Non-pharmacological interventions for Lewy body dementia: a systematic review.

Lewy body dementia (consisting of dementia with Lewy bodies and Parkinson's disease dementia) is a common neurodegenerative disease characterised by visual hallucinations, fluctuating attention, motor disturbances, falls, and sensitivity to antipsychotics. This combination of features presents challenges for pharmacological management. Given this, we sought to review evidence for non-pharmacological interventions with patients with Lewy body dementia and their carers. Bibliographic databases were searched using a wide range of search terms and no restrictions were placed on study design, language, or clinical setting. Two reviewers independently assessed papers for inclusion, rated study quality, and extracted data. The search identified 21 studies including two randomised controlled trials with available subgroup data, seven case series, and 12 case studies. Most studies reported beneficial effects of the interventions used, though the only sizeable study was on dysphagia, showing a benefit of honey-thickened liquids. Given the heterogeneity of interventions and poor quality of the studies overall, no quantitative synthesis was possible. Overall, identified studies suggested possible benefits of non-pharmacological interventions in Lewy body dementia, but the small sample sizes and low quality of studies mean no definite recommendations can be offered. Our findings underscore the clear and urgent need for future research on this topic.

Does attentional dysfunction and thalamic atrophy predict decline in dementia with Lewy bodies?

INTRODUCTION: To evaluate the clinical characteristics of DLB subjects who died within 1 year of assessment compared to those who survived and investigate their patterns of in vivo regional thalamic atrophy using structural MRI. METHODS: Seventy subjects (35 DLB, 35 aged controls) underwent 3 T T1-weighted MR scanning as well as clinical and cognitive assessments, including a computerised assessment of attention. All subjects were contacted after 12 months for reassessment. For both hemispheres, using FSL FIRST, the thalamus was automatically segmented followed by inter-subject vertex-wise analyses involving group comparisons and behavioural correlates. RESULTS: There was significant bilateral atrophy in the ventral-dorsal and pulvinar regions in DLB relative to controls (pcorrected < 0.05). The DLB group was then re-categorised based on 12-month mortality data: DLB-a (n = 26) and DLB-d (n = 9) (a = alive, d = death within 12 months of study assessment). Compared to controls, significant attentional dysfunction and bilateral atrophy of the pulvinar, ventral and dorsal nuclei were observed in DLB-d (pcorrected < 0.05), whereas in DLB-a, atrophy was far less extensive. CONCLUSIONS: Distinct patterns of thalamic atrophy occur in DLB that may relate to the attentional dysfunction and cognitive fluctuations that characterise this disorder. Relative to controls, the extent of attentional impairment and pattern of thalamic degeneration differ in those patients who died within 12 months of assessment, despite having an otherwise similar level of dementia severity. These findings may provide insight into the neurobiological changes underpinning important clinical characteristics and disease heterogeneity.

Clinical practice with anti-dementia drugs: A revised (third) consensus statement from the British Association for Psychopharmacology.

The British Association for Psychopharmacology coordinated a meeting of experts to review and revise its previous 2011 guidelines for clinical practice with anti-dementia drugs. As before, levels of evidence were rated using accepted standards which were then translated into grades of recommendation A-D, with A having the strongest evidence base (from randomised controlled trials) and D the weakest (case studies or expert opinion). Current clinical diagnostic criteria for dementia have sufficient accuracy to be applied in clinical practice (B) and both structural (computed tomography and magnetic resonance imaging) and functional (positron emission tomography and single photon emission computerised tomography) brain imaging can improve diagnostic accuracy in particular situations (B). Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) are effective for cognition in mild to moderate Alzheimer's disease (A), memantine for moderate to severe Alzheimer's disease (A) and combination therapy (cholinesterase inhibitors and memantine) may be beneficial (B). Drugs should not be stopped just because dementia severity increases (A). Until further evidence is available other drugs, including statins, anti-inflammatory drugs, vitamin E, nutritional supplements and Ginkgo biloba, cannot be recommended either for the treatment or prevention of Alzheimer's disease (A). Neither cholinesterase inhibitors nor memantine are effective in those with mild cognitive impairment (A). Cholinesterase inhibitors are not effective in frontotemporal dementia and may cause agitation (A), though selective serotonin reuptake inhibitors may help behavioural (but not cognitive) features (B). Cholinesterase inhibitors should be used for the treatment of people with Lewy body dementias (both Parkinson's disease dementia and dementia with Lewy bodies), and memantine may be helpful (A). No drugs are clearly effective in vascular dementia, though cholinesterase inhibitors are beneficial in mixed dementia (B). Early evidence suggests multifactorial interventions may have potential to prevent or delay the onset of dementia (B). Though the consensus statement focuses on medication, psychological interventions can be effective in addition to pharmacotherapy, both for cognitive and non-cognitive symptoms. Many novel pharmacological approaches involving strategies to reduce amyloid and/or tau deposition in those with or at high risk of Alzheimer's disease are in progress. Though results of pivotal studies in early (prodromal/mild) Alzheimer's disease are awaited, results to date in more established (mild to moderate) Alzheimer's disease have been equivocal and no disease modifying agents are either licensed or can be currently recommended for clinical use.

