Maartje I. Kester

Patients With Alzheimer Disease With Multiple Microbleeds: Relation With Cerebrospinal Fluid Biomarkers and Cognition

Background and Purpose— Microbleeds (MBs) are commonly observed in Alzheimer disease. A minority of patients has multiple MBs. We aimed to investigate associations of multiple MBs in Alzheimer disease with clinical and MRI characteristics and cerebrospinal fluid biomarkers. Methods— Patients with Alzheimer disease with multiple (≥8) MBs on T2*-weighted MRI were matched for age, sex, and field strength with patients with Alzheimer disease without MBs on a 1:2 basis. We included 21 patients with multiple MBs (73±7 years, 33% female) and 42 patients without MBs (72±7 years, 38% female). Mini-Mental State Examination was used to assess dementia severity. Cognitive functions were assessed using neuropsychological tests. Medial temporal lobe atrophy (0 to 4), global cortical atrophy (0 to 3), and white matter hyperintensities (0 to 30) were assessed using visual rating scales. In a subset, apolipoprotein E genotype and cerebrospinal fluid amyloid &bgr; 1-42, total &tgr; and &tgr; phosphorylated at threonine 181 were determined. Results— Patients with multiple MBs performed worse on Mini-Mental State Examination (multiple MB: 17±7; no MB: 22±4, P<0.05) despite similar disease duration. Atrophy was not related to presence of MBs, but patients with multiple MBs had more white matter hyperintensities (multiple MB: 8.8±4.8; no MB: 3.2±3.6, P<0.05). Adjusted for age, sex, white matter hyperintensities, and medial temporal lobe atrophy, the multiple MB group additionally performed worse on Visual Association Test object naming and animal fluency. Patients with multiple MBs had lower cerebrospinal fluid amyloid &bgr; 1-42 levels (307±61) than patients without MBs (505±201, P<0.05). Adjusted for the same covariates, total &tgr;, and &tgr; phosphorylated at threonine 181 were higher in the multiple MB group. Conclusion— Microbleeds are associated with the clinical manifestation and biochemical hallmarks of Alzheimer disease, suggesting possible involvement of MBs in the pathogenesis of Alzheimer disease.

Tau and p-tau as CSF biomarkers in dementia: a meta-analysis

Abstract Background: To evaluate the value of total tau (tau) and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) in the differential diagnosis of dementia, more specifically: dementia with Lewy Bodies (DLB), frontotemporal lobar degeneration (FTLD), vascular dementia (VaD), and Creutzfeldt-Jacob disease (CJD). Methods: A systematic literature search was performed to identify studies on tau and p-tau in DLB, FTLD, VaD and CJD. Tau concentrations were compared to healthy controls and to subjects with Alzheimers disease (AD) using random effect meta-analysis. Outcome measures were Cohens delta, sensitivity and specificity. Results: Compared to controls, tau concentrations are moderately elevated in DLB, FTLD and VaD, while p-tau concentrations are only slightly elevated in DLB and not elevated in FTLD and VaD. Compared to AD, lower tau concentrations differentiated DLB with a sensitivity of 73% and a specificity of 90%, FTLD with sensitivity and specificity of 74%, and VaD with a sensitivity of 73% and a specificity of 86%. Relative to AD, lower p-tau values differentiated FTLD with a sensitivity of 79% and specificity of 83%, and VaD with a sensitivity of 88% and a specificity of 78%. CJD is characterized by extremely elevated tau concentrations with a sensitivity of 91% and a specificity of 98% vs. AD. Conclusions: CSF tau concentrations in DLB, FTLD and VaD are intermediate between controls and AD patients. Overlap with both controls and AD patients results in insufficient diagnostic accuracy, and the development of more specific biomarkers for these disorders is needed. CJD is characterized by extremely increased tau values, resulting in a sensitivity and specificity that exceeds 90%.

