Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson's disease dementia and cognitive impairment in Parkinson's disease

Background - Previous Cochrane reviews have considered the use of cholinesterase inhibitors in both Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB). The clinical features of DLB and PDD have much in common and are distinguished primarily on the basis of whether or not parkinsonism precedes dementia by more than a year. Patients with both conditions have particularly severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using cholinesterase inhibitors may lead to clinical improvement. Objectives - To assess the efficacy, safety and tolerability of cholinesterase inhibitors in dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and cognitive impairment in Parkinson’s disease falling short of dementia (CIND-PD) (considered as separate phenomena and also grouped together as Lewy body disease). Search methods - The trials were identified from a search of ALOIS, the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group (on 30 August 2011) using the search terms Lewy, Parkinson, PDD, DLB, LBD. This register consists of records from major healthcare databases (MEDLINE, EMBASE, PsycINFO, CINAHL) and many ongoing trial databases and is updated regularly. Reference lists of relevant studies were searched for additional trials. Selection criteria - Randomised, double-blind, placebo-controlled trials assessing the efficacy of treatment with cholinesterase inhibitors in DLB, PDD and cognitive impairment in Parkinson’s disease (CIND-PD). Data collection and analysis - Data were extracted from published reports by one review author (MR). The data for each 'condition' (that is DLB, PDD or CIND-PD) were considered separately and, where possible, also pooled together. Statistical analysis was conducted using Review Manager version 5.0. Main results - Six trials met the inclusion criteria for this review, in which a total of 1236 participants were randomised. Four of the trials were of a parallel group design and two cross-over trials were included. Four of the trials included participants with a diagnosis of Parkinson's disease with dementia (Aarsland 2002a; Dubois 2007; Emre 2004; Ravina 2005), of which Dubois 2007 remains unpublished. Leroi 2004 included patients with cognitive impairment and Parkinson's disease (both with and without dementia). Patients with dementia with Lewy bodies (DLB) were included in only one of the trials (McKeith 2000). For global assessment, three trials comparing cholinesterase inhibitor treatment to placebo in PDD (Aarsland 2002a; Emre 2004; Ravina 2005) reported a difference in the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) score of -0.38, favouring the cholinesterase inhibitors (95% CI -0.56 to -0.24, P < 0.0001). For cognitive function, a pooled estimate of the effect of cholinesterase inhibitors on cognitive function measures was consistent with the presence of a therapeutic benefit (standardised mean difference (SMD) -0.34, 95% CI -0.46 to -0.23, P < 0.00001). There was evidence of a positive effect of cholinesterase inhibitors on the Mini-Mental State Examination (MMSE) in patients with PDD (WMD 1.09, 95% CI 0.45 to 1.73, P = 0.0008) and in the single PDD and CIND-PD trial (WMD 1.05, 95% CI 0.42 to 1.68, P = 0.01) but not in the single DLB trial. For behavioural disturbance, analysis of the pooled continuous data relating to behavioural disturbance rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.36 to -0.04, P = 0.01). For activities of daily living, combined data for the ADCS and the Unified Parkinson's Disease Rating Scale (UPDRS) activities of daily living rating scales favoured treatment with cholinesterase inhibitors (SMD -0.20, 95% CI -0.38 to -0.02, P = 0.03). For safety and tolerability, those taking a cholinesterase inhibitor were more likely to experience an adverse event (318/452 versus 668/842; odds ratio (OR) 1.64, 95% CI 1.26 to 2.15, P = 0.0003) and to drop out (128/465 versus 45/279; OR 1.94, 95% CI 1.33 to 2.84, P = 0.0006). Adverse events were more common amongst those taking rivastigmine (357/421 versus 173/240; OR 2.28, 95% CI 1.53 to 3.38, P < 0.0001) but not those taking donepezil (311/421 versus 145/212; OR 1.24, 95% CI 0.86 to 1.80, P = 0.25). Parkinsonian symptoms in particular tremor (64/739 versus 12/352; OR 2.71, 95% CI 1.44 to 5.09, P = 0.002), but not falls (P = 0.39), were reported more commonly in the treatment group but this did not have a significant impact on the UPDRS (total and motor) scores (P = 0.71). Fewer deaths occurred in the treatment group than in the placebo group (4/465 versus 9/279; OR 0.28, 95% CI 0.09 to 0.84, P = 0.03). Authors' conclusions - The currently available evidence supports the use of cholinesterase inhibitors in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remains unclear. There is no current disaggregated evidence to support their use in CIND-PD.

