Prevalence and duration of non-motor symptoms in prodromal Parkinson's disease.

BACKGROUND AND PURPOSE: The prevalence and duration of non-motor symptoms (NMS) in prodromal Parkinson's disease (PD) has not been extensively studied. The aim of this study was to determine the prevalence and duration of prodromal NMS (pNMS) in a cohort of patients with recently diagnosed PD. METHODS: We evaluated the prevalence and duration of pNMS in patients with early PD (n = 154). NMS were screened for using the Non-Motor Symptom Questionnaire (NMSQuest). We subtracted the duration of the presence of each individual NMS reported from the duration of the earliest motor symptom. NMS whose duration preceded the duration of motor symptoms were considered a pNMS. Individual pNMS were then grouped into relevant pNMS clusters based on the NMSQuest domains. Motor subtypes were defined as tremor dominant, postural instability gait difficulty (PIGD) and indeterminate type according to the Movement Disorder Society Unified Parkinson's Disease Rating Scale revision. RESULTS: Prodromal NMS were experienced by 90.3% of patients with PD and the median number experienced was 4 (interquartile range, 2-7). A gender difference existed in the pNMS experienced, with males reporting more sexual dysfunction, forgetfulness and dream re-enactment, whereas females reported more unexplained weight change and anxiety. There was a significant association between any prodromal gastrointestinal symptoms [odds ratio (OR), 2.30; 95% confidence interval (CI), 1.08-4.89, P = 0.03] and urinary symptoms (OR, 2.54; 95% CI, 1.19-5.35, P = 0.016) and the PIGD phenotype. Further analysis revealed that total pNMS were not significantly associated with the PIGD phenotype (OR, 1.10; 95% CI, 0.99-1.21, P = 0.068). CONCLUSIONS: Prodromal NMS are common and a gender difference in pNMS experienced in prodromal PD may exist. The PIGD phenotype had a higher prevalence of prodromal gastrointestinal and urinary tract symptoms.

Cerebral glucose metabolism and cognition in newly diagnosed Parkinson's disease: ICICLE-PD study.

OBJECTIVE: To assess reductions of cerebral glucose metabolism in Parkinson's disease (PD) with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), and their associations with cognitive decline. METHODS: FDG-PET was performed on a cohort of 79 patients with newly diagnosed PD (mean disease duration 8 months) and 20 unrelated controls. PD participants were scanned while on their usual dopaminergic medication. Cognitive testing was performed at baseline, and after 18 months using the Cognitive Drug Research (CDR) and Cambridge Neuropsychological Test Automated Battery (CANTAB) computerised batteries, the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment (MoCA). We used statistical parametric mapping (SPM V.12) software to compare groups and investigate voxelwise correlations between FDG metabolism and cognitive score at baseline. Linear regression was used to evaluate how levels of cortical FDG metabolism were predictive of subsequent cognitive decline rated with the MMSE and MoCA. RESULTS: PD participants showed reduced glucose metabolism in the occipital and inferior parietal lobes relative to controls. Low performance on memory-based tasks was associated with reduced FDG metabolism in posterior parietal and temporal regions, while attentional performance was associated with more frontal deficits. Baseline parietal to cerebellum FDG metabolism ratios predicted MMSE (ß=0.38, p=0.001) and MoCA (ß=0.3, p=0.002) at 18 months controlling for baseline score. CONCLUSIONS: Reductions in cortical FDG metabolism were present in newly diagnosed PD, and correlated with performance on neuropsychological tests. A reduced baseline parietal metabolism is associated with risk of cognitive decline and may represent a potential biomarker for this state and the development of PD dementia.

Cognitive impairment in Parkinson's disease: impact on quality of life of carers.

