It is not clear to which degree limbic TDP-43 pathology associates with a cholinergic deficit in the absence of Alzheimer's disease (AD) pathology.
Replicate and extend recent evidence on cholinergic ...basal forebrain atrophy in limbic TDP-43 and evaluate MRI based patterns of atrophy as a surrogate marker for TDP-43.
We studied ante-mortem MRI data of 11 autopsy cases with limbic TDP-43 pathology, 47 cases with AD pathology, and 26 mixed AD/TDP-43 cases from the ADNI autopsy sample, and 17 TDP-43, 170 AD, and 58 mixed AD/TDP-43 cases from the NACC autopsy sample. Group differences in basal forebrain and other brain volumes of interest were assessed using Bayesian ANCOVA. We assessed the diagnostic utility of MRI based patterns of brain atrophy using voxel-based receiver operating characteristics and random forest analyses.
In the NACC sample, we found moderate evidence for the absence of a difference in basal forebrain volumes between AD, TDP-43, and mixed pathologies (Bayes factor(BF)10 = 0.324), and very strong evidence for lower hippocampus volume in TDP-43 and mixed cases compared with AD cases (BF10 = 156.1). The ratio of temporal to hippocampus volume reached an AUC of 75% for separating pure TDP-43 from pure AD cases. Random-forest analysis between TDP-43, AD, and mixed pathology reached only a multiclass AUC of 0.63 based on hippocampus, middle-inferior temporal gyrus, and amygdala volumes. Findings in the ADNI sample were consistent with these results.
A comparable degree of basal forebrain atrophy in pure TDP-43 cases compared to AD cases encourages studies on the effect of cholinergic treatment in amnestic dementia due to TDP-43. A distinct pattern of temporo-limbic brain atrophy may serve as a surrogate marker to enrich samples in clinical trials for the presence of TDP-43 pathology.
•Limbic TDP-43 has been found as underlying pathology in cases of amnestic dementia.•A cholinergic deficit in limbic TDP-43 pathology is still unresolved.•We confirm atrophy of the cholinergic basal forebrain in limbic TDP-43.•We report a MRI signature to identify people with limbic TDP-43 pathology.•Results were cross-validated across two independent autopsy cohorts.
Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal ...studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1-42 and p-tau181 levels in CSF, and another subset (n = 298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-β pathology and with prospective Alzheimer's disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.
Positron emission tomography (PET) allows detecting molecular brain changes in vivo. However, the accuracy of PET is limited by partial volume effects (PVE) that affects quantitative analysis and ...visual interpretation of the images. Although PVE-correction methods have been shown to effectively increase the correspondence of the measured signal with the true regional tracer uptake, these procedures are still not commonly applied, neither in clinical nor in research settings. Here, we present an implementation of well validated PVE-correction procedures as a SPM toolbox, PETPVE12, for automated processing. We demonstrate its utility by a comprehensive analysis of the effects of PVE-correction on amyloid-sensitive AV45-PET data from 85 patients with Alzheimer's disease (AD) and 179 cognitively normal (CN) elderly. Effects of PVE-correction on global cortical standard uptake value ratios (SUVR) and the power of diagnostic group separation were assessed for the region-wise geometric transfer matrix method (PVEc-GTM), as well as for the 3-compartmental voxel-wise “Müller-Gärtner” method (PVEc-MG). Both PVE-correction methods resulted in decreased global cortical SUVRs in the low to middle range of SUVR values, and in increased global cortical SUVRs at the high values. As a consequence, average SUVR of the CN group was reduced, whereas average SUVR of the AD group was increased by PVE-correction. These effects were also reflected in increased accuracies of group discrimination after PVEc-GTM (AUC=0.86) and PVEc-MG (AUC=0.89) compared to standard non-corrected SUVR (AUC=0.84). Voxel-wise analyses of PVEc-MG corrected data also demonstrated improved detection of regionally increased AV45 SUVR values in AD patients. These findings complement the growing evidence for a beneficial effect of PVE-correction in quantitative analysis of amyloid-sensitive PET data. The novel PETPVE12 toolbox significantly facilitates the application of PVE-correction, particularly within SPM-based processing pipelines. This is expected to foster the use of PVE-correction in brain PET for more widespread use. The toolbox is freely available at http://www.fil.ion.ucl.ac.uk/spm/ext/#PETPVE12.
