Ragnhild Skogseth

Frequency and Case Identification of Dementia with Lewy Bodies Using the Revised Consensus Criteria

Objective: To find the proportion of dementia with Lewy bodies (DLB) in a referral cohort of patients with a first-time diagnosis of mild dementia. Background: The proportion of DLB among the dementia sufferers is not known and the clinical consensus criteria have low sensitivity. We employed the revised DLB criteria to study the proportion with DLB in a community sample of patients with mild dementia. Methods: From March 2005 to March 2007, we included 196 patients from referrals to all geriatric medicine, old age psychiatry and neurology outpatient clinics in Rogaland and Hordaland counties in Western Norway. Standardized clinical instruments and diagnostic criteria were employed. Results: 65% had Alzheimer dementia, 20% DLB (16% probable DLB), 5.6% vascular dementia, 5.6% Parkinson disease with dementia, 2.0% frontotemporal dementia and 1.5% alcoholic dementia. There were no significant differences in the proportion with DLB according to age bands and dementia severity groups. The revised criteria for a clinical diagnosis of DLB increased the proportion of probable DLB by 25% compared to the previous criteria. Conclusion: DLB is common in patients with mild dementia, and is the second most common type of dementia. The introduction of new clinical criteria for DLB leads to an increase in the proportion diagnosed with probable DLB.

Neuropsychiatric Correlates of Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease

Background: The aim of this study was to explore the relationship between cerebrospinal fluid biomarkers and neuropsychiatric symptoms in people with Alzheimer’s disease. Psychosis, agitation, apathy and depression were assessed using standardised measures in 32 patients with mild Alzheimer’s disease. Methods: The levels of the 42-amino-acid form of β-amyloid (Aβ1–42), tau and p-tau (phosphorylated at threonine 181) were quantified using the conventional enzyme-linked immunosorbent assay method. Results: Our result shows that apathy is significantly correlated with tau and p-tau but not with Aβ1–42. There were no significant correlations between indices of psychosis/agitation,or depression and cerebrospinal fluid Aβ1–42, tau or p-tau concentrations. Conclusion: Our finding suggests that apathy is associated with the level of neurofibrillary tangles in people with mild Alzheimer’s disease. In contrast, the overall levels of neurofibrillary tangles or amyloid plaques do not seem to be associated with depression or psychosis, indicating that other brain changes contribute to these symptoms.

CSF Amyloid-beta 38 as a novel diagnostic marker for dementia with Lewy bodies.

Background The clinical distinction between Alzheimers disease (AD) and dementia with Lewy bodies (DLB) is sometimes difficult, particularly in mild cases. Although CSF markers such as amyloid β42 (Aβ42) and P-tau can distinguish between AD and normal controls, their ability to distinguish between AD and DLB is not adequate. Objective This study aims to investigate whether CSF markers, in particular levels of Aβ38, can differentiate between mild AD and DLB. Methods 85 individuals were included after standardised diagnostic procedures: 30 diagnosed as probable AD, 23 probable DLB, 20 probable Parkinsons disease dementia and 12 non-demented control subjects. CSF levels of Aβ38, Aβ40 and Aβ42 were determined using commercially available ultra-sensitive multi-array kit assay (MSD) for human Aβ peptides. Total tau (T-tau) and phosphorylated tau (P-tau) were analysed using ELISA (Innotest). In addition, combinations (Aβ42/Aβ38, Aβ42/Aβ40, Aβ42/P-tau and Aβ42/Aβ38/P-tau) were assessed. Results Significant between group differences were found for all CSF measures, and all except Aβ40, Aβ42 and Aβ42/P-tau differed between AD and DLB. The Aβ42/Aβ38 ratio was the measure that best discriminated between AD and DLB (AUC 0.765; p<0.005), with a sensitivity of 78% and a specificity of 67%. Conclusion This study suggests that the level of Aβ38 can potentially contribute in the diagnostic distinction between AD and DLB when combined with Aβ42. Single measures had low diagnostic accuracy, suggesting that developing a panel of markers is the most promising strategy. Studies with independent and larger samples and a priori cut-offs are needed to test this hypothesis.