BACKGROUND: The quality of life (QoL) of informal caregivers of people with Parkinson's disease (PD) (PwP) can be affected by the caring role. Because of cognitive symptoms and diminished activities of daily living, in addition to the management of motor symptoms, carers of PwP and cognitive impairment may experience increased levels of burden and poorer QoL compared with carers of PwP without cognitive impairment. This study aimed to investigate the impact of cognitive impairment in PD upon QoL of carers. METHODS: Approximately 36 months after diagnosis, 66 dyadic couples of PwP and carers completed assessments. PwP completed a schedule of neuropsychological assessments and QoL measures; carers of PwP completed demographic questionnaires and assessments of QoL. Factor scores of attention, memory/executive function and global cognition, as derived by principal component analysis, were used to evaluate cognitive domains. RESULTS: Hierarchical regression analysis found lower Montreal Cognitive Assessment was a significant independent predictor of poorer carer QoL, in addition to number of hours spent caregiving, carer depression and PD motor severity. Attentional deficits accounted for the largest proportion of variance of carer QoL. Carers of PwP and dementia (n = 9) had significantly poorer QoL scores compared with PwP and mild cognitive impairment (n = 18) or normal cognition (n = 39) carers (p < 0.01). CONCLUSIONS: Attentional deficits were the strongest predictor of carer QoL compared with other cognitive predictors. Carers for those with PD dementia reported the poorest QoL. Interventions such as respite or cognitive behavioural therapy to improve mood and self-efficacy in carers may improve carer QoL. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons, Ltd.

Anxiety and anxious-depression in Parkinson's disease over a 4-year period: a latent transition analysis.

BACKGROUND: Depression and anxiety in Parkinson's disease are common and frequently co-morbid, with significant impact on health outcome. Nevertheless, management is complex and often suboptimal. The existence of clinical subtypes would support stratified approaches in both research and treatment. METHOD: Five hundred and thirteen patients with Parkinson's disease were assessed annually for up to 4 years. Latent transition analysis (LTA) was used to identify classes that may conform to clinically meaningful subgroups, transitions between those classes over time, and baseline clinical and demographic features that predict common trajectories. RESULTS: In total, 64.1% of the sample remained in the study at year 4. LTA identified four classes, a 'Psychologically healthy' class (approximately 50%), and three classes associated with psychological distress: one with moderate anxiety alone (approximately 20%), and two with moderate levels of depression plus moderate or severe anxiety. Class membership tended to be stable across years, with only about 15% of individuals transitioning between the healthy class and one of the distress classes. Stable distress was predicted by higher baseline depression and psychiatric history and younger age of onset of Parkinson's disease. Those with younger age of onset were also more likely to become distressed over the course of the study. CONCLUSIONS: Psychopathology was characterized by relatively stable anxiety or anxious-depression over the 4-year period. Anxiety, with or without depression, appears to be the prominent psychopathological phenotype in Parkinson's disease suggesting a pressing need to understanding its mechanisms and improve management.

Olfaction in Parkin single and compound heterozygotes in a cohort of young onset Parkinson's disease patients.

BACKGROUND: Parkin related Parkinson's disease (PD) is differentiated from idiopathic PD by absent or sparse Lewy bodies, and preserved olfaction. The significance of single Parkin mutations in the pathogenesis of PD is debated. OBJECTIVES: To assess olfaction results according to Parkin mutation status. To compare the prevalence of Parkin single heterozygous mutations in patients diagnosed with PD to the rate in healthy controls in order to establish whether these single mutations could be a risk factor for developing PD. METHODS: Parkin gene mutation testing was performed in young onset PD (diagnosed <50 years old) to identify three groups: Parkin homozygous or compound heterozygote mutation carriers, Parkin single heterozygote mutation carriers, and non-carriers of Parkin mutations. Olfaction was tested using the 40-item British version of the University of Pennsylvania smell identification test (UPSIT). RESULTS: Of 344 young onset PD cases tested, 8 (2.3%) were Parkin compound heterozygotes and 13 (3.8%) were Parkin single heterozygotes. Olfaction results were available in 282 cases (eight compound heterozygotes, nine single heterozygotes, and 265 non-carriers). In Parkin compound heterozygotes, the median UPSIT score was 33, interquartile range (IQR) 28.5-36.5, which was significantly better than in single Parkin heterozygotes (median 19, IQR 18-28) and non-carriers (median score 22, IQR 16-28) (ANOVA P < 0.001). These differences persisted after adjusting for age, disease duration, gender, and smoking (P < 0.001). There was no significant difference in UPSIT scores between single heterozygotes and non-carriers (P = 0.90). CONCLUSIONS: Patients with Parkin compound heterozygous mutations have relatively preserved olfaction compared to Parkin single heterozygotes and non-carriers. The prevalence of Parkin single heterozygosity is similar to the 3.7% rate reported in healthy controls.

