Neuropsychological profile of mild cognitive impairment with Lewy body disease

PhD ThesisObjective: Efforts are being made to identify dementia with Lewy bodies (DLB), the second commonest cause of neurodegenerative dementia after Alzheimer's disease (AD), in the Mild Cognitive Impairment (MCI) phase, during which intervention on the disease processes would likely be most successful. Few studies have targeted this group and the cognitive profile of MCI with Lewy bodies (MCI-LB) is therefore unclear. The present study aims to elucidate the neuropsychology of MCI-LB relative to MCI due to AD (MCI-AD) and healthy controls. Methods: In addition to age-matched controls (n = 31), participants with MCI and symptoms suggestive of LB disease were recruited from local clinics. Baseline assessment of all subjects included clinical examination, imaging (123iodinemetaiodobenzylguanidine [MIBG], dopamine transporter imaging [DaTscan]), and comprehensive neuropsychological assessments. Simple and Choice Reaction Time (SRT and CRT) and a Continuous Performance Test-AX (CPT-AX) were also administered to measure intraindividual variability (IIV) in attention using ex-Gaussian modelling of reaction times. MCI patients were diagnosed firstly following National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria for MCI. Participants with demonstrable cognitive impairment but no clinical symptoms or biomarkers for DLB were considered MCI-AD (n = 18). Within MCI-LB (n = 44), individuals with two or more consensus criteria for the diagnostic features or biomarkers of DLB (McKeith et al., 2017) were considered "Probable" MCI-LB (n = 30). White matter integrity was quantified using diffusion tensor imaging (DTI) and tract-based spatial statistics. Results: While both groups are impaired relative to controls, MCI-LB Probable performed worse than MCI-AD on processing speed (Digit Symbol Substitution Test [DSST, p = .011]), executive function (Verbal Fluency [FAS], p = .027) and visuospatial function (pareidolia task, p = .010; Visual Patterns Test, p = .019) tests. In contrast, MCI-AD scored significantly lower than MCI-LB Probable on tests of verbal learning and memory (Rey Auditory Verbal Learning Test short, p = .047, and long delay, p = .025, and retroactive interference, p = .029). DSST was the best predictor of group allocation using a stepwise discriminant analysis, F(2,76) = 36.89, p < .001, and 92.6% of MCI-LB Probable scored at or below the 16th percentile of control DSST scores. Using hierarchical linear regression, a control-informed processing speed composite fully explained group-associated variance in the visuospatial composite, RAVLT learning and RAVLT short delay recall. In contrast, FAS explained only 25.0% of group variance in the visuospatial composite and is not significantly correlated with RAVLT short delay (p = .132). MCI-LB Probable showed increased IIV using ex-Gaussian tau in CRT (p = .021, d = 1.12) and CPT-AX (p = .007, d =0.80) relative to controls, while MCI-AD differed significantly from controls in SRT tau (p = .002, d = 0.93). No difference between groups was found in white mater integrity, although the DSST showed substantial correlation with fractional anisotropy in the sample as a whole. Conclusions: The present study succeeded in demonstrating that the cognitive dysfunction typical of advanced DLB and AD is observable in the MCI phase of clinically-defined MCI-LB and MCI-AD, respectively. MCI-LB showed visuospatial, attentional and processing speed impairments. Processing speed emerged as particularly important to MCI-LB neuropsychology, suggesting a processing speed, rather than executive, mediated model of decline in MCI-LB. MCI-AD, in contrast, shows verbal learning and memory impairment. Future work should pursue this promising evidence of subtle, aetiologically-specific differences in cognition in MC

Visuo-perceptual and decision-making contributions to visual hallucinations in mild cognitive impairment in Lewy body disease: insights from a drift diffusion analysis

Background: Visual hallucinations (VH) are a common symptom in dementia with Lewy bodies (DLB); however, their cognitive underpinnings remain unclear. Hallucinations have been related to cognitive slowing in DLB and may arise due to impaired sensory input, dysregulation in top-down influences over perception, or an imbalance between the two, resulting in false visual inferences. Methods: Here we employed a drift diffusion model yielding estimates of perceptual encoding time, decision threshold, and drift rate of evidence accumulation to (i) investigate the nature of DLB-related slowing of responses and (ii) their relationship to visuospatial performance and visual hallucinations. The EZ drift diffusion model was fitted to mean reaction time (RT), accuracy and RT variance from two-choice reaction time (CRT) tasks and data were compared between groups of mild cognitive impairment (MCI-LB) LB patients (n = 49) and healthy older adults (n = 25). Results: No difference was detected in drift rate between patients and controls, but MCI-LB patients showed slower non-decision times and boundary separation values than control participants. Furthermore, non-decision time was negatively correlated with visuospatial performance in MCI-LB, and score on visual hallucinations inventory. However, only boundary separation was related to clinical incidence of visual hallucinations. Conclusions: These results suggest that a primary impairment in perceptual encoding may contribute to the visuospatial performance, however a more cautious response strategy may be related to visual hallucinations in Lewy body disease. Interestingly, MCI-LB patients showed no impairment in information processing ability, suggesting that, when perceptual encoding was successful, patients were able to normally process information, potentially explaining the variability of hallucination incidence