Utilidad del [99m] Tc TRODAT-1 en el diagnóstico de la Enfermedad de Parkinson: revisión sistemática de la literatura

Propósito de la revisión: la enfermedad de Parkinson (EP) es un trastorno degenerativo caracterizado clínicamente por presentar temblor en reposo, rigidez y bradicinesia. El propósito es determinar la utilidad de la molécula TRODAT-1 en el diagnóstico de la EP. Metodología: se realizó una búsqueda en las bases de datos: PUBMED, COCHRANE, MEDLINE, LILACS y SCIELO en un período de 10 años desde enero de 1998 a enero de 2008. Se obtuvieron 26 artículos, estos se analizaron y se seleccionaron 10 artículos, de los cuales sólo 6 respondían a las necesidades del estudio, de acuerdo a los criterios de inclusión. De los 6 artículos analizados, 4 fueron clasificados como evidencia grado (+) y los 2 restantes evidencia grado (-) de acuerdo con las guías NICE. Todos los artículos revisados reportan una disminución importante en la captación del TRODAT-1 a nivel estriatal, su utilidad en el diagnóstico de EP en estadios tempranos, bajo costo y seguridad. Sólo tres reportan valores de sensibilidad y especificidad, pero su nivel de calidad no permite hacer una comparación de los mismos. Conclusiones: se propone realizar estudios de prueba diagnóstica comparados con el diagnóstico clínico de la enfermedad, que tengan un acuerdo en la forma de plantear las mediciones semicuantitativas de las unidades de captación utilizando las mismas fórmulas para hacerlos comparables.

Characteristics of visual hallucinations in Parkinson disease dementia and dementia with Lewy bodies

OBJECTIVE Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) have overlapping clinical and pathologic features. Recurrent visual hallucinations (RVH) are common in both disorders. The authors have compared details of hallucination characteristics and associated neuropsychiatric features in DLB and PDD. METHODS This is a descriptive, cross-sectional study using the Institute of Psychiatry Visual Hallucinations Interview (IP-VHI) to explore self-reported frequency, duration, and phenomenology of RVH in PDD and DLB. The caregivers' ratings of hallucinations and other neuropsychiatric features were elicited with the Neuropsychiatric Inventory (NPI). RESULTS Fifty-six patients (35 PDD; 21 DLB) with RVH were assessed. Hallucination characteristics were similar in both disorders. Simple hallucinations were rare. Most patients experienced complex hallucinations daily, normally lasting minutes. They commonly saw people or animals and the experiences were usually perceived as unpleasant. NPI anxiety scores were higher in PDD. Neuropsychiatric symptoms coexisting with hallucinations were apathy, sleep disturbance, and anxiety. CONCLUSIONS Patients with mild to moderate dementia can provide detailed information about their hallucinations. Characteristics of RVH were similar in PDD and DLB, and phenomenology suggests the involvement of dorsal and ventral visual pathways in their generation. The coexistence of RVH with anxiety, apathy, and sleep disturbance is likely to impair patients' quality of life and may have treatment implications.

Saccadic eye movement changes in Parkinson's disease dementia and dementia with Lewy bodies.

