Cognitive dysfunction and dementia in Parkinson's disease

Department of Neurology, Research Institute Neurosciences Vrije Universiteit, VU University Medical Center, Amsterdam, The Netherlands.
Journal of Neural Transmission (Impact Factor: 2.4). 11/2004; 111(10-11):1303-15. DOI: 10.1007/s00702-004-0168-1
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Erik Ch. Wolters, Sep 27, 2015
121 Reads
  • Source
    • "The mesolimbic pathway is mainly associated with reward, while the mesocortical pathway is associated with cognitive function. Aberrant reward processing drives substance abuse disorders, and cognitive dysfunction exists as an often overlooked but devastating feature of many neuropsychiatric disorders (Carter et al., 1998; Bosboom et al., 2004; Medalia and Lim, 2004). Studies of imbalanced mesolimbic and mesocortical DAergic signaling support a potential therapeutic role for DA in reward and cognitive dysfunction in neuropsychiatric disease (Murphy et al., 1996; Volkow et al., 1998; Goldman-Rakic et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders.
    Frontiers in Cellular Neuroscience 12/2013; 7:260. DOI:10.3389/fncel.2013.00260 · 4.29 Impact Factor
  • Source
    • "However, the clinical expression of the disease is more heterogeneous as patients suffer from a variety of additional non-motor symptoms, including sleep disturbances, olfactory deficits, cognitive impairment, neuropsychiatric disorders, and autonomic dysfunction [4], [5]. In particular, the cognitive deficit seen in PD causes disturbances in both executive functions and memory [6] and may lead to dementia in 30 to 40% of the patients as the disease progresses [7], [8]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Intraneuronal inclusions containing alpha-synuclein (a-syn) constitute one of the pathological hallmarks of Parkinson's disease (PD) and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP) in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration.
    PLoS ONE 05/2013; 8(5):e64844. DOI:10.1371/journal.pone.0064844 · 3.23 Impact Factor
  • Source
    • "In contrast, MPTP-infused rats displayed a poor performance in the shortterm retention session (1.5 h after training) of the inhibitory avoidance task (Castro et al., 2012), in the working memory version of the water maze (Prediger et al., 2006) and in the social recognition task (Moreira et al., 2010; Castro et al., 2012). These findings are consistent with the view of human studies suggesting that PD patients present early deficits in working memory and short-term memory tasks mainly dependent on the frontostriatal circuitry (for review see Zgaljardic et al., 2003) with long-term spatial (declarative) memories mostly spared (Dubois and Pillon, 1997; Bosboom et al., 2004). Beyond the cognitive symptoms, depressive disorders commonly occur in PD affecting approximately 40% of the patients during the early stages of the disease (Tolosa et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Affective disorders and memory impairments precede the classical motor symptoms seen in Parkinson's disease (PD) and the currently approved antiparkinsonian agents do not alleviate the non-motor symptoms as well as the underlying dopaminergic neuron degeneration. On the other hand, there is increasing evidence that inflammation plays a key role in the pathophysiology of PD and that the anti-inflammatory actions of statins are related to their neuroprotective properties against different insults in the CNS. The present data indicates that the oral treatment with atorvastatin (10mg/kg/day), once a day during 7 consecutive days, was able to prevent short-term memory impairments and depressive-like behavior of rats assessed in the social recognition and forced swimming tests at 7 and 14 days, respectively, after a single intranasal (i.n.) administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1mg/nostril). Importantly, at this time no significant alterations on the locomotor activity of the animals were observed in the open field test. Moreover, atorvastatin was found to protect against the long-lasting motor deficits evaluated in activity chambers and the loss of dopaminergic neurons in the substantia nigra pars compacta observed at 21 days after i.n. MPTP administration. At this time, despite the absence of spatial memory deficits in the water maze and in concentrations of the cytokines TNF-α, IL-1β and IL-10 in striatum and hippocampus following i.n. MPTP administration, atorvastatin treatment resulted in a significant increase in the striatal and hippocampal levels of nerve growth factor (NGF). These findings reinforce and extend the notion of the neuroprotective potential of atorvastatin and suggest that it may represent a new therapeutic tool for the management of motor and non-motor symptoms of PD.
    Brain research 03/2013; 1513. DOI:10.1016/j.brainres.2013.03.029 · 2.84 Impact Factor
Show more