Jasmine M. Henderson

Comparison of the basal ganglia in rats, marmosets, macaques, baboons, and humans: volume and neuronal number for the output, internal relay, and striatal modulating nuclei.

This study compares the basal ganglia of rats, marmosets, macaques, baboons, and humans. It uses established protocols to estimate the volume and number of neurons within the output nuclei (internal globus pallidus, IGP; and nondopaminergic substantia nigra, SNND), two internal relay and modulating nuclei (subthalamic nucleus, STh; and external globus pallidus, EGP), and a modulator of the striatum (dopaminergic substantia nigra, SND). Nuclear boundaries were defined by using immunohistochemistry for striatal afferents. Total numbers of Nissl‐stained and parvalbumin‐immunoreactive neurons were calculated by using the fractionator technique. Comparisons between species were standardized relative to brain mass (rats < marmosets < macaques < baboons < humans). The EGP consistently had more neurons relative to the IGP, STh, and SND, which had similar neuronal numbers within each species. The SNND had proportionally more neurons in rats than in primates (especially humans). The distribution of SND neurons varied substantially between rats and primates (very few ventrally located neurons in rats) with humans containing fewer SND neurons than other primates. The reduction in SND neurons in humans suggests less dopaminergic regulation of the basal ganglia system compared with other species. The consistency in the number of IGP neurons across all species, combined with the reduction in SNND neurons in humans, suggests a greater emphasis on output pathways through the IGP and that there are proportionally more STh and EGP neurons in humans. J. Comp. Neurol. 445:238–255, 2002.

Degeneration of the Centré median-parafascicular complex in Parkinson's disease

Two major noncortical inputs to the striatum originate from the substantia nigra and the thalamic centré median–parafascicular complex. Although it is established that in Parkinsons disease there is degeneration of the nigral dopaminergic neurons, there has been little analysis of the glutamatergic centré median–parafascicular complex. We therefore evaluated these and neighboring thalamic nuclei (for specificity of any changes) in 9 Parkinsons disease patients and 8 age‐matched controls. Degeneration in the substantia nigra and centré median–parafascicular complex was estimated by using quantitative neuronal counts. On average, 70% of the pigmented nigral neurons degenerated and there was 30% to 40% neuronal loss in the centré median–parafascicular complex in Parkinsons disease. Thalamic degeneration was marked in neuronal subpopulations (50% loss of parvalbumin‐positive neurons in the parafascicular, and 70% loss of non–parvalbumin‐positive neurons in the centré median nuclei). In contrast, adjacent thalamic nuclei did not degenerate, which supports a selective neurodegeneration of the centré median–parafascicular complex. Our results show that the thalamic centré median–parafascicular complex is an additional nondopaminergic site of neurodegeneration in Parkinsons disease. Because this thalamic region provides important sensorimotor feedback to the striatum, degeneration of this region is likely to exacerbate the clinical signs and symptoms of Parkinsons disease. Ann Neurol 2000;47:345–352

Postmortem analysis of bilateral subthalamic electrode implants in Parkinson's disease

This is the second neuropathological report detailing bilateral electrodes targeting the subthalamic nucleus (STN) in idiopathic Parkinsons disease (PD). The patient presented with unilateral tremor‐dominant parkinsonism. Bilateral STN stimulation was carried out 7 years later due to significant disease progression and severe motor fluctuations. The patient exhibited bilateral improvements in rigidity and bradykinesia both intraoperatively and postoperatively. The patient died 2 months later from aspiration pneumonia. Neuropathological examination confirmed both the diagnosis of PD and the electrode placements. The tip of the left electrode was located medially and posteriorly in the left STN and the tip of the right electrode entered the base of the thalamus/zona incerta immediately above the right STN. Tissue changes associated with the subthalamic electrode tracts included mild cell loss, astrogliosis, and some tissue vacuolation. Our postmortem analysis indicates little tissue damage associated with STN stimulation for PD.

Lesion of thalamic centromedian-parafascicular complex after chronic deep brain stimulation

A patient with PD who exhibited disabling tremor and prominent dyskinesia underwent deep brain stimulation (DBS) of the left thalamic ventral intermediate nucleus. The electrode migrated and was replaced but with suboptimal clinical response. Two years later, postmortem analysis found the second electrode tip had entered the thalamic centromedian–parafascicular complex. There was a small thalamotomy and cell loss exceeding that found in PD. Thalamic damage may occur in association with DBS for PD.

Olfactory deficits and sleep disturbances in Parkinson’s disease: a case–control survey

Background: Olfactory and sleep disturbances are common in Parkinson’s disease, and may be early disease indicators. Objective: To obtain information about olfactory and sleep deficits preceding the onset of motor symptoms in Parkinson’s disease. Subjects: 38 community dwelling patients with Parkinson’s disease (73% response rate) and 32 age matched controls (60% response rate). Methods: Using a questionnaire survey, the frequencies, timing, and relations between olfactory and sleep disturbances, drug treatment, mood, and motor deficits in Parkinson’s disease were compared with those in age matched controls. Reliability of information was validated by informant interview in 9% of the sample. Interdependency of factors was assessed using Fisher’s fourfold table test, and differences between populations were analysed using χ2 and unpaired t tests. Results: Microsmia was reported by 26 patients (68%) (and only one control), on average within a year of the diagnosis of Parkinson’s disease. More patients than controls had excessive daytime somnolence (45% v 6%), restless legs (50% v 19%), and abnormal movements during sleep (34% v 0%), which generally occurred three to five years after diagnosis and were independent of mood disorders and drug treatment. Conclusions: Many patients with Parkinson’s disease have microsmia at the onset of motor deficits, but some sleep disorders are a subsequent occurrence.

