Outcomes of Patients With Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease at 3 and 5 Years After Diagnosis.

BACKGROUND AND OBJECTIVES: Retrospective studies indicate that dementia with Lewy bodies (DLB) may be preceded by a mild cognitive impairment (MCI) prodrome. Research criteria for the prospective identification of MCI with Lewy bodies (MCI-LB) have been developed. We aimed to assess the prognosis of a prospectively identified MCI-LB cohort at 2 key milestones, 3- and 5 years after diagnosis, to examine classification stability over time and rates of adverse outcomes (dementia or death). METHODS: This was a retrospective examination of data from 2 longitudinal observational cohort studies where participants with MCI were prospectively recruited from North East England and differentially classified as MCI due to Alzheimer disease (MCI-AD), possible MCI-LB, or probable MCI-LB. Adverse outcomes (DLB/other dementia or death) and stability of disease-specific classifications were examined in each group. RESULTS: Of 152 participants with baseline MCI (54 MCI-AD, 29 possible MCI-LB, and 69 probable MCI-LB), 126 were followed for up to 3 years (mean age 75.3 years; 40% female). We found that prospective probable MCI-LB classifications were both sensitive (91%) and specific (94%) to classifications either remaining as probable MCI-LB or progressing to DLB (in some cases autopsy confirmed) for 3 or more years after. Classifications were at least as stable as those in MCI-AD. In this cohort with disease-specific MCI classifications, rates of progression to dementia were high: 55% of MCI-LB had developed DLB within 3 years. Dementia occurred in 47% of MCI-AD over the same duration (odds ratio 1.68, 95% CI 0.66-4.26, p = 0.278). Premature death was a common competing risk, occurring in 9% of MCI-AD and 11% of MCI-LB within 3 years. DISCUSSION: These findings support that prospectively identified probable MCI-LB is a prodromal presentation of DLB and that disease-specific classifications of MCI may reliably identify different prodromal dementias.

Identifying parkinsonism in mild cognitive impairment.

INTRODUCTION: Clinical parkinsonism is a core diagnostic feature for mild cognitive impairment with Lewy bodies (MCI-LB) but can be challenging to identify. A five-item scale derived from the Unified Parkinson's Disease Rating Scale (UPDRS) has been recommended for the assessment of parkinsonism in dementia. This study aimed to determine whether the five-item scale is effective to identify parkinsonism in MCI. METHODS: Participants with MCI from two cohorts (n = 146) had a physical examination including the UPDRS and [123I]-FP-CIT SPECT striatal dopaminergic imaging. Participants were classified as having clinical parkinsonism (P+) or no parkinsonism (P-), and with abnormal striatal dopaminergic imaging (D+) or normal imaging (D-). The five-item scale was the sum of UPDRS tremor at rest, bradykinesia, action tremor, facial expression, and rigidity scores. The ability of the scale to differentiate P+D+ and P-D- participants was examined. RESULTS: The five-item scale had an AUROC of 0.92 in Cohort 1, but the 7/8 cut-off defined for dementia had low sensitivity to identify P+D+ participants (sensitivity 25%, specificity 100%). Optimal sensitivity and specificity was obtained at a 3/4 cut-off (sensitivity 83%, specificity 88%). In Cohort 2, the five-item scale had an AUROC of 0.97, and the 3/4 cut-off derived from Cohort 1 showed sensitivity of 100% and a specificity of 82% to differentiate P+D+ from P-D- participants. The five-item scale was not effective in differentiating D+ from D- participants. CONCLUSIONS: The five-item scale is effective to identify parkinsonism in MCI, but a lower threshold must be used in MCI compared with dementia.

Clinical symptoms in mild cognitive impairment with Lewy bodies: Frequency, time of onset, and discriminant ability.

