or amyloid beta peptide).

A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1.

We describe a novel variant of Alzheimer's disease (AD) in a Finnish pedigree with 17 affected individuals of both sexes in three generations. The disease is characterized by progressive dementia which is, in most cases, preceded by spastic paraparesis. Neuropathological investigations revealed numerous, distinct, large, round and eosinophilic plaques as well as neurofibrillary tangles and amyloid angiopathy throughout the cerebral cortex. The predominant plaques resembled cotton wool balls and were immunoreactive for Abeta but lacked a congophilic dense core or marked plaque-related neuritic pathology. Molecular genetic analysis revealed that the disease was caused by a deletion of exon 9 (delta9) of the presenilin 1 (PS1) gene from the mRNA: unlike previous examples of the delta9 variant, the deletion was not caused by a splice acceptor site mutation.

Combined use of non-invasive techniques for improved functional localization for a selected group of epilepsy surgery candidates.

Invasive cortical mapping is conventionally required for preoperative identification of epileptogenic and eloquent cortical regions before epilepsy surgery. The decision on the extent and exact location of the resection is always demanding and multimodal approach is desired for added certainty. The present study describes two non-invasive preoperative protocols, used in addition to the normal preoperative work-up for localization of the epileptogenic and sensorimotor cortical regions, in two young patients with epilepsy. Magnetoencephalography (MEG) was used to determine the primary somatosensory cortex (S1) and the ictal onset zones. Navigated transcranial magnetic stimulation (nTMS) was used to determine the location and the extent of the primary motor representation areas. The localization results from these non-invasive methods were used for guiding the subdural grid deployment and later compared with the results from electrical cortical stimulation (ECS) via subdural grids, and validated by surgery outcome. The results from MEG and nTMS localizations were consistent with the ECS results and provided improved spatial precision. Consistent results of our study suggest that these non-invasive methods can be added to the standard preoperative work-up and may even hold a potential to replace the ECS in a subgroup of patients with epilepsy who have the suspected epileptogenic zone near the sensorimotor cortex and seizures frequent enough for ictal MEG.

PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer's disease.

Variant Alzheimer's disease (VarAD) with spastic paraparesis and presenile dementia is associated with certain mutations of the presenilin 1 (PS-1) gene, particularly those leading to deletion of exon 9 (PS-1Delta E9). VarAD is neuropathologically characterized by the presence of unusually large, Abeta42 positive, non-cored 'cotton wool' plaques (CWPs), also devoid of dystrophic neurites. The aim of the present study was to find out whether [(11)C]PIB would show increased uptake and serve as an in vivo biomarker of amyloid accumulation in VarAD. A further aim was to assess the correspondence of the [(11)C]PIB binding to the amount and type of Abeta deposits in another group of deceased VarAD patients' brains. We studied four patients with VarAD and eight healthy controls with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum and region-to-pons ratio in each voxel over 60-90 min. Group differences in [(11)C]PIB uptake were analysed with automated region-of-interest (ROI) analysis. [(11)C]PIB uptake was compared to the immunohistochemically demonstrated deposition of Abeta in the brains of another group of four deceased VarAD patients. Patients with VarAD had significantly higher [(11)C] PIB uptake than the control group in the striatum (caudate nucleus and putamen), anterior and posterior cingulate gyrus, occipital cortex and thalamus. In the caudate and putamen [(11)C]PIB uptake, expressed as region-to-cerebellum ratio, was on the average 43% greater than the mean of the control group. The increases in the anterior (28%) and posterior (27%) cingulate gyrus, occipital cortex (21%) and thalamus (14%) were smaller. All VarAD patients showed this similar topographical pattern of increased [(11)C]PIB uptake. The results were essentially similar when the uptake was expressed as region-to-pons ratios. [(11)C]PIB imaging shows increased uptake in patients with VarAD especially in the striatum, and it can be used to detect amyloid accumulation in vivo in these patients. The pattern of increased [(11)C]PIB uptake is different from that described in sporadic Alzheimer's disease and resembles that seen in Alzheimer's disease patients with certain presenilin-1 mutations or amyloid precursor protein gene duplication showing predominantly striatal increase in [(11)C]PIB uptake.

Stem cell protein BMI-1 is an independent marker for poor prognosis in oligodendroglial tumours.

