Distinct cerebrospinal fluid amyloid-beta peptide signatures in cognitive decline associated with Alzheimer's disease and schizophrenia.

Mild alterations in cognitive function are present in normal aging and severe cognitive alterations are a hallmark of Alzheimer's disease (AD). Cognitive deficits are prevalent in patients with schizophrenia (SCZ) and worsen with old age. We recently reported that elderly SCZ patients show reduced levels of amyloid-beta (Aß)1-42 in cerebrospinal fluid (CSF). To further clarify the role of Aß in cognitive decline, we analyzed the whole panel of CSF Aß isoforms in elderly SCZ patients as well as in sporadic AD using SELDI TOF MS. The immunoproteomic study revealed, in all analyzed CSF samples, the presence of 15 different Aß peptides. In CSF from SCZ, we detected an overall strong reduction of almost all Aß species while in sporadic AD Aß1-42 was the only peptide reduced. A significant independent association between Aß1-40 levels and global cognition was found in SCZ. In addition, in SCZ patients, duration of therapy was positively associated with soluble amyloid precursor protein alpha levels, the total amount of CSF Aß and the most abundant Aß1-40 isoform. These data suggests a dysmetabolism of amyloid precursor protein in older SCZ patients. Thus, the quite comparable reduction of CSF Aß1-42 in AD and in elderly SCZ patients reflects different pathophysiological dynamics in ageing brain.

Cerebrospinal fluid markers for Alzheimer's disease in a cognitively healthy cohort of young and old adults.

BACKGROUND: Low amyloid ß42 (Aß42) and high total tau and phosphorylated tau (p-tau) concentrations in the cerebrospinal fluid (CSF) are biomarkers of Alzheimer's disease (AD), reflecting brain deposition of amyloid plaques and tangles. Age and apolipoprotein E allele E4 are two strong risk factors for AD, but few data are still available on their effect on CSF markers in normal aging. OBJECTIVE: To study the effect of age on CSF Aß42, total tau, and p-tau levels in a well-characterized group of cognitively normal subjects. METHODS: CSF Aß42 levels of 81 subjects (27% female, 53 ± 15.3 years, range: 21-88) were determined with sandwich enzyme-linked immunosorbent assay; of these, total tau and p-tau levels were measured in 61 (75%) and 42 (52%) cases, respectively. A linear regression analysis between age and CSF markers was carried out on the whole sample and separately in apolipoprotein E allele ɛ4 carriers and noncarriers. RESULTS: The median levels of all markers were significantly different between young (<65 years) and old (≥65 years) subjects (Aß42: P = .03; tau: P = .02; p-tau: P = .002; tau/Aß42: P = .004; p-tau/Aß42: P = .03). The association of marker levels with age was confirmed in linear regression models, where a positive relationship with age was observed for total tau (B = 2.3; 95% confidence interval [CI]: 0.89 to 3.7; P = .002), p-tau (B = 0.5; 95% CI: 0.1 to 0.9; P = .02), and tau/Aß42 ratio (B = 0.006; 95% CI: 0.002 to 0.01; P = .002). No subjects showed abnormal tau, whereas 19% showed abnormal CSF Aß42 concentrations. CONCLUSION: In cognitively normal subjects, the concentrations of CSF biomarkers of AD are associated with age. Further longitudinal studies could clarify whether Aß42 low levels represent a preclinical AD biomarker.

Alzheimer's CSF markers in older schizophrenia patients.

