Intrastriatal and intranigral grafting of hNT neurons in the 6-OHDA rat model of Parkinson's disease

The clinical findings on neural transplantation for Parkinson's disease (PD) reported thus far are promising but many issues must be addressed before neural transplantation can be considered a routine therapeutic option for PD. The future of neural transplantation for the treatment of neurological disorders may rest in the discovery of a suitable alternative cell type for fetal tissue. One such alternative may be neurons derived from a human teratocarcinoma (hNT). hNT neurons have been shown to survive and integrate within the host brain following transplantation and provide functional recovery in animal models of stroke and Huntington's disease. In this study, we describe the transplantation of hNT neurons in the substantia nigra (SN) and striatum of the rat model for PD. Twenty-seven rats were grafted with one of three hNT neuronal products; hNT neurons, hNT-DA neurons, or lithium chloride (LiCl) pretreated hNT-DA neurons. Robust hNT grafts could be seen with anti-neural cell adhesion molecule and anti-neuron-specific enolase immunostaining. Immunostaining for tyrosine hydroxylase (TH) expression revealed no TH-immunoreactive (THir) neurons in any animals with hNT neuronal grafts. THir cells were observed in 43% of animals with hNT-DA neuronal grafts and all animals with LiCl pretreated hNT-DA neuronal grafts (100%). The number of THir neurons in these animals was low and not sufficient to produce significant functional recovery. In summary, this study has demonstrated that hNT neurons survive transplantation and express TH in the striatum and SN. Although hNT neurons are promising as an alternative to fetal tissue and may have potential clinical applications in the future, further improvements in enhancing TH expression are needed.     

Simultaneous intrastriatal and intranigral dopaminergic grafts in the parkinsonian rat model: role of the intranigral graft

The current transplantation strategy in experimental and clinical Parkinson's disease (PD) has been to place nigral dopaminergic grafts not in their ontogenic site (substantia nigra) but in their target area (striatum). Although intrastriatal dopaminergic grafts are capable of reinnervating the striatum, they fail to reinnervate the nigra, which may be an important factor limiting the efficacy of fetal tissue transplantation in parkinsonian patients. We have previously shown that simultaneous intrastriatal and intranigral dopaminergic grafts (double grafts) may provide a more complete restoration of the nigrostriatal circuitry (Mendez et al. [1996] J Neurosci 16:7216-7227; Mendez and Hong [1997] Brain Res 778:194-205). In the present study, we investigated the contribution of the intranigral graft to functional recovery in double-grafted hemiparkinsonian rats. Twenty Wistar rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal pathway were divided into two groups and received either double grafts (n = 10) or intrastriatal grafts alone (n = 10). Following transplantation, both intrastriatally and double-grafted animals had a significant decrease in rotational behavior. However, only animals with double grafts exhibited a significant increase in contralateral adjusting step performance. The intranigral graft was subsequently lesioned by a second 6-OHDA injection. Following the second lesion, animals with double grafts exhibited a significant reversal of rotational behavior and a 51% reduction in contralateral adjusting step performance. The reversal in functional recovery correlated with a significant loss of intranigral grafted neurons. These results suggest that the intranigral graft has an important role in the functional recovery of double-grafted animals. Restoration of dopaminergic innervation to both the nigra and the striatum may be crucial for optimizing graft efficacy and may be a superior strategy in neural transplantation for PD.     

NAIP protects the nigrostriatal dopamine pathway in an intrastriatal 6-OHDA rat model of Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder of the basal ganglia, associated with the inappropriate death of dopaminergic neurons of the substantia nigra pars compacta (SNc). Here, we show that adenovirally mediated expression of neuronal apoptosis inhibitor protein (NAIP) ameliorates the loss of nigrostriatal function following intrastriatal 6-OHDA administration by attenuating the death of dopamine neurons and dopaminergic fibres in the striatum. In addition, we also addressed the role of the cysteine protease caspase-3 activity in this adult 6-OHDA model, because a role for caspases has been implicated in the loss of dopamine neurons in PD, and because NAIP is also a reputed inhibitor of caspase-3. Although caspase-3-like proteolysis was induced in the SNc dopamine neurons of juvenile rats lesioned with 6-OHDA and in adult rats following axotomy of the medial forebrain bundle, caspase-3 is not induced in the dopamine neurons of adult 6-OHDA-lesioned animals. Taken together, these results suggest that therapeutic strategies based on NAIP may have potential value for the treatment of PD.     

