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1.  The role of levodopa in the management of dementia with Lewy bodies 
Background: One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for Parkinson's disease (PD), but its use in DLB has been tempered by concerns of exacerbating neuropsychiatric symptoms.
Aim: To assess the efficacy and tolerability of L-dopa in managing EPS in DLB and to compare the motor response with that seen in PD and PD with dementia (PDD).
Method: EPS assessment consisted of the Unified Parkinson's Disease Rating Scale, motor subsection (UPDRS III), and finger tapping and walking tests. Patients with DLB were commenced on L-dopa. After 6 months, patients were examined in the "off" state, given L-dopa and assessed for motor responses. Identical assessments were performed in patients with PD and PDD also receiving L-dopa.
Results: Acute L-dopa challenge in 14 DLB patients yielded a mean 13.8% (p = 0.02) improvement in UPDRS III score, compared with 20.5% in PD (n = 28, p<0.0001) and 23% in PDD (n = 30, p<0.0001) respectively. Finger tapping scores increased (12.3% v 20% and 23%), while walking test scores decreased (32% v 41% and 67%). Of the DLB patients, 36% were classified as "responders" on L-dopa challenge, compared with 70% of the PDD and 57% of the PD patients. Nineteen DLB patients were treated for 6 months with L-dopa (mean daily dose 323 mg). Two withdrew prematurely with gastrointestinal symptoms and two with worsening confusion.
Conclusion: L-dopa was generally well tolerated in DLB but produced a significant motor response in only about one third of patients. Younger DLB cases were more likely to respond to dopaminergic treatment.
doi:10.1136/jnnp.2004.052332
PMCID: PMC1739807  PMID: 16107351
2.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background:
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives:
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods:
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results:
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions:
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
GLOSSARY
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
3.  Rivastigmine for the treatment of dementia associated with Parkinson’s disease 
Parkinson’s disease (PD) afflicts millions of people worldwide and leads to cognitive impairment or dementia in the majority of patients over time. Parkinson’s disease dementia (PDD) is characterized by deficits in attention, executive and visuospatial function, and memory. The clinical diagnostic criteria and neuropathology surrounding PDD remain controversial with evidence of overlap among PDD, dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Cortical cholinergic deficits are greater in PDD than in AD, and are well-correlated with the cognitive and neuropsychiatric dysfunction that occurs in PDD. Inhibition of acetylcholine metabolism is therefore a practical therapeutic strategy in PDD.
This review examines current evidence for rivastigmine (a cholinesterase/butyrylcholinesterase inhibitor) treatment in PDD. In addition to its efficacy, we examine the safety profile, side effects, and cost effectiveness of rivastigmine in PDD. Rivastigmine provides modest benefit in PDD and further long-term studies are needed to determine the effectiveness and safety of rivastigmine over time. Tolerability is a problem for many PDD patients treated with rivastigmine. Future studies of rivastigmine in PDD should focus on pragmatic outcomes such as time to need for nursing home placement, pharmacoeconomic outcomes and simultaneous patient/caregiver quality of life assessments.
PMCID: PMC2656320  PMID: 19300613
Parkinson’s disease; dementia; rivastigmine; cholinesterase inhibitor
4.  Demography, diagnostics, and medication in dementia with Lewy bodies and Parkinson’s disease with dementia: data from the Swedish Dementia Quality Registry (SveDem) 
Introduction
Whether dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD) should be considered as one entity or two distinct conditions is a matter of controversy. The aim of this study was to compare the characteristics of DLB and PDD patients using data from the Swedish Dementia Quality Registry (SveDem).
Methods
SveDem is a national Web-based quality registry initiated to improve the quality of diagnostic workup, treatment, and care of patients with dementia across Sweden. Patients with newly diagnosed dementia of various types were registered in SveDem during the years 2007–2011. The current cross-sectional report is based on DLB (n = 487) and PDD (n = 297) patients. Demographic characteristics, diagnostic workup, Mini-Mental State Examination (MMSE) score, and medications were compared between DLB and PDD groups.
Results
No gender differences were observed between the two study groups (P = 0.706). PDD patients were significantly younger than DLB patients at the time of diagnosis (74.8 versus 76.8 years, respectively; P < 0.001). A significantly higher prevalence of patients with MMSE score ≤24 were found in the PDD group (75.2% versus 67.6%; P = 0.030). The mean number of performed diagnostic modalities was significantly higher in the DLB group (4.9 ± 1.7) than in the PDD group (4.1 ± 1.6; P < 0.001). DLB patients were more likely than PDD patients to be treated with cholinesterase inhibitors (odds ratio = 2.5, 95% confidence interval = 1.8–3.5), whereas the use of memantine, antidepressants, and antipsychotics did not differ between the groups.
Conclusion
This study demonstrates several differences in the dementia work-up between DLB and PDD. The onset of dementia was significantly earlier in PDD, while treatment with cholinesterase inhibitors was more common in DLB patients. Severe cognitive impairment (MMSE score ≤24) was more frequent in the PDD group, whereas more diagnostic tests were used to confirm a DLB diagnosis. Some similarities also were found, such as gender distribution and use of memantine, antidepressants, and antipsychotics drugs. Further follow-up cost-effectiveness studies are needed to provide more evidence for workup and treatment guidelines of DLB and PDD.
doi:10.2147/NDT.S45840
PMCID: PMC3700781  PMID: 23847419
dementia with Lewy bodies; Parkinson’s disease with dementia; age; diagnostic approach; medication; Mini-Mental State Examination
5.  Dementia with Lewy Bodies versus Alzheimer's Disease and Parkinson's Disease Dementia: A Comparison of Cognitive Profiles 
Background and Purpose
It is particularly difficult to differentiate dementia with Lewy bodies (DLB) from the related dementias of Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Few studies have been designed to comparatively analyze detailed neuropsychological assessments of DLB patients and patients with AD and PDD.
