Recognition of cognitive dysfunction in hospitalised older patients: a flash mob study.

BACKGROUND: It is important that healthcare professionals recognise cognitive dysfunction in hospitalised older patients in order to address associated care needs, such as enhanced involvement of relatives and extra cognitive and functional support. However, studies analysing medical records suggest that healthcare professionals have low awareness of cognitive dysfunction in hospitalised older patients. In this study, we investigated the prevalence of cognitive dysfunction in hospitalised older patients, the percentage of patients in which cognitive dysfunction was recognised by healthcare professionals, and which variables were associated with recognition. METHODS: A multicentre, nationwide, cross-sectional observational study was conducted on a single day using a flash mob study design in thirteen university and general hospitals in the Netherlands. Cognitive function was assessed in hospitalised patients aged ≥ 65 years old, who were admitted to medical and surgical wards. A Mini-Cog score of < 3 out of 5 indicated cognitive dysfunction. The attending nurses and physicians were asked whether they suspected cognitive dysfunction in their patient. Variables associated with recognition of cognitive dysfunction were assessed using multilevel and multivariable logistic regression analyses. RESULTS: 347 of 757 enrolled patients (46%) showed cognitive dysfunction. Cognitive dysfunction was recognised by attending nurses in 137 of 323 patients (42%) and by physicians in 156 patients (48%). In 135 patients (42%), cognitive dysfunction was not recognised by either the attending nurse or physician. Recognition of cognitive dysfunction was better at a lower Mini-Cog score, with the best recognition in patients with the lowest scores. Patients with a Mini-Cog score < 3 were best recognised in the geriatric department (69% by nurses and 72% by physicians). CONCLUSION: Cognitive dysfunction is common in hospitalised older patients and is poorly recognised by healthcare professionals. This study highlights the need to improve recognition of cognitive dysfunction in hospitalised older patients, particularly in individuals with less apparent cognitive dysfunction. The high proportion of older patients with cognitive dysfunction suggests that it may be beneficial to provide care tailored to cognitive dysfunction for all hospitalised older patients.

Young-onset dementia in memory clinics in the Netherlands: Study design and description of PRECODE-GP.

The disease trajectory and healthcare requirements of patients with young-onset dementia (YOD) differ from those of older patients. Accurate data about YOD is crucial to improve diagnosis and optimize care. PRECODE-GP aims to set up a prospective national database of patients with YOD to gain insight into the occurrence and characteristics of patients with YOD in memory clinics in the Netherlands. The national database includes data from dementia patients aged <70 years at diagnosis, collected by local memory clinics (MCs). Data included demographic information, clinical variables, and (etiological) diagnoses. Between July 2019 and December 2022, 781 patients with a mean age of 62±6y at diagnosis (range 37 to 69y) were included from 39 MCs. Most (n = 547,70%) were diagnosed with dementia due to Alzheimer's disease (AD). Patients with Frontotemporal lobe dementia (FTD, n = 87, 11%) were youngest (61±6.0y). Over half (55%) of patients were experiencing symptoms for ≥2 years. We initiated a Dutch national YOD database to improve diagnosis and care for this underrepresented and vulnerable patient group. The database provides a basis for future in-depth studies on YOD.

Cerebrospinal Fluid Amyloid-ß Subtypes in Confirmed Frontotemporal Lobar Degeneration Cases: A Pilot Study.

To investigate amyloid-ß (Aß) in frontotemporal dementia (FTD), cerebrospinal fluid (CSF) Aß38, Aß40, and Aß42 in frontotemporal lobar degeneration (FTLD; N = 18 genetically and/or pathologically confirmed and N = 8 FTD with concomitant amyotrophic lateral sclerosis) were compared with Alzheimer's disease (AD; pathological or Pittsburgh-compound-B Positron-emission-tomography (PIB-PET) positive; N = 25) and controls (N = 24). For all the Aß subtypes, group difference was seen and post-hoc analysis revealed lower levels in FTLD compared to controls (p≤0.05). Aß42/40 ratio showed no difference between FTLD and controls; however, a difference was seen between AD versus FTLD (p < 0.01). This is an intriguing finding, suggesting a possible role of Aß in FTLD pathogenesis.

