Isabel Sala

Cerebrospinal fluid β‐amyloid and phospho‐tau biomarker interactions affecting brain structure in preclinical Alzheimer disease

To assess the relationships between core cerebrospinal fluid (CSF) biomarkers and cortical thickness (CTh) in preclinical Alzheimer disease (AD).

Homocysteine and cognitive impairment. Relation with diagnosis and neuropsychological performance.

Background/Aims: Elevated total plasma homocysteine (tHcy) is a risk factor for cardiovascular and cerebrovascular disease, and it has also been proposed as an independent risk factor for dementia and Alzheimer’s disease (AD). Its relationship with cognitive impairment, however, remains unclear. We aimed to determine the relationship of tHcy levels with clinical diagnoses and cognitive performance in a sample of outpatients with cognitive impairment. Methods: Plasma tHcy, folate, vitamin B12 and creatinine levels were assessed in individuals evaluated at the Memory Disorder Unit. Diagnoses included subjective memory complaints (SMC, n = 27), mild cognitive impairment (MCI, n = 142), AD (n = 139) and vascular dementia (VD, n = 17). All patients underwent extensive neuropsychological testing to evaluate attention, memory, language, and visuoconstructional and executive functions, as well as depression and impairments of daily living activities. Results: tHcy levels did not differ between patients with SMC, MCI, AD or VD. Increased tHcy was associated with worse performance in geometric figure copy and clock drawing tests. Conclusions: tHcy levels did not discriminate between diagnostic groups of patients with cognitive impairments. Elevated tHcy levels in these patients appear to have a detrimental effect on visuoconstructional performance.

Relationship Between β-Secretase, Inflammation and Core Cerebrospinal Fluid Biomarkers for Alzheimer's Disease

BACKGROUND Biomarkers in the cerebrospinal fluid (CSF) can track specific pathophysiological pathways underlying Alzheimers disease (AD). The connection between these biomarkers remains unclear. OBJECTIVE To study six CSF biomarkers in a clinical cohort of patients with different neurodegenerative conditions. METHODS We measured markers of amyloid-β protein precursor (AβPP) processing (Aβ42, sAβPPβ, β-secretase activity), neuronal damage (total tau, p-tau), and inflammation (YKL-40) in CSF from 194 participants with the following diagnoses: subjective cognitive impairment or non-amnestic mild cognitive impairment (na-SCI, n = 44), amnestic mild cognitive impairment (aMCI, n = 45), dementia of the Alzheimer type (DAT, n = 59), frontotemporal dementia (FTD, n = 22), and 24 cognitively normal controls. We compared biomarkers between clinical groups and CSF-profile groups, and we analyzed the correlation between biomarkers. RESULTS CSF levels of sAβPPβ were decreased in FTD patients compared to the other groups. YKL-40 was elevated in DAT and FTD, and also in aMCI patients. CSF Aβ42 correlated positively with β-secretase activity (RS = 0.262) and sAβPPβ (RS = 0.341). CSF YKL-40 correlated positively with total tau (RS = 0.467) and p-tau (RS = 0.429). CSF p-tau and sAβPPβ contributed significantly to distinguish DAT from FTD. CONCLUSIONS CSF biomarkers of AβPP processing correlate with each other and are decreased in FTD. The inflammatory marker YKL-40 is increased in different neurodegenerative diseases, even in early stages, and it correlates with biomarkers of neurodegeneration. This suggests that inflammation is a common feature in AD and FTD. A combination of CSF biomarkers tracking distinct pathophysiological processes may be useful to classify subjects with neurodegenerative conditions.

Relationship between cortical thickness and cerebrospinal fluid YKL-40 in predementia stages of Alzheimer's disease

Cerebrospinal fluid YKL-40 has been described as a marker of glial inflammation. We aimed to study the relationship between YKL-40 and brain structure and its interactions with core Alzheimers disease (AD) biomarkers. We measured cortical thickness (CTh) and cerebrospinal fluid biomarkers (amyloid-β 1-42 [Aβ42], total tau, p-tau, and YKL-40) of 80 cognitively normal controls and 27 patients with amnestic mild cognitive impairment. Subjects were classified as Aβ42+ (<550 pg/mL) or Aβ42- (>550 pg/mL). CTh difference maps were derived from the interaction and correlation analyses in the whole sample and within clinical groups. There was a strong correlation between YKL-40 and markers of neurodegeneration (total tau and p-tau). In the whole sample, we found a negative correlation between YKL-40 and CTh in AD vulnerable areas in Aβ42+ subjects but not in Aβ42 participants. Our results suggest that YKL-40 could track the inflammatory processes associated to tau-related neurodegeneration in the presence of the AD pathophysiological process.