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-2β-carbomethoxy-3β-(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

Mild cognitive impairment with Lewy bodies: blood perfusion with arterial spin labelling

Funder: GE Healthcare; doi: http://dx.doi.org/10.13039/100006775Funder: NIHR Newcastle Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100012295Funder: Newcastle UniversityAbstract: Objective: To use arterial spin labelling to investigate differences in perfusion in mild cognitive impairment with Lewy bodies (MCI-LB) compared to Alzheimer type MCI (MCI-AD) and healthy controls. Methods: We obtained perfusion images on 32 MCI-LB, 30 MCI-AD and 28 healthy subjects of similar age. Perfusion relative to cerebellum was calculated, and we aimed to examine differences in relative perfusion between MCI-LB and the other groups. This included whole brain voxelwise comparisons, as well as using predefined region-of-interest ratios of medial occipital to medial temporal, and posterior cingulate to precuneus. Differences in occipital perfusion in eyes open vs eyes closed conditions were also examined. Results: Compared to controls, the MCI-LB showed reduced perfusion in the precuneus, parietal, occipital and fusiform gyrus regions. In our predefined regions, the ratio of perfusion in occipital/medial temporal was significantly lower, and the posterior cingulate/precuneus ratio was significantly higher in MCI-LB compared to controls. Overall, the occipital perfusion was greater in the eyes open vs closed condition, but this did not differ between groups. Conclusion: We found patterns of altered perfusion in MCI-LB which are similar to those seen in dementia with Lewy bodies, with reduction in posterior parietal and occipital regions, but relatively preserved posterior cingulate

Mild cognitive impairment with Lewy bodies: blood perfusion with arterial spin labelling

Funder: GE Healthcare; doi: http://dx.doi.org/10.13039/100006775Funder: NIHR Newcastle Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100012295Funder: Newcastle UniversityAbstract: Objective: To use arterial spin labelling to investigate differences in perfusion in mild cognitive impairment with Lewy bodies (MCI-LB) compared to Alzheimer type MCI (MCI-AD) and healthy controls. Methods: We obtained perfusion images on 32 MCI-LB, 30 MCI-AD and 28 healthy subjects of similar age. Perfusion relative to cerebellum was calculated, and we aimed to examine differences in relative perfusion between MCI-LB and the other groups. This included whole brain voxelwise comparisons, as well as using predefined region-of-interest ratios of medial occipital to medial temporal, and posterior cingulate to precuneus. Differences in occipital perfusion in eyes open vs eyes closed conditions were also examined. Results: Compared to controls, the MCI-LB showed reduced perfusion in the precuneus, parietal, occipital and fusiform gyrus regions. In our predefined regions, the ratio of perfusion in occipital/medial temporal was significantly lower, and the posterior cingulate/precuneus ratio was significantly higher in MCI-LB compared to controls. Overall, the occipital perfusion was greater in the eyes open vs closed condition, but this did not differ between groups. Conclusion: We found patterns of altered perfusion in MCI-LB which are similar to those seen in dementia with Lewy bodies, with reduction in posterior parietal and occipital regions, but relatively preserved posterior cingulate

Utility of the pareidolia test in mild cognitive impairment with Lewy bodies and Alzheimer's disease

Funder: NIHR Newcastle Biomedical Research CentreFunder: Alzheimer's Research UKFunder: GE Healthcare; Id: http://dx.doi.org/10.13039/100006775Abstract: Objectives: Previous research has identified that dementia with Lewy bodies (DLB) has abnormal pareidolic responses which are associated with severity of visual hallucinations (VH), and the pareidolia test accurately classifies DLB with VH. We aimed to assess whether these findings would also be evident at the earlier stage of mild cognitive impairment (MCI) with Lewy bodies (MCI‐LB) in comparison to MCI due to AD (MCI‐AD) and cognitively healthy comparators. Methods: One‐hundred and thirty‐seven subjects were assessed prospectively in a longitudinal study with a mean follow‐up of 1.2 years (max = 3.7): 63 MCI‐LB (22% with VH) and 40 MCI‐AD according to current research diagnostic criteria, and 34 healthy comparators. The pareidolia test was administered annually as a repeated measure. Results: Probable MCI‐LB had an estimated pareidolia rate 1.2–6.7 times higher than MCI‐AD. Pareidolia rates were not associated with concurrent VH, but had a weak association with total score on the North East Visual Hallucinations Inventory. The pareidolia test was not an accurate classifier of either MCI‐LB (Area under curve (AUC) = 0.61), or VH (AUC = 0.56). There was poor sensitivity when differentiating MCI‐LB from controls (41%) or MCI‐AD (27%), though specificity was better (91% and 89%, respectively). Conclusions: Whilst pareidolic responses are specifically more frequent in MCI‐LB than MCI‐AD, sensitivity of the pareidolia test is poorer than in DLB, with fewer patients manifesting VH at the earlier MCI stage. However, the high specificity and ease of use may make it useful in specialist clinics where imaging biomarkers are not available