Methods
Three groups of patients participated in this study: 10 with DLB, 76 with AD, and 17 with PDD, who had been diagnosed as probable DLB, AD, and PDD, respectively, according to the clinical criteria of the consortium on DLB, National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorder Association, and the clinical diagnostic criteria for PDD. All patients were evaluated by careful neurological examination with detailed neuropsychological testing.
Results
Significant differences among the three groups were found for attention, memory, and executive function, which included tasks of backward digit span, three-word recall, verbal delayed recall, and the Stroop test. Post hoc analysis revealed that the deficiencies of attention on the digit span task were greater in the DLB group than in the AD and PDD groups. The scores for episodic verbal memory tasks were significantly lower in the DLB and AD groups than in the PDD group. The performance in frontal executive function, as indicated by the Stroop test, was significantly worse in the DLB and PDD groups than in the AD group.
Conclusions
The results of the present study show that the pattern of cognitive dysfunction, in terms of attention, episodic memory, and executive functions, differ between patients with DLB and patients with AD and PDD.
doi:10.3988/jcn.2011.7.1.19
PMCID: PMC3079155  PMID: 21519522
dementia with lewy bodies; Alzheimer's disease; Parkinson's disease dementia; cognition; neuropsychology
6.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
7.  Verbal Learning and Memory in Patients with Dementia with Lewy Bodies or Parkinson's Disease with Dementia 
This study compared verbal learning and memory in patients with autopsy-confirmed dementia with Lewy Bodies (DLB) and patients with Parkinson's disease with dementia (PDD). Twenty-four DLB patients, 24 PDD patients, and 24 normal comparison participants were administered the California Verbal Learning Test. The three groups were matched on demographic variables and the two patient groups were matched on the Mattis Dementia Rating Scale. The results indicated that DLB patients recalled less information than PDD patients on all but one recall measure and displayed a more rapid rate of forgetting. In contrast, the PDD patients committed a greater percent of perseveration errors than the DLB patients. The two groups did not differ in the percentage of recall intrusion errors or any measures of recognition. A discriminant function analysis (DFA) using short delay cued recall, percent perseveration errors, and list b recall, differentiated the DLB and PDD groups with 81.3% accuracy. The application of the DFA algorithm to another sample of 42 PDD patients resulted in a 78.6% correct classification rate. The results suggest that, despite equivalent levels of general cognitive impairment, patients with DLB or PDD exhibit a different pattern of verbal learning and memory deficits.
doi:10.1080/13803390802572401
PMCID: PMC2935683  PMID: 19221922
8.  Brain amyloid and cognition in Lewy body diseases 
Background
Many patients with Parkinson disease (PD) develop dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account in part for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases.
Methods
29 cognitively normal PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and PiB imaging with PET. Apolipoprotein (APOE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference.
Results
PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the APOEε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition.
Conclusions
DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism.
doi:10.1002/mds.25048
PMCID: PMC3725259  PMID: 22693110
dementia; Lewy; Parkinson; amyloid; PiB
9.  Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease 
Background: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown.
Objectives: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease).
Design: Survey of cognitive features.
Setting: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA.
Patients: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education.
Main outcome measures: Dementia rating scale subscores corrected for age.
Results: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001).
Conclusions: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.
doi:10.1136/jnnp.74.9.1215
PMCID: PMC1738667  PMID: 12933921
10.  Transcranial magnetic stimulation and transcranial direct current stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative dementias? 
Introduction
Two methods of non-invasive brain stimulation, transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), have demonstrable positive effects on cognition and can ameliorate neuropsychiatric symptoms such as depression. Less is known about the efficacy of these approaches in common neurodegenerative diseases. In this review, we evaluate the effects of TMS and tDCS upon cognitive and neuropsychiatric symptoms in the major dementias, including Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD), and frontotemporal dementia (FTD), as well as the potential pre-dementia states of Mild Cognitive Impairment (MCI) and Parkinson’s disease (PD).
Methods
PubMed (until 7 February 2014) and PsycINFO (from 1967 to January Week 3 2014) databases were searched in a semi-systematic manner in order to identify relevant treatment studies. A total of 762 studies were identified and 32 studies (18 in the dementias and 14 in PD populations) were included.
Results
No studies were identified in patients with PDD, FTD or VaD. Of the dementias, 13 studies were conducted in patients with AD, one in DLB, and four in MCI. A total of 16 of the 18 studies showed improvements in at least one cognitive or neuropsychiatric outcome measure. Cognitive or neuropsychiatric improvements were observed in 12 of the 14 studies conducted in patients with PD.
Conclusions
Both TMS and tDCS may have potential as interventions for the treatment of symptoms associated with dementia and PD. These results are promising; however, available data were limited, particularly within VaD, PDD and FTD, and major challenges exist in order to maximise the efficacy and clinical utility of both techniques. In particular, stimulation parameters vary considerably between studies and are likely to subsequently impact upon treatment efficacy.
doi:10.1186/s13195-014-0074-1
PMCID: PMC4255638  PMID: 25478032
11.  A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)  
PLoS Medicine  2008;5(4):e76.
Background
There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.
Methods and Findings
Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.
Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.
Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.
Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.
Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).
Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.
Conclusions
For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.
Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).
In a randomized trial of patients with dementia, Clive Ballard and colleagues show that withdrawal of neuroleptics had no overall detrimental effect, and by some measures improved, functional and cognitive status.
Editors' Summary
Background
The number of people with dementia (currently 25 million worldwide) is expected to increase by 5 million each year. The risk of dementia, including Alzheimer disease, increases sharply with age: Alzheimer's Disease International estimates that 1.4% of people 65–69 have dementia, whereas almost a full quarter of those over the age of 85 years are affected. Almost all older dementia patients will experience, along with the cognitive and functional decline typical of the illness, some neuropsychiatric symptoms. These symptoms can include agitation, aggression, and psychosis, and are often devastating for the older patient and his or her family and caregiver. Managing these symptoms is often a prime concern for health-care providers and families. Neuroleptics (sometimes called antipsychotics) are the class of drugs often used to manage or control neuropsychiatric problems, but there have been questions about their safety and appropriateness. Safety concerns involve risk of stroke, parkinsonism, sedation, edema, and chest infections but also include a worsening of cognitive decline with prolonged use of neuroleptics.
Why Was the Study Done?
Previous studies on the effectiveness and safety of neuroleptics in older people have been short term. Ballard and colleagues wanted to study over a longer period of time the impact of neuroleptic drugs on elderly patients with dementia. Specifically, they wanted to know if being on a neuroleptic was associated with more cognitive decline than coming off the drug. They also wanted to investigate whether discontinuing the drug exacerbated any neuropsychiatric symptoms, Parkinson disease-like symptoms, or other functional, language, and cognition difficulties frequently associated with dementia.
What Did the Researchers Do and Find?
The researchers recruited older patients with Alzheimer disease from across England who had been on neuroleptics for at least three months. They randomised patients to one of two groups: the first group continued taking the same neuroleptic at the same dosage level while the second group was switched to an identical-looking placebo. The researchers assessed the patients' cognitive status and neuropsychiatric symptoms upon their entry into the study. Six and 12 months later the researchers assessed any cognitive decline and the level of neuropsychiatric and other problems that patients were experiencing.
At both 6 and 12 months, the researchers found that there were no differences between the two groups (continued treatment and placebo) in terms of cognitive decline. The placebo group may have had less cognitive decline, but this was not statistically significant. They also found no overall differences between the two groups in the change in the number of neuropsychiatric symptoms over these time periods. Patients with severe neuropsychiatric problems at the outset of the trial did better on continued neuroleptic therapy, but this advantage was not statistically significant. There was a significant decline on the verbal fluency language tests among the patients who continued on their neuroleptic.
What Do these Findings Mean?
The researchers report perhaps the first trial of this duration on continued versus withdrawn neuroleptic treatment among older dementia patients. The findings do not indicate any benefit of continuing neuroleptic therapies in older patients on either cognitive or neuropsychiatric outcomes. The researchers conclude that neuroleptics, with their known safety issues, should not be used as first-line treatment to manage problems such as agitation or aggression. For older dementia patients whose neuropsychiatric symptoms are not remedied by nonpharmaceutical treatments, the researchers advise caution. More studies are urgently needed to find better solutions to help older patients with dementia who have agitation, aggression, and psychosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050076.
Alzheimer's Disease International is an umbrella organisation of organisations worldwide
The Alzheimer's Research Trust in the UK is a charity funding research to cure or prevent dementias
The US National Institutes of Aging has information on Alzheimer Disease in English and Spanish
Two governmental regulatory agencies—the Medicines and Healthcare Products Regulatory Agency in the UK and the Food and Drug Administration in the US—offer information about antipsychotics in people with dementia
doi:10.1371/journal.pmed.0050076
PMCID: PMC2276521  PMID: 18384230
12.  Dynamin1 concentration in the prefrontal cortex is associated with cognitive impairment in Lewy body dementia 
F1000Research  2014;3:108.
Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD) together, represent the second most common cause of dementia, after Alzheimer’s disease (AD). The synaptic dysfunctions underlying the cognitive decline and psychiatric symptoms observed throughout the development of PDD and DLB are still under investigation. In this study we examined the expression level of Dynamin1 and phospho-CaMKII, key proteins of endocytosis and synaptic plasticity respectively, as potential markers of molecular processes specifically deregulated with DLB and/or PDD. In order to measure the levels of these proteins, we isolated grey matter from post-mortem prefrontal cortex area (BA9), anterior cingulated gyrus (BA24) and parietal cortex (BA40) from DLB and PDD patients in comparison to age-matched controls and a group of AD cases. Clinical and pathological data available included the MMSE score, neuropsychiatric history, and semi-quantitative scores for AD pathology (plaques - tangles) and for α-synuclein (Lewy bodies).
Changes in the expression of the synaptic markers, and correlates with neuropathological features and cognitive decline were predominantly found in the prefrontal cortex. On one hand, levels of Dynamin1 were significantly reduced, and correlated with a higher rate of cognitive decline observed in cases from three dementia groups. On the other hand, the fraction of phospho-CaMKII was decreased, and correlated with a high score of plaques and tangles in BA9. Interestingly, the correlation between the rate of cognitive decline and the level of Dynamin1 remained when the analysis was restricted to the PDD and DLB cases, highlighting an association of Dynamin1 with cognitive decline in people with Lewy Body dementia.
doi:10.12688/f1000research.3786.1
PMCID: PMC4309165
Alzheimer’s disease; Dementia with Lewy bodies; Parkinson’s disease with dementia; synaptic dysfunction; vesicle recycling; synaptic plasticity; beta amyloid; tau; cognitive impairment
13.  Cohort study of prevalence and phenomenology of tremor in dementia with Lewy bodies 
Journal of Neurology  2013;260(7):1731-1742.
