Dopaminergic imaging is an established biomarker for dementia with Lewy bodies, but its diagnostic accuracy at the mild cognitive impairment (MCI) stage remains uncertain.
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.
We conducted a prospective diagnostic accuracy study of baseline dopaminergic imaging with 123IN-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.
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.
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.
Background
The early degeneration of the cholinergic nucleus basalis of Meynert (NBM) and its cortical projections is a hallmark of both dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). ...In addition to the NBM, the other major cholinergic projection system originates in the pedunculopontine nucleus (PPN) and provides innervation to the thalamus. Given that visual hallucinations are a hallmark of DLB, but not AD, and have recently been attributed to thalamic degeneration, we tested whether the PPN projection system is differentially altered in DLB compared to AD.
Methods
NBM‐cortical and PPN‐thalamus white matter pathways were tracked using diffusion‐weighted imaging data from 46 patients with AD, 48 with DLB, 35 with mild cognitive impairment (MCI) with AD, 38 with MCI with Lewy bodies, and 71 control participants. A free‐water corrected DTI model was estimated. Free water fraction along the cholinergic pathways was compared between groups controlling for age, sex, and free water fraction from a white matter control mask. Multiple linear regression was applied to test associations with cognitive function, core Lewy body symptoms with a focus on visual hallucinations, and changes in cognition using longitudinal follow‐up data.
Results
Free water fraction in the NBM lateral pathway was increased in both dementia and MCI groups compared to controls and this was associated with performance on overall cognition and phonemic fluency tests as well as with longitudinal changes in cognition (Figure 1). Free water fraction along the PPN‐thalamus tract was increased only in DLB patients while it appeared relatively spared in AD and this increase in the Lewy body patients was related to the presence of visual hallucinations (Figure 2). These results were largely replicated in an independent validation cohort (34 AD, 34 DLB, 35 controls).
Conclusion
Our cross‐validated findings show that the cholinergic input to the thalamus from the PPN is selectively affected in DLB and contributes to visual hallucinations.
To determine whether mild cognitive impairment with Lewy bodies or mild cognitive impairment with Alzheimer 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.
Two prospective longitudinal cohorts including 111 individuals ≥60 years of age 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. Multistate modeling 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.
After a mean follow-up of 2.2 years (range 1-6.7 years), 38 of the 111 (34%) 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% confidence interval 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).
Diagnostic characteristics of Lewy body disease are associated with an increased risk of transition from mild cognitive impairment to dementia.
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).
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.
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.
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.
Background
Blood‐based biomarkers of Alzheimer’s disease (AD) may help to rule AD in, with particular promise at the mild cognitive impairment (MCI) stage when potential disease‐modifying treatments ...may be most effective. However, AD is not the only common cause of cognitive impairment: Lewy body disease and other non‐AD pathologies are common and under‐recognised. Reliance on AD‐specific biomarkers alone may therefore contribute to missed diagnosis of non‐AD aetiologies. We aimed to examine the utility of emerging AD plasma biomarkers in identifying disease‐specific MCI due to AD (MCI‐AD), MCI with Lewy bodies (MCI‐LB) and in disease‐general MCI. We also aimed to compare these with alternative disease‐general biomarkers of neurodegeneration, and examined any change over time.
Method
In a longitudinal study, plasma samples were collected for 172 participants (31 healthy controls, 48 MCI‐AD, 28 possible MCI‐LB and 65 probable MCI‐LB) at baseline, and a subset (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with Simoa assays for Alzheimer’s disease (Aβ42, Aβ40, ptau‐181) and neurodegeneration (GFAP and NfL) biomarkers.
MCI cases were differentially classified as MCI‐AD or MCI‐LB by an expert panel of old age psychiatrists, based on current consensus diagnostic criteria, and including Lewy body disease‐specific imaging biomarkers.
Age‐adjusted mixed effects models assessed any longitudinal changes over time in each biomarker, and associations with severity of cognitive impairment as assessed by the Addenbrooke’s Cognitive Examination – Revised.
Result
GFAP performed comparably to AD‐specific biomarkers in identifying any‐cause MCI (GFAP AUC = 0.75; ptau‐181 = 0.73), while maintaining good accuracy in identifying MCI‐AD specifically. AD biomarkers did not reliably distinguish MCI‐AD from MCI‐LB. Severity of cognitive impairment in any‐cause MCI and MCI‐AD was most strongly correlated with the disease‐nonspecific neurodegenerative biomarker NfL (r = 0.48, p = 0.005; cf. GFAP r = 0.23, p = 0.121), which progressively increased over time.
Conclusion
Given the high prevalence of unrecognised non‐AD pathologies at autopsy (>1/3 cases in UK brain banks), blood biomarkers of neurodegeneration may be a useful alternative to AD‐specific biomarkers in screening for neurodegenerative disease in MCI. As AD biomarkers do not reliably differentiate MCI‐AD from MCI‐LB, there is a need for disease‐specific biomarkers of synucleinopathies.
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.
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).
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.
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.
•We examined factors associated with white matter (WM) disruption in DLB.•DLB (n = 29), AD (n = 17) and controls (n = 20) had DTI and amyloid PET.•DLB and AD groups demonstrated widespread WM disruption compared with controls.•In DLB, WM disruption correlated with decreased grey matter and hippocampal volumes.•There was no correlation between WM disruption and cortical florbetapir SUVR.
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.
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.
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.
The five-item scale is effective to identify parkinsonism in MCI, but a lower threshold must be used in MCI compared with dementia.
•A five-item scale derived from the UPDRS can help identify parkinsonism in dementia.•The scale was tested in mild cognitive impairment (MCI).•It accurately identified MCI with parkinsonism and abnormal dopaminergic imaging.•A lower threshold is required in MCI compared with dementia.•The scale may help identify parkinsonism in clinical and research settings.
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