Neurodegeneration in Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) affect cortical and subcortical networks involved in saccade generation. We therefore expected impairments in saccade performance in both disorders. In order to improve the pathophysiological understanding and to investigate the usefulness of saccades for differential diagnosis, saccades were tested in age- and education-matched patients with PDD (n = 20) and DLB (n = 20), Alzheimer's disease (n = 22) and Parkinson's disease (n = 24), and controls (n = 24). Reflexive (gap, overlap) and complex saccades (prediction, decision and antisaccade) were tested with electro-oculography. PDD and DLB patients had similar impairment in all tasks (P > 0.05, not significant). Compared with controls, they were impaired in both reflexive saccade execution (gap and overlap latencies, P < 0.0001; gains, P < 0.004) and complex saccade performance (target prediction, P < 0.0001; error decisions, P < 0.003; error antisaccades: P < 0.0001). Patients with Alzheimer's disease were only impaired in complex saccade performance (Alzheimer's disease versus controls, target prediction P < 0.001, error decisions P < 0.0001, error antisaccades P < 0.0001), but not reflexive saccade execution (for all, P > 0.05). Patients with Parkinson's disease had, compared with controls, similar complex saccade performance (for all, P > 0.05) and only minimal impairment in reflexive tasks, i.e. hypometric gain in the gap task (P = 0.04). Impaired saccade execution in reflexive tasks allowed discrimination between DLB versus Alzheimer's disease (sensitivity > or =60%, specificity > or =77%) and between PDD versus Parkinson's disease (sensitivity > or =60%, specificity > or =88%) when +/-1.5 standard deviations was used for group discrimination. We conclude that impairments in reflexive saccades may be helpful for differential diagnosis and are minimal when either cortical (Alzheimer's disease) or nigrostriatal neurodegeneration (Parkinson's disease) exists solely; however, they become prominent with combined cortical and subcortical neurodegeneration in PDD and DLB. The similarities in saccade performance in PDD and DLB underline the overlap between these conditions and underscore differences from Alzheimer's disease and Parkinson's disease.

Visual perception in Parkinson disease dementia and dementia with Lewy bodies

OBJECTIVE To quantify visual discrimination, space-motion, and object-form perception in patients with Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD). METHODS The authors used a cross-sectional study to compare three demented groups matched for overall dementia severity (PDD: n = 24; DLB: n = 20; AD: n = 23) and two age-, sex-, and education-matched control groups (PD: n = 24, normal controls [NC]: n = 25). RESULTS Visual perception was globally more impaired in PDD than in nondemented controls (NC, PD), but was not different from DLB. Compared to AD, PDD patients tended to perform worse in all perceptual scores. Visual perception of patients with PDD/DLB and visual hallucinations was significantly worse than in patients without hallucinations. CONCLUSIONS Parkinson disease dementia (PDD) is associated with profound visuoperceptual impairments similar to dementia with Lewy bodies (DLB) but different from Alzheimer disease. These findings are consistent with previous neuroimaging studies reporting hypoactivity in cortical areas involved in visual processing in PDD and DLB.

Role of cholinesterase inhibitors in Parkinson's disease and dementia with Lewy bodies

This article reviews the cholinergic changes in Parkinson's disease and dementia (PDD) and dementia with Lewy bodies (DLB), their potential clinical implications, and the available evidence for cholinesterase inhibitors in the treatment of PDD and DLB. Marked neuronal loss of cholinergic nuclei, reduced cholinergic markers in the neocortex, hippocampus, and selected thalamic nuclei, and receptor changes have been reported. One large and 2 small placebo-controlled trials and nearly 20 open-label studies suggest that cholinesterase inhibitors have a positive effect on cognition, psychiatric symptoms, and global function in patients with DLB and PDD. The treatment is well tolerated in most patients without any apparent worsening of extrapyramidal motor features. Given the high risk of severe sensitivity reactions and increased risk of cerebrovascular incidents during treatment with neuroleptics, more clinical trials of cholinesterase inhibitors are encouraged to establish their precise role in DLB and PDD.

Dementia with Lewy bodies and Parkinson's disease

Lewy bodies (LB) in the central nervous system are associated with several different clinical syndromes including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Long term follow up of PD patients finds up to 78% eventually develop dementia, most of these patients exhibiting fluctuating cognition and visual hallucinations similar to DLB and with extensive cortical LB at autopsy. alpha-Synuclein positive, neuritic pathology, in the putamen of DLB and Parkinson's disease dementia (PDD), may contribute to postural-instability gait difficulty, parkinsonism, diminished levodopa responsiveness and increased neuroleptic sensitivity. Cognitive and neuropsychiatric symptoms improve with cholinesterase inhibitor treatment in both patient groups. DLB and PDD should be seen as different points on a spectrum of LB disease. Distinguishing them as separate disorders may be useful in clinical practice, but may be of limited value in terms of investigating and treating the underlying neurobiology.