BACKGROUND AND PURPOSE: Mild cognitive impairment with Lewy bodies (MCI-LB) is associated with a range of cognitive, motor, neuropsychiatric, sleep, autonomic, and visual symptoms. We investigated the cumulative frequency of symptoms in a longitudinal cohort of MCI-LB compared with MCI due to Alzheimer disease (MCI-AD) and analysed the ability of a previously described 10-point symptom scale to differentiate MCI-LB and MCI-AD, in an independent cohort. METHODS: Participants with probable MCI-LB (n = 70), MCI-AD (n = 51), and controls (n = 34) had a detailed clinical assessment and annual follow-up (mean duration = 1.7 years). The presence of a range of symptoms was ascertained using a modified version of the Lewy Body Disease Association Comprehensive LBD Symptom Checklist at baseline assessment and then annually. RESULTS: MCI-LB participants experienced a greater mean number of symptoms (24.2, SD = 7.6) compared with MCI-AD (11.3, SD = 7.4) and controls (4.2, SD = 3.1; p < 0.001 for all comparisons). A range of cognitive, parkinsonian, neuropsychiatric, sleep, and autonomic symptoms were significantly more common in MCI-LB than MCI-AD, although when present, the time of onset was similar between the two groups. A previously defined 10-point symptom scale demonstrated very good discrimination between MCI-LB and MCI-AD (area under the receiver operating characteristic curve = 0.91, 95% confidence interval = 0.84-0.98), replicating our previous finding in a new cohort. CONCLUSIONS: MCI-LB is associated with the frequent presence of a particular profile of symptoms compared to MCI-AD. Clinicians should look for evidence of these symptoms in MCI and be aware of the potential for treatment. The presence of these symptoms may help to discriminate MCI-LB from MCI-AD.

The relationship between plasma biomarkers and amyloid PET in dementia with Lewy bodies.

INTRODUCTION: Amyloid-ß (Aß) deposition is common in dementia with Lewy bodies (DLB) and has been associated with more rapid disease progression. An effective biomarker that identified the presence of significant brain Aß in people with DLB may be useful to identify and stratify participants for research studies and to inform prognosis in clinical practice. Plasma biomarkers are emerging as candidates to fulfil this role. METHODS: Thirty-two participants with DLB had brain amyloid (18F-florbetapir) PET, of whom 27 also had an MRI to enable the calculation of 18F-florbetapir SUVR. Plasma Aß42/40, phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) were measured using single molecule array (Simoa). The plasma biomarkers were investigated for correlation with 18F-florbetapir SUVR, discriminant ability to identify Aß-positive cases based on a predefined SUVR threshold of 1.10 and correlation with subsequent cognitive decline over one year. RESULTS: All four plasma markers significantly correlated with 18F-florbetapir SUVR (|ß| = 0.40-0.49; p < .05). NfL had the greatest area under the receiver operating characteristic curve to identify Aß-positive cases (AUROC 0.84 (95% CI 0.66, 1); ß = 0.46, p = .001), whereas Aß42/40 had the smallest (AUROC 0.73 (95% CI 0.52, 0.95); ß = -0.47, p = .01). Accuracy was highest when combining all four biomarkers (AUROC 0.92 (95% CI 0.80, 1)). Lower plasma Aß42/40 was significantly associated with more rapid decline in cognition (ß = 0.53, p < .01). CONCLUSIONS: Plasma biomarkers have the potential to identify Aß deposition in DLB. Further work in other cohorts is required to determine and validate optimal cut-offs for these biomarkers.

Transcranial Direct Current Stimulation in the Treatment of Visual Hallucinations in Charles Bonnet Syndrome: A Randomized Placebo-Controlled Crossover Trial.