APOE -by-sex interactions on brain structure and metabolism in healthy elderly controls

Background The APOE effect on Alzheimer Disease (AD) risk is stronger in women than in men but its mechanisms have not been established. We assessed the APOE-by-sex interaction on core CSF biomarkers, brain metabolism and structure in healthy elderly control individuals (HC). Methods Cross-sectional study. HC from the Alzheimer’s Disease Neuroimaging Initiative with available CSF (n = 274) and/or 3T-MRI (n = 168) and/or a FDG-PET analyses (n = 328) were selected. CSF amyloid-β1–42 (Aβ1–42), total-tau (t-tau) and phospho-tau (p-tau181p) levels were measured by Luminex assays. We analyzed the APOE-by-sex interaction on the CSF biomarkers in an analysis of covariance (ANCOVA). FDG uptake was analyzed by SPM8 and cortical thickness (CTh) was measured by FreeSurfer. FDG and CTh difference maps were derived from interaction and group analyses. Results APOE4 carriers had lower CSF Aβ1–42 and higher CSF p-tau181p values than non-carriers, but there was no APOE-by-sex interaction on CSF biomarkers. The APOE-by-sex interaction on brain metabolism and brain structure was significant. Sex stratification showed that female APOE4 carriers presented widespread brain hypometabolism and cortical thinning compared to female non-carriers whereas male APOE4 carriers showed only a small cluster of hypometabolism and regions of cortical thickening compared to male non-carriers. Conclusions The impact of APOE4 on brain metabolism and structure is modified by sex. Female APOE4 carriers show greater hypometabolism and atrophy than male carriers. This APOE-by-sex interaction should be considered in clinical trials in preclinical AD where APOE4 status is a selection criterion.

Rapidly progressive dementia: experience in a tertiary care medical center.

Diagnosis of rapidly progressive dementia (RPD) poses a complex medical challenge that requires an exhaustive evaluation. Although prion diseases, in particular Creutzfeldt-Jakob disease (CJD), are often suspected, many other nonprion diseases may present as RPD. Our aim was to review the causes of RPD in our center to better understand the underlying conditions. We reviewed clinical, neuroimaging, and cerebrospinal fluid data from patients with RPD admitted to our hospital from 1994 to 2009. Forty-nine patients (mean age at onset 72.4 y) with RPD were admitted to our center during the study period. The mean interval between the onset of symptoms and admission was 4.6 months. The final clinical diagnoses were as follows: nonprion neurodegenerative diseases (36.8%), CJD (30.6%), vascular dementia (8.2%), toxic-metabolic conditions (8.2%), and other disorders (16.2%). Among cases with informed death (n=19), the average survival time was 8.6±9.5 months. Survival was shorter among patients with prion disease (n=10) than in those with other diagnoses (n=9, P=0.004). In conclusion, nonprion neurodegenerative diseases are the most common cause of RPD in our center. Our results suggest that although CJD is often suspected as a cause of RPD, its frequency depends on the referral differences across specialized centers

Cerebrospinal Fluid Anti-Amyloid-β Autoantibodies and Amyloid PET in Cerebral Amyloid Angiopathy-Related Inflammation

We report a biomarker and genetic evaluation of four patients with cerebral amyloid angiopathy-related inflammation (CAA-ri) treated with corticosteroids. Patients presented with focal symptomatology and cognitive impairment. MRI revealed cortical microbleeds and asymmetrical hyperintense white matter lesions (WML). Cerebrospinal fluid (CSF) biomarker analyses showed increased anti-Aβ autoantibodies, t-Tau, and p-Tau and decreased Aβ40 and Aβ42. After treatment, focal symptomatology disappeared, and WML and anti-Aβ autoantibodies decreased. The APOEɛ4 allele was overrepresented. Florbetapir-PET showed cortical deposition with lower retention in swollen areas. In the case of suspected CAA-ri, both CSF anti-Aβ autoantibodies levels and Florbetapir-PET could provide highly useful data to guide the correct diagnosis.

Progranulin Protein Levels in Cerebrospinal Fluid in Primary Neurodegenerative Dementias.

BACKGROUND Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown. OBJECTIVE To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects. METHODS We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimers disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals. RESULTS CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOEɛ4 allele did not. Amyloid-β42, t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals. CONCLUSIONS Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN.

Comparison of 2 Diagnostic Criteria for the Behavioral Variant of Frontotemporal Dementia

Objectives The aim of this study was to compare the applicability of the 1998 consensus diagnostic criteria for the behavioral variant of frontotemporal dementia (bvFTD) with the recently proposed diagnostic criteria of the International bvFTD Criteria Consortium (FTDC). Methods We reviewed each individual item in the 1998 and FTDC criteria in 30 patients with bvFTD followed in a memory clinic (including 2 with the C9orf72 gene repeat expansion). Results All patients fulfilled the FTDC criteria (40% possible, 60% probable bvFTD) but only 66.7% fulfilled the 1998 criteria. One of the C9orf72 expansion carriers did not fulfill the 1998 criteria. This discordance was always due to the presence of exclusion features in the 1998 criteria, the most common being spatial disorientation and early severe amnesia. Conclusion The new FTDC criteria are less restrictive and hence more sensitive for the diagnosis of bvFTD.

Cerebral amyloid angiopathy in Down syndrome and sporadic and autosomal-dominant Alzheimer's disease

We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early‐onset forms of Alzheimers disease (AD) (early‐onset AD [EOAD]).