Dementia in Parkinson’s disease Author: Doctor Richard Dodel1, MD Creation date: November 2004 Scientific Editor: Professor Thomas Gasser 1Department of Neurology, Friedrich-Wilhelms-University Bonn, Sigmund-Freudstr. 25, 53105 Bonn. Germany. mailto:[email protected] Abstract Keywords Disease name/synonyms Definition /diagnostic criteria Differential diagnosis Etiology Clinical description Diagnostic methods Epidemiology Management References Abstract Parkinson's disease (PD) is one of the most common neurodegenerative movement disorder, which affects about 1% of the population over age 60. Although PD is often recognized as a motor disorder, there are several non-motor signs and symptoms that may cause a considerable burden to the patient. Especially neuropsychiatric symptoms such as depression, anxiety, cognitive impairment and psychosis may contribute to a reduced quality of life in PD patients. Dementia is common and affects approximately 40% of PD patients during the course of the disease. The risk for the development of dementia in PD patients is approximately 6 times higher than compared to non-PD age matched controls. The dementia associated with PD is characterized by a dysexecutive syndrome affecting mainly executive and visuospatial functions while memory is relatively preserved. In patients with Dementia with Lewy bodies (DLB), dementia is the central feature of the disease. The overlap of clinical symptoms between PDD and DLB suggest that they probably represent different points on a spectrum of lewy body diseases sharing similar underlying processes. Currently, only symptomatic treatment of cognitive impairment is available. Recently, several clinical trials using cholinesterase inhibitors have shown its efficacy in PDD and DLB patients. Keywords Dementia; Cholinesterase inhibitors; Parkinson’s disease; depression; cognition; neuropsychiatry; lewy bodies; lewy body dementia; Alzheimer’s disease Disease name/synonyms may cause a considerable burden to the Parkinson’s disease and Dementia (PDD) patient. Dementia is common and affects approximately 40% of PD patients during the Definition /diagnostic criteria course of the disease. Parkinson's disease (PD) is one of the most Parkinson’s disease dementia (PDD) and common neurodegenerative movement dementia with Lewy bodies (DLB) are two disorder, which affects about 1% of the common syndromes with overlapping clinical population over age 60. Although PD is often symptoms suggesting that they probably recognized as a motor disorder, there are represent different points on a spectrum of several non-motor signs and symptoms that lewy body disease (synucleinopathies) sharing Dodel R. Dementia in Parkinson’s disease. Orphanet Encyclopedia. November 2004. http://www.orpha.net/data/patho/GB/uk-PDD.pdf 1 similar underlying processes. Distinguishing Clinical description them as separate disorders may be useful in In the majority of the patients, cognitive clinical practice, but may be of limited value in impairment manifests subtly in the form of terms of investigating and treating the slowness of thinking (bradyphrenia) and word underlying neurobiology (McKeith and finding difficulties. This is usually not a Mosimann, 2004). Consensus guidelines for significant problem for the patient, as it does dementia with Lewy bodies (DLB) suggest that not hinder daily activities and responsabilities. PD patients, who develop dementia within 12 Dementia refers to cognitive impairment of months after the initial motor symptoms should sufficient magnitude to hinder daily activities. be diagnosed as DLB; if dementia occurs later The dementia associated with PD is in the course of the disease, patients should be characterized by a dysexecutive syndrome. diagnosed as PD with dementia rather than The changes in different cognitive domains DLB (McKeith et al., 1996). have been extensively assessed in several studies and described in detail in a recent Differential diagnosis review (Pillon et al., 2001). Fluctuating The diagnoses most likely to be confounded attention as seen in DLB patients is also a with PDD are DLB, Alzheimer’s disease, feature in PDD, but not in patients with PD vascular dementia, delirium and Creutzfeld- without dementia. The cognitive impairment in Jakob disease. Atypical parkinsonian PDD affects the following domains: syndromes, including progressive supranuclear • Impairment of executive functions palsy and corticobasal ganglionic (ability to plan, organize and perform degeneration, which also lead to cognitive goal-directed behavior) constitutes the impairment, must be considered in the core feature of neuropsychological differential diagnosis of PDD. Currently, there deficits. are no clinically applicable genetic or CSF • Visuospatial dysfunction