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Stereological cell counting was applied to post-mortem neocortices of human brains from 31 normal individuals, age 18-93 years, 18 females (average age 65 years, range 18-93) and 13 males (average age 57 years, range 19-87). The cells were differentiated in astrocytes, oligodendrocytes, microglia and neurons and counting were done in each of the four lobes. The study showed that the different subpopulations of glial cells behave differently as a function of age; the number of oligodendrocytes showed a significant 27% decrease over adult life and a strong correlation to the total number of neurons while the total astrocyte number is constant through life; finally males have a 28% higher number of neocortical glial cells and a 19% higher neocortical neuron number than females. The overall total number of neocortical neurons and glial cells was 49.3 billion in females and 65.2 billion in males, a difference of 24% with a high biological variance. These numbers can serve as reference values in quantitative studies of the human neocortex.

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Since the turn of the last century, the average life expectancy has risen considerably. Lengthening of life span has little merit if the quality of life is not preserved and in the elderly the decline in memory and cognitive abilities is of great concern. We applied a stereological technique, the planar rotator method, in an optical vertical design to get an estimation of the three-dimensional volume of the neocortical nuclei and perikaryon volume in neurons from brain neocortex and the four cortical lobes in 39 normal human subjects ranging from 18 to 93 years old. Although there was a trend with p values of 0.07, the mean global neocortical perikaryon volume was not significantly larger in men compared with women and the mean neuronal nuclear volume was not significantly different in the two sexes. Nonetheless, we found gender differences in both frontal and temporal cortices in the perikaryon volume, but not in the nucleus volume. Earlier findings of a higher neocortical neuron number in men compared with women was repeated in this study and, not unexpectedly, the sum of all neuronal perikaryon volume in neocortex was significantly higher in men than women, primarily as a result of a higher neocortical neuron number.

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Using microautoradiography ex vivo we tested the effect of forced running on a roller drum for 3 h on the nuclear incorporation of [5-(3)H uridine] in mouse brain. Specific neuron types with increased nuclear labelling included primary motor cortex layer 5 nerve cells with nuclei greater than 12 microm (+38%) and large neuron nuclei in putamen (+58%). Mice running for 45 min do not show any change in the labelling of nerve cell nuclei compared with mice moving freely in the cage. The [(3)H]uridine uptake in other cell types, e.g. other neurons in cortical layer 5, neurons in sensory cortex and in the other cell layers in motor cortex, were not different from control mice. We conclude that RNA synthesis is normally low in adult mouse brain, but that physical exercise stimulates RNA synthesis in specific populations of large neurons in the motor system.

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In a stereological study of the human substantia nigra (SN), the total number of melanin-positive and melanin-negative neurones from 28 male subjects aged 19-92 years was estimated using a uniform sampling design and optical disectors. There was a significant decrease in the total number of melanin-positive neurones as a function of age (r(2)=0.18, residual-CV=0.35, 2P=0.032). Using the rotator method, the size distribution of the melanin-positive neurones was estimated and showed a significant difference in mean cell volume of melanin-positive neurones between the seven youngest (21,077 microm(3)) and the seven oldest individuals (32,011 microm(3)), 2P=0.022. Using a combination of the total number of melanin-positive neurones and their size distribution, the total perikaryon volume of melanin-positive neurones could be estimated and showed no decrease with increasing age (r(2)=0.01, residual-CV=0.41, 2P=0.62). Age-related decline in dopamine-transporter neurones within the SN might explain the occurrence of extrapyramidal symptoms in many elderly individuals. Although age-related cell hypertrophy is usually considered to be an indication of cell degeneration or necrosis, this might not always be the case. The fact that motor symptoms, although present in many of the elderly, are of a limited nature despite the high percentage of lost neurones could be due to a compensatory increase in the cell body of dopamine-producing SN neurones. Thus, the total amount of cell substance capable of producing the essential transmitters might not be reduced to a critically low level as a result of ageing.

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Modern stereological methods provide precise and reliable estimates of the number of neurons in specific regions of the brain. The total number of neurons in the neocortex and motor cortex from eight patients suffering from amyotrophic lateral sclerosis (ALS) and nine controls was estimated. No attempt was made to estimate subpopulations of neurons such as the number of giant pyramidal cells of Betz. No difference was found in the average number of neurons in neocortex in ALS and controls, 21.7 and 22.3 x 10(9), respectively, and 1.33 and 1.29 x 10(9) in motor cortex, respectively. In the light of our stereological measurements, results obtained from in-vivo proton magnetic resonance spectroscopy (1H-MRS), suggesting neuronal loss in ALS, may instead be due to neuronal metabolic dysfunction and/or alteration in the size or the volume fraction of the neurons.

