Search

Objective: Clinical trials of fetal neural tissue transplantation for Huntington disease (HD) have been conducted with variable clinical results. However, no long-term analysis of graft survival and integration has been published. Here, we report the pathologic findings in two patients with HD who died 74 and 79 months after transplantation., Methods: Methods used were pathologic examination, histochemistry, and immunohistochemistry., Results: Neostriatum from both patients showed typical neuropathologic changes of advanced HD. Surviving grafts were identified in both patients (6/6 sites and 7/8 sites, respectively) as well-demarcated nests within host neostriatum with associated needle tracts. Grafted neurons adopted either dominant calbindin/parvalbumin or calretinin immunoreactivity (IR). Few neurofilament, MAP-2, DARPP-32, tyrosine hydroxylase, or calbindin IR processes traversed the host parenchyma-graft interface despite minimal junctional gliosis. Immunohistochemistry for CD68 showed microgliosis that was more pronounced in host striatum than graft. Scattered CD45 and CD3 IR cells were present within grafts and host parenchyma. No ubiquitin IR neuronal intranuclear inclusions were identified in graft neurons, although these were prevalent in host cells., Conclusions: These two autopsies confirm previous findings of neuronal differentiation and survival of transplanted fetal tissue from the ganglionic eminence and also demonstrate viability of neurons from fetal transplants in human neostriatum for more than 6 years. Despite prolonged survival, these grafts had poor integration with host striatum that is likely responsible for lack of clear clinical improvement in these patients.

Background: Embryonic nigral cell implants are a novel treatment for Parkinson disease (PD). Reaction time (RT) and movement time (MT) analysis, validated quantitative measures of premovement neural processing and motor execution, can be used as objective physiological markers of motor performance in PD., Objectives: To gauge the change in motor performance in patients with PD who received implants, and to determine whether the physiological findings correlate with clinical outcome measures after transplantation., Design: Double-blind, placebo-controlled trial. Patients Forty patients with levodopa-responsive, Hoehn and Yahr stage III or greater PD., Interventions: Random assignment to embryonic tissue implants or placebo (sham) operation., Main Outcome Measures: Combined RT + MT scores measured preoperatively and at 4 and 12 months postoperatively in the "off" state., Results: The difference in mean RT + MT scores between the sham and implant groups was statistically significant (P =.005) and was greatest in those 60 years or older (P =.003). Changes correlated with Unified Parkinson's Disease Rating Scale off scores at 4 (r = 0.87, P =.001) and 12 (r = 0.75, P =.01) months in those younger than 60 years. There was a significant deterioration in the sham surgery group at 12 months (P =.03) that was thought to be due to worsening in subjects 60 years and older (P<.001)., Conclusions: The physiological measures detected significant changes in patients undergoing embryonic nigral cell implants and correlated directly with clinical outcome measures. Comprehensive analyses of RT paradigms can document subtle changes in motor performance over time, making them useful outcome measures in therapeutic trials of PD. These findings support further research into nigral cell implantation for PD.

Prion diseases include scrapie, BSE and CWD in animals, and spontaneous, familiar and infectious Creutzfeldt-Jakob disease(CJD) in human. Infectious prion diseases include kuru, variant CJD and iatrogenic CJD. CJD has been transmitted from human to human by contaminated cadaveric dura mater grafts and by cadaveric pituitary hormones. To date, CJD associated with dura mater grafts, reaching 156 cases, has been reported in 17 countries. More 2/3 of cases have been reported in Japan. Nationwide survey and recent information documented 105 dura-related cases during the period between 1979 and 2003. At least 91 cases received same brand of dura mater by a single German company. Age at disease onset in cases with dura-related CJD was younger (54.2 +/- 14.2 years) than sporadic CJD (64 +/- 10 years). Two groups of dura-related CJD are manifest in clinical course and pathological characteristics, such as rapidly progressive group and slowly progressive. Rapidly group was similar to cases with classical CJD in clinical features and shot duration to death from onset. Slowly progressive group developed akinetic mutism longer than 1 year, and characterized by florid plaques in the brain (Kitamoto).