Postural changes after lesions of the substantia nigra pars reticulata in hemiparkinsonian monkeys

Current neurosurgical strategies target overactive brain regions including the subthalamic nucleus, globus pallidus and thalamus to control various symptoms of Parkinsons disease. Subthalamotomy improves akinesia and can induce postural deficits in both parkinsonian humans and animals, pallidotomy improves limb dyskinesia and more variably, distal bradykinesia whilst thalamotomy improves tremor. Because the SNr also becomes overactive in PD and there are few surgical studies in parkinsonian primates, we therefore evaluated the effects of lesioning the SNr in hemiparkinsonian marmosets to establish the effects on symptomatology. Nine monkeys received unilateral 6-hydroxydopamine (6-OHDA) lesions. Seven weeks later, four received kainic acid lesions of the SNr. Behavioural tests were performed prior to 6-OHDA surgery and then fortnightly for 14 weeks. Unilateral 6-OHDA lesions induced ipsilateral postural bias, ipsilateral rotation after amphetamine injection and bradykinesia. Whilst, SNr lesions significantly altered the direction of head position and amphetamine-induced rotation relative to 6-OHDA lesions, there was no improvement in 6-OHDA-induced reaching deficits or sensorimotor neglect. Unbiased quantitation of the nigral lesions showed on average 88% loss of dopaminergic neurons after 6-OHDA lesions and 77% loss of non-dopaminergic neurons after SNr lesions. Our results demonstrate that the SNr is important in body orientation changes in parkinsonism.

Convulsive and postural effects of lesioning the mid-substantia nigra pars reticulata in naı̈ve and 6-hydroxydopamine lesioned rats

The subthalamic nucleus is targeted for the treatment of Parkinsons disease. Unilateral lesions improve some aspects of parkinsonism but produce postural abnormalities in animal models but the exact pathways producing these effects remain to be defined. Using a battery of tests we evaluated the effects of lesioning one of the two major subthalamic targets, the substantia nigra pars reticulata in naïve and 6-OHDA lesioned rats. Lesions targeting the mid-substantia nigra pars reticulata resulted in acute tonic-clonic seizures and intense contralateral rotational asymmetry. During the first month after substantia nigra pars reticulata lesions there was normalisation of the ipsilateral head position bias induced by unilateral 6-OHDA lesions, significant contralateral body axis bias but no significant alteration of apomorphine induced rotation and sensorimotor neglect in 6-OHDA lesioned rats. Combined with our previous data, this suggests that subthalamic projections via the substantia nigra pars reticulata are important in seizures and postural behaviours. Therefore unilateral subthalamotomy probably induces postural deficits in hemiparkinsonian animals via projections involving the substantia nigra pars reticulata. This has implications for patients undergoing subthalamotomy for treatment of Parkinsons disease.

Parkinson's disease with late Pick's dementia

We report a case in which typical clinical features of idiopathic Parkinsons disease existed for seven years prior to the development of significant behavioral and cognitive changes and severe dementia. The patient presented with right‐sided resting tremor, bradykinesia, and rigidity, which were highly responsive to levodopa. Serial neuropsychological evaluation revealed no evidence of dementia until late in the disease. The patient deteriorated rapidly eight years into the disease, requiring full care. She died 16 years after symptom onset and post‐mortem neuropathological analysis revealed Lewy body Parkinsons disease and Picks disease. To our knowledge, this is the first non‐familial case with this combination of clinical history and pathologically confirmed disease to be reported in the literature. The absence of a family history of any neurological disease sets this case apart from the recently described genetic cases of frontotemporal dementia with Parkinsonism linked to chromosome 17. In addition, the relatively late onset of dementia in frontotemporal dementia is atypical. While there is considerable debate regarding the cause of dementia in idiopathic Parkinsons disease, our case illustrates that Picks disease is one such cause.

Melanized nigral neuronal numbers in Nigerian and British individuals

The role of genetic and environmental factors in etiopathogenesis of Parkinsons disease (PD) is debated. The prevalence of PD is higher among white than nonwhite populations, yet it is five times higher in nonwhites living in the United States than in Nigeria. We compare counts of melanized nigral neurons between neurologically normal Nigerians and British brains. Neuronal counts were estimated in an age‐matched sample of 23 Nigerian and 7 British brains from neurologically normal individuals who had no Lewy bodies and Lewy neurites on α‐synuclein immunostaining. Two investigators blind to age and ethnicity performed counts of melanized neurons in a single 7‐μm hemisections showing the substantia nigra pars compacta. No significant difference exits in the number of neurons between the Nigerian and the British subjects (P = 0.1, NS). Differences in melanized nigral neuronal numbers may not explain differences in the prevalence of PD between white and nonwhite populations, suggesting factors other than neuronal numbers contribute to differential susceptibility of black vs. white races to PD.

Experimental therapeutics of Parkinson's disease

1. The loss of central dopamine, which characterises Parkinsons disease, led to the main pharmacological strategy for treatment, namely levodopa, a dopamine‐replacement therapy. Several years after treatment, the majority of patients experience dose‐limiting side‐effects and loss of symptom control. There is a resurgence of interest in neurosurgery for treating the Parkinsons disease, particularly in new techniques targeting the subthalamic nucleus (STN), which is overactive in Parkinsons disease and contributes to symptom development.