Amyloid-? associated volume loss occurs only in the presence of phospho-tau.
ABSTRACT: The relationship between neurodegeneration and the 2 hallmark proteins of Alzheimer's disease, amyloid-? (A?) and tau, is still unclear. Here, we examined 286 nondemented participants (107 cognitively normal older adults and 179 memory impaired individuals) who underwent longitudinal magnetic resonance (MR) imaging and lumbar puncture. Using mixed effects models, we investigated the relationship between longitudinal entorhinal cortex atrophy rate, cerebrospinal fluid (CSF) p-tau(181p) and CSF A?(1-42) . We found a significant relationship between elevated entorhinal cortex atrophy rate and decreased CSF A?(1-42) only with elevated CSF p-tau(181p) . Our findings indicate that A?-associated volume loss occurs only in the presence of phospho-tau in humans at risk for dementia.
Project description:Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.To elucidate the relationship between clusterin, amyloid-? (A?), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals.This longitudinal cohort included cognitively normal older participants and individuals with mild cognitive impairment assessed with baseline lumbar puncture and longitudinal structural magnetic resonance imaging. We examined 241 nondemented older individuals from research centers across the United States and Canada (91 participants with a Clinical Dementia Rating score of 0 and 150 individuals with a Clinical Dementia Rating score of 0.5).Using linear mixed-effects models, we investigated interactions between cerebrospinal fluid (CSF) clusterin, CSF A?1-42, and CSF p-tau at threonine 181 (p-tau181p) on the atrophy rate of the entorhinal cortex and hippocampus.Across all participants, we found a significant interaction between CSF clusterin and CSF A?1-42 on the entorhinal cortex atrophy rate but not on the hippocampal atrophy rate. Cerebrospinal fluid clusterin was associated with the entorhinal cortex atrophy rate among CSF A?1-42-positive individuals but not among CSF A?1-42-negative individuals. In secondary analyses, we found significant interactions between CSF A?1-42 and CSF clusterin, as well as CSF A?1-42 and CSF p-tau181p, on the entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the mild cognitive impairment and cognitively normal cohorts.In nondemented older individuals, A?-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on A?-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the Alzheimer disease neurodegenerative process and suggest independent effects of clusterin and p-tau on A?-associated volume loss.
Project description:<h4>Background and purpose</h4>Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (Aβ and τ APOE ε4) and neurodegeneration is not well-understood. Here, we investigated the relationship between Aβ, p-τ, and APOE ε4 on longitudinal brain atrophy in preclinical AD.<h4>Materials and methods</h4>We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the APOE ε4 genotype and CSF Aβ(1-42), CSF p-τ and CSF Aβ(1-42), and the APOE ε4 genotype and CSF p-τ on entorhinal cortex atrophy rate. We also examined the relationship of APOE ε4, CSF p-τ, and CSF Aβ(1-42) on the atrophy rate of other AD-vulnerable neuroanatomic regions.<h4>Results</h4>The full model with main and interactive effects demonstrated a significant interaction only between CSF p-τ and CSF Aβ(1-42) on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aβ(1-42). The APOE ε4 genotype was significantly and specifically associated with CSF Aβ(1-42). However, the interaction between the APOE ε4 genotype and either CSF Aβ(1-42) or CSF p-τ on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions.<h4>Conclusions</h4>On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which APOE ε4 primarily influences the pathology of Alzheimer disease via Aβ-related mechanisms, and in turn, Aβ-associated neurodegeneration occurs only in the presence of p-τ.
Project description:<h4>Background</h4>Epidemiological and molecular findings suggest a relationship between Alzheimer's disease (AD) and dyslipidemia, although the nature of this association is not well understood.<h4>Results</h4>Using linear mixed effects models, we investigated the relationship between CSF levels of heart fatty acid binding protein (HFABP), a lipid binding protein involved with fatty acid metabolism and lipid transport, amyloid-? (A?), phospho-tau, and longitudinal MRI-based measures of brain atrophy among 295 non-demented and demented older individuals. Across all participants, we found a significant association of CSF HFABP with longitudinal atrophy of the entorhinal cortex and other AD-vulnerable neuroanatomic regions. However, we found that the relationship between CSF HABP and brain atrophy was significant only among those with low CSF A?1-42 and occurred irrespective of phospho-tau181p status.<h4>Conclusions</h4>Our findings indicate that A?-associated volume loss occurs in the presence of elevated HFABP irrespective of phospho-tau. This implicates a potentially important role for fatty acid binding proteins in Alzheimer's disease neurodegeneration.