Background: Projections of the size of the Creutzfeldt-Jakob disease (CJD) epidemic are of great importance for future health care and understanding of the natural history of this disease., Objective: We have estimated the incubation period and have projected the number of patients with iatrogenic CJD in Japan, using 75 patients who were transplanted with cadaveric dura mater grafts between 1979 and 1991 and developed CJD by the end of 2000., Methods: Several plausible scenarios, combinations of incubation period distribution forms, competing risks and exposure distributions were evaluated for the projections using data from the Japanese Ministry of Health, Labor and Welfare., Results: The range of median incubation periods from the time of dura mater transplantation to the onset of the disease was 10.8-34.3 years, and the range of the number of new CJD patients between 2001 and 2020 was 21-84., Conclusions: Since the potential incubation period was estimated to be considerably long, as few as 21 and as many as 84 new patients may develop CJD by 2020., (Copyright 2003 S. Karger AG, Basel)

This study presents data on the antemortem evaluations of a cohort of individuals registered in a brain donation program. Clinical evaluation determined that many individuals were unaware they had clinical signs of Parkinson's disease (PD) (rest tremor, bradykinesia, rigidity). Quantitative motor testing (timed tapping test and Purdue pegboard test) revealed a graded reduction in performance in those clinically found to have clinically possible and clinically probable PD. Longitudinal examinations over 4 years revealed some individuals progressed from control to clinically possible PD and clinically possible PD to clinically probable PD. This study underscores the importance of longitudinal antemortem testing of prospective brain donors as well as the potential value of quantitative motor testing.

During the last 30 years, the promise of neural transplantation as a therapeutic strategy for neurodegenerative disease has been slowly recognised. Across the world, clinical transplants of embryonic primary dopamine neurones have been shown to ameliorate some of the motor deficits in Parkinson s disease (PD) patients, and more recently, systematic clinical trials have been initiated for the replacement of striatal projection neurones lost in Huntington's disease (HD). Clinical transplantation as a prospective therapy for HD poses a particular set of difficulties. The hallmarks of this neurodegenerative disease include extensive loss of medium spiny long-distance projection neurones of the caudate and putamen, affecting downstream target nuclei, the globus pallidus and substantia nigra, leading to dysregulation of motor control. In addition, extensive loss of cortical neurones that form the afferent systems to the basal ganglia leads to widespread cognitive decline. If transplantation therapy is to succeed in replacing degenerating neurones in HD and reinstating controlled function of complex basal gan-glia circuitry, the new neurones must be able to develop specific long-distance projections that can form accurate and functional connections with neurones in precise target regions. Our ongoing studies are aimed at addressing how we can improve the function of striatal transplants, in particular to optimise the reformation of precise long-distance connections and to re-establish normal motor and cognitive function. In particular, we have investigated optimal requirements for embryonic primary tissue to achieve these aims, and also the potential of other cell sources to provide long-distance projection neurones and reconnect complex circuitry. This review describes current progress of experiments to optimise the reconstruction of neuronal circuitry using primary embryonic tissue transplants, as well as our current initiatives to use neural stem cells or precursors to replace long distance projection neurones in the degenerating basal ganglia.

The suspension of embryonic locus coeruleus (LC) was transplanted into outbred albino rat hippocampus after its preliminary 6-hydroxy-dopamine-induced denervation. Immunohistochemical and morphometric analysis revealed that 3 months after the transplantation, embryonic noradrenergic LC cells which have completed their histogenesis in recipient hippocampus, appear as differentiated multipolar and fusiform cells, typical to LC. Intrahippocampal allotransplants of rat embryonic LC were also demonstrated to normalize the level of orientation activity in an open area, that was significantly reduced after administration of 6-hydroxy-dopamine to the animals.