For personal use. Only reproduce with permission The Lancet Publishing Group. 456 Reflection & Reaction Neurology Vol 3 August 2004 http://neurology.thelancet.com Dementia in Parkinson’s disease: common and treatable If James Parkinson could travel through time to the 21st century to revise his 1817 monograph on the shaking palsy, 1 my bet is that one of his first changes would be to the often quoted line about “the senses and intellect being uninjured”. We now recognise that cognitive and behavioural symptoms are common in Parkinson’s disease (PD) and are major determinants of patients’ and carers’ distress, often leading to institutionalisation. The organisers of the Movement Disorder Society’s (MDS) Eighth International Conference held from June 14–17 in Rome, Italy, are to be congratulated for emphasising cognitive decline and dementia in PD in their programme. Two platform presentations and many posters drew attention to long-term follow-up studies, which showed that 60–80% of people with PD will develop dementia, typically after 10–15 years of motor disability. 2 This prevalence is much higher than the 20–40% previously derived from cross-sectional surveys of movement-disorder clinic populations. Older age, older age at onset of PD, duration of motor symptoms, akinetic-gait rigidity profile, early hallucinations, and depression are recognised now as predictive factors. 3 The neurobiological basis of PD dementia (PDD) is unknown but atrophy of hippocampus and occipitoparietal cortex can be seen on MRI and severe cholinergic depletion detected in brain-stem nuclei, basal forebrain, thalamus, and cortex at post mortem. The co-occurrence of PD, PDD, and dementia with Lewy bodies within families with a-synuclein gene abnormalities 4 strengthens the case for a unified view of these three clinical presentations as part of a single disease spectrum. 5 It does not support the idea that Alzheimer’s disease (AD) is the major pathological cause of PDD; new studies show associations between the severity of cognitive impairment and -synuclein pathology including cortical Lewy-body and Lewy-neurite densities. 6 Two important steps towards improving our management of PDD were made at the Rome meeting. The first was the establishment of an MDS Task Force to define the concept of dementia in PD, develop criteria and methods for clinical diagnosis, and produce guidance on clinical management. None of these tasks will be easy. Current descriptions of “dementia syndrome”, such as those in the Diagnostic and Statistical Manual of Mental Disorders-IV and International Statistical Classification of Diseases-10, have been heavily influenced by the characteristic features of AD. Impaired episodic memory is a necessary symptom and impairment in activities of daily living defines the severity at which dementia can be diagnosed. However, in PDD, the initial impairment typically involves attention, executive functions, and visuospatial performance, with only mild impairment in memory retrieval. And it can be hard to judge the extent to which functional impairment is attributable to cognitive dysfunction rather than motor disability. Inability to manage one’s social or financial affairs may be a reasonable point to diagnose early AD, but not in a person with PD who is unable to do these functions because of impaired mobility or severe dysphonia. Therefore substantial changes to our current concept of the dementia syndrome may be needed before clinicians have an operational system for its assessment and diagnosis in people with PD. Major changes in clinical practice are often the result of a new treatment, so another important event in Rome was the presentation of the results of the first large-scale cholinesterase-inhibitor treatment study in PDD. Benefits in cognitive function, behavioural symptoms, and global performance were shown in a 24 week randomised, multi-centre, double-blind, placebo- controlled, parallel-group study assessing the efficacy, tolerability, and safety of 3–12 mg of rivastigmine in 541 people with PDD. As with earlier open-label case series and small placebo-controlled studies with cholinesterase-inhibitors—including tacrine, donepezil, rivastigmine, and galantamine—clinically and statistically significant improvements were evident, without worsening of extrapyramidal motor symptoms. 7,8,9 Clinicians with experience of the use of cholinesterase- inhibitors in PDD and particularly in dementia with Lewy bodies 10 report substantial improvements in apathy, anxiety, hallucinations, and sleep disorders in some patients. Now we must determine which of these patients respond best to cholinergic enhancement, and at what stage of illness cholinesterase-inhibitor treatment should be offered. New definitions of PDD and further clinical trials seem ready to transform a neglected area of practice into one in which substantial gains will be possible. Injury to the senses and intellect will continue to occur in PD until we develop disease-modifying treatments. In the meantime, however, we should detect and reduce the effects of such injury with the symptomatic treatments that are available. I think James Parkinson would agree. Ian McKeith Professor of Old Age Psychiatry, Wolfson Research Centre, Newcastle General Hospital, Newcastle upon Tyne, UK. Email i.g.mckeith@ncl.ac.uk Conflict of interest I have received consultancy fees, travel grants and research funding from several pharmaceutical companies manufacturing cholinesterase inhibitors including Novartis. I have no conflict of interest relating to the rivastigmine PDD study described here. I am a co-chair of the MDS Task Force on PDD. References 1 Parkinson J. An essay on the shaking palsy. London: Sherwood, Neely and Jones, 1817. 2 Aarsland D, Andersen K, Larsen JP, Lolk A, Kragh-Sorensen P. Prevalence and characteristics of dementia in Parkinson disease—an 8-year prospective study. Arch Neurol 2003; 60: 387–92. 3 Emre M. Dementia associated with Parkinson's disease. Lancet Neurol 2003; 2: 229–37. 4 Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 2004; 55: 164–73. 5 McKeith IG, Burn D. Spectrum of Parkinson’s disease, Parkinson’s dementia, and Lewy body dementia. In: DeKosky ST, ed. Neurologic clinics. Philadelphia: WB Sauders Company, 2000: 865–83. 6 Gómez-Tortosa E, Newell K, Irizarry MC, Albert M, Growdon JH, Hyman BT. Clinical and quantitative pathological correlates of dementia with Lewy bodies. Neurology 1999; 53: 1284–91. 7 Reading PJ, Luce AK, McKeith IG. Rivastigmine in the treatment of parkinsonian psychosis and cognitive impairment. Mov Disord 2001; 16: 1171–74. 8 Aarsland D. Donepezil for cognitive impairment in Parkinson’s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2002; 72: 708–12. 9 Aarsland D. Donepezil for cognitive impairment in Parkinson’s disease: a randomised controlled study. J Neurol Neurosurg Psychiatry 2002; 73: 354. 10 McKeith I, Del-Ser T, Spano PF, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study. Lancet 2000; 356: 2031–36.