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Ageing and Parkinson's disease: substantia nigra regional selectivity. (1991)

by J M Fearnley, A J Lees
Venue:Brain,
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The correlative triad among aging, dopamine, and cognition: current status and future prospects.

by Lars Ba¨ckman , Lars Nyberg , Ulman Lindenberger , Shu-Chen Li , Lars Farde - Neurosci. & Biobehav. Rev. , 2006
"... Abstract The brain neuronal systems defined by the neurotransmitter dopamine (DA) have since long a recognized role in the regulation of motor functions. More recently, converging evidence from patient studies, animal research, pharmacological intervention, and molecular genetics indicates that DA ..."
Abstract - Cited by 63 (17 self) - Add to MetaCart
Abstract The brain neuronal systems defined by the neurotransmitter dopamine (DA) have since long a recognized role in the regulation of motor functions. More recently, converging evidence from patient studies, animal research, pharmacological intervention, and molecular genetics indicates that DA is critically implicated also in higher-order cognitive functioning. Many cognitive functions and multiple markers of striatal and extrastriatal DA systems decline across adulthood and aging. Research examining the correlative triad among adult age, DA, and cognition has found strong support for the view that age-related DA losses are associated with age-related cognitive deficits. Future research strategies for examining the DA-cognitive aging link include assessing (a) the generality/specificity of the effects; (b) the relationship between neuromodulation and functional brain activation; and (c) the release of DA during actual task performance. r
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...related cognitive decline (Ronnlund et al., 2005). Although the reasons for the discrepant findings remain unclear, it should be noted that most relevant studies involve relatively few subjects, and several studies may not have covered a sufficiently wide age range. Conceivably, these factors underlie the different function forms relating age to DA markers in the extant literature. The age-related loss of DA markers may have multiple loci at a neuronal or molecular level. First, there is an agerelated reduction of DA cell bodies in substantia nigra, with an average loss around 3% per decade (Fearnley and Lees, 1991). In a unique study, post-mortem cell counts in the substantia nigra were highly related to an ante-mortem imaging marker for DA synthesis capacity (Snow et al., 1993). This suggests that neuronal number influences the total synthesis rate of DA. Second, there is a reduction of synapses that progresses from childhood through adulthood to old age, which may reflect both adaptive, plastic processes during development and predominantly non-adaptive loss in late life (Gopnic et al., 1999). Third, there is evidence suggesting an age-related decrease in the number of biomarker proteins per cell. Spe...

Forced limb-use effects on the behavioral and neurochemical effects of 6-hydroxydopamine

by Jennifer L. Tillerson, Ann D. Cohen, Jennifer Philhower, Gary W. Miller, Michael J. Zigmond, Timothy Schallert - J. Neurosci
"... Rats with unilateral depletion of striatal dopamine (DA) show marked preferential use of the ipsilateral forelimb. Previous studies have shown that implementation of motor therapy after stroke improves functional outcome (Taub et al., 1999). Thus, we have examined the impact of forced use of the imp ..."
Abstract - Cited by 20 (2 self) - Add to MetaCart
Rats with unilateral depletion of striatal dopamine (DA) show marked preferential use of the ipsilateral forelimb. Previous studies have shown that implementation of motor therapy after stroke improves functional outcome (Taub et al., 1999). Thus, we have examined the impact of forced use of the impaired forelimb during or soon after unilateral exposure to the DA neurotoxin 6-hydroxydopamine (6-OHDA). In one group of animals, the nonimpaired forelimb was immobilized using a cast, which forced exclusive use of the impaired limb for the first 7 d after infusion. The animals that received a cast displayed no detectable impairment or asymmetry of limb use, could use the contralateral (impaired) forelimb independently for vertical and lateral weight shifting, and showed no contralateral turning to apomorphine. The behavioral effects were maintained throughout the 60 d of observation. In addition to the behavioral

Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson’s disease

by Clemens R. Scherzer, Roderick V. Jensen, Steven R. Gullans, Mel B. Feany , 2003
"... model of Parkinson’s disease ..."
Abstract - Cited by 11 (1 self) - Add to MetaCart
model of Parkinson’s disease
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...) in humans is a slowly progressive neurodegenerative disease that becomes clinically manifest only after an estimated 70% of vulnerable dopaminergic neurons in the substantia nigra have already died =-=(1)-=-. Thus, modeling changes in pre-symptomatic patients is crucial for understanding pathogenesis and, perhaps even more importantly, for identifying therapeutic targets that might help to slow the disea...