Project description:Previously it was reported that Alzheimer's disease (AD) patients have reduced beta amyloid (Abeta(1-42)) and elevated total tau (t-tau) and phosphorylated tau (p-tau(181p)) in the cerebrospinal fluid (CSF), suggesting that these same measures could be used to detect early AD pathology in healthy elderly individuals and those with mild cognitive impairment (MCI). In this study, we tested the hypothesis that there would be an association among rates of regional brain atrophy, the CSF biomarkers Abeta(1-42), t-tau, and p-tau(181p) and apolipoprotein E (ApoE) epsilon4 status, and that the pattern of this association would be diagnosis-specific. Our findings primarily showed that lower CSF Abeta(1-42) and higher tau concentrations were associated with increased rates of regional brain tissue loss and the patterns varied across the clinical groups. Taken together, these findings demonstrate that CSF biomarker concentrations are associated with the characteristic patterns of structural brain changes in healthy elderly and mild cognitive impairment subjects that resemble to a large extent the pathology seen in AD. Therefore, the finding of faster progression of brain atrophy in the presence of lower Abeta(1-42) levels and higher tau levels supports the hypothesis that CSF Abeta(1-42) and tau are measures of early AD pathology. Moreover, the relationship among CSF biomarkers, ApoE epsilon4 status, and brain atrophy rates are regionally varying, supporting the view that the genetic predisposition of the brain to beta amyloid and tau mediated pathology is regional and disease stage specific.
Project description:Age-related hearing loss (ARHL) has been considered as a promising modifiable risk factor for cognitive impairment and dementia. Nonetheless, it is still unclear whether age-related hearing loss associates with neurodegenerative biomarkers of Alzheimer's disease (AD). Participants with ARHL were selected from the established Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In multivariable models, the cross-sectional and longitudinal associations of ARHL with CSF ?-amyloid (A?) and tau measurements, brain A? load, and cortical structural measures were explored. ARHL was associated with higher CSF levels of tau (p < 0.001) or ptau181 (p < 0.05) at baseline as well as faster elevation rates of these two types of biomarkers (p < 0.05). Although the baseline volume/thickness of hippocampus (p < 0.05) and entorhinal cortex (p < 0.0005) were higher in individuals with ARHL, these two regions (p < 0.01 for hippocampus, p < 0.05 for entorhinal cortex) displayed significantly accelerated atrophy in individuals with ARHL. No association of ARHL with CSF or brain A? levels was found. Subgroup analyses indicated that the above effects of ARHL were more significant in non-demented stage. Age-related hearing loss was associated with elevated cerebrospinal fluid tau levels and atrophy of entorhinal cortex.
Project description:The default mode network (DMN) is particularly relevant to Alzheimer's disease (AD) since its structures are vulnerable to deposition of amyloid. Decreased levels of β-amyloid(1-42) (Aβ42) and increased total tau protein (T-tau) and tau phosphorylated at position threonine 181 (P-tau(181p)) in cerebrospinal fluid (CSF) have been established as valid biomarkers for the diagnosis and prognosis of AD. However, the relationship between CSF biomarkers and change in the DMN is still unknown. In this study we investigated the correlation between the functional connectivity within the DMN and the ratio of Aβ42/P-tau(181p) in the CSF. We found that the ratio of Aβ42/P-tau(181p) was moderately positively correlated with the functional connectivity within the DMN in the left precuneus/cuneus. This finding implicates that the brain functional connectivity within DMN is affected by pathological changes at early stage in AD. This may provide a better understanding of AD pathology progression and improve AD diagnosis.