More severe functional impairment in dementia with Lewy bodies than Alzheimer disease is related to extrapyramidal motor dysfunction.

OBJECTIVE The objective of this study was to compare functional impairments in dementia with Lewy bodies (DLB) and Alzheimer disease (AD) and their relationship with motor and neuropsychiatric symptoms. METHODS The authors conducted a cross-sectional study of 84 patients with DLB or AD in a secondary care setting. Patients were diagnosed according to published criteria for DLB and AD. The Bristol Activities of Daily Living Scale (BADLS) was used to assess functional impairments. Participants were also assessed using the Unified Parkinson's Disease Rating Scale (motor section), the Neuropsychiatric Inventory, and the Mini-Mental Status Examination. RESULTS Patients with DLB were more functionally impaired and had more motor and neuropsychiatric difficulties than patients with AD with similar cognitive scores. In both AD and DLB, there were correlations between total BADLS scores and motor and neuropsychiatric deficits. There was more impairment in the mobility and self-care components of the BADLS in DLB than in AD, and in DLB, these were highly correlated with UPDRS score. In AD, orientation and instrumental BADLS components were most affected. CONCLUSION The nature of functional disability differs between AD and DLB with additional impairments in mobility and self-care in DLB being mainly attributable to extrapyramidal motor symptoms. Consideration of these is important in assessment and management. Activities of daily living scales for use in this population should attribute the extent to which functional disabilities are related to cognitive, psychiatric, or motor dysfunction.

Epitope mapping of antibodies to alpha-synuclein in LRRK2 mutation carriers, idiopathic Parkinson disease patients, and healthy controls

Alpha-synuclein (Snca) plays a major role in Parkinson disease (PD). Circulating anti-Snca antibodies has been described in PD patients and healthy controls, but they have been poorly characterized. This study was designed to assess the prevalence of anti-Snca reactivity in human subjects carrying the LRRK2 mutation, idiopathic PD (iPD) patients, and healthy controls and to map the epitopes of the anti-Snca antibodies. Antibodies to Snca were detected by ELISA and immunoblotting using purified recombinant Snca in plasma from individuals carrying LRRK2 mutations (104), iPD patients (59), and healthy controls (83). Epitopes of antibodies were mapped using recombinant protein constructs comprising different regions of Snca. Clear positive anti-Snca reactivity showed no correlation with age, sex, years of evolution, or the disability scores for PD patients and anti-Snca reactivity was not prevalent in human patients with other neurological or autoimmune diseases. Thirteen of the positive individuals were carriers of LRRK2 mutations either non-manifesting (8 out 49 screened) or manifesting (5 positive out 55), three positive (out of 59) were iPD patients, and five positive (out of 83) were healthy controls. Epitope mapping showed that antibodies against the N-terminal (a.a. 1-60) or C-terminal (a.a. 109-140) regions of Snca predominate in LRRK2 mutation carriers and iPD patients, being N122 a critical amino acid for recognition by the anti-C-terminal directed antibodies. Anti-Snca circulating antibodies seem to cluster within families carrying the LRRK2 mutation indicating possible genetic or common environmental factors in the generation of anti-Snca antibodies. These results suggest that case-controls' studies are insufficient and further studies in family cohorts of patients and healthy controls should be undertaken, to progress in the understanding of the possible relationship of anti-Snca antibodies and PD patholog

Age-Associated Changes of Brain Copper, Iron, and Zinc in Alzheimer's Disease and Dementia with Lewy Bodies

Disease-, age-, and gender-associated changes in brain copper, iron, and zinc were assessed in postmortem neocortical tissue (Brodmann area 7) from patients with moderate Alzheimer's disease (AD) (n = 14), severe AD (n = 28), dementia with Lewy bodies (n = 15), and normal age-matched control subjects (n = 26). Copper was lower (20%; p < 0.001) and iron higher (10–16%; p < 0.001) in severe AD compared with controls. Intriguingly significant Group*Age interactions were observed for both copper and iron, suggesting gradual age-associated decline of these metals in healthy non-cognitively impaired individuals. Zinc was unaffected in any disease pathologies and no age-associated changes were apparent. Age-associated changes in brain elements warrant further investigation.