has been markers to support the diagnosis. There are, reported in several studies, and is however, sufficient studies to conclude that more severe than that seen in AD neuroimaging investigations may be helpful in patients with similar dementia severity. supporting the diagnosis (see below). Visuospatial impairment affects all subcategories of visuospatial Etiology functioning without a specific pattern, In his original writings, James Parkinson except for spared visual sensory concluded that “the senses and intellect are abilities and visual recognition. uninjured” in PD. It is now known that changes • Instrumental functions, such as in cognitive function and behaviour occur language and praxis are mildly frequently and form an integral part of the impaired in PDD. Impaired verbal clinical presentation of PD. Although the fluency is the main feature and is more cognitive deficits of idiopathic Parkinson's severe than in AD. disease are now relatively well known, their • Memory functions are relatively neuropsychological and neurobiological basis preserved in PDD. Deficits in new are still discussed. Deficits in dopaminergic, information learning have been cholinergic and noradrenergic mechanisms reported, although they are less have been proposed as the basis of cognitive severe than in AD patients and impairment of PD (Pillon et al., 2003). In a perfomance on recognition tests are recent study, reduced fluorodopa uptake in the better than free recall. This finding caudate nucleus and frontal cortex was related suggests that new information is to impairment in neuropsychological tests stored but is not readily accessible. measuring verbal fluency, working memory, and attentional functioning (Ito et al., 2002). Diagnostic methods The nucleus basalis of Meynert, which Cerebrospinal fluid (Holmberg et al, 2003): degenerates in Alzheimer’s disease, is also cell count, protein content normal; oligoclonal severely affected in PDD (Whitehouse et al., bands negative. 1983), indicating the contribution of a cholinergic deficit to the cognitive impairment. Disease tau Ptau It is controversial whether Lewy bodies, which Aβ1-42 (181P) may be found in the cortex in advanced PDD and DLB, may correlate with the cognitive AD ↓ ↑ ↑ impairment (Hurtig et al., 2000). DLB ↓ n n PDD n n n Dodel R. Dementia in Parkinson’s disease. Orphanet Encyclopedia. November 2004. http://www.orpha.net/data/patho/GB/uk-PDD.pdf 2 Electroencephalogram Epidemiology No difference with AD patients (Barber et al., Cognitive deficits in PD patients are common, 2000). Temporal slow transients (DLB>AD) although they may be subtle. Dementia affects (Briel et al., 1999). a smaller proportion of PD patients, with a frequency variably reported to range from 2% Single Photon Emission Computed in early-onset cases to 81% in an unselected Tomography (SPECT) (Firbank et al., 2003) population. An analysis of 27 studies revealed In 99mcTc-HMPAO-SPECT studies, the an average frequency of 40% (Cummings, precuneus and inferior lateral parietal regions 1988). In cross-sectional studies prevalence showed a perfusion deficit in Parkinson's was reported to vary from 37% to 44% disease with dementia, similar to the pattern (Hobson et al., 1999). Prevalence in patients observed in DLB. In comparison, AD showed a below the age of 50 was 0% and 69% above perfusion deficit in the parietal region, in a the age of 80 years (Mayeux et al., 1992). The more anterior and inferior location than in PDD, risk for the development of dementia in PD involving the posterior cingulate as well as the patients is approximately 6 times higher than precuneus. compared to non-PD age-matched controls. FP-CIT SPECT (O'Brien et al., 2004) Management Significant reductions in FP-CIT binding The dementia in PD poses a significant occurred in the caudate and anterior and therapeutic challenge since these patients are posterior putamens in subjects with DLB quite sensitive to dopaminergic drugs, which compared with subjects with AD and controls. can precipitate confusion and hallucinations. Transporter loss in DLBs was of similar (Friedman et al., 2000). In PD patients who magnitude to that seen in PD, but with a flatter have become acutely confused and psychotic, rostrocaudal (caudate-putamen) gradient. intercurrent infection and subdural hematoma Good separation between DLBs and AD but should be excluded. Non-essential medications not among subjects with DLB, PD, and PD with capable of causing confusion should be dementia. discontinued. Antiparkinsonian medication should be reviewed and a gradual, graded 18F-dopa PET (Ito et al., 2002) withdrawal undertaken in the order of Compared with the normal group, the PDD anticholinergics, amantadine, selegiline, and group showed reduced 18F-dopa bilaterally