Consensus Criteria For Dementia With Lewy Bodies Research Articles

Plasma p‐tau181 levels in Alzheimer’s disease (AD) and Dementia with Lewy Bodies (DLB)

AbstractBackgroundThe fundamental pathological process in AD involves amyloid(Aβ) deposition and Tau hyperphosphorylation (ptau). Plasma ptau has been proven as more accessible and less invasive biomarker than CSF for the assessment of AD pathological features. DLB is another common cause of dementia in the elderly and has overlapping features with AD. Thus, the detection of Alzheimer’s biomarkers might be useful for distinguishing the underlying pathology of AD from other concurrent pathologic processes. In this study, we compared the plasma levels of p‐tau181 in patients with clinically diagnosed DLB and AD.MethodWe examined EDTA plasma samples of patients assessed at the UBC Hospital Clinic for AD. The cohort was clinically characterized as control (n = 89) if no significant cognitive impairment was found, AD (n = 195) if they fulfill the NIA‐AA criteria (McKhann 2011), and DLB (n = 39) if they fulfill the consensus criteria for DLB (McKeith 2005; McKeith 2017). The samples were analyzed by a p‐tau181‐specific Simoa assay.ResultThe mean age of the cohort is 69.2 ± 10.3 with the control 63.4 ± 8.7, AD 70.1 ±9.9 and DLB 77.8 ± 8. There are 74.2% females in the controls, 52.8% in AD, and 35.9% in DLB.).The patients with DLB were older than the cases of AD and controls (p<0.001) and there was no significant effect of age on plasma ptau‐181 concentrations (p = 0.65). There were more females in the controls and AD groups compared to DLB (p<0.001), however, there was no significant correlation between sex and plasma ptau‐181 (p = 0.24). While the plasma p‐tau181 concentrations of cases with AD (74.1 ± 35.6 pg/ml) were slightly higher than DLB (73.2 ± 44.4 pg/ml), they were not significantly different. However, they were significantly higher than the control group (26.5 ± 23 pg/ml) (p < 0.001).ConclusionIn current study, plasma p‐tau181 levels did not differentiate the DLB group from the AD, but both groups were significantly higher than controls. This suggests that DLB often have co‐existing AD pathology, making their p‐tau measurements like the AD group. Further studies with autopsy‐defined samples will be needed to clarify the role of plasma p‐tau181 in DLB.

Accuracy of Clinical Diagnosis of Dementia with Lewy Bodies versus Neuropathology.

The first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally. To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson's disease with dementia (PDD). From a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB. 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n = 11), PDD (n = 5), probable (n = 2) or possible (n = 2) Alzheimer's disease (AD). Of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%. Our findings suggest that the international clinical consensus criteria for DLB perform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy.

Editors' Note

Editors' Note: In “Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials,” Drs. Figueroa and Wright reviewed published clinical trials on the effect of hyperbaric oxygen therapy (HBOT) on mild to moderate traumatic brain injury/persistent postconcussion syndrome (mTBI/PPCS) and concluded that HBOT has therapeutic effects on mTBI/PPCS symptoms and can alleviate posttraumatic stress disorder symptoms secondary to a brain injury. Challenging the review, Drs. Hampson and Holm critique the claim that oxygen content of arterial blood plasma (oxygen dissolved in plasma) during hyperbaric exposure correlates with treatment response. They point out that arterial blood plasma oxygen content was not measured in any of the studies reviewed and that the authors presumably estimated the arterial blood partial pressure of oxygen from the calculated alveolar PO2 using the alveolar gas equation and assumed that the participants had normal metabolism and pulmonary. They also suggest that the authors did not take into consideration the fact that the studies used different treatment times and numbers. Drs. Figueroa and Wright agree that PaO2 was not measured in the published studies but assumed that study participants had normal metabolism and pulmonary function since they were cleared to be placed inside a pressure vessel. They also address the difference in time to HBOT exposure and stress that pressurized air is a biologically active agent, rendering the conclusions of inactivity or placebo effect in HBOT/TBI studies questionable. In the study “Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB,” Thomas et al. showed that 123I-FP-CIT imaging in dementia is a valid and accurate biomarker for dementia with Lewy bodies (DLB) and that the high specificity compared with clinical diagnosis (20% higher) is clinically important. They also concluded that while an abnormal 123I-FP-CIT scan strongly supports Lewy body disease, a normal scan does not exclude DLB with minimal brainstem involvement. Commenting on the study, Professor Abe notes that there are some patients with cognitive and behavioral dysfunction, but without parkinsonism for years. In such situations, he says that he cannot diagnose patients with DLB. In response, Thomas et al. clarify that about 25% of patients with DLB do not show features of parkinsonism. This is recognized in the consensus criteria for DLB, which do not require parkinsonism for diagnosis. They emphasize that DLB can be recognized despite a normal dopaminergic scan if other characteristic symptoms of DLB are present. —Chafic Karam, MD, and Robert C. Griggs, MD Editors' Note: In “Hyperbaric oxygen: B-level evidence in mild traumatic brain injury clinical trials,” Drs. Figueroa and Wright reviewed published clinical trials on the effect of hyperbaric oxygen therapy (HBOT) on mild to moderate traumatic brain injury/persistent postconcussion syndrome (mTBI/PPCS) and concluded that HBOT has therapeutic effects on mTBI/PPCS symptoms and can alleviate posttraumatic stress disorder symptoms secondary to a brain injury.