To study prevalence, specific patterns and response to treatment of tremor in dementia with Lewy bodies (DLB), in comparison with other tremulous disorders prevalence, qualitative and quantitative features of tremor were studied in an incident cohort of 67 dopaminergic treatment naive DLB, 111 Parkinson’s Disease (PD) and 34 Essential Tremor (ET) patients. Tremulous DLB patients (tDLB) were compared with tremulous PD (tPD) and ET patients and followed for 2 years. Double blind placebo-controlled acute drug challenge with l-Dopa and alcohol was performed in all ET, 24 tDLB and 27 tPD. Effects of dopaminergic chronic treatment in all tDLB and tPD patients and primidone in 8 tDLB were also assessed. Tremor occurred in 44.76 % of DLB patients. The tDLB patients presented a complex pattern of mixed tremors, characterized by rest and postural/action tremor, including walking tremor and standing overflow in 50 % tDLB. Standing tremor with overflow was characteristic of tDLB (p < 0.001). Head tremor was more frequent in tDLB than tPD and ET (p = 0.001). The tDLB tremors were reduced by acute and chronic dopaminergic treatments (p < 0.01) but not by alcohol or primidone. Tremor occurs commonly in DLB patients with a complex mixed tremor pattern which shows a significant response to acute and chronic dopaminergic treatments. Recognizing that there is a clinical category of tremulous DLB may help the differential diagnosis of tremors.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-013-6853-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s00415-013-6853-y
PMCID: PMC3705145  PMID: 23400498
Dementia with Lewy bodies; Parkinson’s disease; Tremor; EMG
14.  Incidence of Dementia with Lewy Bodies and Parkinson’s Disease Dementia 
JAMA neurology  2013;70(11):1396-1402.
Importance
Epidemiologic data on dementia with Lewy bodies (LBD) and Parkinson’s disease dementia (PDD) remain limited in the US and worldwide. These data are essential to guide research and clinical or public health interventions.
Objective
To investigate the incidence of DLB among residents of Olmsted County, MN, and compare it to the incidence of PDD.
Design
The medical records-linkage system of the Rochester Epidemiology Project was used to identify all persons who developed parkinsonism and, in particular, DLB or PDD from 1991 through 2005 (15 years). A movement disorders specialist reviewed the complete medical records of each suspected patient to confirm the diagnosis.
Setting
Olmsted County, MN, from 1991 through 2005 (15 years).
Main Outcome Measure
Incidence of DLB and PDD.
Participants
All the residents of Olmsted County, MN who gave authorization for medical record research.
Results
Among 542 incident cases of parkinsonism, 64 had DLB and 46 had PDD. The incidence rate of DLB was 3.5 per 100,000 person-years overall, and it increased steeply with age. Similarly, the incidence of PDD was 2.5 overall and also increased steeply with age. The incidence rate of DLB and PDD combined was 5.9. Patients with DLB were younger at onset of symptoms than patients with PDD and had more hallucinations and cognitive fluctuations. Men had a higher incidence of DLB than women across the age spectrum. The pathology was consistent with the clinical diagnosis in 24 of 31 patients who underwent autopsy (77.4%).
Conclusions
The overall incidence rate of DLB is lower than the rate for Parkinson’s disease. DLB risk increases steeply with age and is markedly higher in men. This men-to-women difference may suggest different etiologic mechanisms.
doi:10.1001/jamaneurol.2013.3579
PMCID: PMC4181848  PMID: 24042491
15.  Motor subtype and cognitive decline in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies 
Background
A previous cross sectional study found over‐representation of a postural instability gait difficulty (PIGD) motor subtype in Parkinson's disease patients with dementia (PDD) and dementia with Lewy bodies (DLB), compared with Parkinson's disease (PD).
Aims
(1) To examine rates of cognitive and motor decline over two years in PD (n = 40), PDD (n = 42) and DLB (n = 41) subjects, compared with age matched controls (n = 41), (2) to record whether motor phenotypes of PD, PDD, and DLB subjects changed during the study, (3) to find out if cognitive and motor decline in PD was associated with baseline motor subtype, and (4) to report the incidence of dementia in PD patients in relation to baseline motor subtype.
Results
Most of PDD and DLB participants were PIGD subtype at baseline assessment. In the non‐demented PD group, tremor dominant (TD) and PIGD subtypes were more evenly represented. Cognitive decline over two years was greater in PDD and DLB groups (mean decline in MMSE −4.5 and −3.9, respectively), compared with PD (−0.2) and controls (−0.3). There was an association between PIGD subtype and increased rate of cognitive decline within the PD group. Of 40 PD patients, 25% of the 16 PIGD subtype developed dementia over two years, compared with none of the 18 TD or six indeterminate phenotype cases (χ2 = 6.7, Fisher's exact test p<0.05).
Conclusion
A PIGD motor subtype is associated with a faster rate of cognitive decline in PD and may be considered a risk factor for incident dementia in PD.
doi:10.1136/jnnp.2005.081711
PMCID: PMC2117449  PMID: 16614017
Lewy body disease; dementia; parkinsonism; motor subtype; progression
16.  Amino acid management of Parkinson’s disease: a case study 
An extensive list of side effects and problems are associated with the administration of l-dopa (l-3, 4-dihydroxyphenylalanine) during treatment of Parkinson’s disease. These problems can preclude achieving an optimal response with l-dopa treatment.
