Sex-specific associations with cerebrospinal fluid biomarkers in dementia with Lewy bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is more prevalent in men than in women. In addition, post-mortem studies found sex differences in underlying pathology. It remains unclear whether these differences are also present antemortem in in vivo biomarkers, and whether sex differences translate to variability in clinical manifestation. The objective of this study was to evaluate sex differences in cerebrospinal fluid (CSF) biomarker concentrations (i.e., alpha-synuclein (α-syn), amyloid ß1-42 (Aß42), total tau (Tau), phosphorylated tau at threonine 181 (pTau)) and clinical characteristics in DLB. METHODS: We included 223 DLB patients from the Amsterdam Dementia Cohort, of which 39 were women (17%, age 70 ± 6, MMSE 21 ± 6) and 184 men (83%, age 68 ± 7, MMSE 23 ± 4). Sex differences in CSF biomarker concentrations (i.e., α-syn, Aß42, Tau, and pTau) were evaluated using age-corrected general linear models (GLM). In addition, we analyzed sex differences in core clinical features (i.e., visual hallucinations, parkinsonism, cognitive fluctuations, and REM sleep behavior disorder (RBD) and cognitive test scores using age- and education-adjusted GLM. RESULTS: Women had lower CSF α-syn levels (F 1429 ± 164 vs M 1831 ± 60, p = 0.02) and CSF Aß42 levels (F 712 ± 39 vs M 821 ± 18, p = 0.01) compared to men. There were no sex differences for (p) Tau concentrations (p > 0.05). Clinically, women were older, had a shorter duration of complaints (F 2 ± 1 vs M 4 ± 3, p < 0.001), more frequent hallucinations (58% vs 38%, p = 0.02), and scored lower on MMSE and a fluency task (MMSE, p = 0.02; animal fluency, p = 0.006). Men and women did not differ on fluctuations, RBD, parkinsonism, or other cognitive tests. CONCLUSIONS: Women had lower Aß42 and α-syn levels than men, alongside a shorter duration of complaints. Moreover, at the time of diagnosis, women had lower cognitive test scores and more frequent hallucinations. Based on our findings, one could hypothesize that women have a more aggressive disease course in DLB compared to men. Future research should investigate whether women and men with DLB might benefit from sex-specific treatment strategies.

Amyloid beta peptides in plasma in early diagnosis of Alzheimer's disease: A multicenter study with multiplexing.

We measured concentrations of Abeta peptides 1-42 and 1-40, and their ratio in plasma of patients carefully categorized clinically and neurochemically as having AD or other dementias with a newly commercially available multiplexing assay, characterized by reasonable laboratory performance (intra-assay imprecision in the range of 1.3-3.8% for Abeta1-42, and 1.8-4.1% for Abeta1-40, inter-assay imprecision for Abeta1-42, Abeta1-40, and Abeta1-42/Abeta1-40 concentration ratio in the range of 2.3-11.5%, 2.2-10.4% and 4.2-9.7%, respectively). Patients with AD or mild cognitive impairment of AD type (MCI-AD) whose clinical diagnosis was supported with CSF biomarkers (n=193) had significantly lower Abeta1-42 plasma concentrations (p<0.007), and Abeta1-42/1-40 ratios (p<0.003) compared to patients with other dementias and MCI of other types (n=64). No significant differences between persons with MCI of AD type and patients with early AD were observed, or between MCI of other types versus patients with early dementia of other types. Our findings reconfirm the hypothesis that alterations of biomarker concentrations occur early in a preclinical AD stage and that these alterations are also reflected in plasma.

Evolution of Abeta42 and Abeta40 levels and Abeta42/Abeta40 ratio in plasma during progression of Alzheimer's disease: a multicenter assessment.