Author response: Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB.

Professor Abe raises the important issue of the involvement of Lewy body disease in the substantia nigra (SN) when making the diagnosis of dementia with Lewy bodies (DLB). It has long been known that, even later on in their illness, about 25% of patients with DLB do not show features of parkinsonism. This is recognized in the consensus criteria for DLB, which do not require parkinsonism for diagnosis. Patients with DLB can have normal dopaminergic imaging because, as with our 3 patients who also had no parkinsonism,1 there is no significant involvement of the SN by Lewy body disease.

Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Patterns of gray matter atrophy in dementia with Lewy bodies: a voxel-based morphometry study

Dementia with Lewy bodies (DLB) is a common form of dementia characterized by visual hallucinations, cognitive fluctuation and parkinsonism. We aimed to compare the patterns of gray matter atrophy in DLB with those in Alzheimer's disease (AD) and normal aging, and to investigate the relationship between atrophy and cognitive measures. We used voxel-based morphometry (VBM) to investigate gray matter (GM) loss in DLB (n = 35; mean age = 78.4; MMSE = 20.3), AD (n = 36; mean age = 78.3; MMSE = 19.5) and similar aged controls (n = 35; mean age = 76.7; MMSE = 29.1). T1 weighted MRI scans were acquired at 3 Tesla from all subjects and analyzed using VBM-DARTEL in SPM8. Cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG). We found reduced gray matter in temporal, parietal, occipital, and subcortical structures in DLB when compared to normal controls. The degree of atrophy was less than that observed in AD. There was significantly more medial temporal lobe atrophy in the AD group when compared with DLB. We did not find a correlation between total CAMCOG score and atrophy, but the CAMCOG memory subscale score correlated with temporal lobe atrophy in both the DLB and combined DLB/AD group. DLB is associated with less gray matter atrophy and relative preservation of the medial temporal lobe when compared to AD. Degree of medial temporal atrophy may be a useful imaging biomarker and our results provide support for its inclusion in the revised consensus criteria for DLB.

Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies

To determine whether adding REM sleep behavior disorder (RBD) to the dementia with Lewy bodies (DLB) diagnostic criteria improves classification accuracy of autopsy-confirmed DLB. We followed 234 consecutive patients with dementia until autopsy with a mean of 4 annual visits. Clinical diagnoses included DLB, Alzheimer disease (AD), corticobasal syndrome, and frontotemporal dementia. Pathologic diagnoses used the 2005 DLB consensus criteria and included no/low likelihood DLB (non-DLB; n = 136) and intermediate/high likelihood DLB (DLB; n = 98). Regression modeling and sensitivity/specificity analyses were used to evaluate the diagnostic role of RBD. Each of the 3 core features increased the odds of autopsy-confirmed DLB up to 2-fold, and RBD increased the odds by 6-fold. When clinically probable DLB reflected dementia and 2 or more of the 3 core features, sensitivity was 85%, and specificity was 73%. When RBD was added and clinically probable DLB reflected 2 or more of 4 features, sensitivity improved to 88%. When dementia and RBD were also designated as probable DLB, sensitivity increased to 90% while specificity remained at 73%. The VH, parkinsonism, RBD model lowered sensitivity to 83%, but improved specificity to 85%. Inclusion of RBD as a core clinical feature improves the diagnostic accuracy of autopsy-confirmed DLB.

Practical suggestions on how to differentiate dementia with Lewy bodies from Alzheimer's disease with common cognitive tests

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, but it is often underdiagnosed and mistaken for Alzheimer's disease (AD) with sometimes lethal consequences. Over 35 studies have established the differences between DLB and AD in neuropsychological tests, but none have provided easy interpretations of common tests suitable for the clinician. The aim of this study was to suggest practical interpretations of the Mini-Mental State Examination (MMSE), clock drawing, and cube-copying to identify DLB and differentiate it from AD. Thirty-three DLB patients were matched according to gender, MMSE, and age with 66 AD patients. The median MMSE score was 24. Easy interpretations of the tests, including the MMSE orientation subscore, were sought for. The identified criteria to separate DLB from AD were (1) the MMSE orientation score x 3 > or = the total MMSE score, (2) an impaired clock drawing, and (3) a non-3D cube-copying. If (1) was fulfilled, the sensitivity and specificity were 100 and 57% in patients with MMSE 21-27. If (1) and (2) were fulfilled in patients with MMSE 21-27, the sensitivity and specificity were 93 and 70%. If at least two of the three criteria were fulfilled, the sensitivity was 85%, and the specificity 75% regardless of MMSE score. If the orientation score x 3 > or = the total MMSE score together with an impaired clock drawing and possibly a non-3D cube-copying, the patient should be thoroughly investigated according to the DLB consensus criteria.