Sustained attention in mild cognitive impairment with Lewy bodies and Alzheimer’s disease

Attentional impairments are common in dementia with Lewy bodies and its prodromal stage of mild cognitive impairment (MCI) with Lewy bodies (MCI-LB). People with MCI may be capable of compensating for subtle attentional deficits in most circumstances, and so these may present as occasional lapses of attention. We aimed to assess the utility of a continuous performance task (CPT), which requires sustained attention for several minutes, for measuring attentional performance in MCI-LB in comparison to Alzheimer’s disease (MCI-AD), and any performance deficits which emerged with sustained effort. Method We included longitudinal data on a CPT sustained attention task for 89 participants with MCI-LB or MCI-AD and 31 healthy controls, estimating ex-gaussian response time parameters, omission and commission errors. Performance trajectories were estimated both cross-sectionally (intra-task progress from start to end) and longitudinally (change in performance over years). Results While response times in successful trials were broadly similar, with slight slowing associated with clinical parkinsonism, those with MCI-LB made considerably more errors. Omission errors were more common throughout the task in MCI-LB than MCI-AD (OR 2.3, 95% CI: 1.1-4.7), while commission errors became more common after several minutes of sustained attention. Within MCI-LB, omission errors were more common in those with clinical parkinsonism (OR 1.9, 95% CI: 1.3-2.9) or cognitive fluctuations (OR 4.3, 95% CI: 2.2-8.8). Conclusions Sustained attention deficits in MCI-LB may emerge in the form of attentional lapses leading to omissions, and a breakdown in inhibitory control leading to commission errors.This study was funded by Alzheimer’s Research UK (ARUK-PG2015-13) and supported by the NIHR Newcastle Biomedical Research Centre. GE Healthcare provided the FP-CIT ligand for this investigator-run study

Mild cognitive impairment with Lewy bodies: neuropsychiatric supportive symptoms and cognitive profile.

BACKGROUND: Recently published diagnostic criteria for mild cognitive impairment with Lewy bodies (MCI-LB) include five neuropsychiatric supportive features (non-visual hallucinations, systematised delusions, apathy, anxiety and depression). We have previously demonstrated that the presence of two or more of these symptoms differentiates MCI-LB from MCI due to Alzheimer's disease (MCI-AD) with a likelihood ratio >4. The aim of this study was to replicate the findings in an independent cohort. METHODS: Participants ⩾60 years old with MCI were recruited. Each participant had a detailed clinical, cognitive and imaging assessment including FP-CIT SPECT and cardiac MIBG. The presence of neuropsychiatric supportive symptoms was determined using the Neuropsychiatric Inventory (NPI). Participants were classified as MCI-AD, possible MCI-LB and probable MCI-LB based on current diagnostic criteria. Participants with possible MCI-LB were excluded from further analysis. RESULTS: Probable MCI-LB (n = 28) had higher NPI total and distress scores than MCI-AD (n = 30). In total, 59% of MCI-LB had two or more neuropsychiatric supportive symptoms compared with 9% of MCI-AD (likelihood ratio 6.5, p < 0.001). MCI-LB participants also had a significantly greater delayed recall and a lower Trails A:Trails B ratio than MCI-AD. CONCLUSIONS: MCI-LB is associated with significantly greater neuropsychiatric symptoms than MCI-AD. The presence of two or more neuropsychiatric supportive symptoms as defined by MCI-LB diagnostic criteria is highly specific and moderately sensitive for a diagnosis of MCI-LB. The cognitive profile of MCI-LB differs from MCI-AD, with greater executive and lesser memory impairment, but these differences are not sufficient to differentiate MCI-LB from MCI-AD

Hippocampal and insula volume in mild cognitive impairment with Lewy bodies.

INTRODUCTION: Diagnostic criteria for prodromal dementia with Lewy bodies have recently been published. These include the use of imaging biomarkers to distinguish mild cognitive impairment with Lewy bodies (MCI-LB) from MCI due to other causes. Two potential biomarkers listed, though not formally included in the diagnostic criteria, due to insufficient evidence, are relatively preserved hippocampi, and atrophy of the insula cortex on structural brain imaging. METHODS: In this report, we sought to investigate these imaging biomarkers in 105 research subjects, including well characterised groups of patients with MCI-LB (n = 38), MCI with no core features of Lewy body disease (MCI-AD; n = 36) and healthy controls (N = 31). Hippocampal and insula volumes were determined from T1 weighted structural MRI scans, using grey matter segmentation performed with SPM software. RESULTS: Adjusting for age, sex and intracranial volume, there were no differences in hippocampal or insula volume between MCI-AD and MCI-LB, although in both conditions volumes were significantly reduced relative to controls. CONCLUSION: Our results do not support the use of either hippocampal or insula volume to identify prodromal dementia with Lewy bodies.This work was supported by Alzheimer’s Research UK (AJT, Grant Number ARUK-PG3026-13) and the NIHR Newcastle Biomedical Research Centre. GE Healthcare provided funding for FP-CIT imaging for this investigator-led study. JOB is supported by the NIHR Cambridge Biomedical Research Centre and the Cambridge Centre for Parkinson’s Plus