Short-term GDNF treatment provides long-term rescue of lesioned nigral dopaminergic neurons in a rat model of Parkinson's disease

by Christian Winkler, Hansjörg Sauer, Chong S. Lee, Anders Björklund , 1996
"... Glial cell line-derived neurotrophic factor (GDNF) has been shown to exert neuroprotective effects on dopamine (DA) neurons in vivo. Here we report long-term rescue of nigral DA neurons after delayed short-term GDNF administration in a rat lesion model that reproduces the slowly progressing degenera ..."
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Glial cell line-derived neurotrophic factor (GDNF) has been shown to exert neuroprotective effects on dopamine (DA) neurons in vivo. Here we report long-term rescue of nigral DA neurons after delayed short-term GDNF administration in a rat lesion model that reproduces the slowly progressing degenerative process seen in Parkinson’s disease. GDNF injected close to the substantia nigra provided near-complete protection and persistent survival of the lesioned nigral neurons for at least 4 months after discontinuation of GDNF treatment. Long-term rescue of the nigral cells, however, was not accompanied by any significant reinnervation of the lesioned striatal target or any signs of functional recovery in either drug-induced or spontaneous motor behaviors. We conclude that not only preservation of the nigral DA neurons but also restoration of striatal DA function is necessary for functional recovery in the rat Parkinson model. Key words: GDNF; substantia nigra; striatum; neurodegeneration; behavior; Parkinson’s disease

Dopamine restores reward prediction errors in old age

by Rumana Chowdhury, Marc Guitart-masip, Christian Lambert, Peter Dayan, Quentin Huys, Emrah Düzel, Raymond J Dolan - Nature Neuroscience , 2013
"... Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. In a human functional magnetic resonance imaging (fMRI) study, we show that healthy older adults have an abnormal signature of expected value resulting in an incomplete reward predictio ..."
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Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. In a human functional magnetic resonance imaging (fMRI) study, we show that healthy older adults have an abnormal signature of expected value resulting in an incomplete reward prediction error signal in the nucleus accumbens, a brain region receiving rich input projections from substantia nigra/ventral tegmental area (SN/VTA) dopaminergic neurons. Structural connectivity between SN/VTA and striatum measured with diffusion tensor imaging (DTI) was tightly coupled to inter-individual differences in the expression of this expected reward value signal. The dopamine precursor levodopa (L-DOPA) increased the task-based learning rate and task performance in some older adults to a level shown by young adults. Critically this drug-effect was linked to restoration of a canonical neural reward prediction error. Thus we identify a neurochemical signature underlying abnormal reward processing in older adults and show this can be modulated by L-DOPA.
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...(Qa(t)(t)) parameter estimates in older adults who performed better on L-DOPA were significantly more negative on L-DOPA compared to placebo (‘win more on L-DOPA’ group, Qa(t)(t)) placebo vs. L-DOPA t=-=(14)-=- = 2.26, p = . 040; Figure 3b). In contrast, L-DOPA did not affect expected value representation in the ‘win less on L-DOPA’ group (t(16) = 1.18, p = .257), or reward representation in either the Chow...