Quantitative Measurement of [Na+] and [K+] in Postmortem Human Brain Tissue Indicates Disturbances in Subjects with Alzheimer's Disease and Dementia with Lewy Bodies

Alzheimer’s disease (AD) is associated with significant disturbances in the homeostasis of Na+ and K+ ions as well as reduced levels of Na+/K+ ATPase in the brain. This study used ICP-MS to accurately quantify Na+ and K+ concentrations in human postmortem brain tissue. We analyzed parietal cortex (Brodmann area 7) from 28 cognitively normal age-matched controls, 15 cases of moderate AD, 30 severe AD, and 15 dementia with Lewy bodies (DLB). Associations were investigated between [Na+] and [K+] and a number of variables including diagnosis, age, gender, Braak tangle stage, amyloid-β (Aβ) plaque load, tau load, frontal tissue pH, and APOE genotype. Brains from patients with severe AD had significantly higher (26%; p<0.001) [Na+] (mean 65.43 ± standard error 2.91 mmol/kg) than controls, but the concentration was not significantly altered in moderate AD or DLB. [Na+] correlated positively with Braak stage (r=0.45; p<0.0001), indicating association with disease severity. [K+] in tissue was 10% lower (p<0.05) in moderate AD than controls. However, [K+] in severe AD and DLB (40.97±1.31 mmol/kg) was not significantly different from controls. There was a significant positive correlation between [K+] and Aβ plaque load (r=0.46; p=0.035), and frontal tissue pH (r=0.35; p=0.008). [Na+] was not associated with [K+] across the groups, and neither ion was associated with tau load or APOE genotype. We have demonstrated disturbances of both [Na+] and [K+] in relation to the severity of AD and markers of AD pathology, although it is possible that these relate to late-stage secondary manifestations of the disease pathology.

Longitudinal testing of visual perception in dementia with Lewy bodies and Alzheimer's disease

Visuo-perceptual abnormalities are a prominent feature in dementia with Lewy bodies (DLB) and also occur in Alzheimer's disease (AD) to a lesser extent. We studied the progression of visuo-perceptual abnormalities over a 12-month period in DLB and AD by using a novel computerised test battery.

Testing visual perception in dementia with Lewy bodies and Alzheimer disease

OBJECTIVE Visuoperceptual deficits are common in dementia with Lewy bodies (DLB) and Alzheimer disease (AD). Testing visuoperception in dementia is complicated by decline in other cognitive domains and extrapyramidal features. To overcome these issues, we developed a computerized test, the Newcastle visuoperception battery (NEVIP), which is independent of motor function and has minimal cognitive load.We aimed to test its utility to identify visuoperceptual deficits in people with dementia. PARTICIPANTS AND MEASUREMENTS We recruited 28 AD and 26 DLB participants with 35 comparison participants of similar age and education. The NEVIP was used to test angle, color, and form discrimination along with motion perception to obtain a composite visuoperception score. RESULTS Those with DLB performed significantly worse than AD participants on the composite visuoperception score (Mann-Whitney U = 142, p = 0.01). Visuoperceptual deficits (defined as 2 SD below the performance of comparisons) were present in 71% of the DLB group and 40% of the AD group. Performance was not significantly correlated with motor impairment, but was significantly related to global cognitive impairment in DLB (rs = -0.689, p <0.001), but not in AD. CONCLUSION Visuoperceptual deficits can be detected in both DLB and AD participants using the NEVIP, with the DLB group performing significantly worse than AD. Visuoperception scores obtained by the NEVIP are independent of participant motor deficits and participants are able to comprehend and perform the tasks.