EFNS/MDS-ES/ENS [corrected] recommendations for the diagnosis of Parkinson's disease.

BACKGROUND: A Task Force was convened by the EFNS/MDS-ES Scientist Panel on Parkinson's disease (PD) and other movement disorders to systemically review relevant publications on the diagnosis of PD. METHODS: Following the EFNS instruction for the preparation of neurological diagnostic guidelines, recommendation levels have been generated for diagnostic criteria and investigations. RESULTS: For the clinical diagnosis, we recommend the use of the Queen Square Brain Bank criteria (Level B). Genetic testing for specific mutations is recommended on an individual basis (Level B), taking into account specific features (i.e. family history and age of onset). We recommend olfactory testing to differentiate PD from other parkinsonian disorders including recessive forms (Level A). Screening for pre-motor PD with olfactory testing requires additional tests due to limited specificity. Drug challenge tests are not recommended for the diagnosis in de novo parkinsonian patients. There is an insufficient evidence to support their role in the differential diagnosis between PD and other parkinsonian syndromes. We recommend an assessment of cognition and a screening for REM sleep behaviour disorder, psychotic manifestations and severe depression in the initial evaluation of suspected PD cases (Level A). Transcranial sonography is recommended for the differentiation of PD from atypical and secondary parkinsonian disorders (Level A), for the early diagnosis of PD and in the detection of subjects at risk for PD (Level A), although the technique is so far not universally used and requires some expertise. Because specificity of TCS for the development of PD is limited, TCS should be used in conjunction with other screening tests. Conventional magnetic resonance imaging and diffusion-weighted imaging at 1.5 T are recommended as neuroimaging tools that can support a diagnosis of multiple system atrophy (MSA) or progressive supranuclear palsy versus PD on the basis of regional atrophy and signal change as well as diffusivity patterns (Level A). DaTscan SPECT is registered in Europe and the United States for the differential diagnosis between degenerative parkinsonisms and essential tremor (Level A). More specifically, DaTscan is indicated in the presence of significant diagnostic uncertainty such as parkinsonism associated with neuroleptic exposure and atypical tremor manifestations such as isolated unilateral postural tremor. Studies of [(123) I]MIBG/SPECT cardiac uptake may be used to identify patients with PD versus controls and MSA patients (Level A). All other SPECT imaging studies do not fulfil registration standards and cannot be recommended for routine clinical use. At the moment, no conclusion can be drawn as to diagnostic efficacy of autonomic function tests, neurophysiological tests and positron emission tomography imaging in PD. CONCLUSIONS: The diagnosis of PD is still largely based on the correct identification of its clinical features. Selected investigations (genetic, olfactory, and neuroimaging studies) have an ancillary role in confirming the diagnosis, and some of them could be possibly used in the near future to identify subjects in a pre-symptomatic phase of the disease.

Frequency, prevalence, incidence and risk factors associated with visual hallucinations in a sample of patients with Parkinson's disease: a longitudinal 4-year study.