AIMS: The polycomb factor BMI-1 has recently been implicated in tumorigenesis of the central nervous system in several experimental animal models. However, the significance of BMI-1 in human glioma has not been investigated. Here we describe expression of the polycomb protein BMI-1 and its downstream targets p16(Ink4a) and MDM2 in both high- and low-grade human glioma. METHODS: Tumour samples were collected from 305 adult patients treated for primary grades 2-4 gliomas between 1980 and 2006 in Finland and Germany. BMI-1, p16 and MDM2 expression was evaluated using immunohistochemistry in representative paraffin-embedded tumour tissue. The significance of observed immunoreactivity, age at onset, gender, histopathological findings and proliferative index was analysed in univariate and multivariate survival models. RESULTS: BMI-1 was expressed in all histologic types of diffuse gliomas. We found a significant correlation (P = 0.007) between the frequency of BMI-1 immunoreactive tumour cells and poor survival in World Health Organization grades II-III oligodendrogliomas and oligoastrocytomas (n = 62). The median survival of patients grouped by low, intermediate or high frequency of BMI-1 immunoreactive tumour cells was 191 months, 151 months and 68 months, respectively. This association was also significant in the Cox multivariate regression model. Nuclear p16 immunopositivity predicted better survival in astrocytomas and an inverse correlation between p16 expression and the Ki-67 mitotic index was also observed. CONCLUSIONS: BMI-1 is found in all histological types of gliomas and the relative protein expression of BMI-1 is a novel independent prognostic marker in oligodendroglial tumours.

Reappraisal of a consecutive autopsy series of patients with primary degenerative dementia: Lewy-related pathology.

Dementia with Lewy bodies (DLB) is a common but underdiagnosed dementing disorder. Its criteria were defined in 1996, and revised in 2005. DLB is characterised neuropathologically by widely distributed cortical Lewy bodies (LBs), usually associated with Alzheimer-type pathology. We have re-evaluated the neuropathology of 55 autopsied patients with clinically diagnosed primary degenerative dementia to determine the frequency of DLB in this cohort, which was originally examined when neither the entity of DLB nor its diagnostic criteria had been defined. We also evaluated how discovery of a new entity affects previous diagnoses. Of the 55 brains, 16 (29%) contained LBs. All 16 originally had a neuropathological diagnosis of Alzheimer's disease (AD). 11 (20%) fulfilled the neuropathological criteria for DLB. Three patients had AD with LBs in the brain stem only, and two patients had LBs in the limbic cortex only. Because the criteria and reliable markers for DLB were not available at the time of the autopsies, the diagnosis of DLB had not been possible. The common co-occurrence of AD-type pathology in DLB makes the clinical diagnosis of DLB problematic even today. This study also raises the question of the relative significances of Lewy-related and AD-type pathologies to the development of dementia.

Peroxiredoxins and antioxidant enzymes in pilocytic astrocytomas.

OBJECTIVE: Peroxiredoxins are antioxidant enzymes (AOEs), which are redox-regulated thiol proteins with potential effects on the growth, invasion and drug resistance of neoplastic cells. In this study, their biology and clinical significance were examined in pilocytic astrocytomas (PAs). MATERIAL AND METHODS: The expression of peroxiredoxins (Prx I-VI) was investigated in 105 PAs by the means of immunohistochemistry and compared with the expression of selected other antioxidant enzymes, cell proliferation, angiogenesis, apoptosis, p53, histopathology and patient survival. RESULTS: Peroxiredoxins were strongly expressed in general suggesting that oxidative damage and consequent defense takes place during the progression of pilocytic astrocytomas. In agreement with this hypothesis, several other AOEs correlated with the degenerative features and angiogenesis possibly associated with reactive oxygen species-derived cellular damage. Moreover, the expression of the AOEs was associated with each other indicating a concurrent activation of the enzymes. With the exception of manganese superoxide dismutase (MnSOD), a strong expression of AOEs was generally associated with higher cell proliferation. Prx VI seemed to have a positive association with a longer recurrence-free interval while other AOEs had no association with patient survival. Many AOEs, such as MnSOD, induce chemo- and radioresistance and are highly elevated in aggressive malignancies. PAs lack this confounding factor, and these tumors are treated only by surgery. CONCLUSIONS: Taken together, the results of this study on pilocytic astrocytomas suggest that the levels of Prxs and other AOEs and their related thiol proteins are generally strongly expressed in these tumors. At least Prx VI can contribute to tumor behavior which can make it a potential prognostic factor.

Patient with multiple acyl-CoA dehydrogenation deficiency disease and FLAD1 mutations benefits from riboflavin therapy.