Tau Rather than TDP-43 Proteins are Potential Cerebrospinal Fluid Biomarkers for Frontotemporal Lobar Degeneration Subtypes: A Pilot Study.

BACKGROUND: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies. OBJECTIVE: To study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and FTLD-TDP subtypes. METHODS: We developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers. RESULTS: In ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients. CONCLUSION: We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology.

Clinico-Pathological Correlations of the Frontal Lobe Syndrome: Results of a Large Brain Bank Study.

AIMS: A clinical frontal lobe syndrome (FLS) is generally attributed to functional or structural disturbances within frontal-subcortical circuits. We studied the distribution of pathological brain changes in FLS. Additionally, the prevalence of FLS among various disorders was studied. METHODS: We systematically screened clinical files of donors to the Netherlands Brain Bank (n = 2,814) for FLS. A total of 262 FLS cases were identified, and the distribution of postmortem pathological changes within the frontal-subcortical circuits was extracted from their neuropathological reports. RESULTS: In 244 out of 262 patients (93%), pathological changes within the frontal-subcortical circuits were found: 90 subjects (34%) with frontal cortical pathology and 18 (7%) with pathology restricted to subcortical grey matter nuclei, whereas 136 subjects (52%) showed both cortical and subcortical pathology. In 18 subjects (7%), no pathology was found in the examined areas. The prevalence of FLS was highest in frontal-temporal lobar degeneration, followed by progressive supranuclear palsy and vascular dementia [χ(2)(6, n = 1,561) = 222.64, p < 0.01]. CONCLUSION: In this large brain bank study, the distribution of pathological changes in subjects with FLS was shown to be frontal-subcortical for the first time. A minority of FLS cases had pathology in the subcortical regions only or no frontal pathology at all.

Discriminative and prognostic potential of cerebrospinal fluid phosphoTau/tau ratio and neurofilaments for frontotemporal dementia subtypes.

INTRODUCTION: A decreased cerebrospinal fluid (CSF) p-Tau181 to total tau ratio (p/t-tau) is a biomarker for frontotemporal lobar degeneration with TDP43 inclusions (FTLD-TDP) and for amyotrophic lateral sclerosis (ALS). CSF light chain neurofilaments (NfL) are increased in ALS. We examined whether CSF p/t-tau and NfL are related to ALS status in FTLD-TDP. METHODS: We compared CSF p/t-tau and NfL levels between patients with FTLD-TDP with ALS (n = 15), FTLD-TDP without ALS (n = 17), FTLD-Tau (n = 6), Alzheimer's disease (AD; n = 25), and subjective memory complaints (SMC, n = 24). RESULTS: Apart from FTLD-Tau, all groups differed significantly with increasing p/t-tau ratios from FTLD-TDP with ALS to FTLD-TDP without ALS to AD and SMC. CSF NfL was very high in FTLD-TDP with ALS followed by FTLD-TDP without ALS, AD, and SMC. Both biomarkers correlated with survival. DISCUSSION: CSF p/t-tau ratio and NfL levels are strongly driven by ALS status. These markers, therefore, appear to be more of prognostic than diagnostic significance.

Immunohistochemical characterization of novel monoclonal antibodies against the N-terminus of amyloid ß-peptide.

Abstract Amyloid ß-peptide (Aß) is a key molecule in Alzheimer's disease (AD). Reliable immunohistochemical (IHC) methods to detect Aß and Aß-associated factors (AAF) in brain specimens are needed to determine their role in AD pathophysiology. Formic acid (FA) pre-treatment, which is generally used to enable efficient detection of Aß with IHC, induces structural modifications within the Aß, as well as in AAF. Consequently, interpretation of double IHC stainings becomes difficult. Therefore, serial stainings of two newly produced monoclonal antibodies (mAbs) VU-17 and IC16 and two other mAbs (6E10 and 3D6) were performed with four different pre-treatments (no pre-treatment, Tris/EDTA, citrate and FA) and additionally six IHC characteristics were scored: diffuse/compact/classic plaques, arteries with cerebral Aß angiopathy, dyshoric angiopathy, capillaries with dyshoric angiopathy. Subsequently, these stainings were compared with IHC procedures, which are frequently used in a diagnostic setting, employing mAbs 4G8 and 6F/3D with FA pre-treatment. IHC Aß patterns obtained with VU-17 and, IC16 and 3D6 without the use of FA pre-treatment were comparable to those obtained with 4G8 and 6F/3D upon FA pre-treatment. Omission of FA pre-treatment gives the advantage to allow double IHC stainings, detecting both Aß and AAF that otherwise would have been structural modificated upon FA pre-treatment.