OBJECTIVE: To examine the prevalence, incidence and risk factors associated with visual hallucinations (VHs) amongst people suffering from Parkinson's disease (PD). METHODS: We recruited 513 patients with PD from movement disorder and PD clinics within three sites in the UK. Patients were interviewed using a series of standardised clinical rating scales at baseline, 12, 24 and 36 months. Data relating to VHs were collected using the North-East Visual Hallucinations Interview. Prevalence rates for VHs at each assessment were recorded. Associations were determined using multiple regression analysis. RESULTS: Cross-sectional prevalence rates for VHs at baseline, 12, 24 and 36 months indicated VHs in approximately 50% of patients. A cumulative frequency of 82.7% of cases at the end of the study period exhibited VHs. The incidence rate for VHs was 457 cases per 1000 population. Longer disease duration, greater impairment in activities of daily living and higher rates of anxiety were most commonly associated with VHs. No factors predictive of VHs could be ascertained. CONCLUSIONS: When examined longitudinally, VHs affect more patients than is commonly assumed in cross-sectional prevalence studies. Clinicians should routinely screen for VHs throughout the disease course. Disease duration, impairment in activities of daily living and anxiety presented as co-morbidities associated with VHs in PD, and therefore those presenting with VHs should be screened for anxiety disorder and vice versa.

Coping in Parkinson's disease: an examination of the coping inventory for stressful situations.

BACKGROUND: Parkinson's disease (PD) brings with it a range of stresses and challenges with which a patient must cope. The type of coping strategies employed can impact upon well-being, although findings from coping studies in PD remain inconsistent. The variety of coping scales used without validation in PD has been cited as a possible cause of this inconsistency. The present study sought to examine the validity of the coping inventory for stressful situations (CISS) in a sample of patients with PD. METHODS: Five hundred and twenty-five patients with PD were recruited as part of a longitudinal investigation of mood states in PD. Four hundred and seventy-one participants completed the CISS. Confirmatory factor analysis was used to explore the structural validity of the scale. Internal reliability, test-retest reliability, convergent validity and discriminant validity were assessed using Cronbach's alpha, intraclass correlations and Pearson's correlations. RESULTS: Both three and four factor solutions were examined. The four factor model was found to provide a better fit of the data than the three factor model. The internal reliability, discriminant validity, convergent validity, and test-retest reliability of the CISS scales were shown to be good. Use of emotion-focused coping was associated with greater depression and anxiety whilst, task-oriented coping was associated with better psychological well-being. CONCLUSION: The results provide support for the validity and reliability of the CISS as a measure of coping in patients with PD. Further research into the relationship between coping and well-being is warranted. The identification of helpful and unhelpful coping strategies may guide the development of evidence-based therapies to improve well-being in patients with PD.

Trajectories of pain over 6 years in early Parkinson's disease: ICICLE-PD.

INTRODUCTION: Pain is a common non-motor symptom in Parkinson's disease (PD), affecting up to 85% of patients. The frequency and stability of pain over time has not been extensively studied. There is a paucity of high-quality studies investigating pain management in PD. To develop interventions, an understanding of how pain changes over the disease course is required. METHODS: One hundred and fifty-four participants with early PD and 99 age-and-sex-matched controls were recruited as part of a longitudinal study (Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in PD, ICICLE-PD). Pain data were collected at 18-month intervals over 72 months in both groups using the Nonmotor Symptom Questionnaire (NMSQ), consisting of a binary yes/no response. Two questions from the Parkinson's Disease Questionnaire (PDQ-39) were analysed for the PD group only. RESULTS: Unexplained pain was common in the PD group and occurred more frequently than in age-matched controls. 'Aches and pains' occurred more frequently than 'cramps and muscle spasms' at each time point (p < 0.001) except 54 months. CONCLUSIONS: This study shows that pain is prevalent even in the early stages of PD, yet the frequency and type of pain fluctuates as symptoms progress. People with PD should be asked about their pain at clinical consultations and given support with describing pain given the different ways this can present.

Progression of Neuropsychiatric Symptoms over Time in an Incident Parkinson's Disease Cohort (ICICLE-PD).

