Nigrostriatal Pathology Research Articles

The l-dopa response in vascular parkinsonism

Objective: To determine whether a positive l-dopa response in vascular parkinsonism (VP) is correlated with the presence of nigrostriatal pathology due to either vascular damage or neuronal cell loss. Methods:...

Estrogen as neuroprotectant of nigrostriatal dopaminergic system: laboratory and clinical studies.

In this review, we relate both laboratory and clinical evidence associated with the capacity for estrogen to function as a modulator of nigrostriatal dopaminergic pathology. To accomplish this goal, we have divided this review into three parts. In Part 1, we provide a brief historical perspective of studies that have laid the groundwork for demonstrating the existence of hormonal- nigrostriatal interactions. In Part 2, we focus specifically on laboratory data that show the ability and conditions by which estrogen may function as a neuroprotectant of the nigrostriatal dopaminergic system. Finally, in Part 3, we review the clinical literature related to this issue as a means for consideration of estrogen as a modulator, neuroprotectant, and therapy for Parkinson disease.

Age and severity of nigrostriatal damage at onset of Parkinson's disease

The clinical evolution of Parkinson's disease (PD) is known to be partly dependent on the age of onset. For example, motor complications associated with chronic dopaminomimetic treatment occur more often in younger patients. However, few attempts have been made to characterize the functional pathological differences underlying this age effect. We investigated the relationship between age and severity of nigrostriatal damage at onset of PD. Twenty patients with early PD (symptom duration <or=5 years) with onset before age 50 (n = 10) and with onset after age 50 (n = 10) were studied. The two groups were compared with respect to severity of nigrostriatal damage as evaluated by positron emission tomography (PET) scanning with 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ), and d-threo-[(11)C]methylphenidate ([(11)C]MP). We found no significant differences between younger- and older-onset PD patients with regard to any of the three presynaptic markers. For putamen, the P-values corresponding to the different PET measurements ranged from P = 0.34 ([(18)F]-dopa) to P = 0.79 ([(11)C]DTBZ). However, after adjusting for treatment and PD duration, regression analysis showed that [(18)F]-dopa uptake correlated positively with age of onset (r = 0.59; P = 0.010). No correlation was found between [(11)C]DTBZ and [(11)C]MP binding potentials and age of onset (P = 0.26 and P = 0.90, respectively). These data suggest that age-of-onset-dependent differences in clinical evolution are not likely to reflect early differences in nigrostriatal pathology in PD. Age-related differences in [(18)F]-dopa uptake may be related to changes in dopamine turnover.

Decreased striatal monoaminergic terminals in Huntington disease.

To evaluate the integrity of the dorsal striatal dopaminergic innervation in rigid and choreic Huntington disease (HD). Some patients with HD have an akinetic-rigid phenotype. It has been suggested that nigrostriatal in addition to striatal pathology is present in this subgroup. The authors sought to determine whether in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding could distinguish patients with akinetic-rigid (HDr) from typical choreiform (HDc) HD. Nineteen patients with HD (mean age 48 +/- 16 years) and 64 normal controls (mean age 50 +/- 14 years) underwent (+)-alpha-[11C]dihydrotetrabenazine (DTBZ) PET imaging. DTBZ blood to brain ligand transport (K1) and tissue to plasma distribution volume (DV) in the caudate nucleus, anterior putamen, and posterior putamen were normalized to the occipital cortex. The normalized striatal specific DV was reduced in HDr (n = 6) when compared with controls: caudate nucleus -33% (p < 0.001), anterior putamen -56% (p < 0.0001), and posterior putamen -75% (p < 0.0001). Patients with HDc (n = 13) also had reduced striatal DV: caudate nucleus -6% (NS), anterior putamen -19% (p < 0.01), and posterior putamen -35% (p < 0.0001). Patients with HDr had significantly lower striatal (+)-alpha-[11C]DTBZ binding than HDc patients. After correction for tissue atrophy effects, normalized DV differences were less significant, with values somewhat increased in the caudate, slightly reduced in the anterior putamen, and moderately decreased in the posterior putamen. There were no significant regional differences in K1 reductions among caudate, anterior, and posterior putamen in HD. Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype. Striatal DV reductions were most prominent in the posterior putamen, similar to PD.

Decreased striatal monoaminergic terminals in olivopontocerebellar atrophy and multiple system atrophy demonstrated with positron emission tomography.

We used [11C]dihydrotetrabenazine, a new ligand for the type 2 vesicular monoamine transporter (VMAT2), with positron emission tomography to study striatal monoaminergic presynaptic terminals in 4 patients with multiple system atrophy, 8 with sporadic olivopontocerebellar atrophy, and 9 normal control subjects. Specific binding in the striatum was significantly reduced in the multiple system atrophy patients as compared with the normal control group, with average reductions of 61% in the caudate nucleus (p = 0.002) and 58% in the putamen (p = 0.009). Smaller reductions were found in the sporadic olivopontocerebellar atrophy group, averaging 26% in the caudate nucleus (p = 0.05) and 24% in the putamen (p = 0.11). Mean blood-to-brain [11C]dihydrotetrabenazine transport (K1) was significantly different between groups only in the cerebellum, with values for the sporadic olivopontocerebellar atrophy group diminished compared with the normal control group. Cerebellar K1 was not significantly decreased in the multiple system atrophy group. The finding of reduced striatal VMAT2 in sporadic olivopontocerebellar atrophy patients suggests nigrostriatal pathology, indicating that some may later develop symptomatic extrapyramidal disease.

The influence of injections of 6-hydroxydopamine into the nucleus accumbens and the substantia nigra on the behavior of rats.

Bilateral injections of 6-hydroxydopamine into the nucleus accumbens of rats with destroyed dopaminergic neurons of the substantia nigra leads to an increase in the horizontal motoric activity in the open field and accelerates the appearance of conditioned reflex responses in the course of the postoperative restoration of the skill as compared with these indices in rats in which the neurotoxin was injected only into the substantia nigra. Thus, destructions of the dopaminergic system of the nucleus accumbens can compensate to a certain degree for the consequences of nigrostriatal pathology.

Neurobiological studies of transmitter systems in aging and in Alzheimer-type dementia.

Dysfunction and death of specific neuronal systems are important processes occurring in aging and in Alzheimer's and in Parkinson's disease. The neuropathology and neurochemistry of some of the neuronal systems at risk in these settings are subjects of active research; the nature and consequences of these cellular pathologies have begun to be clarified. The availability of animal models (including aged monkeys, macaques with cholinergic deficiencies, and monkeys with MPTP-induced nigrostriatal pathology, all of which recapitulate certain features of human aging or disease) allow the opportunity to assess the efficacies of new pharmacotherapies, neural grafts, and trophic factors. These approaches can be monitored by behavioral testing and, in some instances, by in vivo imaging methods, which can in turn be correlated with morphologic and chemical analyses of brain. Demonstration of the efficacy of these procedures in nonhuman primates would have profound implications on the development of new therapies designed to alleviate the effects of aging and disease on the human brain.