D.A. McRitchie

Regional specificity of brain atrophy in Huntington's disease

The present study analyzes the relationship between cortical and subcortical brain volumes in patients with Huntingtons disease. The brains of seven patients with a clinical diagnosis and positive family history of Huntingtons disease and 12 controls were collected at autopsy with consent from relatives. Detailed clinical assessments were available for all study subjects with genotype confirmation for patients with Huntingtons disease. Volume analysis of the brain on serial 3-mm coronal slices was performed as previously described. All patients with Huntingtons disease exhibited significant brain atrophy resulting from volume reductions in both cortical and subcortical grey matter. Atrophy of the cortex was relatively uniform, although the medial temporal lobe structures were spared. The caudate nucleus and putamen were strikingly reduced in all cases and this atrophy correlated with the severity of cortical atrophy, suggesting an associated disease process. The rate of cortical but not subcortical atrophy correlated with CAG repeat numbers. Loss of frontal white matter correlated with both cortical and striatal atrophy. Age of onset of chorea correlated with the amount of subcortical atrophy, while duration of chorea correlated negatively with atrophy of the white matter. These results suggest a more widespread and global disease process in patients with Huntingtons disease.

Cytoarchitectural distribution of calcium binding proteins in midbrain dopaminergic regions of rats and humans

The present study compares the distribution of three calcium binding proteins, calbindin‐D28k, calretinin, and parvalbumin, in the midbrain tegmentum of rats and humans. In order to compare the distributions of these proteins directly, the cytoarchitecture of this region was evaluated by using immunohistochemistry for tyrosine hydroxylase and substance P in serial sections in both transverse and horizontal planes.

Specific A10 dopaminergic nuclei in the midbrain degenerate in Parkinson's disease.

Using unbiased quantitative techniques, we evaluated the effect of Parkinsons disease on the regional size and the number of tyrosine hydroxylase-producing neurons and all neurons in the midbrain A8 and A10 dopaminergic cell groups located adjacent to the substantia nigra. Seven patients with Lewy body Parkinsons disease were evaluated and compared with five controls. Four of the patients with Parkinsons disease had additional neuropathology, and the effect of concomitant pathology on A10 populations was also determined. Degeneration was not observed in the A8 regions of any patient, and only certain A10 nuclei were affected by the disease. The parabrachial pigmented nucleus situated dorsal to the substantial nigra, and the parapeduncular nucleus located rostromedially were significantly reduced by 40-50% in patients with Parkinsons disease. Few differences were found between patients with or without additional pathology, suggesting a similar pathogenic mechanism to that observed in the substantia nigra of these patients. However, patients with additional pathology also had serotonergic cell loss in the caudal linear nucleus. There was a reduction in tyrosine hydroxylase immunoreactivity but no overt neurodegeneration in other A10 regions, suggesting the disease may also influence the production of dopamine in some surviving neurons.

Midbrain neuropathology in idiopathic Parkinson's disease and diffuse Lewy body disease

We have quantified midbrain cell loss in idiopathic Parkinsons disease (PD) compared with controls; six patients had PD with onset before 70 years, five patients had late onset PD (>70 years) and nine patients had diffuse Lewy body disease. The pattern of cell loss in these last two groups has not been previously described. No age associated neuronal loss was seen in controls. There was cell loss and reduced area of the pars compacta in all cases but no difference in the pattern of cell loss, which was predominantly ventral. The amount of cell loss in the dorsolateral cluster correlated with the duration of Parkinsonian symptoms, while greater cell loss in the dorsomedial cluster correlated with the presence of tremor and the absence of early dementia. These results suggest that the topography of midbrain pathology does not assist in differentiating these overlapping syndromes.

Regional Brain Atrophy in Idiopathic Parkinson's Disease and Diffuse Lewy Body Disease

This study measured brain atrophy in patients with idiopathic Parkinsons disease and diffuse Lewy body disease, all of whom had equivalent loss of midbrain dopammergic neurons and absence of Alzheimers disease. Characteristic patterns of volume loss were found throughout the brain, depending on the age of onset and clinical signs. An equivalent loss of medial temporal lobe structures occurred in all parkinsonian patients. This atrophy was similar in magnitude to that seen in Alzheimers disease and is likely to be the anatomical substrate for the memory deficits found in each of these patients groups. Frontal lobe atrophy was a feature of both late-onset Parkinsons disease (mild atrophy) and diffuse Lewy body disease (significant atrophy) groups, with all cases analyzed having dementia. Atrophy of frontal lobes correlated with the duration of motor symptoms in these patients and may suggest an association between dopammergic deafferentation, frontal atrophy and dementia.

Diffuse Lewy body disease: clinical features in nine cases without coexistent Alzheimer's disease.

OBJECTIVE--To further elucidate the relation between diffuse Lewy body disease and Parkinsons disease. METHODS AND RESULTS--The clinical features of nine cases of pure diffuse Lewy body disease without pathological evidence of coexisting Alzheimers neuritic pathology were reported. All patients were aged less than 70 years at onset (mean 62 years). Five patients presented with clinical features, which included assymetric resting tremor had levodopa responsiveness, which were initially indistinguishable from idiopathic Parkinsons disease. All five patients later became demented (mean of three years after presentation). Two further patients presented with parkinsonism and dementia and two patients presented with dementia and developed parkinsonism at a later stage. Hallucinations appeared 2.5-9 years after the onset of symptoms in six patients and were a presenting feature in one patient. All patients met the pathological criteria of idiopathic Parkinsons disease, with respect to the midbrain changes, in addition to having diffuse cortical Lewy bodies. CONCLUSIONS--Diffuse Lewy body disease may present a parkinsonism, dementia, or both depending on whether the Lewy body pathology begins in the midbrain, the cortex, or both together. When it begins in the midbrain, diffuse Lewy body disease is indistinguishable initially from idiopathic Parkinsons disease. Diffuse Lewy body disease may be a common cause of dementia complicating Parkinsons disease.