Multiple acyl-CoA dehydrogenation deficiency is genetically heterogenous metabolic disease with mutations in genes involved in electron transfer to the mitochondrial respiratory chain. Disease symptoms vary from severe neonatal form to late-onset presentation with metabolic acidosis, lethargy, vomiting, muscle pain and weakness. Riboflavin therapy has been shown to ameliorate diseases symptoms in some of these patients. Recently, mutations in FAD synthase have been described to cause multiple acyl-CoA dehydrogenation deficiency. We describe here the effect of riboflavin supplementation therapy in a previously reported adult patient with multiple acyl-CoA dehydrogenation deficiency having compound heterozygous gene variations in FLAD1 (MIM: 610595) encoding FAD synthase. We present thorough clinical history including laboratory investigations, muscle MRI, muscle biopsy and spiroergometric analyses comprising of a follow-up of 20 years. Our data suggest that patients with adult-onset multiple acyl-CoA dehydrogenation deficiency with FLAD1 gene mutations also benefit from long-term riboflavin therapy.

Independent component analysis to proton spectroscopic imaging data of human brain tumours.

In proton magnetic resonance spectroscopic imaging (1H MRSI), the recorded spectra are often linear combinations of spectra from different cell and tissue types within the voxel. This produces problems for data analysis and interpretation. A sophisticated approach is proposed here to handle the complexity of tissue heterogeneity in MRSI data. The independent component analysis (ICA) method was applied without prior knowledge to decompose the proton spectral components that relate to the heterogeneous cell populations with different proliferation and metabolism that are present in gliomas. The ability to classify brain tumours based on IC decomposite spectra was studied by grouping the components with histopathology. To this end, 10 controls and 34 patients with primary brain tumours were studied. The results indicate that ICA may reveal useful information from metabolic profiling for clinical purposes using long echo time MRSI of gliomas.

Proliferative activity and DNA index do not significantly predict survival in primary central nervous system lymphoma.

Proliferative activity and DNA index were analyzed and correlated with histology and survival in 30 primary central nervous system lymphomas (PCNSL) in immunocompetent patients. Proliferative activity was determined using mitotic activity index and volume-corrected mitotic index, percentage of Ki-67 (MIB-1) immunopositive nuclei and flow cytometric S-phase fraction. Twenty-nine PCNSL were of B-cell origin and one of T-cell; by Kiel classification there were 23% low grade and 77% high grade and by Working Formulation there were 7%, 73% and 20% low, intermediate and high grade tumors, respectively. Mean survival time for non-survivors (n = 26) was 11.5 months and median 6.5 months. When indicators of proliferative activity were evaluated against histological grading, correlation existed only between mitotic activity index and Kiel classification. None of the proliferation markers or DNA index correlated significantly with survival, but there was a trend for patients with higher volume-corrected mitotic index to have shorter survival. In conclusion, most PCNSL have poor prognosis irrespective of their histological grade and proliferative activity. Furthermore, because at present stereotactic biopsy is recommended for establishing the diagnosis, exact histological subtyping and determination of proliferation activity in such small samples appears to be of only marginal significance.

Variant Alzheimer disease with spastic paraparesis: neuropathological phenotype.

Variant Alzheimer disease (varAD) is clinically characterized by the combination of presenile dementia with spastic paraparesis and is caused by certain mutations of the presenilin 1 (PS-1) gene. We now present the unusual neuropathological phenotype of varAD as seen in 5 affected members of the original Finnish family with a genomic deletion encompassing exon 9 of the PS-1 gene. Their primary and association cortices and hippocampus showed a profusion of eosinophilic, roundish structures with distinct borders termed "cotton wool" plaques (CWPs). The CWPs were immunoreactive for Abeta42/43 but weakly or not at all for Abeta40 isoforms of the amyloid beta peptide (Abeta). They were devoid of a congophilic core, and fibrillar amyloid could not be identified within them by electron microscopy. Confocal microscopy showed reduced density of axons within individual CWPs and only few CWP-related PHF-tau-positive dystrophic neurites. CWPs were particularly numerous in the medial motor cortex representing the lower extremities, and degeneration of the lateral corticospinal tracts was observed at the level of the medulla oblongata and the spinal cord. In addition to the predominant CWPs, variable numbers of diffuse and cored plaques were found in the cerebral cortex. Diffuse and non-neuritic cored amyloid plaques but no CWPs occurred in the cerebellum. In conclusion, varAD in this Finnish family is distinct from classic AD because of the degeneration of lateral corticospinal tracts, predominance of CWPs devoid of fibrillar amyloid cores in the cerebral cortex, and presence of non-neuritic amyloid plaques in the cerebellum.

Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke.

BACKGROUND AND PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) is detected in ischemic brain cells in experimental animal models and is believed to play an important role in apoptosis. However, the natural expression of TNF-alpha during human stroke is not known. METHODS: We examined TNF-alpha immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) in brain samples of stroke victims (n=16) after variable survival (15 hours to 18 days). Systemic TNF-alpha content from a separate cohort including severe or lethal stroke cases (n=26) was also assayed. RESULTS: Neuronal TNF-alpha was demonstrated from 0.6 to 5.4 days after the onset of stroke symptoms, peaking bilaterally during days 2 and 3. Bilateral glial TNF-alpha immunoreactivity was detected during the acute phase, with the astrocytic TNF-alpha expression dominating in later phases and persisting contralaterally to the infarct in more matured phases (17 to 18 days). Invading inflammatory cells were TNF-alpha immunopositive beginning on the third day. Besides, vascular wall structures showed immunoreactivity sporadically. TNF-alpha levels were mostly nondetectable in peripheral blood. TUNEL labeling and TNF-alpha staining overlapped, although not completely, during the first days. CONCLUSIONS: The data support the hypothesis that TNF-alpha may be involved both in the acute propagation of inflammatory processes and cell death and possibly in the more delayed reconstitutive processes of human ischemic stroke.

Ovarian hyperstimulation caused by gonadotroph adenoma secreting follicle-stimulating hormone in 28-year-old woman.

Ovarian hyperstimulation caused by a gonadotroph adenoma in premenopausal women has been described only twice before this report. A 28-yr-old woman presented with menstrual disturbances and pelvic pains that began after stopping the use of contraceptive pills. Transvaginal ultrasound revealed enlarged ovaries with multiple cysts. The patient had elevated serum estradiol (up to 2900 pmol/L; normal, 80-300 pmol/L in the follicular phase) and inhibin (6.4 kU/L; normal, 0.5-2.5 kU/L) levels. Serum LH was appropriately suppressed (0.6 IU/L), but serum FSH varied from 4.9-8.1 IU/L. Both gonadotropins as well as the free alpha-subunit showed a paradoxical response to the stimulus by TRH. A nuclear magnetic resonance study unraveled a pituitary tumor, 12-14 mm in diameter, extending up to the suprasellar cistern. After pituitary surgery, all hormone values normalized, and the patient resumed regular ovulatory cycles. In immunostaining, 20-30% of the cells of the tumor stained positively for FSHbeta. We conclude that a gonadotropin-producing adenoma must be considered in the differential diagnosis of a patient presenting with large multicystic ovaries and high estradiol levels in the absence of exogenous gonadotropins.

Classic amyotrophic lateral sclerosis with dementia.

Documented cases of classic amyotrophic lateral sclerosis (ALS) combined with severe dementia are few and come from the isolated populations of the Western Pacific. In this report, three women had a clinically and neuropathologically documented combination of ALS and dementia. In all cases the symptoms and signs of ALS were mainly bulbar. In two of them dementia appeared first, followed by ALS. At autopsy, there was a marked discrepancy between the severe degree of dementia of Alzheimer's type and the sight nonspecific neuropathologic findings without Alzheimer's changes. Our cases bear a close resemblance to recently published Japanese cases. It may be concluded that the combination of sporadic ALS and progressive dementia seems to be a clinical entity without consistent neuropathologic changes and that it also occurs in the western countries.

Adult-onset autosomal recessive ataxia with thalamic lesions in a Finnish family.

OBJECTIVE: To describe an unusual kindred with adult-onset ataxia and thalamic lesions detected by brain MRI. METHODS: The authors characterized clinical, laboratory, and pathologic features of the disease and sought linkage to previously recognized ataxia loci. RESULTS: Two sisters and a brother developed progressive ataxia, dysarthria, mild cognitive impairment, and sensorimotor neuropathy at age 30, combined with epilepsy in one sibling. MRI showed symmetric thalamic lesions, changes in brainstem gray matter, and white matter changes in the cerebellum. Autopsy in one of the patients revealed neuronal degeneration with a peculiar vacuolar change in thalamus, probably representing transsynaptic degeneration in response to deafferentation. Neuronal and secondary tract degeneration was observed in the spinal cord, cerebellum, and brainstem suggesting a spinocerebellar degeneration. The disorder appears to be transmitted as an autosomal recessive trait. Genetic and sequence analysis of the FRDA gene and comprehensive laboratory examinations excluded Friedreich's ataxia and other similar recessive diseases. CONCLUSION: Adult-onset recessive ataxia with bilateral thalamic lesions in this family may represent a distinct hereditary spinocerebellar ataxia.

Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients.

OBJECTIVE: To study the long-term effects of radiotherapy on cognitive function in adult patients operated on for low-grade glioma. METHODS: A cohort of 160 patients who underwent surgery for low-grade gliomas of cerebral hemisphere between 1980 and 1992 in a single institution serving a defined population was studied. At a mean follow-up time of 7 years, 28 of the 101 patients who had postoperative irradiation (and no second surgery or chemotherapy) were still alive and eligible for MRI and neuropsychological study. Twenty-three of 59 patients who did not have radiotherapy, second surgery, or chemotherapy were alive and eligible at a mean of 10 years. RESULTS: The group that had postoperative irradiation performed significantly worse than the group that did not in cognitive tests. This difference was not accounted for by histologic diagnosis; location, extent of removal, or progression of the tumor; or any patient factor. Leukoencephalopathy was more severe in the group that had postoperative irradiation than in the group without radiotherapy, and correlated to poor memory performances only in the postoperative radiotherapy group. Average Karnofsky performance scale score was significantly lower in the group that had postoperative irradiation than in the group that did not. CONCLUSION: In adults with low-grade glioma, postoperative radiotherapy poses a significant risk of long-term leukoencephalopathy and cognitive impairment.

Autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA: clinical, biochemical, and molecular genetic features of the 10q-linked disease.

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disease characterized by accumulation of multiple large deletions of mtDNA in patients' tissues. We previously showed that the disease is genetically heterogeneous by assigning two nuclear loci predisposing to mtDNA deletions: one on chromosome 10q 23.3-24.3 in a Finnish family and one on 3p 14.1-21.2 in three Italian families. To reveal any locus-specific disease features, we report here the clinical, biochemical, and molecular genetic characteristics of the 10q-linked disease in the single family reported to date. All seven patients and four asymptomatic subjects had ragged-red fibers and multiple deletions of mtDNA in their muscle. Ptosis and external ophthalmoplegia were the major clinical findings, and depression or avoidant personality traits were frequently, but not consistently, present in the subjects carrying mutant mtDNA. In six of the subjects with mutant mtDNA, the activities of the respiratory chain complexes I or IV, or both, were below or within the low normal range. Two autopsy studies revealed the characteristic distribution of mutant mtDNA in these patients: highest proportion of mutant mtDNA is found in different parts of the brain, followed by the skeletal and ocular muscle, and the heart.

Monoclonal antibody NB84 in the differential diagnosis of neuroblastoma and other small round cell tumors.

Two hundred fifty-five well-characterized formaldehyde-fixed and paraffin-embedded small round cell tumors mainly from children and young adults including 105 neuroblastomas were immunohistochemically analyzed with the NB84 monoclonal antibody raised to neuroblastoma cells. Most of the undifferentiated neuroblastomas (21 of 22) and all 83 differentiated neuroblastomas reacted with NB84, but none of these tumors were CD99 positive. Compared with synaptophysin, NB84 was more sensitive, although less specific, in the identification of neuroblastoma in formaldehyde-fixed tissue. In addition to neuroblastoma, skeletal and extraskeletal Ewing's sarcoma and medulloblastoma showed NB84 reactivity in approximately 20% of cases, and 50% of desmoplastic small round cell tumors showed positive cells, usually in smaller numbers than the neuroblastomas. The NB84 reactivity was seen slightly more commonly in morphologically defined (rosette-positive) cases of peripheral primitive neuroectodermal tumors than in Ewing's sarcoma. However, the NB84 positivity did not correlate with the expression of other neural markers (neurofilament proteins, CD57, and synaptophysin) in these tumors. All other small round cell tumors including rhabdomyosarcomas, Wilms' tumors, and lymphomas were NB84 negative. In the case of NB84-positive tumors other than neuroblastoma, their specific reactivity for other markers was useful (Ewing's sarcoma CD99 positive, desmoplastic small round cell tumor desmin and keratin positive). The NB84 monoclonal antibody is a useful reagent to separate neuroblastoma from other small round cell tumors. In problem cases it is best used in a panel together with other markers that address the significant differential diagnostic alternatives.