Effects of dopaminergic medications on psychosis and motor function in dementia with Lewy bodies

Dopaminergic treatment in dementia with Lewy bodies (DLB) requires balancing risk of worsened psychosis and potential motor benefit. We assessed the effects of increased dopaminergic medication on psychosis and motor function in DLB. We studied 19 subjects fulfilling probable DLB Consensus criteria before and after increased dopaminergic medications. Standard clinical measures included: Thought Disorder score from the Unified Parkinson's disease Rating Scale (UPDRS) Part I, total motor score (UPDRS Part III), and Hoehn-Yahr (H&Y) stage. Motor benefit defined as >10% improvement over baseline UPDRS Part III score, occurred in only one-third of subjects. In this group, worsened hallucinations or psychosis developed in one-third. Considering motor benefit without exacerbation of psychosis as our aim, only 4 DLB subjects (22%) achieved this goal. Our results suggest that dopaminergic medications have limited benefit in DLB because of the low likelihood of motor improvement and the risk of psychosis exacerbation.

Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study

Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important differences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimer's disease or most other dementia subtypes, offering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specificity, in the ante-mortem differentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand (123)I-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ((123)I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included. We did a phase III study in which we used a (123)I-FP-CIT SPECT scan to assess 326 patients with clinical diagnoses of probable (n=94) or possible (n=57) DLB or non-DLB dementia (n=147) established by a consensus panel (in 28 patients no diagnosis could be made). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The study had 90% power to detect the differences between our anticipated sensitivity (0.80) and specificity (0.85) targets and prespecified lower thresholds (sensitivity 0.65, specificity 0.73) using one-sided binomial tests with a significance level of alpha=0.025. Abnormal scans had a mean sensitivity of 77.7% for detecting clinical probable DLB, with specificity of 90.4% for excluding non-DLB dementia, which was predominantly due to Alzheimer's disease. A mean value of 85.7% was achieved for overall diagnostic accuracy, 82.4% for positive predictive value, and 87.5% for negative predictive value. Inter-reader agreement for rating scans as normal or abnormal was high (Cohen's kappa=0.87). The procedure was well tolerated with few adverse events. A revision of the International Consensus Criteria for DLB has recommended that low DAT uptake in the basal ganglia, as shown by SPECT or PET imaging, be a suggestive feature for diagnosis. Our findings confirm the high correlation between abnormal (low binding) DAT activity measured with (123)I-FP-CIT SPECT and a clinical diagnosis of probable DLB. The diagnostic accuracy is sufficiently high for this technique to be clinically useful in distinguishing DLB from Alzheimer's disease.

Fluctuating cognition in dementia with Lewy bodies and Alzheimer’s disease is qualitatively distinct

Objectives: To document and illustrate qualitative features of fluctuating cognition as described by care givers of patients with probable dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). To determine...

Demencia y cuerpos de Lewy

Consensus diagnostic criteria for dementia with Lewy bodies (DLB) proposed in 1996 have provided a useful foundation for research in the field. As a clinicopathologically defined entity, DLB has overlapping features of both Alzheimer s disease (AD) and Parkinson's disease (PD). Consensus criteria for DLB distinguish it from PD dementia by the earlier appearance of motor signs in the latter. Studies evaluating the standardized clinical diagnostic criteria for DLB have generally found them to be highly predictive of Lewy body pathology. However, many cases with Lewy body pathology and concomitant pathological features of AD elude clinical detection. Emerging data suggests that AD pathological features mask the clinical expression of concomitant Lewy body pathology, and that DLB and PD dementia may be more similar than distinct.

Efficacy of Olanzapine in the Treatment of Psychosis in Dementia with Lewy Bodies