OBJECTIVE: To investigate the potential therapeutic benefits and tolerability of inhibitory transcranial direct current stimulation (tDCS) on the remediation of visual hallucinations in Charles Bonnet syndrome (CBS). DESIGN: Randomized, double-masked, placebo-controlled crossover trial. PARTICIPANTS: Sixteen individuals diagnosed with CBS secondary to visual impairment caused by eye disease experiencing recurrent visual hallucinations. INTERVENTION: All participants received 4 consecutive days of active and placebo cathodal stimulation (current density: 0.29 mA/cm2) to the visual cortex (Oz) over 2 defined treatment weeks, separated by a 4-week washout period. MAIN OUTCOME MEASURES: Ratings of visual hallucination frequency and duration following active and placebo stimulation, accounting for treatment order, using a 2 × 2 repeated-measures model. Secondary outcomes included impact ratings of visual hallucinations and electrophysiological measures. RESULTS: When compared with placebo treatment, active inhibitory stimulation of visual cortex resulted in a significant reduction in the frequency of visual hallucinations measured by the North East Visual Hallucinations Interview, with a moderate-to-large effect size. Impact measures of visual hallucinations improved in both placebo and active conditions, suggesting support and education for CBS may have therapeutic benefits. Participants who demonstrated greater occipital excitability on electroencephalography assessment at the start of treatment were more likely to report a positive treatment response. Stimulation was found to be tolerable in all participants, with no significant adverse effects reported, including no deterioration in preexisting visual impairment. CONCLUSIONS: Findings indicate that inhibitory tDCS of visual cortex may reduce the frequency of visual hallucinations in people with CBS, particularly individuals who demonstrate greater occipital excitability prior to stimulation. tDCS may offer a feasible intervention option for CBS with no significant side effects, warranting larger-scale clinical trials to further characterize its efficacy.

Investigation of structural brain changes in Charles Bonnet Syndrome.

BACKGROUND AND OBJECTIVES: In Charles Bonnet Syndrome (CBS), visual hallucinations (VH) are experienced by people with sight loss due to eye disease or lesional damage to early visual pathways. The aim of this cross-sectional study was to investigate structural brain changes using magnetic resonance imaging (MRI) in CBS. METHODS: Sixteen CBS patients, 17 with eye disease but no VH, and 19 normally sighted people took part. Participants were imaged on a 3T scanner, with 1 mm resolution T1 weighted structural imaging, and diffusion tensor imaging with 64 diffusion directions. RESULTS: The three groups were well matched for age, sex and cognitive scores (MMSE). The two eye disease groups were matched on visual acuity. Compared to the sighted controls, we found reduced grey matter in the occipital cortex in both eye disease groups. We also found reductions of fractional anisotropy and increased diffusivity in widespread areas, including occipital tracts, the corpus callosum, and the anterior thalamic radiation. We did not find any significant differences between the eye disease participants with VH versus without VH, but did observe a negative association between hippocampal volume and VH severity in the CBS group. DISCUSSION: Our findings suggest that although there are cortical and subcortical effects associated with sight loss, structural changes do not explain the occurrence of VHs. CBS may relate instead to connectivity or excitability changes in brain networks linked to vision.

Progression to Dementia in Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease.

OBJECTIVE: To determine whether mild cognitive impairment with Lewy bodies or Alzheimer's disease differ in their rates of clinical progression to dementia, we undertook longitudinal observation of mild cognitive impairment cases with detailed clinical assessment of Lewy body diagnostic characteristics. METHODS: Two prospective longitudinal cohorts combining to 111 individuals aged 60 years or older with mild cognitive impairment were assessed annually to track cognitive and clinical progression, including the presence or absence of core clinical features and proposed biomarkers of dementia with Lewy bodies. Multi-state modelling was used to assess the associations of diagnostic characteristics of dementia with Lewy bodies with clinical progression from mild cognitive impairment to dementia, with death as a competing outcome. RESULTS: After a mean follow-up of 2.2 years (range = 1-6.7 years), 38/111 (34%) of the participants progressed to dementia: 10 with AD, 3 with possible dementia with Lewy bodies and 25 with probable dementia with Lewy bodies. The presence of any Lewy body disease characteristic was associated with an increased hazard of transition to dementia; this risk further increased as more diagnostic characteristics were observed (Hazard ratio = 1.33 per characteristic, 95% CI: 1.11-1.60), and was especially high for those experiencing complex visual hallucinations (Hazard ratio = 1.98, 95% CI: 0.92-4.29) or cognitive fluctuations (Hazard ratio = 3.99, 95% CI: 2.03-7.84). CONCLUSIONS: Diagnostic characteristics of Lewy body disease are associated with an increased risk of transition from mild cognitive impairment to dementia.

