Cerebrospinal fluid biomarkers and cerebral atrophy in distinct clinical variants of probable Alzheimer's disease

Abstract

Different clinical variants of probable Alzheimer’s disease (AD) share underlying plaques and tangles but show distinct atrophy patterns. We included 52 posterior cortical atrophy (PCA), 29 logopenic variant primary progressive aphasia (lvPPA), 53 early-onset (EOAD) and 42 late-onset AD (LOAD) patients, selected for abnormal CSF-Aβ42, with CSF and MRI data available. Bootstrapping revealed no differences in the prevalence of abnormal CSF total-tau and phosphorylated-tau between probable AD variants (range total-tau: 84.9–92.3%, phosphorylated-tau: 79.2–93.1%, p>0.05). Voxel-wise linear regressions showed various relationships between lower CSF-Aβ42 and syndrome-specific atrophy, involving precuneus, posterior cingulate, and medial temporal lobe (MTL) in EOAD, occipital cortex and middle temporal gyrus in PCA; anterior cingulate, insular cortex and precentral gyrus (left>right) in lvPPA; and MTL, thalamus, and temporal pole in LOAD (all at p<0.001 uncorrected). In contrast, CSF-tau was not related to gray matter atrophy in any group. Our findings suggest that lower CSF-Aβ42 – and not increased total-tau and phosphorylated-tau – relates to reduced gray matter volumes, mostly in regions that are typically atrophied in distinct clinical variants of probable AD.

Selective vulnerability in neurodegeneration: insights from clinical variants of Alzheimer's disease

“…The recent development of τ PET imaging now allows this to be tested in living patients. One recent case report of a patient with PCA showed a strong spatial overlap between τ pathology visualised by τ PET imaging using the 18F-AV1451 tracer and hypometabolism visualised by FDG-PET imaging,45 findings which have subsequently been replicated in larger case series 35. Notably, although CSF P-τ concentrations correlate with neurofibrillary pathology in AD,46 47 the marker does not provide information on the anatomic location of the pathology, making it less useful than τ PET imaging in the study of selective vulnerability-related issues.…”

“…Given that Aβ pathology is likely to develop several years or decades prior to clinical onset, it remains possible that Aβ pathology starts to develop in different networks in different AD variants29 before converging at a relatively early stage; this could explain why patients with PCA may have slightly increased occipital Aβ accumulation compared to other AD variants 31. In relation to this, one may also consider findings from a recent cerebrospinal fluid (CSF-MRI) study (restricted to patients with AD with pathological levels of CSF Aβ42),35 where—contrary to the authors’ hypothesis—there were associations between lower CSF Aβ42 (but not CSF τ) and syndrome-specific variations of atrophy, which may suggest that a more advanced Aβ pathology is associated with AD variant-specific patterns of neuronal injury.…”

Early-Onset Alzheimer Disease

“…Similar to typical LOAD, amyloid β42 (Aβ) peptide levels are decreased and total tau and phospho-tau levels are increased in CSF in EOAD and its variants 96 . Some studies suggest phenotypic variations in these CSF biomarkers, particularly lower tau levels in PCA 54,97,98 , but this is not confirmed across studies and with neuropathology.…”

“…Some studies suggest phenotypic variations in these CSF biomarkers, particularly lower tau levels in PCA 54,97,98 , but this is not confirmed across studies and with neuropathology. Where EOAD differs from LOAD is the better correspondence of lower Aβ levels, rather than increased tau levels, with GM atrophy 96 . One possible explanation for this difference is the decreased release of tau into the ventricular space in EOAD in light of the neurodegeneration occurring further from the ventricular surface (e.g.…”

Cognitive subtypes of probable Alzheimer's disease robustly identified in four cohorts

“…A minority of patients has a prominent and relatively focal cognitive presentation, such as logopenic-variant primary progressive aphasia, posterior cortical atrophy, or a behavioral/dysexecutive subtype [2–5]. Atypical variants have been associated with specific demographic, genetic, and neuroimaging/biomarker findings that are distinct from those of typical amnestic patients (e.g., age at onset, apolipoprotein E [ APOE ] genotype, distribution of cortical atrophy, hypometabolism, tau deposition, cerebrospinal fluid (CSF) biomarker concentrations, and pathologic findings) [6–10]. However, even patients who do not display a defined subtype also show a considerable variation in patterns of cognitive impairment.…”