Objective: This study sought to determine whether patients with dementia with Lewy bodies (DLB) and psychosis responded to treatment with olanzapine. Methods: This was a post hoc analysis of a subgroup of patients with DLB included in a larger double-blind, placebo-controlled, randomized parallel group trial of olanzapine for the treatment of psychosis in patients with Alzheimer’s disease. Patients meeting the consensus criteria for DLB and exhibiting parkinsonism and visual hallucinations were selected from the initial study. Psychosis was assessed with the Neuropsychiatric Inventory/Nursing Home (NPI-NH) version and the Brief Psychiatric Rating Scale (BPRS). Extrapyramidal symptoms were evaluated with the Simpson-Angus scale. Results: Twenty-nine patients met the criteria for DLB; 10 were randomized to placebo, 5 received 5 mg of olanzapine, 7 received 10 mg of olanzapine and 7 received 15 mg of olanzapine. Patients with DLB treated with 5 mg of olanzapine showed significant reductions in delusions and hallucinations. Patients treated with 10 mg showed a significant reduction in the NPI-NH delusion subscale score. No significant differences were found between the 15-mg group and the placebo group. Confirmatory findings emerged from an analysis of the BPRS. Caregivers reported decreased disruptions in their occupational routines for the group receiving 5 or 10 mg of olanzapine. There was no significant exacerbation of parkinsonian symptoms in any study group, no decrement in Mini-Mental State Examination scores in any of the treatment groups, and symptoms suggestive of anticholinergic toxicity did not differ among treatment groups. Conclusions: This preliminary analysis suggests that olanzapine (5 or 10 mg) reduces psychosis in patients with DLB without worsening parkinsonism.

Attention and fluctuating attention in patients with dementia with Lewy bodies and Alzheimer disease.

Attentional deficits are described in the consensus clinical criteria for the operationalized diagnosis of dementia with Lewy bodies (DLB) as characteristic of the condition. In addition, preliminary studies have indicated that both attentional impairments and fluctuation of attentional impairments are more marked in patients with DLB than in patients with Alzheimer disease (AD), although neuropsychological function has not previously been examined in a large prospective cohort with confirmed diagnostic accuracy against postmortem diagnosis. A detailed evaluation of attention and fluctuating attention was undertaken in 155 patients with dementia (85 with DLB and 80 with AD) from a representative hospital dementia case register and 35 elderly controls using the Cognitive Drug Research Computerized Assessment System for Dementia Patients computerized neuropsychological battery. Operationalized clinical diagnosis was made using the consensus criteria for DLB and the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD. High levels of sensitivity and specificity have been achieved for the first 50 cases undergoing postmortem examination. The groups were well matched for severity of cognitive impairments, but the AD patients were older (mean age, 80 vs 78 years) and more likely to be female (55% vs 40%). Patients with DLB were significantly more impaired than patients with AD on all measures of attention and fluctuating attention (for all comparisons, t > or = 2.5, P<.001), and patients from both dementia groups were significantly more impaired than elderly controls for all comparisons other than cognitive reaction time, which was significantly more impaired in DLB patients than controls but was comparable in controls and AD patients. There were, however, significant associations between the severity of cognitive impairment and the severity of both attentional deficits and fluctuations in attention. This large prospective study confirms that slowing of cognitive processing, attention, and fluctuations of attention are significantly more pronounced in DLB and AD patients, although fluctuating attention is common in patients with moderate-to-severe AD. Deficits of cognitive reaction time appear to be specific to DLB, except in severe dementia. A detailed evaluation of attentional performance could make an important contribution to differential diagnosis, although the results need to be interpreted within the context of the overall severity of cognitive deficits.

Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies.

To determine the validity of a clinical diagnosis of probable or possible dementia with Lewy bodies (DLB) made using International Consensus criteria. Validation studies based on retrospective chart reviews of autopsy-confirmed cases have suggested that diagnostic specificity for DLB is acceptable but case detection rates as low as 0.22 have been suggested. We evaluated the first 50 cases reaching neuropathologic autopsy in a cohort to which Consensus clinical diagnostic criteria for DLB, National Institute for Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD, and National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria for vascular dementia (VaD) had been prospectively applied. Twenty-six clinical diagnoses of DLB, 19 of AD, and 5 of VaD were made. At autopsy, 29 DLB cases, 15 AD, 5 VaD, and 1 progressive supranuclear palsy were identified. The sensitivity and specificity of a clinical diagnosis of probable DLB in this sample were 0.83 and 0.95. Of the five cases receiving a false-negative diagnosis of DLB, significant fluctuation was present in four but visual hallucinations and spontaneous motor features of parkinsonism were generally absent. Thirty-one percent of the DLB cases had additional vascular pathology and in two cases this contributed to a misdiagnosis of VaD. No correlations were found between the distribution of Lewy bodies and clinical features. The Consensus criteria for DLB performed as well in this prospective study as those for AD and VaD, with a diagnostic sensitivity substantially higher than that reported by previous retrospective studies. DLB occurs in the absence of extrapyramidal features and in the presence of comorbid cerebrovascular disease. Fluctuation is an important diagnostic indicator, reliable measures of which need to be developed further.

Clinical criteria for three types of dementia had low sensitivity and high specificity

Holmes C, Cairns N, Lantos P, et al. Validity of current clinical criteria for Alzheimer's disease, vascular dementia and dementia with Lewy bodies. Br J Psychiatry1999 Jan; 174 : 45...