Accuracy of dopaminergic imaging as a biomarker for mild cognitive impairment with Lewy bodies.

BACKGROUND: Dopaminergic imaging is an established biomarker for dementia with Lewy bodies, but its diagnostic accuracy at the mild cognitive impairment (MCI) stage remains uncertain. AIMS: To provide robust prospective evidence of the diagnostic accuracy of dopaminergic imaging at the MCI stage to either support or refute its inclusion as a biomarker for the diagnosis of MCI with Lewy bodies. METHOD: We conducted a prospective diagnostic accuracy study of baseline dopaminergic imaging with [123I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane single-photon emission computerised tomography (123I-FP-CIT SPECT) in 144 patients with MCI. Images were rated as normal or abnormal by a panel of experts with access to striatal binding ratio results. Follow-up consensus diagnosis based on the presence of core features of Lewy body disease was used as the reference standard. RESULTS: At latest assessment (mean 2 years) 61 patients had probable MCI with Lewy bodies, 26 possible MCI with Lewy bodies and 57 MCI due to Alzheimer's disease. The sensitivity of baseline FP-CIT visual rating for probable MCI with Lewy bodies was 66% (95% CI 52-77%), specificity 88% (76-95%) and accuracy 76% (68-84%), with positive likelihood ratio 5.3. CONCLUSIONS: It is over five times as likely for an abnormal scan to be found in probable MCI with Lewy bodies than MCI due to Alzheimer's disease. Dopaminergic imaging appears to be useful at the MCI stage in cases where Lewy body disease is suspected clinically.

Prospective predictors of decline v. stability in mild cognitive impairment with Lewy bodies or Alzheimer's disease.

BACKGROUND: Mild cognitive impairment (MCI) may gradually worsen to dementia, but often remains stable for extended periods of time. Little is known about the predictors of decline to help explain this variation. We aimed to explore whether this heterogeneous course of MCI may be predicted by the presence of Lewy body (LB) symptoms in a prospectively-recruited longitudinal cohort of MCI with Lewy bodies (MCI-LB) and Alzheimer's disease (MCI-AD). METHODS: A prospective cohort (n = 76) aged ⩾60 years underwent detailed assessment after recent MCI diagnosis, and were followed up annually with repeated neuropsychological testing and clinical review of cognitive status and LB symptoms. Latent class mixture modelling identified data-driven sub-groups with distinct trajectories of global cognitive function. RESULTS: Three distinct trajectories were identified in the full cohort: slow/stable progression (46%), intermediate progressive decline (41%) and a small group with a much faster decline (13%). The presence of LB symptomology, and visual hallucinations in particular, predicted decline v. a stable cognitive trajectory. With time zeroed on study end (death, dementia or withdrawal) where available (n = 39), the same subgroups were identified. Adjustment for baseline functioning obscured the presence of any latent classes, suggesting that baseline function is an important parameter in prospective decline. CONCLUSIONS: These results highlight some potential signals for impending decline in MCI; poorer baseline function and the presence of probable LB symptoms - particularly visual hallucinations. Identifying people with a rapid decline is important but our findings are preliminary given the modest cohort size.

Cognitive Decline in Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease: A Prospective Cohort Study.