Purpose:
To present a case study outlining a novel approach for the treatment of Parkinson’s disease that allows for management of problems associated with l-dopa administration and discusses the scientific basis for this treatment.
Patients and methods:
The case study was selected from a database containing 254 Parkinson’s patients treated in developing and refining this novel approach to its current state. The spectrum of patients comprising this database range from newly diagnosed, with no previous treatment, to those who were diagnosed more than 20 years before and had virtually exhausted all medical treatment options. Parkinson’s disease is associated with depletion of tyrosine hydroxylase, dopamine, serotonin, and norepinephrine. Exacerbating this is the fact that administration of l-dopa may deplete l-tyrosine, l-tryptophan, 5-hydroxytryptophan (5-HTP), serotonin, and sulfur amino acids. The properly balanced administration of l-dopa in conjunction with 5-HTP, l-tyrosine, l-cysteine, and cofactors under the guidance of organic cation transporter functional status determination (herein referred to as “OCT assay interpretation”) of urinary serotonin and dopamine, is at the heart of this novel treatment protocol.
Results:
When 5-HTP and l-dopa are administered in proper balance along with l-tyrosine, l-cysteine, and cofactors under the guidance of OCT assay interpretation, the long list of problems that can interfere with optimum administration of l-dopa becomes controllable and manageable or does not occur at all. Patient treatment then becomes more effective by allowing the implementation of the optimal dosing levels of l-dopa needed for the relief of symptoms without the dosing value barriers imposed by side effects and adverse reactions seen in the past.
doi:10.2147/IJGM.S16621
PMCID: PMC3068871  PMID: 21475622
Parkinson’s; Parkinsonism; Parkinson’s disease; l-dopa; 5-HTP
17.  Altered Resting State Cortico-Striatal Connectivity in Mild to Moderate Stage Parkinson's Disease 
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by dopamine depletion in the striatum. One consistent pathophysiological hallmark of PD is an increase in spontaneous oscillatory activity in the basal ganglia thalamocortical networks. We evaluated these effects using resting state functional connectivity MRI in mild to moderate stage Parkinson's patients on and off l-DOPA and age-matched controls using six different striatal seed regions. We observed an overall increase in the strength of cortico-striatal functional connectivity in PD patients off l-DOPA compared to controls. This enhanced connectivity was down-regulated by l-DOPA as shown by an overall decrease in connectivity strength, particularly within motor cortical regions. We also performed a frequency content analysis of the BOLD signal time course extracted from the six striatal seed regions. PD off l-DOPA exhibited increased power in the frequency band 0.02–0.05 Hz compared to controls and to PD on l-DOPA. The l-DOPA associated decrease in the power of this frequency range modulated the l-DOPA associated decrease in connectivity strength between striatal seeds and the thalamus. In addition, the l-DOPA associated decrease in power in this frequency band correlated with the l-DOPA associated improvement in cognitive performance. Our results demonstrate that PD and l-DOPA modulate striatal resting state BOLD signal oscillations and cortico-striatal network coherence.
doi:10.3389/fnsys.2010.00143
PMCID: PMC3009475  PMID: 21206528
dopamine; Parkinson's disease; fMRI; functional connectivity; striatum; neural oscillation
18.  REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century(e–Pub ahead of print)(CME) 
Neurology  2010;75(6):494-499.
Background:
Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]).
Methods:
We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome.
Results:
Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients.
Conclusions:
These cases illustrate that the α-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.
GLOSSARY
= dementia with Lewy bodies;
= mild cognitive impairment;
= multiple system atrophy;
= Parkinson disease;
= PD with associated mild cognitive impairment;
= Parkinson disease dementia;
= polysomnogram;
= REM sleep behavior disorder.
doi:10.1212/WNL.0b013e3181ec7fac
PMCID: PMC2918473  PMID: 20668263
19.  Thalamic cholinergic innervation is spared in Alzheimer disease compared to Parkinsonian disorders 
Neuroscience Letters  2012;514(2):169-172.
OBJECTIVE
There are two major sources of cholinergic projections in the brain. The nucleus basalis of Meynert provides the principal cholinergic input of the cortical mantle and the pedunculopontine nucleus-laterodorsal tegmental complex (PPN-LDTC; hereafter referred to as PPN) provides the major cholinergic input to the thalamus. Cortical cholinergic denervation has previously been shown to be part of Alzheimer and parkinsonian dementia but there is less information about subcortical thalamic cholinergic denervation. We investigated thalamic cholinergic afferent integrity by measuring PPN-Thalamic (PPN-Thal) acetylcholinesterase (AChE) activity via PET imaging in Alzheimer (AD), Parkinson disease without dementia (PD), Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB).
METHODS
AD (n=13; mean age 75.4±5.5), PD (n=11; age 71.4±6.4), PDD (n=6; age 70.8±4.7), DLB (n=6; age 68.0±8.6) and normal controls (NC; n=14; age 69.0±7.5) subjects underwent AChE [11C]-methyl-4-piperidinyl propionate (PMP) PET imaging. PPN-Thal PET data were analyzed using the Nagatsuka method.
RESULTS
There were no significant differences in mean age between the groups (F=1.86, p=0.134). Kruskal-Wallis testing demonstrated a significant group effect for PPN-Thal AChE hydrolysis rates (F=9.62, P<0.0001). Compared to NC, reduced thalamic k3 hydrolysis rate was noted in subjects with PDD (−19.8%; AChE k3 hydrolysis rates 0.1072±0.0143 min−1), DLB (−17.4%; 0.1103±0.0112 min−1) and PD (−12.8%; 0.1165±0.0114 min−1). Each of these 3 subgroups were statistically different from AD subjects (−0.7%; 0.1326±0.0095 min−1) who showed relatively spared thalamic k3 hydrolysis rates which were comparable to NC (0.1336±0.0142 min−1).