Depression and synaptic zinc regulation in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia.

OBJECTIVE: Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study. METHODS: We examined brains from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison subjects without depression or dementia (N = 24). Individuals were categorized according to the presence and severity of depression (on a scale of 0-3) based on standardized assessments during life (principally Neuropsychiatric Inventory). Western blotting was used to determine ZnT3 levels in Brodmann area 9 (BA9), and regression analysis was used to determine the relationship between ZnT3 and depression. RESULTS: Reductions in ZnT3 in BA9 were significantly associated with elevated depression scores in the study cohort (ß = -0.351, df = 93, t = -3.318 p = 0.0004). This association remained when only individuals with DLB, PDD, and no dementia or depression were examined (ß = -0.347, df = 78, t = -3.271, p = 0.002) or only individuals with AD and no dementia or depression were examined (ß = -0.433, df = 37, t = -2.924, p = 0.006). CONCLUSION: Although decreased zinc levels have been implicated in the genesis of depression in animal models and in major depressive disorder in humans, this study provides the first evidence of a role for zinc in depression in people with dementia and highlights zinc metabolism as a therapeutic target.

Subcortical connectivity in dementia with Lewy bodies and Alzheimer's disease.

BACKGROUND: Resting-state functional magnetic resonance imaging (fMRI) can be used to measure correlations in spontaneous low-frequency fluctuations in the blood oxygen level-dependent (BOLD) signal which represent functional connectivity between key brain areas. AIMS: To investigate functional connectivity with regions hypothesised to be differentially affected in dementia with Lewy bodies (DLB) compared with Alzheimer's disease and controls. METHOD: Fifteen participants with probable DLB, 16 with probable Alzheimer's disease and 16 controls were scanned in the resting-state using a 3T scanner. The BOLD signal time-series of fluctuations in seed regions were correlated with all other voxels to measure functional connectivity. RESULTS: Participants with DLB and Alzheimer's disease showed greater caudate and thalamic connectivity compared with controls. Those with DLB showed greater putamen connectivity compared with those with Alzheimer's disease and the controls. No regions showed less connectivity in DLB or Alzheimer's disease v. controls, or in DLB v. Alzheimer's disease. CONCLUSIONS: Altered connectivity in DLB and Alzheimer's disease provides new insights into the neurobiology of these disorders and may aid in earlier diagnosis.

Characterizing dementia with Lewy bodies by means of diffusion tensor imaging.

OBJECTIVE: To investigate patterns of in vivo white matter tract change using diffusion tensor imaging (DTI), we conducted a cross-sectional study of dementia with Lewy bodies (DLB) in comparison with Alzheimer disease (AD) and normal aging. METHODS: The study included 106 subjects (35 with DLB, 36 with AD, and 35 elderly controls) who underwent clinical and neuropsychological assessment and diffusion tensor MRI. We used tract-based spatial statistics to investigate patterns of reduced fractional anisotropy (FA) and increased mean diffusivity (MD) across the entire white matter tract skeleton and also investigated correlations with clinical features. RESULTS: Areas of reduced FA in subjects with DLB vs controls were found primarily in parieto-occipital white matter tracts; in AD, the changes were much more diffuse. DLB was also associated with reduced FA in the pons and left thalamus, in comparison with AD. The pattern of MD increase was diffuse in AD and DLB. We found an association between DTI parameters and impaired episodic memory, letter fluency, and severity of motor parkinsonism in DLB. CONCLUSIONS: Despite a similar level of dementia severity, patterns of DTI changes in AD and DLB differed significantly. The selective involvement of the visual association areas and subcortical structures and the significant clinical correlations highlight the potential importance of white matter tract change in the pathogenesis of DLB. DTI may be a useful technique to investigate early and possible preclinical changes in DLB and warrants further investigation.

Post-stroke dementia: the contribution of thalamus and basal ganglia changes.

BACKGROUND: The neurobiological basis of increased risk of dementia in stroke patients is unclear, though there are several related pathological changes, including white matter hyperintensities (WMH), and medial temporal atrophy. Subcortical gray matter structures have also been implicated in dementia resulting from vascular pathology, particularly vascular dementia. This study aimed to investigate the contribution of changes in subcortical gray matter structures to post-stroke dementia (PSD). METHODS: T1- and T2-weighted images and T2-weighted fluid-attenuated inversion recovery (FLAIR) images were obtained on a 3-Tesla magnetic resonance (MR) system, in four groups aged over 75 years: post-stroke with dementia (PSD; 8), post-stroke no dementia (PSnoD; 33), Alzheimer's disease (AD; 26) and controls (30). Automated software was used to measure the volume of thalamus, putamen, caudate nucleus, and hippocampus as well as total WMH volume. The number of subcortical lacunes was also counted. RESULTS: The number of caudate lacunes was higher in the PSnoD group, compared with AD (p = 0.029) and controls (p = 0.019). The putamen volume was smaller in the stroke and AD groups, when compared with controls. In the whole stroke group, putamen lacunes were correlated with impairment in memory (Rey test; ρ = -0.365; p = 0.031), while WMH and hippocampal volume both correlated with global dysfunction. CONCLUSION: Our findings implicate a variety of neurobiological substrates of dementia, such as small vessel disease and Alzheimer pathology, which develop after stroke in an old older population, with a contribution from subcortical brain structures.