OBJECTIVE: We explored whether the mild cognitive impairment (MCI) stages of dementia with Lewy bodies (DLB) and Alzheimer disease (AD) differ in their cognitive profiles, and longitudinal progression. DESIGN: A prospective, longitudinal design was utilized with annual follow-up (Max 5 years, Mean 1.9, standard deviation 1.1) after diagnosis. Participants underwent repeated cognitive testing, and review of their clinical diagnosis and symptoms, including evaluation of core features of DLB. SETTING: This was an observational study of independently living individuals, recruited from local healthcare trusts in North East England, UK. PARTICIPANTS: An MCI cohort (n = 76) aged ≥60 years was utilized, differentially diagnosed with MCI due to AD (MCI-AD), or possible/probable MCI with Lewy bodies (MCI-LB). MEASUREMENTS: A comprehensive clinical and neuropsychological testing battery was administered, including ACE-R, trailmaking tests, FAS verbal fluency, and computerized battery of attention and perception tasks. RESULTS: Probable MCI-LB presented with less impaired recognition memory than MCI-AD, greater initial impairments in verbal fluency and perception of line orientation, and thereafter demonstrated an expedited decline in visuo-constructional functions in the ACE-R compared to MCI-AD. No clear diagnostic group differences were found in deterioration speeds for global cognition, language, overall memory, attention or other executive functions. CONCLUSION: These findings provide further evidence for differences in severity and decline of visuospatial dysfunctions in DLB compared with AD; further exploration is required to clarify when and how differences in attention, executive, and memory functions emerge, as well as speed of decline to dementia.

Diffusion imaging in dementia with Lewy bodies: Associations with amyloid burden, atrophy, vascular factors and clinical features.

INTRODUCTION: White matter disruption in dementia has been linked to a variety of factors including vascular disease and cortical pathology. We aimed to examine the relationship between white matter changes on diffusion tensor imaging (DTI) in DLB and factors including vascular disease, structural atrophy and amyloid burden. METHODS: Participants with DLB (n = 29), Alzheimer's disease (AD, n = 17) and healthy controls (n = 20) had clinical and neuropsychological assessments followed by structural and diffusion tensor 3T MRI and 18F-Florbetapir PET-CT imaging. Voxelwise statistical analysis of white matter fractional anisotropy (FA) and mean diffusivity (MD) was carried out using Tract-Based Spatial Statistics with family-wise error correction (p < 0.05). RESULTS: DLB and AD groups demonstrated widespread increased MD and decreased FA when compared with controls. There were no differences between the DLB and AD groups. In DLB, increased MD and decreased FA correlated with decreased grey matter and hippocampal volumes as well as vascular disease. There was no correlation with cortical florbetapir SUVR. The relationship between DTI changes and grey matter/hippocampal volumes remained after including Cumulative Illness Rating Scale-Geriatric vascular score as a covariate. CONCLUSIONS: Widespread disruption of white matter tracts is present in DLB and is associated with vascular disease, reduced hippocampal volume and reduced grey matter volume, but not with cortical amyloid deposition. The mechanism behind the correlation observed between hippocampal volume and white matter tract disruption should be investigated in future cohorts using tau imaging, as hippocampal atrophy has been shown to correlate with tau deposition in DLB.

Prospective longitudinal evaluation of cytokines in mild cognitive impairment due to AD and Lewy body disease.