BACKGROUND: Cross-sectional studies have identified that the prevalence of neuropsychiatric symptoms (NPS) in Parkinson's disease (PD) ranges from 70-89%. However, there are few longitudinal studies determining the impact of NPS on quality of life (QoL) in PD patients and their caregivers. We seek to determine the progression of NPS in early PD. METHODS: Newly diagnosed idiopathic PD cases (n = 212) and age-matched controls (n = 99) were recruited into a longitudinal study. NPS were assessed using the Neuropsychiatric Inventory with Caregiver Distress scale (NPI-D). Further neuropsychological and clinical assessments were completed by participants, with reassessment at 18 and 36 months. Linear mixed-effects modelling determined factors associated with NPI-D and QoL over 36 months. RESULTS: Depression, anxiety, apathy and hallucinations were more frequent in PD than controls at all time points (p < 0.05). Higher motor severity at baseline was associated with worsening NPI-D scores over time (ß = 0.1, p < 0.05), but not cognition. A higher NPI total score was associated with poorer QoL at any time point (ß = 0.3, p < 0.001), but not changed in QoL scores. CONCLUSION: NPS are significantly associated with poorer QoL, even in early PD. Screening for NPS from diagnosis may allow efficient delivery of better support and treatment to patients and their families.

Swallowing problems in Parkinson disease: frequency and clinical correlates.

BACKGROUND: Changes to the efficiency and integrity of swallowing mechanisms are inevitable in Parkinson disease (PD); however, it remains unclear how many people with PD are at risk of dysphagia. The aim of this study was to establish the frequency of impaired swallowing in people with PD and the relationship between swallowing performance and indicators of disease progression. METHODS: A community-based and hospital-based cohort of 137 individuals with PD were asked to drink 150 ml of water as quickly as possible while in an 'off drug' state. RESULTS: Thirty-one (23%) patients could not completely drink the full 150 ml. Swallowing rate (ml/sec) fell to more than 1 SD below published norms for 115 (84%) patients and to more than 2SD below for 44 (32%) individuals. There were moderate correlations between rate of swallowing and disease severity, depression and cognition, but not between swallowing speed and disease duration. There was poor correlation between subjective reports of dysphagia and performance on the water swallow test. CONCLUSIONS: Swallowing problems are frequent in PD. Self-report of 'no difficulty' is not a reliable indicator of swallowing ability. Studies employing more-objective assessment of aspiration risk to compare with water swallow test performance are advocated.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Impaired attention predicts falling in Parkinson's disease.

BACKGROUND: Cognitive deficits, in particular deficits of attention and executive function, may affect postural sway and balance in Parkinson's disease (PD). Our objective was to determine whether measures of attention were associated with falls in a large cohort of subjects with PD studied prospectively. METHODS: Patients meeting UK PD Society Brain Bank Criteria were included. Assessment included UPDRS III and the Cognitive Drug Research computerised assessment battery (CDR) from which Power of Attention, Continuity of Attention, cognitive reaction time and reaction time variability were derived. Falls were assessed prospectively using monthly fall diaries returned over a year following baseline assessment. RESULTS: One hundred and sixty four subjects completed fall diary datasets. One hundred and three (63%) fell one or more times during the 12 month period. Regression analysis revealed an association of fall frequency with poorer Power of Attention and increased reaction time variability, which was retained after correcting for UPDRS scores. CONCLUSIONS: Reduced power of attention and increased reaction time variability are associated with increased fall frequency in PD. This has implications for the identification of those most at risk of falling, and for the management and prevention of falls in this patient group.

Poor attentional function predicts cognitive decline in patients with non-demented Parkinson's disease independent of motor phenotype.