OBJECTIVE: To better understand the seemingly contradictory plasma beta-amyloid (Abeta) results in Alzheimer's disease (AD) patients by using a newly developed plasma Abeta assay, the INNO-BIA plasma Abeta forms, in a multicenter study. METHODS: A combined retrospective analysis of plasma Abeta isoforms on mild cognitive impairment (MCI) from three large cross-sectional studies involving 643 samples from the participating German and Swedish centers. RESULTS: Detection modules based on two different amino (N)-terminal specific Abeta monoclonal antibodies demonstrated that Abeta in plasma could be reliable quantified using a sandwich immunoassay technology with high precision, even for low Abeta42 plasma concentrations. Abeta40 and Abeta42 concentrations varied consistently with the ApoE genotype, while the Abeta42/Abeta40 ratio did not. Irrespective of the decrease of the Abeta42/Abeta40 ratio with age and MMSE, this parameter was strongly associated with AD, as defined in this study by elevated hyperphosphorylated (P-tau181P) levels in cerebrospinal fluid (CSF). CONCLUSION: A highly robust assay for repeatedly measuring Abeta forms in plasma such as INNO-BIA plasma Abeta forms might be a useful tool in a future risk assessment of AD.

The influence of matrix type, diurnal rhythm and sample collection and processing on the measurement of plasma beta-amyloid isoforms using the INNO-BIA plasma Abeta forms multiplex assay.

OBJECTIVE: The aim of the study was to determine the extent to which plasma matrix types, diurnal rhythm and sample collection and processing procedures contribute to overall variability of measurements with the INNO-BIA plasma Abeta forms assay. METHODS: Plasma samples from healthy volunteers were collected at BARC-CRI. Analyte concentrations from various plasma matrix types (EDTA, heparin, fluoride) were compared to serum after collection of blood in commercial plastic and glass tubes. Sample processing variables including time and temperature before and after centrifugation, centrifugal force and plasma dilution factor were also investigated. Diurnal variability in plasma Abeta isoforms was determined in 29 healthy volunteers by analysis of EDTA plasma specimens serially collected over 24 hours and stored frozen following oral administration of a placebo treatment. All plasma samples from a given individual and experiment were analyzed in a single analytical run. RESULTS: Highest Abeta levels were obtained using EDTA-plasma samples (in contrast to serum, heparin, citrate, or fluoride). Addition of aprotinin to EDTA plasma had no effect on Abeta peptide recovery. The elapsed time and temperature exposure, before and after sample processing affects the recovery of Abeta isoforms. Analyte recovery was not significantly affected by the presence of platelets in plasma samples. At the subject level, analysis of serially collected EDTA plasma specimens from healthy volunteers revealed no evidence of diurnal variation in any of the Abeta isoforms investigated and results from samples collected on a monthly basis showed only very limited intra-individual variation. CONCLUSIONS: Optimal recovery of Abeta peptides was obtained from blood drawn into EDTA tubes and processed within 4 h. Plasma that was refrigerated after separation and analysed within 4 h gave comparable results to samples immediately processed and frozen at -70 degrees C.

Trabalho de consenso de força-tarefa da WFSBP sobre marcadores biológicos das demências: contribuição da análise do LCR e do sangue para o diagnóstico precoce e diferencial das demências / Consensus Paper of the WFSBP Task Force on Biological Markers of Dementia: The role of CSF and blood analysis in the early and differential diagnosis of dementiaWorld J Biol Psychiatry