OBJECTIVES: We conducted a prospective longitudinal study of plasma cytokines during the Mild Cognitive Impairment (MCI) stage of Lewy body disease and Alzheimer's disease, hypothesizing that cytokine levels would decrease over time and that this would be correlated with decline in cognition. METHODS: Older (≥60) people with MCI were recruited from memory services in healthcare trusts in North East England, UK. MCI was diagnosed as due to Alzheimer's disease (MCI-AD) or Lewy body disease (MCI-LB). Baseline and repeat annual clinical and cognitive assessments were undertaken and plasma samples were obtained at the same time. Cytokine assays were performed on all samples using the Meso Scale Discovery V-Plex Plus Proinflammatory Panel 1, which included IFNγ, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 and TNFα. RESULTS: Fifty-six patients (21 MCI-AD, 35 MCI-LB) completed prospective evaluations and provided samples up to 3 years after baseline. Six cytokines (IFNγ, IL-1ß, IL-2, IL-4, IL-6 and IL-10) showed highly significant (P < .002) decreases over time. AD and LB did not differ in rate of decrease nor were there any effects related to age or general morbidity. Decrease in five of these cytokines (IFNγ, IL-1ß, IL-2, IL-4, and IL-10) was highly correlated with decrease in cognition (P < .003). CONCLUSIONS: Peripheral inflammation decreased in both disease groups during MCI suggesting this may be a therapeutic window for future anti-inflammatory agents.

Visual hallucinations in neurological and ophthalmological disease: pathophysiology and management.

Visual hallucinations are common in older people and are especially associated with ophthalmological and neurological disorders, including dementia and Parkinson's disease. Uncertainties remain whether there is a single underlying mechanism for visual hallucinations or they have different disease-dependent causes. However, irrespective of mechanism, visual hallucinations are difficult to treat. The National Institute for Health Research (NIHR) funded a research programme to investigate visual hallucinations in the key and high burden areas of eye disease, dementia and Parkinson's disease, culminating in a workshop to develop a unified framework for their clinical management. Here we summarise the evidence base, current practice and consensus guidelines that emerged from the workshop.Irrespective of clinical condition, case ascertainment strategies are required to overcome reporting stigma. Once hallucinations are identified, physical, cognitive and ophthalmological health should be reviewed, with education and self-help techniques provided. Not all hallucinations require intervention but for those that are clinically significant, current evidence supports pharmacological modification of cholinergic, GABAergic, serotonergic or dopaminergic systems, or reduction of cortical excitability. A broad treatment perspective is needed, including carer support. Despite their frequency and clinical significance, there is a paucity of randomised, placebo-controlled clinical trial evidence where the primary outcome is an improvement in visual hallucinations. Key areas for future research include the development of valid and reliable assessment tools for use in mechanistic studies and clinical trials, transdiagnostic studies of shared and distinct mechanisms and when and how to treat visual hallucinations.

Microbleeds in dementia with Lewy bodies.

INTRODUCTION: Microbleeds are associated with the development of dementia in older people and are common in Alzheimer's disease (AD). Their prevalence and clinical importance in dementia with Lewy bodies (DLB) is unclear. The objective of this study was to compare the rates of microbleeds in DLB with those in AD and healthy older people, and investigate associations between microbleeds and amyloid deposition, vascular risk and disease severity in DLB. METHODS: DLB (n = 30), AD (n = 18) and control (n = 20) participants underwent clinical assessment at baseline and 1 year in this longitudinal observational study. 3T MRI (including T2* susceptibility weighted imaging) and florbetapir PET were carried out at baseline. Microbleeds were rated visually and a standardised uptake value ratio (SUVR) was calculated from florbetapir PET scans. RESULTS: 40% of DLB subjects had microbleeds compared with 50% of AD and 15% of controls. Compared to DLB without microbleeds, those with microbleeds had higher systolic BP (156 ± 26 v. 135 ± 19 mmHg; p = 0.03), but did not have greater levels of vascular disease or amyloid deposition (SUVR 1.25 ± 0.24 v. 1.25 ± 0.22; p = 0.33). There was evidence of less severe dementia in DLB participants with microbleeds, but these differences may have been driven by a shorter disease duration in those with microbleeds. CONCLUSION: The presence of microbleeds in DLB is associated with higher blood pressure, but not with other measures of vascular disease or amyloid deposition. The relationship between microbleeds and clinical presentation remains unclear.

Amyloid Imaging and Longitudinal Clinical Progression in Dementia With Lewy Bodies.