Associations between Cerebrospinal Fluid Biomarkers and Cognition in Early Untreated Parkinson’s Disease

BACKGROUND Mild cognitive impairment and dementia are common, clinically important features of Parkinsons disease (PD). The underlying disease pathology is heterogeneous and not yet well characterized. Biomarkers for cognitive impairment in PD could aid in diagnostic and prognostic evaluation and in the development of new cognitive enhancing treatments. OBJECTIVE To examine the relationship between CSF markers and cognition in a large, multicenter, cohort study of early, untreated PD, and compare marker concentrations between PD patients with and without MCI and healthy, age-matched controls. METHODS 414 early, untreated PD (34% with mild cognitive impairment) and 189 healthy, cognitively intact controls with baseline neuropsychological testing and CSF abeta42, t-tau, p-tau181 and α-synuclein results were included. Multiple linear regression models were constructed with a composite cognition factor, or memory-, or visuospatial- or executive-attention domains as dependent variables, and CSF markers, demographic characteristics and MDS-UPDRS III score as predictors. RESULTS Lower α-synuclein was associated with reduced performance on the executive-attention domain and the composite cognition factor in the whole PD-group. Abeta42 was significantly decreased in PD with mild cognitive impairment compared with controls after adjusting for covariates, while values in PD without MCI were identical to healthy controls. CONCLUSIONS The association between reduced CSF α-synuclein concentrations and cognition suggests that α-synuclein pathology contributes to early cognitive impairment in PD, in particular to executive-attentional dysfunction. Longitudinal analyses are needed to determine if this and other CSF biomarkers in early Parkinsons disease are associated with the risk of future cognitive decline and dementia.

Cognitive decline in dementia with Lewy bodies: a 5-year prospective cohort study.

Objectives We report the cognitive decline in persons diagnosed with mild dementia with Lewy bodies (DLB) and mild Alzheimers disease (AD) during 5 years of annual follow-ups. Methods Patients were recruited into the study from geriatric, psychiatric and neurology clinics in Western Norway during 2005–2013. They were diagnosed according to clinical consensus criteria, based on standardised clinical rating scales. Autopsy-based diagnoses were available for 20 cases. Cognitive decline for up to 5 years was assessed using the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Examination (MMSE). Survival analysis including Cox regression (time to reach severe dementia) and linear mixed-effects (lme) modelling were used to model the decline on MMSE. Results At least one follow-up assessment was available for 67 patients with DLB and 107 patients with AD, with a median follow-up time of 4.3 years. The time to reach severe dementia was significantly shorter in DLB (median 1793 days) compared with AD (1947 days; p=0.033), and the difference remained significant in the multiple Cox regression analysis (HR=2.0, p<0.02). In the adjusted lme model, MMSE decline was faster in DLB (annual decline 4.4 points) compared with AD (3.2 points; p<0.008). Conclusions Our findings show that from the mild dementia stage, patients with DLB have a more rapid cognitive decline than in AD. Such prognostic information is vital for patients and families and crucial for planning clinical trials and enabling health economic modelling.

Accuracy of Clinical Diagnosis of Dementia with Lewy Bodies versus Neuropathology

BACKGROUND 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. OBJECTIVE To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinsons disease with dementia (PDD). METHODS 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. RESULTS 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) Alzheimers 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%. CONCLUSION 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.

Cerebrospinal Fluid Levels of sAPPα and sAPPβ in Lewy Body and Alzheimer's Disease: Clinical and Neurochemical Correlates

We measured cerebrospinal fluid (CSF) levels of the soluble isoforms of amyloid precursor protein (APP; sAPPα sAPPβ) and other CSF biomarkers in 107 patients with Alzheimers disease (AD), dementia with Lewy body dementia (DLB), Parkinsons disease dementia (PDD), and normal controls (NC) using commercial kits. DLB and PDD were combined in a Lewy body dementia group (LBD). No differences were observed in sAPPα and sAPPβ levels between the groups. Significant correlations were observed between sAPPα and sAPPβ and between sAPPβ and Mini-Mental State Examination scores in the total group analysis as well as when LBD and AD groups were analyzed separately. sAPPα and sAPPβ levels correlated with Aβ38, Aβ40, Aβ42, and Tau in the LBD group. In AD, sAPPα correlated with p-Tau and sAPPβ with Aβ40. The differential association between sAPPα and sAPPβ with Aβ and Tau species between LBD and AD groups suggests a possible relationship with the underlying pathologies in LBD and AD.