大鼠帕金森病模型的建立及其评价

目前越来越多的神经科学家致力于帕金森病的研究 ,并且已经建立了几种不同的动物模型 (如小鼠、大鼠和猴子模型 )。其中 ,大鼠模型应用最为广泛。本文对几种常用的大鼠帕金森病模型造模方法进行了简要的概述和评价。     

Neural grafting for Parkinson's disease: challenges and prospects

Parkinson's disease (PD) is a neurodegenerative condition which causes a characteristic movement disorder secondary to loss of dopaminergic neurons in the substanitia nigra. The motor disorder responds well to dopamine-replacement therapies, though these result in significant adverse effects due to non-physiolog-ical release of dopamine in the striatum, and off-target effects. Cell-based regenerative treatments offer a potential means for targeted replacement of dopamine, in a physiological manner. Dopaminergic neurons for cell-based therapies can be obtained from several sources. Fetal ventral mesencephalon tissue contains dopaminergic neuron progenitors, and has been transplanted into the striatum of PD patients with good results in a number of cases. However, the ethical implications and logistical challenges of using fetal tissue mean that fetal ventral mesencephalon is unlikely to be used in a widespread clinical setting. Induced plu-ripotent stem cells can be used to generate dopaminergic neurons for transplantation, providing a source of autologous tissue for grafting. This approach means that challenges associated with allografts, such as the potential for immune rejection, can be circumvented. However, the associated cost and difficulty in producing a standardized product from different cell lines means that, at present, this approach is not com-mercially viable as a cell-based therapy. Dopaminergic neurons derived from embryonic stem cells offer the most promising basis for a cell-based therapy for Parkinson's disease, with trials due to commence in the next few years. Though there are ethical considerations to take into account when using embryonic tissue, the possibility of producing a standardized, optimized cell product means that this approach can be both effective, and commercially viable.     

BDNF and TrkB expression in intrastriatal ventral mesencephalic grafts in a rat model of Parkinson's disease

Summary. We investigated the expression of BDNF and its high affinity receptor trkB in fetal dopaminergic grafts in a rat model of Parkinson's disease. Grafts were allowed to differentiate for 7, 14, 28, or 56 days, respectively and were analyzed immunocytochemically thereafter with antibodies directed against tyrosine hydroxylase, BDNF and trkB. At all time points investigated, grafts contained tyrosine hydroxylase immunoreactive neurons. Immature grafts (7 days) displayed no immunoreactivity for BDNF which was restricted to glial cells at the graft-host interface. After longer differentiation periods BDNF-immunoreactivity was detectable in neurons and astrocytes within the grafts. No trkB immunoreactivity was found in immature grafts but a strong signal for trkB emerged in grafted neurons older than 14 days whereas glial cells remained unlabeled at all time points investigated. Expression of BDNF and trkB in grafted neurons and of BDNF in sourrounding glial cells suggests an autocrine or paracrine action of BDNF on dopaminergic neurons possibly mediated by activated glia. Accepted December 15, 1997; received October 28, 1997     

Parallel relationship between microglial activation and substantia nigra damage in a rotenone-induced Parkinson's disease rat model

BACKGROUND:Inflammatory injury induced by microglial activation plays an important role in the occurrence and development of Parkinson’s disease (PD). However, few studies have examined the relationship between microglia and substantia nigra damage or dopaminergic neuron loss in animals with rotenone-induced PD. OBJECTIVE: To explore the relationship between activated microglia and loss of the substantia nigra, and the changes in concentration and dose of rotenone in the brain of rats with rotenone-induced ...     