OBJECTIVE: Significant amyloid deposition is present in approximately half of all cases of dementia with Lewy bodies (DLB). We sought to determine whether amyloid deposition was associated with more rapid clinical decline over 1 year. METHODS: Twenty-eight participants had a baseline clinical assessment and amyloid PET scan, followed by a further clinical assessment after 1 year. Changes in clinical measures were compared with amyloid deposition assessed by visual rating and cortical standardized uptake value ratio. RESULTS: Amyloid deposition on visual rating was associated with greater decline in Mini-Mental State Examination and daily function over 1 year. There was no correlation between cortical standardized uptake value ratio and clinical measures. CONCLUSIONS: This study provides further evidence for a link between amyloid deposition and clinical progression in DLB. Pathologies such as amyloid, and their interaction with α-synuclein, remain possible treatment targets in DLB.

Inflammation in mild cognitive impairment due to Parkinson's disease, Lewy body disease, and Alzheimer's disease.

BACKGROUND: Inflammation appears to play a role in the progression of neurodegenerative diseases. However, little is known about inflammation during early stages of cognitive decline or whether this differs in different disease groups. We sought to investigate this by assessing the inflammatory profile in patients with Parkinson disease with the early stages of cognitive impairment (PD-MCI), patients with prodromal Alzheimer disease (MCI-AD), prodromal Lewy body disease (MCI-LB), and controls. METHODS: We obtained venous blood samples from participants with PD-MCI (n = 44), PD-normal cognition (n = 112), MCI-LB (n = 38), MCI-AD (n = 21), and controls (n = 84). We measured 10 cytokines using Meso Scale Discovery V-Plex Plus including interferon gamma, interleukin (IL)-10, IL-12p70, IL-13, IL-1beta, IL-2, IL-4, IL-6, IL-8, and tumour necrosis factor alpha. High-sensitivity C-reactive protein was measured. RESULTS: There was a higher level of inflammation in patients with MCI-AD and MCI-LB compared with controls. PD noncognitively impaired had higher inflammatory markers than controls, but there was no difference between PD-MCI and controls. There was a decrease in inflammatory markers with increasing motor severity based on the Unified Parkinson's Disease Rating Scale. CONCLUSIONS: Inflammation may be involved in the onset of cognitive decline in patients with MCI-AD and MCI-LB but appears to be less prominent PD-MCI albeit in a small data set. This suggests that anti-inflammatory medications may have most benefit at the earliest stages of neurodegenerative diseases. For PD cases, this might be in advance of the development of MCI.

Peripheral inflammation in mild cognitive impairment with possible and probable Lewy body disease and Alzheimer's disease.

ABSTRACTObjectives and design:To Investigate the peripheral inflammatory profile in patients with mild cognitive impairment (MCI) from three subgroups - probable Lewy body disease (probable MCI-LB), possible Lewy body disease, and probable Alzheimer's disease (probable MCI-AD) - as well as associations with clinical features. SETTING: Memory clinics and dementia services. PARTICIPANTS: Patients were classified based on clinical symptoms as probable MCI-LB (n = 38), possible MCI-LB (n = 18), and probable MCI-AD (n = 21). Healthy comparison subjects were recruited (n = 20). MEASUREMENTS: Ten cytokines were analyzed from plasma samples: interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and tumor necrosis factor (TNF)-alpha. C-reactive protein levels were investigated. RESULTS: There was a higher level of IL-10, IL-1beta, IL-2, and IL-4 in MCI groups compared to the healthy comparison group (p < 0.0085). In exploratory analyses to understand these findings, the MC-AD group lower IL-1beta (p = 0.04), IL-2 (p = 0.009), and IL-4 (p = 0.012) were associated with increasing duration of memory symptoms, and in the probable MCI-LB group, lower levels of IL-1beta were associated with worsening motor severity (p = 0.002). In the possible MCI-LB, longer duration of memory symptoms was associated with lower levels of IL-1beta (p = 0.003) and IL-4 (p = 0.026). CONCLUSION: There is increased peripheral inflammation in patients with MCI compared to healthy comparison subjects regardless of the MCI subtype. These possible associations with clinical features are consistent with other work showing that inflammation is increased in early disease but require replication. Such findings have importance for timing of putative therapeutic strategies aimed at lowering inflammation.