Project description:Measures of neuronal loss are likely good surrogates for clinical and radiological disease progression in Alzheimer disease (AD). Cerebrospinal fluid (CSF) markers of neuronal injury or neurodegeneration may offer usefulness in predicting disease progression and guiding outcome assessments and prognostic decisions in clinical trials of disease-modifying therapies. Visinin-like protein 1 (VILIP-1) has demonstrated potential usefulness as a marker of neuronal injury in AD.To investigate the usefulness of CSF VILIP-1, tau, p-tau181, and A?42 levels in predicting rates of whole-brain and regional atrophy in early AD and cognitively normal control subjects over time.Longitudinal observational study of brain atrophy in participants with early AD and cognitively normal controls. Study participants had baseline CSF biomarker measurements and longitudinal magnetic resonance imaging assessments for a mean follow-up period of 2 to 3 years. Mixed linear models assessed the ability of standardized baseline CSF biomarker measures to predict rates of whole-brain and regional atrophy over the follow-up period. The setting was The Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine in St Louis. Participants (mean age, 72.6 years) were individuals with a clinical diagnosis of very mild AD (n = 23) and cognitively normal controls (n = 64) who were enrolled in longitudinal studies of healthy aging and dementia. The study dates were 2000 to 2010.Correlations between baseline CSF biomarker measures and rates of whole-brain or regional atrophy in the AD and control cohorts over the follow-up period.Baseline CSF VILIP-1, tau, and p-tau181 levels (but not A?42 levels) predicted rates of whole-brain and regional atrophy in AD over the follow-up period. Baseline CSF VILIP-1 levels predicted whole-brain (P =?.006), hippocampal (P =?.01), and entorhinal (P =?.001) atrophy rates at least as well as tau and p-tau181 in early AD. Cognitively normal controls whose CSF VILIP-1, tau, or p-tau181 levels were in the upper tercile had higher rates of whole-brain (P =?.02, P =?.003, and P =?.02, respectively), hippocampal (P =?.001, P =?.01, and P =?.02, respectively), and entorhinal (P =?.007, P =?.01, and P =?.01, respectively) atrophy compared with those whose levels were in the lower 2 terciles.Cerebrospinal fluid VILIP-1 levels predict rates of whole-brain and regional atrophy similarly to tau and p-tau181 and may provide a useful CSF biomarker surrogate for neurodegeneration in early symptomatic and preclinical AD.
Project description:Cognitive decline associated with Parkinson disease (PD) is common and highly disabling. Biomarkers that help identify patients at risk for cognitive decline would be useful additions to the clinical management of the disease.A total of 45 patients with PD were enrolled in this prospective cohort study and had at least 1 yearly longitudinal follow-up evaluation. CSF was collected at baseline and cognition was assessed at baseline and follow-up visits using the Mattis Dementia Rating Scale (DRS-2). CSF was tested for amyloid ? 1-42 (A?(1-42)), p-tau(181p), and total tau levels using the Luminex xMAP platform. Mixed linear models were used to test for associations between baseline CSF biomarker levels and change in cognition over time.Lower baseline CSF A?(1-42) was associated with more rapid cognitive decline. Subjects with CSF A?(1-42) levels ?192 pg/mL declined an average of 5.85 (95% confidence interval 2.11-9.58, p = 0.002) points per year more rapidly on the DRS-2 than subjects above that cutoff, after adjustment for age, disease duration, and baseline cognitive status. CSF total tau and p-tau(181p) levels were not significantly associated with cognitive decline.Reduced CSF A?(1-42) was an independent predictor of cognitive decline in patients with PD. This observation is consistent with previous research showing that Alzheimer disease pathology contributes to cognitive impairment in PD. This biomarker may provide clinically useful prognostic information, particularly if combined with other risk factors for cognitive impairment in PD.