帕金森病与阿尔茨海默病

普遍认为帕金森病和阿尔茨海默病是两个独立的、有着显著判别的疾病。但是,相当数量为证据表明,二者具有相互重叠的临床和神经病理特征、相似的病因和病变发生机制。因此,现在有人认为这两种疾病的部分病例可能是同一种神经元退行性变疾病的不同表现形式。本文拟对此作一介绍。     

Neuroprotective and restorative effects of intrastriatal grafting of encapsulated GDNF-producing cells in a rat model of Parkinson's disease

Glial cell line-derived neurotrophic factor (GDNF) has been shown to possess potent neurotrophic effects on dopaminergic (DA) neurons. We attempted the transplantation of encapsulated GDNF-producing cells to generate a stable supply of GDNF in the brain to promote neuroprotective and restorative effects for DA neurons. We established baby hamster kidney (BHK) cells and introduced GDNF cDNA to produce human GDNF (BHK-GDNF). These BHK-GDNF cells, or nontransfected BHK cells (BHK-Control), were encapsulated into hollow fibers, and the polymer encapsulated cells were unilaterally implanted into the striatum of adult rats, either before or after the administration of 6-hydroxydopamine into the same striatum. The encapsulated BHK-GDNF cells produced GDNF continuously in the striatum for up to 6 months. The rats that received a BHK-GDNF capsule showed a significant decrease in rotational behaviour compared to those that received a BHK-control capsule. Preservation of the nigrostriatal pathway was significantly greater in those that received a BHK-GDNF capsule than in those that received a BHK-control capsule. This indicates that encapsulated GDNF-producing cells can supply GDNF in a stable fashion and have protective and restorative effects on host DA neurons. Our results support a role for this grafting technique in the treatment of Parkinson's disease.     

重组人促红细胞生成素(rhEPO)对帕金森病大鼠模型小胶质细胞活化的影响

目的探讨重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)对6-羟基多巴胺(6-OHDA)诱导的SD大鼠帕金森病(PD)模型小胶质细胞活化的影响。方法 40只SD大鼠随机分为A组(rhEPO+6-OHDA)、B组(生理盐水+6-OHDA)、C组(6-OHDA)、D组(生理盐水),每组10只。(1)A组:右侧纹状体内立体定向注射重组促红细胞生成素(rhEPO),24h后同侧黒质内立体定向注射6-OHDA;(2)B组:右侧纹状体内立体定向注射与rhEPO等量的生理盐水,24h后同侧黒质内立体定向注射6-OHDA;(3)C组:右侧黒质内立体定向注射6-OHDA;(4)D组:右侧黒质内立体定向注射与6-OHDA等量的生理盐水。4w后采用免疫组化检测黒质内酪氨酸羟化酶(TH)阳性神经元和CD11b阳性细胞数量及CD11b阳性细胞形态变化。结果与D组比较,A组大鼠黒质TH阳性神经元明显减少,CD11b阳性细胞明显增多,大部分小胶质细胞胞体小,突起细长;与B组和C组比较,A组大鼠黒质TH阳性神经元显著增多,CD11b阳性细胞显著减少,仅有少量小胶质细胞胞体大,突起短粗。结论重组人促红细胞生成素(rhEPO)可能通过抑制小胶质细胞活化,减轻6-OHDA对多巴胺(DA)能神经元的毒性损害,对DA能神经元产生神经保护作用。     

Behavioral and morphological effects of minocycline in the 6-hydroxydopamine rat model of Parkinson's disease

The neuropathology in many neurodegenerative diseases is mediated by inflammatory cascades that influence neuronal dysfunction and death. Minocycline reduces the neurodegeneration observed in various models of Parkinson's. We exploited the unilateral 6-hydroxydopamine (6-OHDA) lesion model to assess the effect of minocycline on related neurodegeneration. Thirty Fisher 344 rats were divided into three daily treatment groups: (1) after: 45 mg/kg of minocycline beginning 24 h after lesioning; (2) before: 45 mg/kg of minocycline beginning 3 days before 6-OHDA lesioning; (3) control: corresponding saline-treated controls. Animals were assessed for apomorphine-induced rotations for 4 weeks. A longitudinal model for repeated measures showed that both after and before groups had significantly lower rotations than controls (P < 0.001 for both comparisons). Pair-wise group comparisons showed that the before animals rotated less compared to controls (mean rotations: 164 +/- 38 versus 386 +/- 49, respectively, P = 0.001). After animals also rotated significantly less then controls (mean rotations: 125 +/- 41 versus 386 +/- 49, respectively, P < 0.001). Animals receiving minocycline displayed reduced tyrosine hydroxylase-positive cell loss in the lesioned nigra versus contralateral nonlesioned nigra, compared to controls (mean differences: 5065 for after, 3550 for before, and 6483 for controls; P = 0.158 for after versus controls, P = 0.019 for before versus controls). The remaining lesioned nigral cells of both minocycline-treated groups were larger than controls, with the most robust cell size and fiber density observed in the after group. These data suggest that the therapeutic potential of minocycline may depend on the time of drug administration relative to neuropathogenic event.     