BACKGROUND: Postural instability gait difficulty (PIGD) motor phenotype in Parkinson's disease (PD) is associated with a faster rate of cognitive decline than in tremor dominant cases and may be a risk factor for incident dementia. People with PD display attentional deficits; however, it is not clear whether attentional deficits in patients with non-demented PD are associated with (i) PIGD phenotype and/or (ii) subsequent cognitive decline. AIMS: (i) To examine rates of cognitive decline (Mini-Mental State Examination (MMSE) and Cambridge Cognitive Examination (CAMCOG)) over 3 years in subjects with non-demented PD aged over 65 years, (ii) using Cognitive Drug Research computerised assessment test battery, determine the rate of change in power of attention (PoA) scores over time (sum of mean choice reaction time, simple reaction time and digit vigilance reaction time scores), (iii) determine whether the PIGD phenotype is associated with changes in PoA and (iv) establish whether baseline PoA is associated with subsequent cognitive decline. RESULTS: 14 subjects (38%) were classified as PIGD motor phenotype at baseline. Cognitive decline was greater in PIGD compared with non-PIGD subjects (p < or = 0.02). PIGD phenotype was not associated with baseline PoA score although it was associated with subsequent worsening in PoA (mean PoA increase/year: non-PIGD subjects 11.4 ms; PIGD subjects 244.0 ms; p = 0.01). Higher baseline PoA scores were associated with greater cognitive decline (MMSE, p = 0.03; CAMCOG, p = 0.05) independent of PIGD status. CONCLUSION: PIGD phenotype and attention deficits are independently associated with a greater rate of cognitive decline in patients with non-demented PD. We propose that subtle attentional deficits in patients with non-demented PD predict subsequent cognitive impairment.

The basal ganglia cholinergic neurochemistry of progressive supranuclear palsy and other neurodegenerative diseases.

BACKGROUND: Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disorder involving motor and cognitive dysfunction. Currently, there is no effective treatment either for symptomatic relief or disease modification. This relates, in part, to a lack of knowledge of the underlying neurochemical abnormalities, including cholinergic receptor status in the basal ganglia. AIM: To measure muscarinic M2 and M4 receptors in the basal ganglia in PSP. METHODS: The muscarinic M2 (presynaptic) and M4 (postsynaptic) receptors in the striatum, pallidum and adjacent insular cortex were autoradiographically measured in pathologically confirmed cases of PSP (n = 18), and compared with cases of Lewy body dementias (LBDs; n = 45), Alzheimer's disease (AD; n = 39) and controls (n = 50). RESULTS: In cases of PSP, there was a reduction in M2 and M4 receptors in the posterior caudate and putamen compared to controls, but no significant changes in the pallidum. Cases with AD showed lower M2 receptors in the posterior striatum. Groups with LBD and AD showed higher M2 binding in the insular cortex compared with controls. CONCLUSIONS: The results suggest loss of posterior striatal cholinergic interneurones in PSP, and reduction in medium spiny projection neurones bearing M4 receptors. These results should be taken in the context of more widespread pathology in PSP, but may have implications for future trials of cholinergic treatments.

A multicentre longitudinal observational study of changes in self reported health status in people with Parkinson's disease left untreated at diagnosis.

BACKGROUND: The issue of when to start treatment in Parkinson's disease (PD) remains controversial. Some favour treatment at diagnosis while others opt for a "wait and watch" policy. The effect of the latter policy on the self reported health status of people with PD is unknown. AIMS: To record self reported health status through longitudinal use of a validated PD specific questionnaire (PDQ-39) in untreated PD patients in multiple centres in the UK. To compare patients who were left untreated with those who were offered treatment during follow-up. METHODS: A multicentre, prospective, "real life" observational audit based study addressing patient reported outcomes in relation to self reported health status and other sociodemographic details. RESULTS: 198 untreated PD were assessed over a mean period of 18 months. During two follow-up assessments, the self reported health status scores in all eight domains of the PDQ-39 and the overall PDQ-39 summary index worsened significantly (p<0.01) in patients left untreated. In a comparative group in whom treatment was initiated at or soon after diagnosis, there was a trend towards improvement in self reported health status scores after treatment was started. CONCLUSIONS: This study addresses for the first time self reported health status, an indicator of health related quality of life, in untreated PD. The findings may strengthen the call for re-evaluation of the policy to delay treatment in newly diagnosed patients with PD.

Effect of levodopa on cognitive function in Parkinson's disease with and without dementia and dementia with Lewy bodies.