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Fourteen male Göttingen minipigs were used in this study. Nine were administered N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dosage of 1 mg/kg/day, SC, for 6 days, the last five pigs received saline injections for 6 days. All MPTP-treated animals developed Parkinson symptoms, i.e., muscle rigidity, hypokinesia, and impaired coordination within 5 days. The brain levels of dopamine (DA), and its major metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined in caudatum and putamen 2, 14, and 93 days (n = 3/time point) after the last drug administration. In eight of the MPTP-treated animals, striatal DA, DOPAC, and HVA concentrations were reduced from 50 to 95% compared to control animals at all time intervals. Animals with the lowest striatal DA concentrations showed the most severe signs of Parkinsonism. The number of cells in substantia nigra (SN) showed a decline only 3 months after MPTP treatment. The minipigs represent a nonprimate model of MPTP-induced parkinsonism syndromes lasting at least months.

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In this Danish-Norwegian randomized double-blind parallel-group multicentre study, we compared the therapeutic response of slow-release Madopar HBS to standard Madopar in 134 de novo patients with idiopathic Parkinson's disease during a 5-year period. The drugs were dosed according to the individual need of the patients. The Webster, NUDS, UPDRS and Hoehn & Yahr scales were used for evaluation of symptoms. Addition of a morning dose of standard Madopar 62.5 mg was allowed after 6 months. Bromocriptine could be administered but not Selegiline. Sixty-five patients got Madopar HBS and 69 standard Madopar. Surprisingly, no differences were found as to the mean daily levodopa dose, the mean number of daily doses or the use of the doses of bromocriptine. Unexpectedly, we found a trend towards a more frequent use of a morning dose of standard Madopar in the group treated with the standard formulation. No differences were observed in the occurrence of motor fluctuations or dyskinesia, the incidence of which was relatively low. Sustained-release Madopar (HBS) thus proved to be as effective as standard Madopar in the long-term treatment of de novo parkinsonian patients, but the drug showed no advantage in postponing or reducing the long-term levodopa treatment problems.

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The number of pigmented and non-pigmented neurons in the substantia nigra (SN) of 10 old and six young female Macaca mulatta monkeys and in three old alpha male monkeys were estimated using new stereological cell counting methods. No systematic right-left differences were noted, nor were old animals different from young ones with respect to SN volume (68.9 mm3 vs. 62.8 mm3) or absolute number of nerve cells (320,000 vs. 312,000). However, the total number of pigmented neurons was about eight times higher in old animals compared with young ones (166,000 vs. 21,400) while the total number of non-pigmented SN neurons was less than half in old animals compared with young ones (139,000 vs. 285,000). These differences create difficulties in generalizing experimental results from the rhesus animal model to man. It seems unlikely that a simple correlation can be made between pigmented and tyrosine hydroxylase (TH) positive neurons in SN in monkeys. Instead of estimating the total number of pigmented and non-pigmented cells, only SN neurons positive for TH using immunohistochemical techniques might be used an indicator of the total number of dopaminergic neurons in SN in monkeys.

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OBJECTIVE: To investigate endogenous cerebrospinal fluid catecholamines in Parkinson's disease. MATERIAL AND METHODS: Basal concentrations of free norepinephrine (NE), dopamine (DA), epinephrine (E), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylalanine (DOPA) in cerebrospinal fluid (csf) and plasma were measured using reverse-phase HPLC with electrochemical detection in 16 patients with Parkinson's disease and 21 control patients with low back pain. RESULTS: Parkinsonian patients had significantly decreased values of csf NE and DOPAC, the strong relationship between plasma and csf NE was disrupted and neither was there any age related increase of plasma NE. In l-DOPA treated patients plasma DA and DOPA concentrations were raised and csf DOPAC values were inversely related to severity of disease (Hoehn and Yahr score). Csf E concentrations were also reduced in parkinsonian patients whereas csf DA concentrations were unchanged. Csf DOPA concentrations were insignificantly decreased in parkinsonian patients. CONCLUSIONS: These results point towards a diffuse neuronal dysfunction in Parkinson's disease and indicate that lumbar csf NE and csf DOPAC are of central nervous origin.

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Dyskinetic syndromes are conditions with involuntary movements. They can have different causes, but are often due to dysfunction of the basal ganglias. The clinical picture varies but all show spontaneous alterations in intensity as well as deterioration with stress. This often leads to misjudgment of cases of dyskinesia. It is however important to be aware of these syndromes as medical treatment is effective in many cases. The treatment of tremor, tics, chorea, myoclonus, dystonia and medically induced dyskinesia is reviewed and the clinical pictures are briefly described.