CONCLUSIONS
Thalamic cholinergic denervation is present in PD, PDD, and DLB but not in AD. Neurodegenerative involvement of thalamic cholinergic afferent projections may contribute to disease-specific motor and cognitive abnormalities.
doi:10.1016/j.neulet.2012.02.083
PMCID: PMC3320689  PMID: 22414859
Acetylcholine; [11C] PMP PET; Alzheimer disease; Parkinson disease; PPN; Parkinson disease with dementia
20.  Therapeutic interventions and adjustments in the management of Parkinson disease: role of combined carbidopa/levodopa/entacapone (Stalevo®) 
Parkinson disease (PD) is a neurodegenerative disorder characterized by 3 cardinal motor symptoms: resting tremor, rigidity, and bradykinesia. Since its introduction 40 years ago, levodopa has represented the gold standard for dopaminergic stimulation therapy in patients with PD. Levodopa is routinely combined with a dopa-decarboxylase inhibitor (DDCI) to prevent the conversion of levodopa into dopamine in peripheral circulation. However, up to 80% of patients treated with continuous levodopa manifest the onset of disabling motor complications capable of producing an adverse effect on quality of life as the disease progresses. In recent years, a new, safe, and efficacious armamentarium of treatment options has been provided by the marketing of the catechol-O-methyltransferase (COMT) inhibitor, entacapone, a peripheral blocker of dopa to 3-0-methyldopa metabolism, which increments levodopa brain availability. When administered with levodopa, entacapone conjugates the rapid onset of levodopa-induced effects with a protracted efficiency, thus providing additional benefits to classic levodopa treatment by increasing “on” time in fluctuating PD patients, and theoretically providing a more continuous and physiological-like stimulation of dopamine receptors implying a reduced risk of motor complications. In this context, the use of a single administration of combined carbidopa/ levodopa/entacapone (Stalevo®) in the treatment of PD affords clinical improvements similar to those obtained by 2 separate tablets (ie, levodopa/DDCI and entacapone), although the former produces a more positive effect on quality of life than the latter. Additionally, the STalevo Reduction In Dyskinesia Evaluation (STRIDE-PD) study was designed with the aim of demonstrating that the combination of levodopa, carbidopa, and entacapone, used as initial levodopa therapy, significantly delays the onset of dyskinesias compared with the conventional levodopa/carbidopa formulation. Unfortunately, STRIDEPD failed to prove the benefit of continuous dopaminergic stimulation with triple therapy in a clinical setting. Recently, the effect of combined COMT inhibitor with levodopa administration in reducing homocysteine synthesis has been described. To this regard, clear evidence has been presented indicating homocysteine as a risk factor for vascular diseases, cognitive impairment, and dementia. Several studies have discussed the potential of entacapone as adjunct to levodopa/ DDCI in reducing plasma homocysteine levels with contrasting results.
PMCID: PMC2938297  PMID: 20856911
Parkinson disease; carbidopa/levodopa/entacapone
21.  Dementia 
Clinical Evidence  2010;2010:1001.
Introduction
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments on cognitive symptoms of dementia (Alzheimer's, Lewy body, or vascular)? What are the effects of treatments on behavioural and psychological symptoms of dementia (Alzheimer's, Lewy body, or vascular)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 33 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine), antidepressants (clomipramine, fluoxetine, imipramine, sertraline), antipsychotics (haloperidol, olanzapine, quetiapine, risperidone), aromatherapy, benzodiazepines (diazepam, lorazepam), cognitive behavioural therapy (CBT), cognitive stimulation, exercise, ginkgo biloba, memantine, mood stabilisers (carbamazepine, sodium valproate/valproic acid), music therapy, non-steroidal anti-inflammatory drugs (NSAIDs), omega 3 (fish oil), reminiscence therapy, and statins.
Key Points
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Median life expectancy for people with Alzheimer's and Lewy body dementia is about 6 years after diagnosis, although many people may live far longer.
RCTs of dementia are often not representative of all people with dementia; most are 6 months or less, not in primary care, and most RCTs are in people with Alzheimer's disease. There are fewer RCTs in people with vascular dementia, and fewer still in people with Lewy body dementia.
Cognitive symptoms of dementia can be improved by acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine). Acetylcholinesterase inhibitors seem to improve cognitive function, global state, and activities of daily living scores compared with placebo at 26 weeks in people with Alzheimer's disease.However, they may be associated with an increase in adverse effects, particularly GI symptoms (anorexia, nausea, vomiting, or diarrhoea).
We don't know whether cognitive stimulation, music therapy, reminiscence therapy, omega 3 fish oil, statins, or NSAIDs are effective at improving cognitive outcomes in people with cognitive symptoms of dementia, as we found insufficient evidence.
In people with cognitive symptoms, memantine may improve global state and activities of daily living scores in people with moderate to severe Alzheimer's disease over 24 to 28 weeks, but we don't know about these in mild to moderate Alzheimer's disease. Although memantine is associated with a statistically significant increase in cognition scores in some population groups, the clinical importance of these results is unclear.
Ginkgo biloba is unlikely to improve cognitive function in people with Alzheimer's disease or vascular dementia. However, evidence is of poor quality so this conclusion should be interpreted with caution.