O envelhecimento da população e o aumento da expectativa de vida resultam em um número cada vez maior de pacientes com demência. Os déficits cognitivos podem ser manifestações de uma doença curável do sistema nervoso central (por exemplo, neuroinflamação), como também de uma doença atualmente considerada irreversível, como a doença de Alzheimer (DA). Tendo em vista as novas abordagens terapêuticas para a DA, em que se avalia o potencial modificador da patogenia, torna-se necessário o estabelecimento de um diagnóstico confiável em vida. Embora a análise do líquido cefalorraquidiano (LCR) e do soro seja realização de rotina em doenças neuroinflamatórias, ainda necessita de padronização para ser usada como instrumento auxiliar no diagnóstico clínico da DA. Vários parâmetros relacionados à DA (tau total, formas fosforiladas de tau, peptídeos Aβ, genótipo ApoE, p97 etc.) podem ser determinados no LCR. A combinação de alguns desses parâmetros proporciona sensibilidade e especificidade na faixa de 85 por cento para o diagnóstico da DA, um valor usualmente atribuído a um bom instrumento de diagnóstico. Nesta revisão, são discutidas as publicações mais recentes sobre os marcadores neuroquímicos para o diagnóstico clínico das demências, com ênfase no diagnóstico precoce e diferencial da DA. Discutem-se brevemente as novas perspectivas oferecidas por tecnologias recentes, tais como a FCS (fluorescence correlation spectroscopy) e a técnica de espectrometria de massa pelo método SELDI-TOF (surface enhanced laser desorption/ionization time-of-flight mass spectrometry).

Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Aß peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85 percent, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

Increased Abeta1-42 production sensitizes neuroblastoma cells for ER stress toxicity.

Alzheimer's disease (AD) is characterized by the aggregation and subsequent deposition of misfolded beta-amyloid (Abeta) peptide. The unfolded protein response (UPR) is activated by misfolded protein stress in the endoplasmic reticulum (ER). In previous studies we demonstrated mild activation of the UPR by extracellularly applied oligomeric but not fibrillar Abeta1-42. In addition, we showed that oligomeric Abeta1-42 is internalized by cells, whereas fibrillar Abeta1-42 remains on the outside of the cell. Inhibition of Abeta uptake specifically inhibits toxicity of Abeta1-42 oligomers, underscoring the toxic potential of intracellular Abeta. Therefore, in the present study, we investigated the connection between intracellularly produced Abeta and the ER stress response, using human neuroblastoma cells overexpressing either wild type APP695 (APPwt) or APP695V717F (APPmut). Both cell lines secrete higher levels of Abeta1-40 and Abeta1-42 compared to the parental line. In addition, APPmut produces more Abeta1-42 than APPwt. Whereas the basal levels of UPR markers are not different, we find augmented UPR induction in response to ER stress in both APP overproducing cell lines compared to the parental cell line, with the strongest UPR activation in APPmut cells. In addition, ER stress toxicity was highest in APPmut cells, strongly suggesting a connection with the production of Abeta1-42. The difference in ER stress mediated toxicity between the APPwt and APPmut cell lines is alleviated by pretreatment with gamma-secretase inhibitor, indicating that it is dependent on Abeta production and in particular on Abeta1-42. Our data indicate that increased Abeta1-42 production sensitizes neuroblastoma cells for ER stress toxicity.

Growth-associated protein 43 in lesions and cerebrospinal fluid in multiple sclerosis.

Axonal damage in multiple sclerosis (MS) is correlated to disease progression. Early axonal damage may be compensated for by regenerative processes. Growth-associated protein 43 (GAP-43) is a marker for axonal growth and synaptogenesis in various neurodegenerative diseases. We investigated the expression of GAP-43 in 48 MS grey and white matter lesions of different stages. Decreased GAP-43 expression was found in 74% of the white matter lesions, independent of the lesion stage. In 19 out of 35 white matter lesions, areas of increased GAP-43 expression were present immediately adjacent to the lesions. Increased or unaltered expression was observed in remyelinated lesions. GAP-43 was expressed in neurofilament-positive structures. GAP-43 expression appeared unchanged in grey matter lesions. Macrophages were present in the areas of changed GAP-43 expression. cerebrospinal fluid GAP-43 levels were negatively correlated with magnetic resonance imaging measures of whole-brain atrophy (r = -0.30). In conclusion, these results indicate that decreased GAP-43 immunopositivity reflects axonal damage in MS lesions, which may again be reflected in decreased cerebrospinal fluid levels. The increased levels of GAP-43 in remyelinated or nondemyelinated white matter close to MS lesions may reflect regenerative attempts by damaged axons.

Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia.

Aging of population, and increasing life expectancy result in an increasing number of patients with dementia. This symptom can be a part of a completely curable disease of the central nervous system (e.g, neuroinflammation), or a disease currently considered irreversible (e.g, Alzheimer's disease, AD). In the latter case, several potentially successful treatment approaches are being tested now, demanding reasonable standards of pre-mortem diagnosis. Cerebrospinal fluid and serum analysis (CSF/serum analysis), whereas routinely performed in neuroinflammatory diseases, still requires standardization to be used as an aid to the clinically based diagnosis of AD. Several AD-related CSF parameters (total tau, phosphorylated forms of tau, Abeta peptides, ApoE genotype, p97, etc.) tested separately or in a combination provide sensitivity and specificity in the range of 85%, the figure commonly expected from a good diagnostic tool. In this review, recently published reports regarding progress in neurochemical pre-mortem diagnosis of dementias are discussed with a focus on an early and differential diagnosis of AD. Novel perspectives offered by recently introduced technologies, e.g, fluorescence correlation spectroscopy (FCS) and surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) are briefly discussed.

The effect of simvastatin treatment on the amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer's disease.

During the last years, several clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in Alzheimer's disease (AD) in humans. We present an open biochemical study where 19 patients with AD have been treated with simvastatin (20 mg/day) for 12 months. The aim was to further investigate the effect of simvastatin treatment on cerebrospinal fluid (CSF) biomarkers of APP processing, AD biomarkers as total tau and tau phosphorylated at threonine 181, brain cholesterol metabolism as well as on cognitive decline in patients with AD. Despite biochemical data suggesting that treatment with 20 mg/day of simvastatin for 12 months does affect the brain cholesterol metabolism, we did not find any change in CSF or plasma levels of beta-amyloid (Abeta)(1-42). However, by analysis of APP isoforms, we found that statin treatment may favor the nonamyloidogenic pathway of APP processing. The relevance and mechanism between statin treatment and AD has to be further elucidated by using statins of different lipophility in different dosages over a longer period of time.

Glycosylation of acetylcholinesterase and butyrylcholinesterase changes as a function of the duration of Alzheimer's disease.

The identification of biochemical markers of Alzheimer's disease (AD) may help in the diagnosis of the disease. Previous studies have shown that Abeta(1-42) is decreased, and tau and phospho-tau are increased in AD cerebrospinal fluid (CSF). Our own studies have identified glycosylated isoforms of acetylcholinesterase (Glyc-AChE) and butyrylcholinesterase (Glyc-BuChE) that are increased in AD CSF. Glyc-AChE is increased in APP (SW) Tg2576 transgenic mice prior to amyloid plaque deposition, which suggests that Glyc-AChE may be an early marker of AD. The aim of this study was to determine whether Glyc-AChE or Glyc-BuChE is increased in CSF at early stages of AD and to compare the levels of these markers with those of Abeta(1-42), tau and phospho-tau. Lumbar CSF was obtained ante mortem from 106 non-AD patients, including 15 patients with mild cognitive impairment (MCI), and 102 patients with probable AD. Glyc-AChE, tau and phospho-tau were significantly increased in the CSF of AD patients compared to non-neurological disease (NND) controls. Abeta(1-42) was lower in the AD patients than in NND controls. A positive correlation was found between the levels of Glyc-AChE or Glyc-BuChE and disease duration. However, there was no clear correlation between the levels of tau, phospho-tau or Abeta(1-42) and disease duration. The results suggest that Glyc-AChE and Glyc-BuChE are unlikely to be early markers of AD, although they may have value as markers of disease progression.

Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt-Jakob disease from other dementias.