Establishment of a Parkinson's disease model in rats via striatal one-site double injection Feasibility observation

BACKGROUND: To date, many 6-hydroxydopamine (6-OHDA)-lesioned rat models have been established by injecting 6-OHDA into two or more sites in the substantia nigra pars compacta, striatum or median forebrain bundle. The success rate of models established by this method is satisfactory, but it can raise the death rate, and is elaborate and tedious to perform.OBJECTIVE: To observe the difference between injections of 6-OHDA into the striatum from one site and two sites, and to explore the feasibility of establishing Parkinson's disease rat models via striatal one-site double injection.DESIGN, TIME AND SETTING: A randomized, controlled animal experiment based on a modeling comparison was performed at the Pharmacology Laboratory of Traditional Chinese Medicine, Academy of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine between August 2005 and April 2006.MATERIALS: A total of 46 male Wistar rats were purchased from Beijing Weitong Lihua Experimental Animal Technical Co., Ltd., China. 6-OHDA hydrogen bromide was sourced from Sigma Co., Ltd., USA.METHODS: All 46 rats were randomized to three groups: one-site injection (n = 18), two-site injection (n = 18), and control (n = 10). Lesions in rat brains were established by infusing 5 p g 6-OHDA into the striatum at the following coordinates: anteroposterior (AP) 1.0 ram, mediolateral (ML) 2.7 mm,dorsoventral (DV) -5.2 or -6.0 mm for the one-site injection group, and AP 1.0 mm, ML 2.5 ram, DV -4.5 mm/AP -0.4 ram, ML 3.5 mm, DV -4.5 mm for the two-site injection group, respectively. Rats in the control group were injected with the same volume of 0.01% ascorbic acid as above.MAIN OUTCOME MEASURES: Tyrosine hydroxylase-positive neurons were detected by immunohistochemistry. Success rates of PD models established by one-site and two-site injection techniques were examined.RESULTS: One rat died in the one-site injection group and four in the two-site injection group. Thus behavioral testing was performed on 31 rats. There was no significant difference in the success rate of PD model establishment between one-site injection and two-site injection groups [82% (14/17) vs. 86% (12/14), P > 0.05]. The numbers of tyrosine hydroxylase -positive neurons in one-site injection and two-site injection groups were not significantly different ( P > 0.05), but they were significantly lower than in the control group(P < 0.01 ).CONCLUSION: A Parkinson's disease model can be established in rats via striatal one-site double injection.     

Behavioral and structural effects of unilateral intrastriatal injections of botulinum neurotoxin a in the rat model of Parkinson's disease

Botulinum neurotoxin (BoNT) inhibits the release of acetylcholine from presynaptic vesicles through its proteinase activity cleaving the SNARE complex. Parkinson's disease (PD) is associated with locally increased cholinergic activity in the striatum. Therefore, the present study investigates the effect of unilateral intrastriatal BoNT‐A injection in naïve rats on striatal morphology; i.e., the total number of Nissl‐stained neurons and the volume of caudate‐putamen (CPu) were estimated. Furthermore, stainings for markers of gliosis (glial fibrillary acidic protein) and microglia (Iba1) were performed. In addition, the potential beneficial effects of a unilateral intrastriatal injection of BoNT‐A on motor activity in the rat model of hemi‐PD were evaluated. Hemi‐PD was induced by unilateral injection of 6‐hydroxydopamine (6‐OHDA) into the right medial forebrain bundle. Six weeks later, rats received an ipsilateral intrastriatal injection of BoNT‐A. Behaviorally, motor performance was tested. The total number of CPu neurons and the striatal volume were not significantly different between the BoNT‐A‐injected right and the intact left hemispheres of naïve rats. In hemi‐PD rats, intrastriatal BoNT‐A abolished apomorphine‐induced rotations, increased amphetamine‐induced rotations, and tended to improve left forelimb usage. Forced motor function in the accelerod test was not significantly changed by BoNT‐A, and open field activity was also unaltered compared with sham treatment. Thus, intrastriatal BoNT‐A affects spontaneous motor activity of hemi‐PD rats to a minor degree compared with drug‐induced motor function. In the future, tests assessing the cognitive and emotional performance should be performed to ascertain finally the potential therapeutic usefulness of intrastriatal BoNT‐A for PD. © 2013 Wiley Periodicals, Inc.     