Cognitive correlates of cerebrospinal fluid biomarkers in frontotemporal dementia.

OBJECTIVE: In this study we investigated the relationships between cerebrospinal fluid (CSF) biomarkers (tau and amyloid-ß1-42 [Aß1-42]) and cognition or behavior in patients with frontotemporal dementia (the behavioral variant, bvFTD). METHODS: We included 58 patients with bvFTD. All patients underwent a neuropsychological assessment and lumbar puncture. Relationships between CSF biomarkers and cognition or behavior were assessed with linear regression analysis. RESULTS: After correction for age, sex, and education, CSF tau levels were found to be negatively related to the Visual Association Test (standardized ß = -0.3, P < .05), whereas CSF Aß1-42 levels were found to be positively related to the Mini-Mental State Examination (ß = 0.3, P < .05), the frontal assessment battery (ß = 0.5, P < .05), and digit span backwards test (ß = 0.3, P = .01). We did not find relations between CSF biomarkers and behavior (measured by the neuropsychiatric inventory). After excluding all patients with a CSF biomarker profile often seen in Alzheimer's disease (high levels of tau and low levels of Aß1-42), we still found relations between CSF Aß1-42 levels and Visual Association Test object naming (ß = 0.4, P < .05), as well as between CSF Aß1-42 levels and the frontal assessment battery (ß = 0.5, P < .05, but there was no relation between CSF tau and cognition. CONCLUSION: Low CSF Aß1-42 levels are associated with worse general cognitive function and worse executive function in patients with bvFTD. Our results provide circumstantial evidence for a pathophysiological role of Aß1-42 in bvFTD.

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 (Aß40 and Aß42), 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 Alzheimer's 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.

Microbleeds relate to altered amyloid-ß metabolism in Alzheimer's disease.

Cerebral microbleeds (MBs) may relate to amyloid in dementia. We selected 26 probable Alzheimer's disease (AD) patients with MBs, 26 age- and sex-matched AD patients without MBs, 11 vascular dementia (VaD) patients, and 22 patients with subjective complaints. We measured amyloid beta 1-42 (Aß42) and 1-40 (Aß40) in cerebrospinal fluid (CSF) and plasma, and blood-brain barrier (BBB) function using albumin ratios. CSF Aß42 was lowest in AD with MBs, whereas Aß40 was selectively decreased in VaD. In plasma, amyloid-beta was nonsignificantly elevated in VaD compared with controls. Higher albumin ratios in VaD suggested blood-brain barrier dysfunction. A MB pattern suggestive of cerebral amyloid angiopathy (CAA) related to lower CSF Aß42, while a non-cerebral amyloid angiopathy specific MB distribution related to higher plasma Aß40. Amyloid-beta is differentially implicated in AD with MBs and VaD. MB distribution related to different amyloid profiles, supporting distinct etiologies. Our results suggest that Aß42 is retained in cerebrovasculature of AD patients with MBs, while in contrast, VaD patients may possibly drain amyloid.

Cerebrospinal fluid ß-amyloid and tau are not associated with risk of delirium: a prospective cohort study in older adults with hip fracture.