Early clinical symptoms of sporadic Creutzfeldt-Jakob disease (CJD) may overlap with other neurodegenerative diseases like Alzheimer's disease (AD) and frontotemporal degeneration (FTD). On entering an era in which pharmaceutical treatment of CJD occurs, reliable diagnostic markers like immunodetection of 14-3-3 proteins in the cerebrospinal fluid (CSF) are required. However, false negative results in autopsy-proven, sporadic CJD cases, as well as false positive results in several other disorders including AD and FTD showing high CSF tau protein levels, limit the potential of this marker. Due to neuronal lysis the cytosolic fraction of total tau containing phosphorylated and non-phosphorylated isoforms is partially liberated into the CSF. Since hyperphosphorylation of tau may specifically occur in neurodegenerative diseases associated with neurofibrillary changes, we hypothesized that the phospho-tau (P-tau)/total tau ratio in CSF may be a useful marker to discriminate CJD from other neurodegenerative disorders. The P-tau/total tau ratio discriminated patients with CJD from all other neuro-degenerative disorders including patients with AD and FTD without any overlap. Although the results have to be confirmed in a larger sample, the preliminary data suggest that simultaneous measurement of total tau and P-tau in CSF may be useful to identify patients with CJD.

Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds.

Deposition of beta-amyloid (Abeta) is an early pathogenic event in Alzheimer's disease (AD). We measured Abeta42 and Abeta40 in cerebrospinal fluid (CSF) in a population-based sample of 85-year-olds, 27 demented and 35 non-demented. During the following 3 years, 7 of the 35 non-demented individuals had developed dementia, while 28 remained non-demented. Reduced CSF levels of both Abeta42 (p = 0.001) and Abeta40 (p = 0.0001) were found in patients with manifest AD and vascular dementia at the age of 85. Non-demented individuals who developed dementia during follow-up had lower levels of CSF- Abeta42 (p = 0.003), but not CSF-Abeta40 (p = 0.96), than those who remained non-demented. The odds ratio for development of dementia was 8.2 (p = 0.027) for individuals in the lower 50th percentile of CSF-Abeta42, while none of those in the highest 33rd percentile of CSF-Abeta42 developed dementia during follow-up. There were no significant differences between carriers and non-carriers of the apolipoprotein E epsilon4 allele regarding CSF-Abeta42 or CSF-Abeta40. Our study suggests that low CSF-Abeta42 is found also in an unselected population-based sample of old demented patients and provides the first evidence of a disturbance in the metabolism of Abeta, specifically involving Abeta42, before the onset of clinical symptoms in AD.

Phosphorylated tau in cerebrospinal fluid as a marker for Creutzfeldt-Jakob disease.

OBJECTIVE: To determine the concentrations of microtubule associated protein tau and multiple phosphorylated tau epitopes in the cerebrospinal fluid of patients with sporadic Creutzfeldt-Jakob disease (sCJD), dementias, and controls, in order to evaluate their diagnostic use and clinical relevance. METHODS: The CSF concentrations of total tau and phosphorylated tau at epitope 181 were determined by enzyme linked immunosorbent assay in 66 definite and nine probable sCJD patients, and in 97 controls. Other phosphorylated tau epitopes were investigated by western blot. RESULTS: In the sCJD population, determination of 14-3-3 protein and total tau protein concentrations was of the highest diagnostic value, with a sensitivity of 96% and 92%, respectively, and a specificity of 94% and 97%. Two distinct subgroups could be identified among the 75 sCJD patients based on the detection of phosphorylated tau at threonine 181 and serines 199, 202, and 404. A high phosphorylated tau concentration was clinically correlated with a significantly shorter disease duration, early onset of akinetic mutism, and a higher rate of typical EEGs (p < 0.05). CONCLUSIONS: Although the determination of phosphorylated tau levels cannot be used as a diagnostic biomarker, it may prove useful for estimating the prognosis of an sCJD patient. These experiments reconfirm that sCJD is a disease with a complex pathology.