JV: Ageing, neurodegeneration and Parkinson’s disease

by John V. Hindle - Age Ageing
"... Age is the largest risk factor for the development and progression of Parkinson’s disease (PD). Ageing affects many cellular processes that predispose to neurodegeneration, and age-related changes in cellular function predispose to the pathogenesis of PD. The accumulation of age-related somatic dama ..."
Abstract - Cited by 8 (0 self) - Add to MetaCart
Age is the largest risk factor for the development and progression of Parkinson’s disease (PD). Ageing affects many cellular processes that predispose to neurodegeneration, and age-related changes in cellular function predispose to the pathogenesis of PD. The accumulation of age-related somatic damage combined with a failure of compensatory mechanisms may lead to an acceleration of PD with age. The formation of Lewy bodies may represent a marker for protective mechanisms against age-related dysfunction and degeneration of the nervous system. Mild parkinsonian signs may be present in older people, which are associated with reduced function. These may be due to age-related decline in dopaminergic activity, incidental Lewy body disease, degenerative pathologies (early PD and Alzheimer’s disease) or vascular pathology. Ageing may affect the clinical pres-entation of PD with altered drug side effects, increased risk of developing dementia and an increased likelihood of admission to a nursing home. Progression of PD, including the development of dementia, and hallucinations is related to the age of the patient rather than the age of disease onset. PD may reflect a failure of the normal cellular compensatory mechanisms in vulnerable brain regions, and this vulnerability is increased by ageing. PD is one of the best examples of an age-related disease.
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.... Cell loss in PD mainly occurs in the ventral tier of the SNc. At post mortem, only a quarter of cells in the SNc remain in PD compared with normal, with the surviving cells being in the dorsal tier =-=[21]-=-. In normal ageing, the dorsal tier is preferentially affected by a ratio of over 3:1 [11] with a 5% loss per decade after the age of 40 years. The pattern of cell loss seen in PD does not occur in ot...

http://www.webcitation.org/6ahTy5pIm.. Accessed

by Gustavo Vasconcelos Alves , Ana Paula Santin , Tania Weber Furlanetto , 2015
"... Differentiated thyroid cancer (DTC) is the second most common cancer in pregnancy. Its management is a challenge for both doctors and patients, and the best timing for surgery is unclear. A systematic review evaluating the prognosis of DTC in pregnant patients was conducted. After reviewing 401 uni ..."
Abstract - Cited by 7 (2 self) - Add to MetaCart
Differentiated thyroid cancer (DTC) is the second most common cancer in pregnancy. Its management is a challenge for both doctors and patients, and the best timing for surgery is unclear. A systematic review evaluating the prognosis of DTC in pregnant patients was conducted. After reviewing 401 unique citations and 54 full texts, 4 studies that compared the prognosis of patients with DTC related to pregnancy (DTC diagnosed during pregnancy or within 12 months after childbirth) or not were included. In two studies the primary outcome was overall survival, in one study the primary outcomes were recurrent disease and death related to thyroid cancer, and in one study the primary outcome was recurrent or persistent disease. In the first two studies, there was no difference in overall survival in patients with pregnancy-related DTC, when compared with matched controls; in one study, there was no difference in death caused by DTC nor recurrence in DTC related to pregnancy. Nevertheless, in a recent retrospective study, a higher rate of recurrent or persistent DTC was observed in patients with DTC related to pregnancy. There are not many studies on which to base treatment decisions in pregnant patients with DTC.
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...gic neurons [32]. Moreover, despite the fact that TH is the rate limiting enzyme in catecholamine synthesis there is no clear correlation between the degree of NM pigmentation and TH immunoreactivity =-=[33,34]-=-. We therefore asked, whether ΔmtDNA levels are generally higher in catecholaminergic than in non-catecholaminergic neurons. We found that in noradrenergic neurons of the LC, ΔmtDNA were not elevated ...

Factors affecting the clinical outcome after neural transplantation in Parkinson’s disease

by Paola Piccini, Nicola Pavese, Peter Hagell, Jan Reimer, Anders Björklund, Wolfgang H. Oertel, Niall P. Quinn, David J. Brooks, Olle Lindvall
"... Intrastriatal grafts of embryonic mesencephalic tissue can survive in the brains of patients with Parkinson’s disease, but the degree of symptomatic relief is highly variable and some cases develop troublesome dyskinesias. Here we explored, using clinical assessment and 18 F-dopa and 11 C-raclopride ..."
Abstract - Cited by 6 (0 self) - Add to MetaCart
Intrastriatal grafts of embryonic mesencephalic tissue can survive in the brains of patients with Parkinson’s disease, but the degree of symptomatic relief is highly variable and some cases develop troublesome dyskinesias. Here we explored, using clinical assessment and 18 F-dopa and 11 C-raclopride PET, factors which may influence the functional outcome after transplantation. We observed increased 18 F-dopa uptake in the grafted putamen, signifying continued survival of the transplanted dopaminergic neurons, in parallel with a progressive reduction of 18 F-dopa uptake in non-grafted regions for the whole patient group. The patients with the best functional outcome after transplantation exhibited no dopaminergic denervation in areas outside the grafted areas either preoperatively or at 1 or 2 years post-operatively. In contrast, patients with no or modest clinical benefit showed reduction of 18 F-dopa in ventral striatum prior to or following transplantation, which may have limited graft-induced improvement. We obtained no evidence that dyskinesias were caused by abnormal dopamine (DA) release from the grafts. As has been observed for intrinsic dopaminergic neurons, there was a significant correlation between 18 F-dopa uptake and methamphetamine-induced change of 11 C-raclopride binding (as a measure of DA release) in the putamen containing the graft. Furthermore, we