OBJECTIVES: To examine the association between cerebrospinal fluid (CSF) ß-amyloid (Aß1-42), tau, and hyperphosphorylated tau (Ptau) and risk of delirium in older adults with hip fracture. DESIGN: Prospective cohort study. SETTING: University-affiliated general hospital in Alkmaar, the Netherlands. PARTICIPANTS: Seventy-six participants aged 75 and older admitted for surgical repair of acute hip fracture. MEASUREMENTS: Presurgical baseline screening and assessment included the Informant Questionnaire on Cognitive Decline-short form (IQCODE-N), Mini-Mental State Examination, standardized Snellen test for visual impairment, Geriatric Depression Scale, Barthel Index (BI), and Lawton Instrumental Activity of Daily Living (IADL) scale. The number of medical comorbidities and medications at home, American Society of Anesthesiologists score, and Acute Physiology and Chronic Health Evaluation II score were determined according to chart review. Delirium was diagnosed using the Confusion Assessment Method. CSF was collected at the onset of spinal anesthesia. RESULTS: Postoperative delirium occurred in 30 (39.5%) participants. Participants with delirium were older, showed more signs of cognitive decline, were more dependent at home in activity of daily living and IADL functioning, and used more medications before admission. Preoperative CSF Aß1-42, tau, and Ptau levels were not significantly different in participants who did and did not develop delirium during subsequent hospitalization. In contrast, prefracture cognitive decline (IQCODE-N) was significantly related to delirium (odds ratio=9.43, 95% confidence interval=2.45-36.31). CONCLUSION: Cognitive impairment predisposes to delirium, but in this study, postoperative delirium was not associated with baseline CSF Aß1-42, tau, and Ptau levels. These findings suggest that CSF markers for plaque and tangle formation are not strongly associated with delirium risk in older adults with hip fracture.

Progression from MCI to AD: predictive value of CSF Aß42 is modified by APOE genotype.

OBJECTIVE: To study CSF biomarkers amyloid-beta 1-42 (Aß42) and total tau (tau) in relation to APOE genotype in their ability to predict progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: In 100 MCI patients CSF Aß42, tau and APOE genotype were determined. At follow-up of 18 (13-24) months 58 patients remained non-progressive and 42 progressed to AD. RESULTS: Cox proportional hazards models showed an interaction between Aß42 and APOE genotype (p<0.05). Stratification for APOE revealed HR (95% CI) for abnormal Aß42 of 8.2 (2.1-31.9) for ε4 non-carriers, 3.9 (0.8-18.5) for heterozygotes and 0.3 (0.0-1.7) for homozygotes. Inversely, stratification for Aß42 revealed that in patients with normal levels of Aß42, ε4 homozygotes had a strongly increased risk of progression to AD with HR (95% CI) 20.8 (2.4-182.8). Tau and APOE independently predicted progression to AD. CONCLUSIONS: Aß42 was a stronger predictor of progression to AD in APOE ε4 non-carriers than in carriers. Furthermore, the risk of progression for ε4 homozygotes was very high, also in patients with normal levels of Aß42.

Additional value of CSF amyloid-beta 40 levels in the differentiation between FTLD and control subjects.

To determine the additional value of cerebrospinal fluid (CSF)amyloid-beta1-40 (Abeta40) next to amyloid-beta1-42 (beta42), total tau (Tau), and tau phosphorylated at threonine-181 (pTau) to distinguish patients with frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and controls, we measured CSF levels of Abeta40, Abeta42, pTau, and Tau in 55 patients with FTLD, 60 with AD, and 40 control subjects. Logistic regression was used to identify biomarkers that best distinguished the groups. Additionally, a decision tree (cost=test method; Matlab 7.7) was used to predict diagnosis selecting the best set of biomarkers with the optimal cut-off. Logistic regression showed that Abeta42 and pTau CSF levels provided optimal distinction between AD and FTLD. A combination of Abeta42, Tau, and Abeta40 optimally discriminated FTLD from controls and AD from controls. The decision tree used Abeta42 (cut-off 578 pg/ml) to identify AD (positive predictive value (PPV) 97%), followed by Tau(cut-off 336 pg/ml) to identify FTLD (PPV 67%), and in the last step,Abeta40 (cut-off 10 ng/ml) was used to differentiate controls (PPV68%). Applying CSF Abeta40 levels in the model, the PPV of diagnosis increased to 75% as opposed to 70% when only Abeta42 and Tau were used. CSF Abeta40 levels added to the conventional CSF biomarkers increases the potential to discriminate subjects with dementia from controls. Our findings favor the implementation of CSF Abeta40 in differential diagnosis between FTLD, AD, and control subjects.

Amyloid-beta(1-42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease.