Association of CSF apolipoprotein E, Abeta42 and cognition in Alzheimer's disease.

A significant association between CSF Abeta42 and cognition in patients with Alzheimer's disease (AD) homozygous for the epsilon3 allele of the apolipoprotein E (apoE) has been described. In this study we extended our observations on apoE, as another plaque component, and investigated the association between CSF apoE concentrations and cognitive performance after stratification for the apoE genotype in 62 patients with AD, 19 other forms of dementia and 18 controls. CSF Abeta42 and apoE concentrations were significantly and positively associated with Mini Mental State Examination (MMSE) score in AD (Abeta42: r = 0.332; P = 0.026; apoE: r = 0.386; P = 0.006). For Abeta42 this association was exclusively present in epsilon3 homozygotes (r = 0.44; P = 0.014), whereas apoE was correlated with MMSE in epsilon4 hetero- or homozygotes subjects (epsilon4/epsilonX: r = 0.638; P = 0.004: epsilon4/epsilon4; r = 0.812; P = 0.05). No association was observed between CSF concentrations of Abeta42 and apoE. The significant relationship between MMSE and CSF Abeta42 in epsilon3 homozygotes and apoE in epsilon4 hetero- and homozygotes respectively may suggest that both proteins may be associated independently from each other with cognitive decline.

Cerebrospinal fluid tau and beta-amyloid(1-42) in dementia disorders.

The reliability of cerebrospinal fluid (CSF)-tau and CSF-beta-amyloid assays for diagnosis of Alzheimer's disease and other dementing disorders such as frontotemporal dementia (FTD), dementia with Lewy bodies (DLB) and Creutzfeldt-Jakob disease (CJD) is reviewed. CSF assessment of the two proteins is useful in early diagnosis of AD and to differentiate it from FTD and DLB. Extremely high CSF-tau levels can discriminate CJD from AD.

Tau and Abeta42 in cerebrospinal fluid from healthy adults 21-93 years of age: establishment of reference values.

BACKGROUND: Tau protein and the 42-amino acid form of beta-amyloid (Abeta42) measured in cerebrospinal fluid (CSF) have been proposed as potential biochemical diagnostic markers for Alzheimer disease. For the introduction of these assays in clinical practice, adequate reference values are of importance. METHODS: CSF samples were obtained from 231 neurologically and psychiatrically healthy individuals, 21-93 years of age, all with a MiniMental State examination score of 28 or above. Standardized ELISAs were used to measure tau and Abeta42 in CSF. Following IFCC recommendations, we used a rank-based method; the 0.90 and 0.10 fractiles were estimated to establish reference values for CSF-tau and CSF-Abeta42, respectively. Putative confounding factors, such as the influence of the passage of proteins from peripheral blood to CSF, influence of dysfunction of the blood-brain barrier, and freezing and thawing of CSF, were investigated. RESULTS: A correlation with age was found for CSF-tau (r = 0.60; P <0.001). Therefore, separate reference values for different age groups were established for CSF-tau: <300 ng/L in the group 21-50 years of age, <450 ng/L in the group 51-70 years of age, and <500 ng/L in the group 71-93 years of age. CSF-Abeta42 did not correlate with age (r = -0.045), and the reference value was set to >500 ng/L. No correlation was found between blood-brain barrier function and CSF-tau or CSF-Abeta42. CONCLUSIONS: These reference values can be applied when using CSF-tau and CSF-Abeta42 in clinical practice.

The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein.