BACKGROUND: Levodopa (L-dopa) is the gold standard treatment for Parkinson's disease, but a lack of clear efficacy combined with a perceived liability to neuropsychiatric side effects has limited L-dopa use in patients with parkinsonism and dementia. Therefore, the effect of L-dopa on the cognitive profile of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unclear. AIM: To ascertain the acute and long-term effects of L-dopa on aspects of attention and cognition in patients with DLB and PDD, and to compare these with the effects in Parkinson's disease. METHOD: Baseline cognitive and motor function was assessed off L-dopa in patients with Parkinson's disease (n = 22), PDD (n = 27) and DLB (n = 11) using standard "bedside" measures and a computerised programme detecting reaction times and accuracy. All patients then underwent an acute L-dopa challenge with subsequent subjective and objective analysis of alertness, verbal recall, reaction times and accuracy. The same parameters were measured after 3 months on L-dopa to assess the prolonged effect. RESULTS: Acute L-dopa challenge considerably improved motor function and subjective alertness in all patients without compromising either reaction times or accuracy, but increased fluctuations were noted in both groups with dementia. Neuropsychiatric scores improved in patients with Parkinson's disease both with and without dementia on L-dopa at 3 months. Although patients with Parkinson's disease also had better mean global cognitive function at this time, mean verbal attention and memory deteriorated, and patients with PDD had slower reaction times in some tests. No patient had a marked deterioration over this time. Patients with DLB did not experience any adverse cognitive or neuropsychiatric effects after 3 months of L-dopa treatment. CONCLUSION: The use of L-dopa in patients with parkinsonism with dementia does not adversely affect cognitive function.

Parkinson's disease dementia: what's in a Lewy body?

This brief review deals with pathological aspects of dementia associated with Parkinson's disease (PDD). PDD has been variably linked with cortical Lewy body topography and density. alpha-Synuclein and Alzheimer-type pathology frequently co-exist, suggesting that a combination of pathology related to protein dysmetabolism, possibly with synergistic protein-protein interaction, underpins the cognitive impairment in PDD. Dementia may therefore ensue when a "toxic threshold" is reached, irrespective of the combination of pathologies involved in reaching that threshold. The nature of this putative protein-protein interaction needs to be further elucidated, and also whether there are specific clinical correlates of the pathological substrate. Serum and cerebrospinal fluid proteins or imaging techniques may be useful in future as biomarkers to identify the relative contribution of Lewy-related and Alzheimer-type pathology in a given case of PDD and to inform the rational use of drugs that can reduce alpha-synuclein aggregation and beta-amyloid production.

Cholinergic systems in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a progressive neurodegenerative disease characterized by akinetic-rigid features, falls, a supranuclear gaze palsy and subcortical dementia. Pathologically, there is abnormal accumulation of tau protein. Cholinergic deficits are thought to underlie the postural instability and cognitive impairment of PSP, but trials of cholinergic agonists and cholinesterase inhibitors have failed to show improvement in motor function, quality of life and cognitive impairment. The five cortico-basal ganglia loops, linking functionally related areas of the brain, are damaged in PSP, leading to specific clinical deficits. Cholinergic dysfunction is related to loss of cholinergic interneurons in the striatum, compounded by reduced inputs into the circuits from other cholinergic nuclei, such as the pedunculopontine nucleus and nucleus basalis of Meynert. Normal cholinergic transmission requires the presence of intact cholinergic neurons capable of releasing sufficient acetylcholine, and functional muscarinic and nicotinic receptors. Whilst there is evidence from autopsy and in vivo studies of loss of cholinergic neurons in PSP, the receptor status is unknown. This may be critical to understanding the basis for the poor therapeutic response to cholinomimetics. Symptomatic treatment using cholinergic drugs may thus be improved by more specific targeting of cholinergic receptors or nuclei. There is also evidence that cholinergic agents may have disease-modifying effects. This article reviews the key clinical features of PSP, along with normal basal ganglia anatomy and cholinergic transmission. Cholinergic deficits based on clinical and neurochemical parameters are then discussed, before concluding with suggested future directions for cholinergic treatments.

Exome sequencing in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE ɛ4 allele increased the risk of disease (P=0.0001), conferred a shorter disease duration (P=0.043) and earlier age of death (P=0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE ɛ4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.