Implicit Category Learning Performance Predicts Rate of Cognitive Decline in Nondemented Patients With Parkinson’s Disease

by J. Vincent Filoteo, Diego Healthcare System, David P. Salmon, W. Todd Maddox, David D. Song, Diego Healthcare System
"... Nondemented patients with Parkinson’s disease (PD) are impaired in learning to categorize simple perceptual stimuli when category membership is defined by a nonlinear relationship between stimulus dimensions but not when the relationship is linear (J. V. Filoteo, W. T. Maddox, D. P. Salmon, & D ..."
Abstract - Cited by 6 (3 self) - Add to MetaCart
Nondemented patients with Parkinson’s disease (PD) are impaired in learning to categorize simple perceptual stimuli when category membership is defined by a nonlinear relationship between stimulus dimensions but not when the relationship is linear (J. V. Filoteo, W. T. Maddox, D. P. Salmon, & D. D. Song, 2005). In the present study, the authors examined whether performance in either of these 2 category learning conditions was predictive of global cognitive decline following a mean of 1.6 years since the time patients were 1st seen. Results indicated that final block accuracy in the nonlinear condition, but not the linear condition, predicted global cognitive decline. Performance on the Wisconsin Card Sorting Test (WCST) did not significantly predict global cognitive decline, although there was a trend for this to be the case. In addition, the association between nonlinear category learning and global cognitive decline
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...f the186 FILOTEO, MADDOX, SALMON, AND SONG SNpc are primarily affected early in the course of PD, but as the disease progresses more medial portions of the SNpc become involved (Damier et al., 1999; =-=Fearnley & Lees, 1991-=-; Gibb, 1991; Rinne et al., 1989). This pattern of neuropathological progression is consistent with the clinical observation that motor functions are affected first in PD and that cognitive functions ...

Changes in network activity with the progression of Parkinson's disease

by Chaorui Huang, Andrew Feigin, Martin Lesser, Yilong Ma, Michael Pourfar, Vijay Dhawan, David Eidelberg - Brain , 2007
"... Parkinson’s disease (PD) is associated with abnormal activity in spatially distributed neural systems mediating the motor and cognitive manifestations of this disorder. Metabolic PET studies have demonstrated that this illness is characterized by a set of reproducible functional brain networks that ..."
Abstract - Cited by 6 (0 self) - Add to MetaCart
Parkinson’s disease (PD) is associated with abnormal activity in spatially distributed neural systems mediating the motor and cognitive manifestations of this disorder. Metabolic PET studies have demonstrated that this illness is characterized by a set of reproducible functional brain networks that correlate with these clinical features.The time at which these abnormalities appear is unknown, as is their relationship to concurrent clinical and dopaminergic indices of disease progression. In this longitudinal study, 15 early stage PD patients (age 58.010.2 years;Hoehn and Yahr Stage 1.2 0.3) were enrolled within 2 years of diagnosis. The subjects underwent multitracer PET imaging at baseline, 24 and 48 months. At each timepoint they were scanned with [18F]-fluorodeoxyglucose (FDG) to assess longitudinal changes in regional glucose utilization and in the expression of the PD-related motor (PDRP) and cognitive metabolic covariance patterns (PDCP). At each timepoint the subjects also underwent PET imaging with [18F]-fluoropropyl CIT (FP-CIT) to quantify longitudinal changes in caudate and putamen dopamine transpor-ter (DAT) binding. Regionalmetabolic changes across the three timepoints were localized using statistical para-metric mapping (SPM). Longitudinal changes in regional metabolism and network activity, caudate/putamen DAT binding, and Unified Parkinson’s Disease Rating Scale (UPDRS) motor ratings were assessed using repeated measures analysis of variance (RMANOVA). Relationships between these measures of disease
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