The subthalamic nucleus in Parkinson's disease and progressive supranuclear palsy.

The subthalamus has become a promising target for the neurosurgical treatment of parkinsonian symptoms. We have used unbiased counting techniques to quantify the neuronal populations of the subthalamic nucleus in patients with idiopathic Parkinsons disease and progressive supranuclear palsy. In addition, the type of calcium binding proteins contained within these subthalamic neurons was established using immunohistochemistry. Most of the 550,000 subthalamic neurons contain either parvalbumin or calretinin calcium binding proteins, and patients with idiopathic Parkinsons disease sustained no damage to this nucleus. This is consistent with current theories of basal ganglia circuitry, which postulate that overstimulation of this excitatory nucleus contributes to the inhibition of the motor thalamus via the activation of inhibitory relays. In contrast, we found that there was substantial cell loss in the subthalamus in progressive supranuclear palsy (45 to 85% neuronal reduction) and that both cell types were equally affected. Extracellular neurofibrillary tangles as well as tau-positive glia were observed in the subthalamus of these cases. As the patients, with Parkinsons disease and progressive supranuclear palsy all had overlapping parkinsonian symptoms, the loss of subthalamic stimulation within the basal ganglia of progressive supranuclear palsy cases is puzzling, unless their parkinsonian symptoms were generated by an alternate mechanism.

Calbindin D28k-containing neurons are restricted to the medial substantia nigra in humans

A controversy exists in the literature as to whether neurons containing the calcium binding protein calbindin-D28k are located within the human substantia nigra. The point of variance between reports, however, is not the anatomical distribution of these neurons, but rather the delineation of the dorsal border of the substantia nigra. It has been suggested that the dense substance P striatonigral innervation delimits the substantia nigra in the human. The aim of the present study is to re-examine the distribution of calbindin-D28k-positive neurons throughout the substantia nigra using substance P to delimit its borders. Although a few calbindin-D28k-positive neurons were found in the medial cell group of the substantia nigra, the vast majority of positive neurons were located in the adjacent A8 and A10 dopaminergic cell groups. This anatomical location of calbindin-D28k-positive neurons is consistent with previous reports, though our results indicate that when the striatonigral projection is used to define the substantia nigra, calbindin-D28k is not a notable feature of these neurons. This questions the neuroprotective role of this protein in Parkinsons disease.

Progressive supranuclear palsy affects both the substantia nigra pars compacta and reticulata.

We have analyzed the neuropathology of the substantia nigra in four cases of progressive supranuclear palsy compared with age-matched controls and patients with Parkinsons disease. Although there are many reports of severe dopaminergic cell loss in progressive supranuclear palsy, the fate of the GABAergic pars reticulata neurones remains unclear. Serial section analysis and fractional counts of pars compacta neurones (identified by their neuromelanin pigment) and pars reticulata neurones (identified using parvalbumin immunohistochemistry) were performed, and the type and distribution of neuropathology were described. Severe neurodegeneration within the dopaminergic pars compacta was seen in all cases of progressive supranuclear palsy and all cases of Parkinsons disease compared with controls. Lewy body pathology was found only in cases of Parkinsons disease, while neurofibrillary tangles were seen only in cases of progressive supranuclear palsy. Tau-positive astrocytes and neuropil threads were occasionally seen in controls and cases of Parkinsons disease (particularly those of advanced age) but were extremely numerous in all cases of progressive supranuclear palsy. There was a similar decrease in parvalbumin immunoreactivity within the pars reticulata in both progressive supranuclear palsy and Parkinsons disease. However, there was a striking 70% reduction in the number of pars reticulata neurones in progressive supranuclear palsy, with no cell loss observed in Parkinsons disease compared with controls. Our results show that both the dopaminergic pars compacta and the GABAergic pars reticulata are significantly damaged in cases of progressive supranuclear palsy. The distribution of neurodegeneration in patients with Parkinsons disease and progressive supranuclear palsy is discussed with respect to the current theories on pathophysiology in basal ganglia circuitry.

Quantitative analysis of the variability of substantia nigra pigmented cell clusters in the human

At present there is no consensus concerning the internal organization of the human substantia nigra, despite its pivotal role in neurodegenerative conditions. We have quantitatively analysed the variability in the pattern of clusters of melanin-pigmented neurons in the human substantia nigra using serial section analysis and computer reconstructions. The substantia nigra pars compacta showed a bilaminar organization consisting of the pars medialis and pars lateralis, as well as dorsal and ventral tiers as described previously [D. A. McRitchie et al. (1995) J. comp. Neurol. (in press)]. Both the dorsal and ventral tiers could be further subdivided into three mediolateral cell columns based on position and cell density. The presence and arrangement of these cell clusters was most variable in transverse sections (the plane currently used for diagnostic neuropathology). Quantitative assessment of the topographical pattern of cell loss within single transverse sections of the human substantia nigra should therefore be treated with some caution. In contrast, the full rostrocaudal extent of the cell columns could be seen in horizontal sections. Thus, consistent samples of larger numbers of pigmented neurons per region were found in this section plane, although only two cell columns were found in most sections. Our results show that greater quantitative reliability can be achieved with horizontal sections of the substantia nigra.