Parkinson's disease and dementia

Cash, Roland; Dennis, Trevor; L'Heureux, Rémy; Raisman, Rita; Javoy‐Agid, F.; Scatton, B.

doi:10.1212/wnl.37.1.42

Cited by 195 publications

(83 citation statements)

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“…Current thinking now recognises the heterogeneity in disease pathology and that this mirrors the complexity of the non-motor symptoms also associated with the disorder (Chaudhuri et al, 2006). Indeed, beyond causing pronounced dopaminergic disturbances, the degeneration also involves the serotonergic, noradrenergic and cholinergic systems as evidenced by neuronal losses and inclusion pathology in the locus coeruleus (Cash et al, 1987;Zarow et al, 2003), dorsal raphé nuclei (Scatton et al, 1983) and the basal nucleus of Meynert (Mann and Yates, 1983) respectively. The disorder is associated with a large number of intrinsic non-motor symptoms such as visuospatial deficits, autonomic dysfunction, cognitive impairment and neuropsychiatric problems.…”

Section: Discussionmentioning

confidence: 99%

The effect of additional noradrenergic and serotonergic depletion on a lateralised choice reaction time task in rats with nigral 6-OHDA lesions

Lindgren

Demirbugen

Bergqvist

et al. 2014

Experimental Neurology

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Parkinson's disease (PD) patients often suffer from visuospatial deficits, which may results from a disruption of the representation of external space. The lateralised choice reaction time (CRT) task is an operant task for rodents in which similar visuospatial deficits can be assessed. Specific parameters in this task are disrupted after unilateral nigrostriatal injections of 6-hydroxydopamine (6-OHDA), directly linked to the severe striatal dopamine (DA) depletion that inevitably follows this type of lesion. However, studies have demonstrated that this type of lesion also affects the serotonergic (5HT) and noradrenergic (NA) midbrain pathways. The influence of these systems on visuospatial parameters in the CRT task had not yet been investigated.To this end, rats were pretrained on the CRT task before receiving selective lesions of the DAergic system, either alone or in combination with bilateral depletion of the NA-or 5HT system. All rats with a 6-OHDA lesion displayed a gradual decline in the selection, initiation and execution of lateralised movements on the side contralateral to the lesion compared to sham-lesion controls. They also displayed a reduced number of useable trials as well as an increased number of procedural errors. Interestingly, the group with an additional noradrenergic lesion was significantly slower in reacting to lateralised stimuli throughout the testing period, as compared to the other two groups with a 6-OHDA lesion. There was however, no pronounced difference between the three different lesion groups in any other parameters assessed in the task.These data confirm previous findings demonstrating that that majority of the parameters assessed in the lateralised CRT task are strongly dependent on DA. However, an important new finding in this study is the illustration of a putative role for the NAergic system in contributing to the attentive performance influencing the animals' capacity to react to the presented lateralised stimuli.

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Section: Discussionmentioning

confidence: 99%

The effect of additional noradrenergic and serotonergic depletion on a lateralised choice reaction time task in rats with nigral 6-OHDA lesions

Lindgren

Demirbugen

Bergqvist

et al. 2014

Experimental Neurology

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“…Neuronal loss in locus coeruleus (LC) and noradrenergic deficiency in the cortex were reported to be associated with dementia in PD (Cash, 1987). However, in other studies, this relationship could not be found (Paulus, 1991;Chan-Palay, 1989).…”

Section: Pathophysiology Of Cognitive Deficits and Dementia In Pdmentioning

confidence: 97%

Cognitive dysfunction and dementia in Parkinson?s disease

2004

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Summary. Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder mainly characterized by degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area, in combination with a varying loss of central noradrenergic (locus coeruleus), cholinergic (nucleus basalis of Meynert) and serotonergic (dorsal raphe nuclei) integrity, leading to a multitude of motor and non-motor behavioral disturbances.Apart from the clinical motor hallmarks, in the early stages of disease, subtle cognitive dysfunction might be seen comprising mainly executive dysfunction, with secondary visuospatial and mnemonic disturbances. In about 20-40% of patients, these problems may eventually proceed to dementia, which constitutes an important risk factor for caregiver distress, decreased quality of life and nursing home placement. Dementia in PD is typically characterized by a progressive dysexecutive syndrome with attentional deficits and fluctuating cognition, often accompanied by psychotic symptoms. It is thought to be the result of a combination of both subcortical and cortical changes. PD-related dopaminergic deficiency in the nucleus caudatus and mesocortical areas (due to degeneration of projections from the substantia nigra and ventral tegmental area) and cholinergic deficiency in the cortex (due to degeneration of ascending projections from the nucleus basalis of Meynert), combined with additional Alzheimer-pathology and cortical Lewy bodies, may greatly contribute to dementia.Current treatment of dementia in PD is based on compensation of the profound cholinergic deficiency. Recent studies with the cholinesterase inhibitors galantamine, donepezil and rivastigmine show promising results in improving cognition and ameliorating psychotic symptoms, which must further be confirmed in randomized controlled trials.