Biomarkers in spinal fluid of patients with dementia

BACKGROUND We wanted to assess whether biomarkers abeta42, tau and p-tau could differentiate between Alzheimers disease and other dementia illnesses. MATERIAL AND METHODS Following systematic Pubmed searches, 25 articles which reported sensitivity and specificity for Alzheimers disease and other dementias were included. RESULTS Most studies showed significant differences for all three markers between Alzheimers disease and other dementia illnesses, except abeta42 which did not differ between Alzheimers disease and dementia with Lewy bodies. Alzheimers disease was distinguished from vascular dementia with sensitivities and specificities 77 % - 87 % and 62-80 % (abeta42); 79-100 % and 14-100 % (tau); and 78-80 % and 63-96 % (p-tau181). Alzheimers disease and dementia with Lewy bodies were differentiated by tau and p-tau181 with sensitivities and specificities of 72-94 % and 53-92 %, and of 68-85 % and 61-85 %. Markers separated Alzheimers disease from frontal lobe dementia with sensitivities and specificities of 37-91 % and 59-92 % (abeta42), 58-88 % and 68-92 % (tau) and 44-91 % and 79-100 % (p-tau181). INTERPRETATION Methodological weaknesses impede the interpretation. CSF markers are not yet sufficient to differentiate between Alzheimers disease and other forms of dementia.

Risk of nursing home placement in dementia with Lewy bodies and Alzheimer's dementia

AD pathology in healthy elderly(CN) and mild cognitive impairment(MCI).We tested the hypothesis that there would be an association between rates of regional brain atrophy with baseline AD biomarkers p-tau and Ab1-42 concentrations. Methods: We examined the rate of change in tissue volume across brain in age-matched 70 CN(mean ADAS-cog 6.09), 119 MCI(mean ADAS-cog 12.11),and 46 AD patients(mean ADAS-cog 19.30).Structural brain MRI scans at three time points(baseline,6 and 12 months) were acquired at multiple ADNI sites using 1.5TMRI scanners.Using FreeSurfer4.1,a total of 94 cortical and sub-cortical volumes were automatically measured at baseline scans and longitudinal processing was utilized to estimated the corresponding volumes at 6 and 12 months scans.In each diagnostic group,linear mixed effect models followed by pair-wise maximum likelihood test were performed to determine if baseline biomarker levels predict regional absolute volumes as well as volume change over time after accounting for variations in ADAS-cog scores at scan times. Results: Lower Ab1-42 levels were associated with(i)higher annual atrophy rates of hippocampus in AD(p < 0.01),(ii)increased rates of ventricular enlargement and medial temporal lobe atrophy in CN,and(iii)increase rates of atrophy prominently in cortical regions,stretching from the medial to inferior temporal and frontal cortices in MCI.In contrast to Ab1-42,p-tau levels were not significantly associated with any brain volume changes in AD.In CN and MCI,however,the association between higher levels of p-tau and increased rates of brain atrophy largely mirrored the pattern seen for Ab1-42,though associations with p-tau involved fewer regions in MCI.Neither absolute volume measure nor decline rate in ADAS-cog correlated with baseline biomarker concentrations significantly,in any of the diagnostic group. Conclusions: The finding of faster progression of brain atrophy in presence of lower baseline Ab1-42 and higher p-tau levels supports the hypothesis that Ab1-42 and tau are measures of early AD pathology.Therefore,we propose that Ab1-42 and p-tau could serve as ‘‘predictors’’ and rates of brain atrophy(and ventricular expansion) could serve as ‘‘outcome measures’’ in AD prevention trials of healthy elderly and MCI, greatly improving the power of such trials,compared to clinical/cognitive measures.

CLINICO-PATHOLOGIC CORRELATIONS IN DEMENTIA WITH LEWY BODIES (DLB): A PROSPECTIVE COHORT STUDY

O3-04-02 CLINICO-PATHOLOGIC CORRELATIONS IN DEMENTIAWITH LEWY BODIES (DLB): A PROSPECTIVE COHORT STUDY Dag Aarsland, Ragnhild E. Skogseth, Luiza Jadwiga Chwiszczuk, Hogne Sonnesyn, Arvid Rongve, Clive Ballard, Tibor Hortobagyi, 1 King’s College London, London, United Kingdom; 2 Stavanger University Hospital, Stavanger, Norway; 3 Haraldsplass Deaconess Hospital, Bergen, Norway; Helse Fonna, Haugesund, Norway. Contact e-mail: daarsland@ gmail.com