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: 2.87). 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.

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Available from: Erik Ch. Wolters, Jul 29, 2015
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    • "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). "
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    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 · 2.83 Impact Factor
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    • "Central cholinergic disturbances are present in many neuropsychiatric and neurodegenerative diseases. In various forms of dementia, such as Alzheimer's dementia (AD) or Lewy body dementia, cholinergic deficits in the brain [1] [2] are associated with cognitive decline [3] [4] [5] and are thought to precede clinical symptoms. "
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    ABSTRACT: Disturbances of the cerebral cholinergic neurotransmitter system are present in neurodegenerative disorders. SPECT or PET imaging, using radiotracers that selectively target muscarinic receptor subtypes, may be of value for in vivo evaluation of such conditions. 6β-acetoxynortropane, a potent muscarinic M2 receptor agonist, has previously demonstrated nanomolar affinity and high selectivity for this receptor. Based on this compound we synthesized four nortropane derivatives that are potentially suitable for SPECT imaging of the M2 receptor. 6β-acetoxynortropane and the novel derivatives were tested in vitro for affinity to the muscarinic M1−3 receptors. The original 6β-acetoxynortropane displayed high affinity (Ki = 70–90 nM) to M2 receptors and showed good selectivity ratios to the M1 (65-fold ratio) and the M3 (70-fold ratio) receptors. All new derivatives showed reduced affinity to the M2 subtype and loss of subtype selectivity. It is therefore concluded that the newly synthesized derivatives are not suitable for human SPECT imaging of M2 receptors.
    06/2011; 2011:709416. DOI:10.1155/2011/709416
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    • "There is evidence that already a slight deterioration of cognition may enhance the risk of conversion to dementia in PD [4] [5]. However, not all PD patients with such a cognitive profile develop dementia (PDD), and early identification of these patients with particularly increased risk is still not possible with sufficient accuracy [5] [6] [7]. Therefore, a lot of effort has been put on the identification of a clinical risk profile and especially in the characterization of mild cognitive deficits in patients who are later on developed dementia [8]. "
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    ABSTRACT: Comparable to Alzheimer's disease, mild cognitive impairment in Parkinson's disease (PD-MCI) is associated with an increased risk for dementia. However different definitions of PD-MCI may have varying predictive accuracy for dementia. In a cohort of 101 nondemented Parkinson patients who underwent neuropsychological testing, the frequency of PD-MCI subjects and PD-MCI subtypes (i.e., amnestic/nonamnestic) was determined by use of varying healthy population-based cut-off values. We also investigated the association between defined PD-MCI groups and ADL scales. Varying cut-off values for the definition of PD-MCI were found to affect frequency of PD-MCI subjects (9.9%-92.1%) and, maybe more important, lead to a "shift" of proportion of detected PD-MCI subtypes especially within the amnestic single-domain subtype. Models using a strict cut-off value were significantly associated with lower ADL scores. Thus, the use of defined cut-off values for the definition of PD-MCI is highly relevant for comparison purposes. Strict cut-off values may have a higher predictive value for dementia.
    05/2011; 2011:540843. DOI:10.4061/2011/540843
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