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Precise estimates of total neuron numbers in neocortices of 11 women, mean age 82.6 years (range 79-88) with severe senile dementia of the Alzheimer's type (SDAT) were compared with similar estimates in 10 cognitively normal women of comparable mean age (84.1 years; range 74-92). The total mean nerve cell number in the SDAT group was 16.9 x 10(9) with a coefficient of variation (CV = SD/mean) = 0.14, whereas mean total neuron number in the control group was 18.1 x 10(9), CV = 0.18. In a material of this size the reduction of 6% in neocortical cell number in the SDATs is neither statistically nor biologically significant. Nevertheless, all patients with SDAT were severely demented, having a mean score of 5.6 on a 1-7-scale of dementia. This contrasts with the nondemented individuals who had lived an independent life at home until shortly before death. The SDAT patients showed a rather consistent reduction in cortical volume by 14%, an atrophy that was solely due to a reduced cortical thickness. In addition, all had multiple neocortical plaques (Bielschowsky silver stain).

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Dyskinetic syndromes are conditions with involuntary movements. They can have different causes, but are often due to dysfunction of the basal ganglias. The clinical picture varies, but all show spontaneous alterations in intensity as well as deterioration with stress. This often leads to misjudgement of cases of dyskinesia. It is however important to be aware of these syndromes as medical treatment is effective in many cases. The treatment of tremor, tics, chorea, myoclonus, dystonia and medically induced dyskinesia is reviewed and the clinical pictures are briefly described.

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Assuming that uridine uptake is correlated to RNA synthesis, and thereby to nerve cell function, the distribution of 5-[H3]-uridine-labelled nerve cell nuclei in the cerebral cortex of three hemispheres from two grivet monkeys was examined by microautoradiography. The labelling pattern for 50 cells in layers 2-6 of 10 cortical locations were different in many locations, but in each location they were generally similar. The precentral areas had relatively high labelling, while the motor cortex relatively low, paralleling the bloodflow in these regions. The labelling of layer 4 and 6 was lower than in the other layers of cortex. These measurements provide basic information about the pattern of uridine labelling on the cellular level in primate cortex from animals moving freely in the cage.

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A case report and a review of the literature concerning electroconvulsive therapy (ECT) in the treatment of Parkinson's disease with special reference to the therapy of "on-off" phenomena is given. The first report of positive effect appeared in 1959 and, with a single exception, all published articles on this topic point to a positive outcome of ECT. There seems to be a specific anti-Parkinsonian effect alongside the well-known effect on various psychotic conditions. ECT thus must be considered a valuable intervention when drug therapy is insufficient, when prolonged medication leads to decreased efficacy, or when patients develop neuro-psychiatric manifestations. A short review of the pathophysiological mechanisms which may underly the effect of ECT in Parkinson's disease is given.

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Using an unbiased stereological technique, the total numbers of pigmented and non-pigmented neurons were estimated in the substantia nigra of seven patients with Parkinson's disease and seven control patients. Compared with the controls, in which the average total number of pigmented neurons was 550,000, the number of neurons was reduced by 66% in the patients. The average total number of non-pigmented neurons was 260,000 in controls and reduced by 24% in the patients. A significant correlation (r = 0.81) existed between the total numbers of pigmented and non-pigmented neurons in the controls, whereas a similar correlation (r = 0.72) in the patients fell just short of statistical significance. The stereological estimates made in this study are unbiased, in that they are independent of nerve cell size, section thickness and of dimensional changes in brain tissue induced by histological procedures. The stereological method is considerably more efficient than previous conventional methods.

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An efficient method for the unbiased estimation of the total number of neurons in rat brain cortex is presented. The method is reasonable fast, the counting procedure takes 2-3 h per rat, and gives an estimate of the total neuron number in cortex cerebri with an CE of 0.10. The rat cerebral cortex is found to have a mean volume of 253 mm3 and to contain a mean of 21 million neurons. The method has been used in a neurotoxicologic study, in which rats were given toluene perorally in doses of 200, 400 and 800 mg/kg/day, respectively, for 12 weeks, followed by an exposure-free period of 4 weeks. The total number of neurons in rat brain cortex cerebri showed no significant difference between exposed and non-exposed animals. The applicability of the method is discussed.

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The acute effect of intravenous injections of biperiden and clonazepam was investigated in 14 patients with various forms of dystonia (segmental dystonia, 2; generalized dystonia, 6; and Meige's syndrome, 6). Eleven patients had primary dystonia, and 3 patients had a secondary form of dystonia. Doses of 5 mg of biperiden reduced dystonia when evaluated by total scores, global scores, and subjective scores. Two patients had marked side effects in the form of dizziness. Doses of 1 mg of clonazepam significantly reduced total scores and subjective scores, but the reduction in global score was insignificant. No patient had marked side effects following injection with clonazepam. These results correspond with earlier investigations of the long-term effects of anticholinergics and benzodiazepines. It is concluded that in some cases, intravenous injections can be used as a test for evaluating both effects and side effects of antidystonic medication prior to the institution of oral treatment. Long-term intravenous treatment might be considered in individual cases.

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