BACKGROUND: To improve ante mortem diagnostic accuracy of Alzheimer disease (AD), measurement of the biomarkers amyloid-beta(1-42) (Abeta42), total tau (Tau), and tau phosphorylated at threonine(181) (pTau) in cerebrospinal fluid (CSF) has been proposed. We have used these markers and evaluated their performance. METHODS: From January 2001 to January 2007, we assessed Abeta42, Tau, and pTau by commercial ELISAs in CSF from 248 consecutive AD patients and 131 patients with subjective memory complaints attending our outpatient memory clinic. Diagnoses were made blind to the results of the biomarker assays. We assessed sensitivity and specificity and analyzed trends over time. RESULTS: Interassay CVs from analysis of pools of surplus CSF specimens were mean 11.3% (SD 4.9%) for Abeta42; 9.3% (1.5%) for Tau, and 9.4% (2.5%) for pTau, respectively (n = 7-18). To achieve 85% sensitivity, cutoff values were 550 (95% CI 531-570) ng/L for Abeta42; 375 (325-405) ng/L for Tau, and 52 (48-56) ng/L for pTau. Corresponding specificities were 83% (95% CI 76%-89%) for Abeta42, 78% (70%-85%) for Tau, and 68% (60%-77%) for pTau. Logistic regression to investigate the simultaneous impact of the 3 CSF biomarkers on the diagnosis yielded a sensitivity of 93.5% and specificity of 82.7%, at a discrimination line of Abeta42 = 373 + 0.82 x Tau. The area under the ROC curves of Tau and pTau showed significant fluctuation over time. CONCLUSIONS: CSF biomarkers Abeta42 and Tau can be used as a diagnostic aid in AD. pTau did not have additional value over these 2 markers. Cutoff values, sensitivities, specificities, and discrimination lines depend on the patient groups studied and laboratory experience.

Relationship of cerebrospinal fluid markers to 11C-PiB and 18F-FDDNP binding.

UNLABELLED: The purpose of this study was to investigate the potential relationships between cerebrospinal fluid (CSF) measurements of beta-amyloid-1-42 (Abeta(1-42)) and total tau to (11)C-Pittsburgh compound B ((11)C-PiB) and 2-(1-{6-[(2-(18)F-fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile ((18)F-FDDNP) binding as measured using PET. METHODS: A total of 37 subjects were included, consisting of 15 patients with Alzheimer disease (AD), 12 patients with mild cognitive impairment, and 10 healthy controls. All subjects underwent a lumbar puncture and PET using both (11)C-PiB and (18)F-FDDNP. For both PET tracers, parametric images of binding potential were generated. Potential associations of CSF levels of Abeta(1-42) and tau with (11)C-PiB and (18)F-FDDNP binding were assessed using Pearson correlation coefficients and linear regression analyses. RESULTS: For both global (11)C-PiB and (18)F-FDDNP binding, significant correlations with CSF levels of Abeta(1-42) (r = -0.72 and -0.37, respectively) and tau (r = 0.58 and 0.56, respectively) were found across groups (all P < 0.001, except P < 0.05 for correlation between (18)F-FDDNP and Abeta(1-42)). Linear regression analyses showed that, adjusted for regional volume, age, sex, and diagnosis, global (11)C-PiB uptake had an inverse association with Abeta(1-42) CSF levels (standardized beta = -0.50, P < 0.001), whereas there was a positive association between global (18)F-FDDNP binding and tau CSF levels (standardized beta = 0.62, P < 0.01). CONCLUSION: The good agreement between these 2 different types of biomarkers (i.e., CSF and PET) provides converging evidence for their validity. The inverse association between (11)C-PiB and CSF tau Abeta(1-42) confirms that (11)C-PiB measures amyloid load in the brain. The positive association between (18)F-FDDNP and CSF tau suggests that at least part of the specific signal of (18)F-FDDNP in AD patients is due to tangle formation.

Quantification of amyloid-beta 40 in cerebrospinal fluid.