Project description:Positive cerebrospinal fluid (CSF) biomarkers of tau and amyloid beta42 suggest possible active underlying Alzheimer's disease (AD) including neurometabolic dysfunction and neurodegeneration leading to eventual cognitive decline. But the temporal relationship between CSF, imaging markers of neural function, and cognition has not been described. Using a statistical mediation model, we examined relationships between cerebrospinal fluid (CSF) analytes (hyperphosphorylated tau (p-Tau(181p)), ?-amyloid peptides 1-42 (A?(1-42)), total tau (t-Tau), and their ratios); change in cognitive function; and change in [18F]fluorodeoxyglucose (FDG) uptake using positron emission tomography (PET). We hypothesized that a) abnormal CSF protein values at baseline, result in cognitive declines by decreasing neuronal glucose metabolism across time, and b) the role of altered glucose metabolism in the assumed causal chain varies by brain region and the nature of CSF protein alteration. Data from 412 individuals participating in Alzheimer's Disease Neuroimaging (ADNI) cohort studies were included in analyses. At baseline, individuals were cognitively normal (N = 82), or impaired: 241 with mild cognitive impairment, and 89 with Alzheimer's disease. A parallel-process latent growth curve model was used to test mediational effects of changes in regional FDG-PET uptake over time in relation to baseline CSF biomarkers and changes in cognition, measured with the 13-item Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-Cog). Findings suggested a causal sequence of events; specifically, FDG hypometabolism acted as a mediator between antecedent CSF biomarker alterations and subsequent cognitive impairment. Higher baseline concentrations of t-Tau, and p-Tau(181p) were more predictive of decline in cerebral glucose metabolism than lower baseline concentrations of A?(1-42). FDG-PET changes appeared to mediate t-Tau or t-Tau/A?(1-42)-associated cognitive change across all brain regions examined. Significant direct effects of alterations in A?(1-42) levels on hypometabolism were observed in a single brain region: middle/inferior temporal gyrus. Results support a temporal framework model in which reduced CSF amyloid-related biomarkers occur earlier in the pathogenic pathway, ultimately leading to detrimental cognitive effects. Also consistent with this temporal framework model, baseline markers of neurofibrillary degeneration predicted changes in brain glucose metabolism in turn causing longitudinal cognitive changes, suggesting that tau-related burden precedes neurometabolic dysfunction. While intriguing, the hypothesized mediational relationships require further validation.
Project description:<h4>Purpose</h4>Studies comparing CSF and PET tau biomarkers have included only commercial CSF assays examining specific phosphorylation sites (e.g. threonine 181, P-tau<sub>181p</sub>) and mid-domain tau (i.e. total tau, T-tau). Moreover, these studies did not examine CSF tau levels in relation to cerebral glucose metabolism. We thus aimed to examine CSF tau measures, using both commercial and novel assays, in relation to [<sup>18</sup>F]THK5317 (tau) and [<sup>18</sup>F]FDG PET (glucose metabolism).<h4>Methods</h4>Fourteen Alzheimer's disease (AD) patients (seven prodromal, seven dementia) underwent [<sup>18</sup>F]THK5317 and [<sup>18</sup>F]FDG PET studies, with follow-up performed in ten subjects (six prodromal, four dementia) after 17 months. In addition to commercial assays, novel measures capturing N-terminus+mid-domain (tau N-Mid) and C-terminally truncated (tau-368) fragments were included.<h4>Results</h4>While the levels of all forms of CSF tau were found to be inversely associated with baseline [<sup>18</sup>F]FDG uptake, associations with baseline [<sup>18</sup>F]THK5317 uptake varied in relation to the degree of isocortical hypometabolism ([<sup>18</sup>F]FDG SUVR). Changes in the levels of the novel CSF markers tracked longitudinal changes in tracer uptake better than changes in P-tau<sub>181p</sub> and T-tau levels, and improved concordance with dichotomized regional [<sup>18</sup>F]THK5317 measures.<h4>Conclusion</h4>Our findings suggest that neurodegeneration may modulate the relationship between CSF and PET tau biomarkers, and that, by comparison to P-tau<sub>181p</sub> and T-tau, tau-368 and tau N-Mid may better capture tau pathology and synaptic impairment.