Prevalence of radiological and clinical cerebrovascular disease in idiopathic Parkinson's disease

Comorbid cerebrovascular disease (CVD) can occur in idiopathic Parkinson's disease (IPD) but its reported prevalence varies considerably. CVD may alter the clinical presentation, course and prognosis in IPD. We aimed to determine the prevalence of radiological and clinical CVD in a neurology clinic IPD population. We undertook a retrospective case-control study of neurology clinic patients with IPD for whom cerebral imaging was available, and excluding probable vascular parkinsonism. IPD diagnosis was validated against UK PDS brain bank criteria. Age and sex-matched controls were identified from patients attending neurology clinics with headache. The presence of radiological cerebrovascular disease, symptomatic CVD (stroke and TIA), and CVD risk factors was recorded for cases and controls. Radiological findings were validated by an experienced consultant neuroradiologist using a structured proforma. Eighty-five cases and 85 controls were studied, based on the number of cases for whom brain imaging existed (CT in 50, MRI in 35) and the number of cases for whom suitable controls could be identified. Indications for brain imaging amongst cases were varied. Cases and controls comprised 55(65%) males, mean (±SD) age (years) 67.4 ± 10.1 (cases), 66.6 ± 9.9 (controls). Radiological CVD was significantly commoner amongst cases (39%) than controls (22%) (p = 0.02, chi-square; odds ratio 2.2, 95% CI: 1.1-4.6). Cases also had significantly more symptomatic CVD, but not CVD risk factors, than controls. Our findings suggest a higher prevalence of radiological and clinical CVD in patients with IPD compared to controls.     

Epidemiology of Parkinson's disease

The incidence of Parkinson syndrome in North America is 20.5/10⁵, adjusted to 1970 US population, and there has been no significant change between 1935 and 1979. The composition of different Parkinson variants in the general population, however, has altered remarkably during recent decades. Arteriosclerotic Parkinsonism is very rarely diagnosed now, post-encephalitic Parkinsonism is extinct and drug induced Parkinsonism, first identified in the 1950s, is now the second most common variant in the combined community and institutionalised population survey. There has been a trend to higher incidence of Parkinson's disease in recent decades and it is predicted that the incidence would rise further if the current population survival trends continue. There is no race or gender difference for the risk of Parkinson's disease. Survival in Parkinson's disease has increased since the widespread use of levodopa. The prevalence rate of Parkinson syndrome in North America is estimated at 300/105. Increased risk of Parkinson's disease in essential tremor patients and the reported protective effect of smoking are artifactual. Twin studies show a concordance rate of 10.5% in monozygotic and 10.8% in dizygotic twins, indicating against a major genetic basis for Parkinson's disease. Several large Parkinson's disease families with autosomal dominant inheritance are well documented. In one such family, linkage to chromosome 4 is reported and mutation in the a-synuclein gene has been identified. In several other families, linkage to that region was not detected. These families are believed to inherit a Parkinson's disease susceptibility trait.     

脑内移植骨髓间质干细胞治疗帕金森病模型大鼠的实验研究

目的 探讨骨髓间质干细胞(mesenchymal stem cells,MSCs)移植治疗帕金森病(parkinson's disease,PD)大鼠的可行性及可能的机制.方法 移植Brdu标记的MSCs到模型大鼠的纹状体内.术后4个月中,定期对大鼠进行旋转行为学实验测试.并分别在术后2周和4个月时进行脑内针道处及移植区免疫组化检测TH和Brdu的表达.结果 Brdu标记的MSCs移植到模型大鼠的纹状体内,术后2周时移植针道处及针道周围可见Brdu阳性外源MSCs,并有外源性细胞表达TH,术后4个月时移植针道内仍可以看到MSCs存活.MSCs移植的PD模型大鼠症状较PBS注射组行为学明显改善.结论 移植MSCs到大鼠PD模型的纹状体内能成活,且分化细胞能表达TH蛋白,大鼠PD模型行为学症状明显改善.     