We investigated the relationship between PS1 and gamma-secretase processing of amyloid precursor protein (APP) in primary cultures of neurons. Increasing the amount of APP at the cell surface or towards endosomes did not significantly affect PS1-dependent gamma-secretase cleavage, although little PS1 is present in those subcellular compartments. In contrast, almost no gamma-secretase processing was observed when holo-APP or APP-C99, a direct substrate for gamma-secretase, were specifically retained in the endoplasmic reticulum (ER) by a double lysine retention motif. Nevertheless, APP-C99-dilysine (KK) colocalized with PS1 in the ER. In contrast, APP-C99 did not colocalize with PS1, but was efficiently processed by PS1-dependent gamma-secretase. APP-C99 resides in a compartment that is negative for ER, intermediate compartment, and Golgi marker proteins. We conclude that gamma-secretase cleavage of APP-C99 occurs in a specialized subcellular compartment where little or no PS1 is detected. This suggests that at least one other factor than PS1, located downstream of the ER, is required for the gamma-cleavage of APP-C99. In agreement, we found that intracellular gamma-secretase processing of APP-C99-KK both at the gamma40 and the gamma42 site could be restored partially after brefeldin A treatment. Our data confirm the "spatial paradox" and raise several questions regarding the PS1 is gamma-secretase hypothesis.

The cerebrospinal fluid levels of tau, growth-associated protein-43 and soluble amyloid precursor protein correlate in Alzheimer's disease, reflecting a common pathophysiological process.

Cerebrospinal fluid (CSF) levels of tau (total tau), growth-associated protein-43 (GAP-43), soluble amyloid precursor protein (sAPP; i.e. total sAPP), and beta-amyloid(42) (Abeta(42)) were studied in patients with frontotemporal dementia (FTD; n = 14), Alzheimer's disease (AD; n = 47) and vascular dementia (VAD; n = 16), and in age-matched controls (n = 12). CSF-tau was increased in AD compared to controls and FTD (p < 0.001 for both). CSF-GAP-43 was increased in AD compared to controls (p < 0.05), and both CSF-GAP-43 and CSF-sAPP were increased in AD compared to FTD (p < 0.01). Positive and highly significant correlations were found between CSF-tau and CSF-GAP-43 in all groups and between CSF-tau, CSF-GAP-43 and CSF-sAPP in AD. The correlations found may reflect a common pathophysiologic process such as axonal degeneration.

Both total and phosphorylated tau are increased in Alzheimer's disease.

BACKGROUND: [corrected] Pathological tau protein concentrations in CSF are found in both Alzheimer's disease (AD) and frontotemporal dementia (FTD), but studies on brain tissue have suggested that the tau pathology in AD differs from that in FTD and that the difference may be related to the degree of phosphorylation. As CSF tau protein is increased after stroke, tau may also be implicated in the pathophysiology of vascular dementia, of which subcortical arteriosclerotic encephalopathy (SAE) is a putative subtype. OBJECTIVES: To investigate the nature of tau protein in CSF and the involvement of total CSF tau and phosphorylated CSF tau (phosphotau) in various types of dementia. METHODS: Using ELISAs for total tau and tau phosphorylated at Thr181 (phosphotau), the CSF concentrations of total tau and phosphotau were determined in patients with probable and possible AD (n=41 and 19, respectively), FTD (n=18), SAE (n=17), and Parkinson's disease (PD; n=15) and in age matched controls (n=17). All the antibodies stained the lower molecular weight bands, whereas only the antibodies that recognise phosphorylated tau stained the higher molecular bands. RESULTS: Both CSF tau and CSF phosphotau were increased in probable AD compared with FTD (p<0.001), SAE (p<0.001), PD (p<0.001), and controls (p<0.001). CSF phosphotau was increased in possible AD compared with FTD (p<0.001) and SAE (p<0.001). CSF tau and CSF phosphotau were positively correlated in all the groups. Molecular weight forms of tau ranging from 25 kDa to 80 kDa were found in the CSF CONCLUSION: Both phosphorylated and unphosphorylated tau isoforms were present in the CSF, and tau protein appeared in both truncated and full length forms. The results suggest that the CSF concentrations of tau and phosphotau are increased in about two thirds of patients with probable AD and in half of those with possible AD but are normal in FTD, SAE, and PD compared with normal aging. Values in the normal range do not exclude AD.