OBJECTIVES: Cognitive impairment is prevalent in older schizophrenia patients but its biological basis is unknown. Neuropathological studies have not revealed Alzheimer disease (AD) lesion burden but in vivo data are lacking. METHOD: We investigated the concentrations of CSF biomarkers of brain amyloidosis (Abeta42) and neurodegeneration (total and p-tau) in a group of older schizophrenia patients and related them to cognitive and MRI measures. Older schizophrenia (n = 11), AD patients (n = 20) and elderly controls (n = 6) underwent cognitive testing, lumbar puncture, and MRI scanning. Abeta42 and total and p-tau concentrations were assayed in the CSF. MRI volumes were assessed using both voxel-based (cortical pattern matching) and region-of-interest analyses. RESULTS: CSF tau concentration in older schizophrenia patients was within normal limits (total tau 171 ± 51 pg/ml, p-tau 32 ± 8 pg/ml), while CSF Abeta42 (465 ± 112 pg/ml) levels were significantly lower compared to healthy elders (638 ± 130 pg/ml) but higher than in AD patients (352 ± 76 pg/ml). There was a strong positive relationship between CSF total or p-tau levels and MMSE scores in schizophrenia patients but not in AD, where higher concentrations of total tau were correlated with higher volumes in the occipital cortex (r = 0.63, p = 0.036), while in AD a significant correlation was found between lower Abeta42 concentrations and lower gray matter volume in the cingulate and lateral orbital cortices (r > 0.46, p < 0.05). CONCLUSIONS: Older schizophrenia patients show a peculiar pattern of CSF Abeta42 and tau concentrations that relates to cognitive and structural markers but is not consistent with neurodegeneration and could be secondary to neurodevelopmental or drug treatment effects.

Markers of Alzheimer's disease in a population attending a memory clinic.

BACKGROUND: New marker-based criteria for the diagnosis of Alzheimer's disease (AD) were recently proposed. We describe their operational translation in 144 consecutive patients referred to our Memory Clinic. METHODS: Visual ratings of hippocampal atrophy and of cortical glucose hypometabolism in magnetic resonance imaging and positron emission tomography, and concentrations of total tau and Abeta1-42 in cerebrospinal fluid were assessed in 12 patients with subjective memory complaints (SMCs) (Mini-Mental State Examination [MMSE] score, 28.0 +/- 1.1 [mean +/- SD]), 37 with mild cognitive impairment (MCI) (MMSE, 25.1 +/- 3.6), 55 with AD (MMSE, 21.1 +/- 3.5), and 40 with non-AD dementia (MMSE, 21.6 +/- 5.5). RESULTS: The sensitivity for AD of each individual biomarker was higher (65% to 87%) than for MCI (18% to 50%). Each biomarker's specificity for SMC and non-AD dementias was good to moderate (83% and 53%). Positivity for at least one marker increased the probability 38 times of belonging to the AD group (P < 0.0001). CONCLUSION: The new diagnostic criteria can be operationalized in clinical routines, but longitudinal studies of MCI patients will need to assess the criteria's prognostic value.

Supporting evidence for using biomarkers in the diagnosis of MCI due to AD.

The aim of this study is to support the use of biomarkers in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) according to the revised NIA-AA diagnostic criteria. We compared clinical features and conversion to AD and other dementias among groups of MCI patients with different abnormal biomarker profiles. In this study, we enrolled 58 patients with MCI, and for each of them AD biomarkers (CSF Abeta42 and tau, temporoparietal hypometabolism on 18F-FDG PET, and hippocampal volume) were collected. Patients were divided into three groups: (i) no abnormal biomarker, (ii) AD biomarker pattern (including three subgroups of early = only abnormal Abeta42, intermediate = abnormal Abeta42 and FDG PET or tau, and late = abnormal Abeta42, FDG PET or tau, and HV), and (iii) any other biomarker combination. MCI patients with AD biomarker pattern had lower behavioural disturbances than patients with any other biomarker combination (p < 0.0005). This group also showed lower performance on verbal and non-verbal memory than the other two groups (p = 0.07 and p = 0.004, respectively). Within the three subgroups with AD biomarker patterns we observed a significant trend toward a higher rate of conversion to dementia (p for trend = 0.006). With regard to dementia conversion, 100 % of patients with an AD biomarker pattern developed AD, but none of the patients with no abnormal biomarker and 27 % of patients with any other biomarker combination (p = 0.002) did so. We also described some clinical cases representative for each of these three groups. The results of this study provide evidence in favour of the use of biomarkers for the diagnosis of MCI due to AD, in line with recently published research criteria.