Acetylcholinesterase inhibitors may marginally improve neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but they are also associated with adverse effects.
Antidepressants (clomipramine, fluoxetine, imipramine, sertraline) may improve depressive symptoms compared with placebo in people with Alzheimer's disease associated with depression. However, RCTs were small and short term, and adverse effects were sparsely reported.
Memantine may be associated with a small improvement in neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but it is also associated with adverse effects.
We don't know whether diazepam, lorazepam, aromatherapy, CBT, exercise, carbamazepine, or sodium valproate/valproic acid are effective at improving neuropsychiatric symptoms in people with behavioural and psychological symptoms of dementia, as we found insufficient evidence.
Some antipsychotics may improve neuropsychiatric symptoms or aggression in people with behavioural and psychological symptoms of dementia, but antipsychotics are also associated with an increase risk of severe adverse events such as stroke, TIA, or death.
CAUTION: Regulatory bodies have issued alerts that both conventional and atypical antipsychotics are associated with an increased risk of death in elderly people treated for dementia-related psychosis.
PMCID: PMC2907611  PMID: 21726471
22.  Evaluating the relationship between amyloid-β and α-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson’s disease 
Introduction
Lewy body and Alzheimer-type pathologies often co-exist. Several studies suggest a synergistic relationship between amyloid-β (Aβ) and α-synuclein (α-syn) accumulation. We have explored the relationship between Aβ accumulation and the phosphorylation of α-syn at serine-129 (pSer129 α-syn), in post-mortem human brain tissue and in SH-SY5Y neuroblastoma cells transfected to overexpress human α-syn.
Methods
We measured levels of Aβ40, Aβ42, α-syn and pSer129 α-syn by sandwich enzyme-linked immunosorbent assay, in soluble and insoluble fractions of midfrontal, cingulate and parahippocampal cortex and thalamus, from cases of Parkinson’s disease (PD) with (PDD; n = 12) and without dementia (PDND; n = 23), dementia with Lewy bodies (DLB; n = 10) and age-matched controls (n = 17). We also examined the relationship of these measurements to cognitive decline, as measured by time-to-dementia and the mini-mental state examination (MMSE) score in the PD patients, and to Braak tangle stage.
Results
In most brain regions, the concentration of insoluble pSer129 α-syn correlated positively, and soluble pSer129 α-syn negatively, with the levels of soluble and insoluble Aβ. Insoluble pSer129 α-syn also correlated positively with Braak stage. In most regions, the levels of insoluble and soluble Aβ and the proportion of insoluble α-syn that was phosphorylated at Ser129 were significantly higher in the PD and DLB groups than the controls, and higher in the PDD and DLB groups than the PDND brains. In PD, the MMSE score correlated negatively with the level of insoluble pSer129 α-syn. Exposure of SH-SY5Y cells to aggregated Aβ42 significantly increased the proportion of α-syn that was phosphorylated at Ser129 (aggregated Aβ40 exposure had a smaller, non-significant effect).
Conclusions
Together, these data show that the concentration of pSer129 α-syn in brain tissue homogenates is directly related to the level of Aβ and Braak tangle stage, and predicts cognitive status in Lewy body diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s13195-014-0077-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13195-014-0077-y
PMCID: PMC4248436  PMID: 25452767
23.  Dementia 
Clinical Evidence  2012;2012:1001.
Introduction
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments on cognitive symptoms of dementia (Alzheimer's, Lewy body, or vascular)? What are the effects of treatments on behavioural and psychological symptoms of dementia (Alzheimer's, Lewy body, or vascular)? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 49 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review, we present information relating to the effectiveness and safety of the following interventions: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine), antidepressants (clomipramine, fluoxetine, imipramine, sertraline), antipsychotics (haloperidol, olanzapine, quetiapine, risperidone), aromatherapy, benzodiazepines (diazepam, lorazepam), cognitive behavioural therapy (CBT), cognitive stimulation, exercise, ginkgo biloba, memantine, mood stabilisers (carbamazepine, sodium valproate/valproic acid), music therapy, non-steroidal anti-inflammatory drugs (NSAIDs), omega 3 (fish oil), reminiscence therapy, and statins.
Key Points
Dementia is characterised by chronic, global, non-reversible deterioration in memory, executive function, and personality. Speech and motor function may also be impaired.
Median life expectancy for people with Alzheimer's and Lewy body dementia is about 6 years after diagnosis, although many people may live far longer.
RCTs of dementia are often not representative of all people with dementia; most are of 6 months' duration or less, not in primary care, and in people with Alzheimer's disease. Few RCTs address vascular dementia, and fewer still Lewy body dementia.
Some cognitive symptoms of dementia may be improved by acetylcholinesterase inhibitors (donepezil, galantamine, and rivastigmine). Acetylcholinesterase inhibitors may improve cognitive function and global function scores compared with placebo at 12 to 26 weeks in people with Alzheimer's disease. However, they may be associated with an increase in adverse effects, particularly GI symptoms (anorexia, nausea, vomiting, or diarrhoea).
We don't know whether cognitive stimulation, music therapy, reminiscence therapy, omega 3 fish oil, statins, or NSAIDs are effective at improving cognitive outcomes in people with cognitive symptoms of dementia, as we found insufficient evidence.
In people with cognitive symptoms, memantine may modestly improve cognitive function and global function scores in people with Alzheimer's disease over 24 to 28 weeks, and may modestly improve activities of daily living scores in people with moderate to severe Alzheimer's disease. Although memantine is associated with a statistically significant increase in cognition scores in some population groups, the clinical importance of some of these results is unclear.