Functional connectivity in late-life depression using resting-state functional magnetic resonance imaging.

OBJECTIVE: To investigate whether there are differences in brain connectivity in late-life depression (LLD) and nondepressed subjects using the left and right heads of caudate nuclei (hCN) as the seed regions. DESIGN: Resting-state functional magnetic resonance imaging (fMRI) data were collected using a 3-Tesla MRI System. SETTING: Subjects were recruited from primary or secondary care services in the Newcastle area. PARTICIPANTS: Thirty-three subjects aged 65 years and older; 16 who had a recent episode of LLD and 17 nondepressed subjects. MEASUREMENTS: Functional connectivity was analyzed by extracting the temporal signal variation from the left and right hCN and cross correlating with the rest of the brain. RESULTS: Significant connectivity between the hCN and frontal areas was observed in the nondepressed group, whereas in LLD, connectivity was seen over a much wider area. Regions showing significantly greater connectivity (p < or =0.05) in LLD compared with the nondepressed group were frontal (precentral, subgyral, middle frontal, and paracentral lobule), sublobar (thalamus and insula), limbic (cingulate), parietal (postcentral gyrus, precuneus, inferior parietal lobule, and supramarginal gyrus), and temporal (superior temporal gyrus). Conversely, no brain regions showed greater connectivity in the nondepressed group than LLD. In both groups, the right hCN showed significantly greater connectivity than the left in numerous brain regions, but connectivity for the left hCN did not exceed the right in any brain regions. CONCLUSIONS: This resting-state study showed increased connectivity in specific brain regions in LLD compared with the nondepressed group, which supports the view that functional connectivity is altered in depression.

Vascular factors and depression.

OBJECTIVE: This paper examines possible mechanisms that may explain the bi-directional relationship between vascular disease and depression. DESIGN: A literature review was carried out using Medline from 1996 to 2007, using relevant key words including vascular depression, and supplemented by key references to earlier work. RESULTS: Several mechanisms were considered including: autonomic dysfunction, platelet activation, hypothalamic pituitary axis activation, endothelial dysfunction, cytokines, omega 3 fatty acids, genetics, homocysteine and effects of treatment. CONCLUSIONS: The relationship between vascular disease and depression cannot solely be explained by current established risk factors or the effects of treatment for depression. Other mechanisms must apply, and there is some evidence for common genetic factors. Promising future lines of investigation include homocysteine, cytokines and endothelial dysfunction. More longitudinal studies combined with measurements of these biomarkers are needed.

Aromatherapy as a safe and effective treatment for the management of agitation in severe dementia: the results of a double-blind, placebo-controlled trial with Melissa.

BACKGROUND: Behavioral and psychological symptoms in dementia are frequent and are a major management problem, especially for patients with severe cognitive impairment. Preliminary reports have indicated positive effects of aromatherapy using select essential oils, but there are no adequately powered placebo-controlled trials. We conducted a placebo-controlled trial to determine the value of aromatherapy with essential oil of Melissa officinalis (lemon balm) for agitation in people with severe dementia. METHOD: Seventy-two people residing in National Health Service (U.K.) care facilities who had clinically significant agitation in the context of severe dementia were randomly assigned to aromatherapy with Melissa essential oil (N = 36) or placebo (sunflower oil) (N = 36). The active treatment or placebo oil was combined with a base lotion and applied to patients' faces and arms twice a day by caregiving staff. Changes in clinically significant agitation (Cohen-Mansfield Agitation Inventory [CMAI]) and quality of life indices (percentage of time spent socially withdrawn and percentage of time engaged in constructive activities, measured with Dementia Care Mapping) were compared between the 2 groups over a 4-week period of treatment. RESULTS: Seventy-one patients completed the trial. No significant side effects were observed. Sixty percent (21/35) of the active treatment group and 14% (5/36) of the placebo-treated group experienced a 30% reduction of CMAI score, with an overall improvement in agitation (mean reduction in CMAI score) of 35% in patients receiving Melissa balm essential oil and 11% in those treated with placebo (Mann-Whitney U test; Z = 4.1, p < .0001). Quality of life indices also improved significantly more in people receiving essential balm oil (Mann-Whitney U test; percentage of time spent socially withdrawn: Z = 2.6, p = .005; percentage of time engaged in constructive activities: Z = 3.5, p = .001). CONCLUSION: The finding that aromatherapy with essential balm oil is a safe and effective treatment for clinically significant agitation in people with severe dementia, with additional benefits for key quality of life parameters, indicates the need for further controlled trials.