Protective effect of caffeine against neurodegeneration in a model of Parkinson's disease in rat: behavioral and histochemical evidence

Epidemiological studies have consistently demonstrated an inverse association between coffee consumption and Parkinson's disease (PD). This study was designed to investigate the beneficial effect of caffeine at a dose comparable to that of human exposure in a model of PD. For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated with caffeine (20 mg/kg; i.p.) 1 h before surgery and treated twice a day (10 mg/kg) for 1 month. Apomorphine-induced rotations and number of Nissl-stained neurons of substantia nigra pars compacta (SNC) were counted. The results demonstrated that caffeine administration for 1 month could attenuate the rotational behavior in lesioned rats and protect the neurons of SNC against 6-OHDA toxicity.     

Neurochemical findings in the MPTP model of Parkinson's disease

Summary. Animal models are a very important approach to study the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. For instance, the application of the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is able to produce striking similarities to Parkinson's disease (PD) diagnosed in humans. MPTP is thought to selectively damage dopaminergic neurons predominantly those originating in the substantia nigra pars compacta (SNc) which leads to impaired dopaminergic neurotransmission accompanied by a loss of dopaminergic nerve terminals in the striatum. MPTP-induced neurochemical, behavioral, and histopathological alterations replicate very closely the clinical symptoms of PD patients, which will be discussed in this paper and render the MPTP model currently the most favored PD model to study therapeutic intervention strategies in an easy and reliable way in preclinical studies. We and many other research groups propose that the knowledge about the neurotoxic mechanisms of MPTP such as mitochondrial dysfunction with breakdown of energy metabolism and free radical production will help us to understand the underlying mechanisms of PD, which are not fully understood yet. In particular, the novel aspects of inflammatory processes and the involvement of reactive nitrogen species in addition to reactive oxygen species seem to be important milestones for a better understanding of the neurodegenerative effects of MPTP. In this review we focus on the MPTP mouse model which is easy practicable and widely used in neuroscience research and draw comparisons to the human pathology in PD. Received March 1, 2001; accepted July 11, 2001     

RNA干扰沉默Synphilin-1可提高帕金森病大鼠黑质超氧化物歧化酶表达：一种假设的验证？

目的 研究灵芝孢子对帕金森病（PD）动物模型黑质神经细胞凋亡的影响,以探讨灵芝孢子对帕金森病的脑保护作用。方法 120只SD大鼠随机分为三组, PD组：向黑质部立体定向注入6－羟多巴,术后一周腹腔注入阿朴吗啡观察30分钟大鼠旋转的次数,连续至第四周每分钟大于6次者为成功的帕金森模型;灵芝孢子组：先用灵芝孢子粉灌胃三天,立体定向注入6－羟多巴, 继续灌胃4周,直至处死;正常对照组：向黑质部立体定向注入抗坏血酸生理盐水。处死后制作快速冰冻切片用免疫组化检测Caspase 3阳性细胞数,用原位杂交法检测Caspase 3 mRNA的阳性细胞数,用Western blot检测Caspase 3的半定量变化。结果 免疫组化显示灵芝组术侧黑质Caspase 3阳性神经元数量较PD组明显降低,原位杂交显示灵芝组术侧黑质Caspase 3 mRNA阳性神经元数量较PD组明显降低,Western blot显示Caspase 3蛋白灵芝组较PD组显著降低。结论 灵芝孢子能够降低Caspase 3的表达,对PD有脑保护作用。     

Tyrosine hydroxylase-like (TH) immunoreactivity in Parkinson's disease and Alzheimer's disease

Summary We used tyrosine hydroxylase immunoreactivity (TH) to mark dopaminergic fibers in cerebral tissue from adult persons with Parkinson's disease (PD) or Alzheimer's disease (AD). In the PD cases we found a loss of dopaminergic neurons in the ventral tegmental area (VTA), severely reduced TH fibers in dopaminergic terminal fields (particularly in the hippocampal perforant pathway) and neurofibrillary tangles (NFT), that occurred only in the perforant pathway. In contrast, AD cases were characterized by a lack of significant neuron loss in the VTA and by mild loss of TH fibers. A decreased dopaminergic innervation of the perforant pathway in cases of PD appears to be associated with the occurrence of NFT in these structures.