We found inconsistent evidence on the effects of ginkgo biloba on cognitive outcomes, which varied by the analysis performed. We found no evidence that ginkgo biloba improves activities of daily living outcomes, but the available evidence was weak.
Acetylcholinesterase inhibitors may marginally improve neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but they are also associated with adverse effects.
We don't know whether antidepressants (clomipramine, fluoxetine, imipramine, sertraline) improve depressive symptoms in people with Alzheimer's disease associated with depression. Many RCTs were small and short term, and adverse effects were sparsely reported.
Memantine may be associated with a small improvement in neuropsychiatric symptoms compared with placebo in people with behavioural and psychological symptoms of dementia, but it is also associated with adverse effects.
We don't know whether diazepam, lorazepam, aromatherapy, CBT, exercise, carbamazepine, or sodium valproate/valproic acid are effective at improving neuropsychiatric symptoms in people with behavioural and psychological symptoms of dementia, as we found insufficient evidence.
Some antipsychotics may improve neuropsychiatric symptoms or aggression in people with behavioural and psychological symptoms of dementia, but antipsychotics are also associated with an increased risk of severe adverse events such as stroke, TIA, or death.
CAUTION: Regulatory bodies have issued alerts that both conventional and atypical antipsychotics are associated with an increased risk of death in older people treated for dementia-related psychosis.
PMCID: PMC3437526  PMID: 23870856
24.  Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer's disease: a cohort study 
BMJ Open  2012;2(1):e000380.
Objectives
Dementia with Lewy bodies (DLB) accounts for 10%–15% of dementia cases at autopsy and has distinct clinical features associated with earlier institutionalisation and a higher level of carer distress than are seen in Alzheimer's disease (AD). At present, there is on-going debate as to whether DLB is associated with a more rapid cognitive decline than AD. An understanding of the rate of decline of cognitive and non-cognitive symptoms in DLB may help patients and carers to plan for the future.
Design
In this cohort study, the authors compared 100 AD and 58 DLB subjects at baseline and at 12-month follow-up on cognitive and neuropsychiatric measures.
Setting
Patients were recruited from 40 European centres.
Participants
Subjects with mild–moderate dementia. Diagnosis of DLB or AD required agreement between consensus panel clinical diagnosis and visual rating of 123I-FP-CIT (dopamine transporter) single photon emission computed tomography neuroimaging.
Outcome measures
The Cambridge Cognitive Examination including Mini-Mental State Examination and Neuropsychiatric Inventory (NPI).
Results
The AD and DLB groups did not differ at baseline in terms of age, gender, Clinical Dementia Rating score and use of cholinesterase inhibitors or memantine. NPI and NPI carer distress scores were statistically significantly higher for DLB subjects at baseline and at follow-up, and there were no differences between AD and DLB in cognitive scores at baseline or at follow-up. There was no significant difference in rate of progression of any of the variables analysed.
Conclusions
DLB subjects had more neuropsychiatric features at baseline and at follow-up than AD, but the authors did not find any statistically significant difference in rate of progression between the mild–moderate AD and DLB groups on cognitive or neuropsychiatric measures over a 12-month follow-up period.
Article summary
Article focus
Dementia with Lewy bodies (DLB) has distinct neuropsychiatric features.
At present, we do not know whether the poorer prognosis of DLB is due to a more rapid cognitive decline compared with Alzheimer's disease (AD).
Key messages
In this fairly large cohort of patients with DLB and AD, while there was no difference in level of cognitive impairment (Cambridge Cognitive Examination (CAMCOG) score) at baseline and at 12-month follow-up, DLB patients had significantly higher Neuropsychiatric Inventory (NPI) and NPI carer distress scores both at baseline and at 12-month follow-up.
Therefore, the worse prognosis of DLB is likely to be mediated by neuropsychiatric or other symptoms and not only by cognitive decline.
Strengths and limitations of this study
Inclusion of high number of subjects from 40 European clinical centres.
Well-characterised cases with both consensus panel clinical diagnosis (three clinical experts) and dopaminergic transporter single photon emission computed tomography imaging.
No autopsy data were available and therefore it is possible that more rapid cognitive decline may be present in pure DLB.
Only 1 year of follow-up.
There was higher attrition rate (no-follow-up assessment) in the DLB group, and DLB patients that did not return for follow-up were more impaired than AD patients.
doi:10.1136/bmjopen-2011-000380
PMCID: PMC3330257  PMID: 22318660
25.  Visual recognition memory differentiates dementia with Lewy bodies and Parkinson's disease dementia 
Objective
To compare cognitive impairments in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), to discriminate between the two entities.
Methods
10 DLB and 12 PDD consecutive patients performed a neuropsychological battery designed to assess several cognitive domains: verbal and visual memory (Delayed Matching to Sample (DMS)‐48), language, gnosia, praxia and executive functions.
Results
DLB patients had poorer performances in orientation (p<0.05), Trail Making Test A (p<0.05) and reading of names of colours in the Stroop Test (p<0.05). Their scores were also lower in the visual object recognition memory test (DMS‐48), in both immediate (p<0.05) and delayed recognition (p<0.05). No differences were observed in the other tests.
Conclusion
Despite global similarities in cognitive performances between DLB and PDD patients, we observed important differences: in particular, DMS‐48, a test of visual object recognition memory and visual storage capacity, was poorer in DLB patients.
doi:10.1136/jnnp.2006.104257
PMCID: PMC2117680  PMID: 17287240

Results 1-25 (1379914)