CSF biomarkers predict rate of cognitive decline in Alzheimer disease

Objective: CSF biomarkers amyloid beta 1-42 (Aβ42), total tau (tau), and tau phosphorylated at threonine 181 (p-tau-181) are useful diagnostic markers for Alzheimer disease (AD). Less is known about these biomarkers as predictors for further cognitive decline in patients with AD. We hypothesized that high tau, especially in combination with relatively low p-tau-181, is a marker of rapid decline, since it has been associated with fast neuronal degeneration. Methods: A total of 151 patients with AD of whom we had baseline CSF were included from our memory clinic. All patients had at least 2 Mini-Mental State Examination (MMSE) scores, obtained no less than 1 year apart. Linear mixed models were used to assess associations between CSF biomarkers and the rate of cognitive decline as measured with the MMSE. CSF biomarkers were used in quintiles, random intercept and random slope with time were assumed, and the analyses were corrected for sex and age. Results: The patients with AD (45% women, age 66 ± 9 years, baseline MMSE 22 ± 4) had a follow-up period of 2.0 (1.0–5.0) years. Linear mixed models revealed no relations between any CSF biomarker and baseline MMSE. However, CSF biomarkers did predict cognitive decline over time. A low p-tau-181/tau ratio was the strongest predictor with a dose-dependent effect (lowest vs highest quintile: 2.9 vs 1.3 MMSE points annual decline, p for trend <0.001). In addition, low Aβ42, high tau, and high tau/Aβ42-ratio were associated with rapid cognitive decline (p < 0.05). Conclusion: At the time of diagnosis, a combination of high CSF tau without proportionally elevated p-tau-181 is associated with a faster rate of cognitive decline.

Associations Between Cerebral Small-Vessel Disease and Alzheimer Disease Pathology as Measured by Cerebrospinal Fluid Biomarkers

IMPORTANCE It remains unclear if and how associations between cerebral small-vessel disease and Alzheimer disease (AD) pathology lead to cognitive decline and dementia. OBJECTIVE To determine associations between small-vessel disease and AD pathology. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study from January 2002 to December 2012 using the memory clinic-based Amsterdam Dementia Cohort. The study included 914 consecutive patients with available cerebrospinal fluid (CSF) and magnetic resonance imaging; 547 were patients diagnosed as having AD (54% female, mean [SD], 67 [8]; Mini-Mental State Examination score, mean [SD], 21 [5]), 30 were patients diagnosed as having vascular dementia (37% female, mean [SD], 76 [9]; Mini-Mental State Examination score, mean [SD], 24 [4]), and 337 were control participants with subjective memory complaints (42% female, mean [SD], 59 [59]; Mini-Mental State Examination score, mean [SD], 28 [2]). Linear regressions were performed with CSF biomarkers (log transformed) as dependent variables and magnetic resonance imaging measures (dichotomized) as independent, adjusted for sex, age, mediotemporal lobe atrophy, and diagnosis. An interaction term for diagnosis by magnetic resonance imaging measures was used for estimates per diagnostic group. MAIN OUTCOMES AND MEASURES We examined the associations of magnetic resonance imaging white matter hyperintensities (WMH), lacunes, microbleeds with CSF β-amyloid 42 (Aβ42), total tau, and tau phosphorylated at threonine 181 (P-tau181) as well as for a subset of apolipoprotein E (APOE) ε4 carriers and noncarriers. RESULTS Microbleed presence was associated with lower CSF Aβ42 in AD and vascular dementia (standardized beta = -0.09, P = .003; standardized beta = -0.30, P = .01), and higher CSF tau in controls (standardized beta = 0.10, P = .03). There were no effects for P-tau181. The presence of WMH was associated with lower Aβ42 in control participants and patients with vascular dementia (standardized beta = -0.18, P = .002; standardized beta = -0.32, P = .02) but not in patients with AD. There were no effects for tau or P-tau181. The presence of lacunes was associated with higher Aβ42 in vascular dementia (standardized beta = 0.17, P = .07) and lower tau in AD (standardized beta = -0.07, P = .05) but there were no effects for Aβ42 or P-tau181. Stratification for apolipoprotein E genotype revealed that these effects were mostly attributable to ε4 carriers. CONCLUSIONS AND RELEVANCE Deposition of amyloid appears aggravated in patients with cerebral small-vessel disease, especially in apolipoprotein E ε4 carriers, providing evidence for pathophysiological synergy between these 3 biological factors.

Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease

IMPORTANCE Neurogranin (NGRN) seems to be a promising novel cerebrospinal fluid (CSF) biomarker for synaptic loss; however, clinical, and especially longitudinal, data are sparse. OBJECTIVE To examine the utility of NGRN, with repeated CSF sampling, for diagnosis, prognosis, and monitoring of Alzheimer disease (AD). DESIGN, SETTING, AND PARTICIPANTS Longitudinal study of consecutive patients who underwent 2 lumbar punctures between the beginning of 1995 and the end of 2010 within the memory clinic-based Amsterdam Dementia Cohort. The study included 163 patients: 37 cognitively normal participants (mean [SE] age, 64 [2] years; 38% female; and mean [SE] Mini-Mental State Examination [MMSE] score, 28 [0.3]), 61 patients with mild cognitive impairment (MCI) (mean [SE] age, 68 [1] years; 38% female; and mean [SE] MMSE score, 27 [0.3]), and 65 patients with AD (mean [SE] age, 65 [1] years; 45% female; and mean [SE] MMSE score, 22 [0.7]). The mean (SE) interval between lumbar punctures was 2.0 (0.1) years, and the mean (SE) duration of cognitive follow-up was 3.8 (0.2) years. Measurements of CSF NGRN levels were obtained in January and February 2014. MAIN OUTCOME AND MEASURE Levels of NGRN in CSF samples. RESULTS Baseline CSF levels of NGRN in patients with AD (median level, 2381 pg/mL [interquartile range, 1651-3416 pg/mL]) were higher than in cognitively normal participants (median level, 1712 pg/mL [interquartile range, 1206-2724 pg/mL]) (P = .04). Baseline NGRN levels were highly correlated with total tau and tau phosphorylated at threonine 181 in all patient groups (all P < .001), but not with Aβ42. Baseline CSF levels of NGRN were also higher in patients with MCI who progressed to AD (median level, 2842 pg/mL [interquartile range, 1882-3950 pg/mL]) compared with those with stable MCI (median level, 1752 pg/mL [interquartile range, 1024-2438 pg/mL]) (P = .004), and they were predictive of progression from MCI to AD (hazard ratio, 1.8 [95% CI, 1.1-2.9]; stratified by tertiles). Linear mixed-model analyses demonstrated that within-person levels of NGRN increased over time in cognitively normal participants (mean [SE] level, 90 [45] pg/mL per year; P < .05) but not in patients with MCI or AD. CONCLUSIONS AND RELEVANCE Neurogranin is a promising biomarker for AD because levels were elevated in patients with AD compared with cognitively normal participants and predicted progression from MCI to AD. Within-person levels of NGRN increased in cognitively normal participants but not in patients with later stage MCI or AD, which suggests that NGRN may reflect presymptomatic synaptic dysfunction or loss.

Standardization of Assay Procedures for Analysis of the CSF Biomarkers Amyloid β(1-42), Tau, and Phosphorylated Tau in Alzheimer's Disease: Report of an International Workshop

Large variation in assay performance and outcomes of CSF Aβ1-42, total Tau (Tau), and phosphorylated Tau (pTau) (at amino acid 181) levels is observed between laboratories. The aim of this study was to assess the differences in assay procedures between several experienced international laboratories, as potential sources of error. 14 groups performed the Aβ42, Tau, and pTau assays according to the guidelines of the manufacturer. Differences in analytical procedures between the laboratories were monitored. At least 23 items in assay procedures were identified that varied between the laboratories, including procedures for washing, pipetting, incubation, finishing, and sample handing. In general, the inter- and intra-assay variation between the groups was generally below 10% for all three assays. We concluded that 17 international centers that use the same assays for Aβ42, Tau and pTau on a regular basis do not uniformly adhere to the procedures recommended by the manufacturer. For harmonization of intercenter results of these biomarkers standardization of protocols is highly needed.

Serial CSF sampling in Alzheimer's disease: specific versus non-specific markers

In this longitudinal study we investigated change over time in cerebrospinal fluid (CSF) levels of amyloid-beta 40 and 42 (Aβ40 and Aβ42), total tau (tau), tau phosphorylated at threonine 181 (ptau-181), isoprostane, neurofilaments heavy (NfH) and light (NfL). Twenty-four nondemented subjects, 62 mild cognitive impairment (MCI) and 68 Alzheimers disease (AD) patients underwent 2 lumbar punctures, with minimum interval of 6, and a mean ± SD of 24 ± 13 months. Linear mixed models were used to assess change over time. Amyloid-beta 42, tau, and tau phosphorylated at threonine 181, differentiated between diagnosis groups (p < 0.05), whereas isoprostane, neurofilaments heavy, and NfL did not. In contrast, effects of follow-up time were only found for nonspecific CSF biomarkers: levels of NfL decreased, and levels of isoprostane, amyloid-beta 40, and tau increased over time (p < 0.05). Isoprostane showed the largest increase. In addition, increase in isoprostane was associated with progression of mild cognitive impairment to AD, and with cognitive decline as reflected by change in Mini Mental State Examination (MMSE). Contrary to AD-specific markers, nonspecific CSF biomarkers, most notably isoprostane, showed change over time. These markers could potentially be used to monitor disease progression in AD.