BACKGROUND: Truncated forms and full-length forms of the amyloid-beta 40 (Abeta40) are key molecules in the pathogenesis of dementia, and are detectable in CSF. Reliable methods to detect these biomarkers in CSF are of great importance for understanding the disease mechanisms and for diagnostic purposes. METHODS: VU-alpha-Abeta40, a monoclonal antibody (mAb) specifically detecting Abeta40, was generated and characterized by solid and fluid phase ELISA, surface plasmon resonance spectroscopy (SPRS), immunoprecipitation (IP), immunohistochemical and Western blot (WB) analysis. In addition, an ELISA with VU-alpha-Abeta40 as catching and 6E10 as detecting mAbs was set up and validated. This ELISA was used to measure Abeta40 in CSF of controls (N=27), patients with Alzheimer's disease (AD; N=20), frontotemporal lobe dementia (FTLD; N=14), noninflammatory (N=15) and inflammatory (N=15) neurological conditions. RESULTS: VU-alpha-Abeta40 specifically recognizes Abeta40 with high affinity (K(A)=1.3x10(9) M(-1)) and detects Abeta40 in AD brain specimens. The developed sandwich ELISA has a detection limit of 0.21 ng/mL, a mean recovery of 90%, and an intra- and inter-assay CV of 1.4% and 7.3%. FTLD patients had a lower mean level of Abeta40 (8.8 (1.9) ng/mL) than controls (12.0 (1.7) ng/mL); p<0.01). CONCLUSIONS: VU-alpha-Abeta40 was successfully implemented in an ELISA which enables us to measure Abeta40 accurately in human CSF. Clinical validation revealed lower levels of Abeta40 in FTLD patients. This finding opens new possibilities for early and differential diagnosis of dementia.

CSF biomarker levels in early and late onset Alzheimer's disease.

OBJECTIVE: To compare CSF levels of beta-amyloid 1-42 (Abeta(1-42)), total tau (tau) and tau phosphorylated at threonine 181 (ptau-181) between AD patients and controls according to age. METHODS: 248 AD patients (48% men) and 127 controls (51% men, 22 volunteers and 105 subjective complainers) underwent lumbar puncture. Both patients and controls were divided into a young (<65 years) and old (>or=65 years) group. RESULTS: All three biomarkers showed main effects of diagnosis (p<0.001). There was an interaction between diagnosis and age for all three biomarkers (p<0.05), as old controls had lower Abeta(1-42) and higher (p)tau than young controls (Abeta(1-42) 699+/-250 versus 866+/-191pg/ml, tau 408+/-245 versus 243+/-102pg/ml, ptau-181 60+/-28 versus 42+/-15pg/ml), but there was no difference according to age among AD patients (Abeta(1-42) 451+/-178 versus 425+/-146pg/ml, tau 741+/-460 versus 798+/-467pg/ml, ptau-181 91+/-42 versus 91+/-41pg/ml). CONCLUSION: We found that the older control group had lower Abeta(1-42) and higher (p)tau compared to the younger control group. This suggests that older individuals may have AD pathology, even in the absence of objective cognitive impairment.

Serum amyloid p component as a biomarker in mild cognitive impairment and Alzheimer's disease.

BACKGROUND: Serum amyloid P component (SAP), present in amyloid-beta (Abeta) plaques in Alzheimer's disease (AD), may protect Abeta deposits against proteolysis, thereby promoting plaque formation. The aim was to investigate if SAP levels in cerebrospinal fluid (CSF) and serum can be used to discriminate controls, AD and mild cognitive impairment (MCI) patients, and to identify incipient AD among MCI patients. METHODS: SAP levels in CSF and serum were determined in 30 controls, 67 MCI and 144 AD patients. At follow-up, 39 MCI patients had progressed to dementia, while 25 had remained stable (mean follow-up time: 2.6 +/- 1.0 and 2.1 +/- 0.8 years). RESULTS: Cross-sectionally no differences were found in SAP levels in CSF and serum between the groups. MCI patients that had progressed to dementia at follow-up had lower CSF SAP levels (13 microgram/l, range 3.3-199.3 microgram/l) than MCI nonprogressors (20.2 microgram/l, range 7.0-127.7 microgram/l; p < 0.05) [corrected]. A low CSF SAP level was associated with a 2-fold increased risk of progression to AD (hazard ratio = 2.2; 95% confidence interval = 0.9-5.4). CONCLUSION: Our data suggest that measurement of CSF SAP levels can aid in the identification of incipient AD among MCI patients.