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“…Despite the focus on DA, PD is more accurately described as a multisystem disorder that features a profound albeit underappreciated loss of locus coeruleus (LC) neurons, as well as variable damage to other brain regions (4)(5)(6). Postmortem studies indicate that neuronal degeneration in the LC is comparable to that in the substantia nigra pars compacta, and that it may actually precede DA degeneration in PD (5,7,8).…”

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confidence: 99%

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

Rommelfanger¹,

Edwards

Freeman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

176

116

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Although Parkinson's disease (PD) is characterized primarily by loss of nigrostriatal dopaminergic neurons, there is a concomitant loss of norepinephrine (NE) neurons in the locus coeruleus. Dopaminergic lesions induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are commonly used to model PD, and although MPTP effectively mimics the dopaminergic neuropathology of PD in mice, it fails to produce PD-like motor deficits. We hypothesized that MPTP is unable to recapitulate the motor abnormalities of PD either because the behavioral paradigms used to measure coordinated behavior in mice are not sensitive enough or because MPTP in the absence of NE loss is insufficient to impair motor control. We tested both possibilities by developing a battery of coordinated movement tests and examining motor deficits in dopamine ␤-hydroxylase knockout (Dbh؊/؊) mice that lack NE altogether. We detected no motor abnormalities in MPTP-treated control mice, despite an 80% loss of striatal dopamine (DA) terminals. Dbh؊/؊ mice, on the other hand, were impaired in most tests and also displayed spontaneous dyskinesias, despite their normal striatal DA content. A subset of these impairments was recapitulated in control mice with 80% NE lesions and reversed in Dbh؊/؊ mice, either by restoration of NE or treatment with a DA agonist. MPTP did not exacerbate baseline motor deficits in Dbh؊/؊ mice. Finally, striatal levels of phospho-ERK-1/2 and ⌬FosB/FosB, proteins which are associated with PD and dyskinesias, were elevated in Dbh؊/؊ mice. These results suggest that loss of locus coeruleus neurons contributes to motor dysfunction in PD.dopamine ͉ Parkinson's disease ͉ dyskinesias ͉ dopamine ␤-hydroxylase P arkinson's disease (PD) affects Ϸ1% of the world's aging population (1). Despite this high prevalence and intensive research into its origins, the etiology of PD remains largely unknown. The disease is characterized by degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SN), and symptoms, which tend to manifest when Ϸ80% of striatal DA is lost, include bradykinesia, postural instability, rigidity, and resting tremor. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin, is known to produce parkinsonism in humans and causes severe DA loss in animals (2). Because of its ability to recapitulate the neuropathology of PD, MPTP is used widely in PD research. However, MPTP has been unable to reliably reproduce the motor symptoms of PD in mice, which limits the utility of MPTP-treated mice as an animal model of the disease (3). Differences in mouse strain and experimental paradigms may at least partially account for these inconsistencies.Despite the focus on DA, PD is more accurately described as a multisystem disorder that features a profound albeit underappreciated loss of locus coeruleus (LC) neurons, as well as variable damage to other brain regions (4-6). Postmortem studies indicate that neuronal degeneration in the LC is comparable to that in the substantia nigra pars compacta, and that it may a...

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Parkinson's disease and dementia

Cited by 195 publications

References 0 publications

The effect of additional noradrenergic and serotonergic depletion on a lateralised choice reaction time task in rats with nigral 6-OHDA lesions

The effect of additional noradrenergic and serotonergic depletion on a lateralised choice reaction time task in rats with nigral 6-OHDA lesions

Cognitive dysfunction and dementia in Parkinson?s disease

Norepinephrine loss produces more profound motor deficits than MPTP treatment in mice

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