TorsinB expression in the developing human brain.

Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. The majority of cases are caused by a 3-bp deletion (GAG) in the coding region of the DYT1 (TOR1A) gene. The cellular and regional distribution of torsinA protein, which is restricted to neuronal cells and present in all brain regions by the age of 2 months has been described recently in human developing brain. TorsinB is a member of the same family of proteins and is highly homologous with its gene adjacent to that for torsinA on chromosome 9q34. TorsinA and torsinB share several remarkable features suggesting that they may interact in vivo. This study examined the expression of torsinB in the human brain of fetuses, infants and children up to 7 years of age. Our results indicate that torsinB protein expression is temporarily and spatially regulated in a similar fashion as torsinA. Expression of torsinB protein was detectable beginning at four to 8 weeks of age in the cerebellum (Purkinje cells), substantia nigra (dopaminergic neurons), hippocampus and basal ganglia and was predominantly restricted to neuronal cells. In contrast to torsinA, torsinB immunoreactivity was found more readily in the nuclear envelope. High levels of torsinB protein were maintained throughout infancy, childhood and adulthood suggesting that torsinB is also needed for developmental events occurring in the early postnatal phase and is necessary for functional activity throughout life.

HIV leucoencephalopathy and TNFalpha expression in neurones.

BACKGROUND: Human immunodeficiency virus (HIV) leucoencephalopathy (HIVL) is an uncommon and rapidly progressive form of AIDS dementia complex (ADC) that has remained poorly understood. Tumour necrosis factor alpha (TNFalpha), which has been implicated in the pathogenesis of ADC, is predominantly localised in macrophages in the HIV infected brain, although in vitro studies indicate that neurones can express this cytokine. OBJECTIVE: To examine the clinical/neuroradiological features of HIVL and the expression of TNFalpha in HIVL. METHODS: Six patients who presented with rapidly progressive dementia within four to 12 weeks of the primary manifestation of their HIV infection were evaluated. Clinical history, treatment regimens, and imaging studies were reviewed, and brain samples from three of the patients were studied by means of immunohistochemistry. RESULTS: Imaging studies showed diffuse bilateral deep white matter changes in all six patients. Clinical and imaging abnormalities improved in five of the six patients within weeks after initiation of antiretroviral treatment. Brain biopsies of two showed pronounced microglia/macrophage activation, but only scant viral protein (gp41) expression. Staining for TNFalpha was found in microglia/macrophages, and surprisingly, in neurones also. Postmortem analysis of a third patient also showed TNFalpha expression in neurones of the frontal cortex and basal ganglia. CONCLUSION: This study provides the first demonstration of staining for TNFalpha in the neurones of the HIV infected brain, and suggests that the process underlying this rapidly progressive form of ADC may reflect indirect mechanisms mediated by host factors, particularly TNFalpha.

TorsinA expression is detectable in human infants as young as 4 weeks old.

Familial, early onset, generalized torsion dystonia is the most common and severe primary dystonia. The majority of cases are caused by a 3-bp deletion (GAG) in the coding region of the DYT1 (TOR1A) gene. The cellular and regional distribution of torsinA protein and its message has been described previously in several regions of normal adult human and rodent brain. This study examines the expression of torsinA in the developing human brain of fetuses, infants and children up to 7 years of age in four selected brain regions. Expression of torsinA protein was detectable beginning at 4 to 8 weeks of age postnatally in the cerebellum (Purkinje cells), substantia nigra (dopaminergic neurons), hippocampus and basal ganglia. Prominent torsinA immunoreactivity was not seen before 6 weeks of age postnatally, a period associated with synaptic remodeling, process elimination and the beginning of myelination. Our results indicate that torsinA protein expression is temporally and spatially regulated and is present in all brain regions studied by the age of 2 months on into adulthood.

Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia.

Hippocampal sclerosis dementia (HSD) is a disease of unknown etiology and pathogenesis. To determine whether HSD cases could be reclassified as variants of frontotemporal dementia (FTD), a heterogeneous group of disorders, 18 brain autopsy cases previously diagnosed as HSD were re-evaluated. In 11 cases, ubiquitinated neuronal inclusions, similar to those of motor neuron disease inclusion dementia (MNDID), were found. Brain levels of soluble and insoluble tau were normal. Most patients with pathologic findings of HSD may actually have the MNDID variant of FTD.

Tau protein expression in frontotemporal dementias.

The syndrome of frontotemporal dementia represents a diverse group of diseases presenting with behavioral and cognitive disturbances. The expression of the microtubule-associated protein tau was studied in postmortem samples of frontal cortex of 19 cases (12 Pick's disease A, B, C; 4 dementia lacking distinct histology; 3 motor neuron disease type) by Western blotting with a phosphorylation-independent anti-tau antibody. The presence of tau protein was detected in all cases evaluated, including the 11 brains classified as frontotemporal lobe degeneration (diagnostic categories Pick's disease B, C and dementia lacking distinct histology). These findings indicate that the recently reported decreased expression of tau protein in frontotemporal lobe degeneration represents pathogenic mechanism of neurodegeneration detectable only in a special subset of these disorders.