Prevalence and severity of symptoms suggestive of gastroparesis in prodromal dementia with Lewy bodies.

INTRODUCTION: Lewy body disease is postulated, by the Braak model, to originate in the enteric nervous system, before spreading to the central nervous system. Therefore, a high prevalence of gastroparesis symptoms would be expected in prodromal dementia with Lewy bodies (DLB) and be highest in those with a dopaminergic deficit on imaging. The aim of this study was to explore whether gastroparesis symptoms are an early diagnostic marker of prodromal DLB and explore the relationship between symptoms and dopaminergic imaging findings on FP-CIT SPECT. METHODS: We recruited 75 patients over 60 with mild cognitive impairment (MCI), 48 with MCI with suspected Lewy body disease (MCI-LB) and 27 with MCI with suspected Alzheimer's disease (MCI-AD). All patients completed the Gastroparesis Cardinal Symptom Index (GSCI) questionnaire and also underwent FP-CIT [123 I-N-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)] dopaminergic imaging. RESULTS: At least one symptom suggestive of gastroparesis was reported in 48% (n = 23) MCI-LB vs 37% MCI-AD (n = 10) (P = 0.36). Rates of definite symptoms of gastroparesis, as defined by a GCSI total score ≥ 1.90, were rare and rates in MCI-LB were not different from MCI-AD (6% vs 0%, p = 0.55). After adjusting for gender differences between groups, no difference in gastroparesis symptom prevalence (2.27 vs 0.81 P = 0.05) or severity score (0.62 vs 0.28, p = 0.28) was noted between normally and abnormally visually rated FP-CIT SPECT scans. CONCLUSION: The GCSI is not a useful tool for differentiating MCI-LB from MCI-AD. A low rate of definite gastroparesis was detected in prodromal DLB. No association was found between gastroparesis symptoms and FP-CIT SPECT findings.

Diagnostic accuracy of dopaminergic imaging in prodromal dementia with Lewy bodies.

BACKGROUND: Dopaminergic imaging has high diagnostic accuracy for dementia with Lewy bodies (DLB) at the dementia stage. We report the first investigation of dopaminergic imaging at the prodromal stage. METHODS: We recruited 75 patients over 60 with mild cognitive impairment (MCI), 33 with probable MCI with Lewy body disease (MCI-LB), 15 with possible MCI-LB and 27 with MCI with Alzheimer's disease. All underwent detailed clinical, neurological and neuropsychological assessments and FP-CIT [123I-N-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)] dopaminergic imaging. FP-CIT scans were blindly rated by a consensus panel and classified as normal or abnormal. RESULTS: The sensitivity of visually rated FP-CIT imaging to detect combined possible or probable MCI-LB was 54.2% [95% confidence interval (CI) 39.2-68.6], with a specificity of 89.0% (95% CI 70.8-97.6) and a likelihood ratio for MCI-LB of 4.9, indicating that FP-CIT may be a clinically important test in MCI where any characteristic symptoms of Lewy body (LB) disease are present. The sensitivity in probable MCI-LB was 61.0% (95% CI 42.5-77.4) and in possible MCI-LB was 40.0% (95% CI 16.4-67.7). CONCLUSIONS: Dopaminergic imaging had high specificity at the pre-dementia stage and gave a clinically important increase in diagnostic confidence and so should be considered in all patients with MCI who have any of the diagnostic symptoms of DLB. As expected, the sensitivity was lower in MCI-LB than in established DLB, although over 50% still had an abnormal scan. Accurate diagnosis of LB disease is important to enable early optimal treatment for LB symptoms.