Dementia: THE BARE ESSENTIALS

Dementia is a syndrome characterised by progressive deterioration of cognitive function, most commonly of memory, but other domains such as language, praxis, visual perception and most notably executive function are also often affected. Most of the causes of this syndrome are progressive, but not invariably so. As cognitive function worsens, there is increasing interference with the patients’ daily activities leading to loss of independence and eventually for some the need for nursing home care. The patients usually survive 5–10 years. Dementia is common and already places a tremendous burden, not only on patients and their carers, but also on society, a burden that will increase as life expectancy increases. Because of these worrying facts and the development of the first symptomatic treatments, dementia is of growing interest to medical professionals and the public. Furthermore, because disease modifying treatments may be on the horizon, it is ever more important to understand the pathophysiology of the different causes and types of dementia, and to make the diagnosis early—it will probably be easier to stop the damage than to undo it.Procedure Appropriateness Category Relative Radiation Level MRI head without IV contrast Usually Appropriate O CT head without IV contrast Usually Appropriate ☢☢☢ Amyloid PET/CT brain May Be Appropriate ☢☢☢ FDG-PET/CT brain May Be Appropriate ☢☢☢☢ MRI head without and with IV contrast Usually Not Appropriate O HMPAO SPECT or SPECT/CT brain Usually Not Appropriate ☢☢☢☢ MR spectroscopy head without IV contrast Usually Not Appropriate O MRI functional (fMRI) head without IV contrast Usually Not Appropriate O CT head with IV contrast Usually Not Appropriate ☢☢☢ CT head without and with IV contrast Usually Not Appropriate ☢☢☢

CSF Biomarkers in Alzheimer's Disease and Controls: Associations with APOE Genotype are Modified by Age

The object of this study was to elucidate the effect of age in the relationship between APOE genotype and CSF biomarkers amyloid-beta1-42 (Abeta42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) in AD and controls. 302 AD patients and 174 controls were categorized into APOE epsilon4 carriers and non-carriers, and into younger and older (65years). In controls, older age and APOE epsilon4 were independently associated with lower Abeta42 and higher tau and ptau-181 levels (p < 0.05). For tau and ptau-181, there were also interactions (p < 0.10): older carriers had higher levels than older non-carriers, without effect for younger controls. In AD, APOE epsilon4 genotype had a main effect on Abeta42, but there was also an interaction: older carriers had lower Abeta42 than older non-carriers, without effect for younger AD patients (p < 0.05). For tau and ptau-181, there were only interactions: older carriers had higher levels than older non-carriers, while younger AD patients showed the opposite (p 0.05). Association between CSF biomarkers and APOE genotype were modified by age in both controls and AD patients. This suggests that cognitively healthy APOE epsilon4 carriers are more prone to develop AD pathology with aging. For AD patients, this provides support for the existence of subtypes within the disease.

Diagnostic impact of CSF biomarkers in a local hospital memory clinic.

Background: CSF biomarkers amyloid-β 1–42 (Aβ42), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) are useful diagnostic markers for Alzheimer’s disease (AD). We examined the impact of these biomarkers in the diagnostic process in a non-academic memory clinic. Methods: One hundred and nine patients with available CSF were included from the local hospital memory clinic. Initially, patients were clinically diagnosed, and the clinician indicated their confidence in the diagnosis. Next the CSF results were presented, and the clinician re-evaluated his initial diagnosis. The main outcomes were changes in initial diagnosis and diagnostic confidence. Results: Forty-seven patients were initially diagnosed with AD, 26 were diagnosed with another type of dementia, 18 were diagnosed with mild cognitive impairment, and 18 received a non-dementia diagnosis. All biomarkers distinguished between AD and non-dementia (p < 0.01); tau and ptau-181 also distinguished AD from other types of dementia (p < 0.001). After CSF biomarker levels were revealed, 11 diagnoses changed. In 31% of the diagnoses, the clinician gained confidence, while in 10% confidence decreased. Conclusion: We found that knowledge of CSF biomarker profiles changed the diagnosis in 10% of the cases, and confidence in the diagnosis increased for one third of the patients.