Human immunodeficiency virus infection, inducible nitric oxide synthase expression, and microglial activation: pathogenetic relationship to the acquired immunodeficiency syndrome dementia complex.

The regional expression of immune-mediated and neurotoxic events in the human immunodeficiency virus (HIV)-infected brain in relationship to the acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) and brain pathology remains uncertain. The extent of gp41, inducible nitric oxide synthase (iNOS), and HLA-DR expression was examined in the frontal lobe and basal ganglia of 25 patients at varying stages of ADC. The expression of gp41 and iNOS was present predominantly in perivascular cells and most often in the basal ganglia. Staining for gp41 correlated significantly with iNOS in the basal ganglia, whereas the severity of staining for gp41 and iNOS in the basal ganglia and white matter was significantly greater in subjects with moderate to severe dementia compared with those with milder impairment. The degree of macrophage staining in the white matter and basal ganglia also correlated significantly with ADC severity and was more abundant than gp41 or iNOS staining, particularly in the white matter. Logistic regression analysis revealed that staining for iNOS and gp41 increased linearly with ADC severity and was significantly more abundant in the basal ganglia compared with the white matter. Double-immunolabeling studies colocalized iNOS predominantly to macrophage/microglia and to gp41-positive cells. The expression of iNOS and gp41 in the basal ganglia combined with immune activation contributes to the development and progression of the clinical syndrome.

Tyrosine hydroxylase-immunoreactive elements in the human globus pallidus and subthalamic nucleus.

In contrast to the well-established dopaminergic innervation of the neostriatum, the existence of dopaminergic innervation of the subthalamic nucleus and globus pallidus is controversial. In the present study, tyrosine hydroxylase (TH)-immunoreactive elements were observed by light microscopy after antigen retrieval in the subthalamic nucleus and in the internal and external segments of the globus pallidus in postmortem human brain. Small islands of apparent neostriatal tissue with abundant arborization of fine, TH-immunoreactive axons in the vicinity of calbindin-positive small neurons resembling neostriatal medium spiny neurons were present in the external segment of the globus pallidus. Large numbers of medium-large, TH-immunoreactive axons were observed passing above and through the subthalamic nucleus and through both pallidal segments; these are presumed to be axons of passage on their way to the neostriatum. In addition, fine, TH-immunoreactive axons with meandering courses, occasional branches, and irregular outlines, morphologically suggestive of terminal axon arborizations with varicosities, were seen in both pallidal segments, including the ventral pallidum, and the subthalamic nucleus, consistent with a catecholaminergic (probably dopaminergic) innervation of these nuclei. This finding suggests that, in Parkinson's disease and in animal models of this disorder, loss of dopaminergic innervation might contribute to abnormal neuronal activation in these three nuclei.

Lost caps in histological counting methods.

BACKGROUND: In methods with the goal of counting objects in a sectioned tissue volume by examining their profiles or segments in the sections, lost caps, i.e., small object fragments unnoticed or missing at the section surfaces, are an unavoidable issue. METHODS AND RESULTS: The problem of lost caps is examined as it applies to four methods for counting in histological sections, the method usually referred to as the Abercrombie correction, the empirical method, the optical disector, and the physical disector. CONCLUSIONS: Lost caps are an insoluble problem in the Abercrombie method; the lost caps error correction factor should be incorporated into the Abercrombie equation. Lost caps cancel out in the optical disector. The empirical method logically requires, to avoid lost caps error, either a preliminary blind identification of object segments in the serial sections or identification of segments with reference to adjacent sections in the counting sections. Similarly, the physical disector method requires either a preliminary blind identification of object segments in both look-up and sampling sections, or use of three sections rather than two.

What was wrong with the Abercrombie and empirical cell counting methods? A review.

When a tissue volume is sectioned, cells or other objects are cut into segments by the sectioning process. The Abercrombie and empirical methods count object segments in histological sections and then apply a correction formula to convert the segment count to object number. There has been considerable recent controversy over whether these methods should be abandoned (in favor of the disector). Although both methods appear unbiased as thought experiments on paper, regardless of variation in object size, shape, or orientation, in practice two problems are inherent in the segment-counting approach: the practical problem of lost caps and a conceptual flaw that becomes apparent only when a need for unbiased estimation of certain factors in the correction formulae is seriously addressed. The Abercrombie method is inevitably biased by lost caps, whereas in the empirical method, this potential bias can be avoided. In the Abercrombie formula, the relevant factor to be estimated (aside from section thickness) is H, mean object height in the axis perpendicular to the section plane, and in the empirical method, it is the ratio of segment number to object number. In both methods, the factor in question should be estimated from an unbiased sample of the total population of objects. But unbiased selection of a statistically adequate number of objects for this estimation constitutes an unbiased, statistically adequate count. Once this is done, there is no reason to complete the steps for estimation of the factor; the count in this specimen is finished. It is shown that the empirical method's serial section procedure can be used to estimate H. This estimate is more sensitive to lost caps than the Abercrombie equation, but, when the formula for H is substituted into the Abercrombie equation, the lost caps error disappears. However, this approach is useless, as making this substitution transforms the Abercrombie equation into the empirical method equation.