•Partial volume effects (PVE) introduce significant bias in PET imaging studies.•PETPVE12 is a user-friendly toolbox for PVE correction within SPM software.•We evaluate the toolbox on AV45 PET images from AD patients and controls.•PVE correction improves diagnostic group separation based on AV45 PET scans.•Results underline the benefit of PVEc for quantitative amyloid PET analysis.
See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.
Cognitive impairments in Parkinson's disease show variable onset, severity and progression. Ray et ...al. demonstrate that the future cognitive status of newly diagnosed patients can be predicted from the volume of the nucleus basalis of Meynert, with implications for the development of interventions for cognitive decline in Parkinson's disease dementia.
Abstract
See Gratwicke and Foltynie (doi:10.1093/brain/awx333) for a scientific commentary on this article.
Cognitive impairments are a prevalent and disabling non-motor complication of Parkinson's disease, but with variable expression and progression. The onset of serious cognitive decline occurs alongside substantial cholinergic denervation, but imprecision of previously available techniques for in vivo measurement of cholinergic degeneration limit their use as predictive cognitive biomarkers. However, recent developments in stereotactic mapping of the cholinergic basal forebrain have been found useful for predicting cognitive decline in prodromal stages of Alzheimer's disease. These methods have not yet been applied to longitudinal Parkinson's disease data. In a large sample of people with de novo Parkinson's disease (n = 168), retrieved from the Parkinson's Progressive Markers Initiative database, we measured cholinergic basal forebrain volumes, using morphometric analysis of T1-weighted images in combination with a detailed stereotactic atlas of the cholinergic basal forebrain nuclei. Using a binary classification procedure, we defined patients with reduced basal forebrain volumes (relative to age) at baseline, based on volumes measured in a normative sample (n = 76). Additionally, relationships between the basal forebrain volumes at baseline, risk of later cognitive decline, and scores on up to 5 years of annual cognitive assessments were assessed with regression, survival analysis and linear mixed modelling. In patients, smaller volumes in a region corresponding to the nucleus basalis of Meynert were associated with greater change in global cognitive, but not motor scores after 2 years. Using the binary classification procedure, patients classified as having smaller than expected volumes of the nucleus basalis of Meynert had ∼3.5-fold greater risk of being categorized as mildly cognitively impaired over a period of up to 5 years of follow-up (hazard ratio = 3.51). Finally, linear mixed modelling analysis of domain-specific cognitive scores revealed that patients classified as having smaller than expected nucleus basalis volumes showed more severe and rapid decline over up to 5 years on tests of memory and semantic fluency, but not on tests of executive function. Thus, we provide the first evidence that volumetric measurement of the nucleus basalis of Meynert can predict early cognitive decline. Our methods therefore provide the opportunity for multiple-modality biomarker models to include a cholinergic biomarker, which is currently lacking for the prediction of cognitive deterioration in Parkinson's disease. Additionally, finding dissociated relationships between nucleus basalis status and domain-specific cognitive decline has implications for understanding the neural basis of heterogeneity of Parkinson's disease-related cognitive decline.
This scientific commentary refers to ‘Age-related and amyloid-beta-independent tau deposition and its downstream effects’ by Wuestefeld et al. (https://doi.org/10.1093/brain/awad135).
The integrity of the cholinergic system plays a central role in cognitive decline both in normal aging and neurological disorders including Alzheimer’s disease and vascular cognitive impairment. Most ...of the previous neuroimaging research has focused on the integrity of the cholinergic basal forebrain, or its sub-region the nucleus basalis of Meynert (NBM). Tractography using diffusion tensor imaging data may enable modelling of the NBM white matter projections. We investigated the contribution of NBM volume, NBM white matter projections, small vessel disease (SVD), and age to performance in attention and memory in 262 cognitively normal individuals (39–77 years of age, 53% female). We developed a multimodal MRI pipeline for NBM segmentation and diffusion-based tracking of NBM white matter projections, and computed white matter hypointensities (WM-hypo) as a marker of SVD. We successfully tracked pathways that closely resemble the spatial layout of the cholinergic system as seen in previous post-mortem and DTI tractography studies. We found that high WM-hypo load was associated with older age, male sex, and lower performance in attention and memory. A high WM-hypo load was also associated with lower integrity of the cholinergic system above and beyond the effect of age. In a multivariate model, age and integrity of NBM white matter projections were stronger contributors than WM-hypo load and NBM volume to performance in attention and memory. We conclude that the integrity of NBM white matter projections plays a fundamental role in cognitive aging. This and other modern neuroimaging methods offer new opportunities to re-evaluate the cholinergic hypothesis of cognitive aging.
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•Cholinergic pathways can be modelled in vivo with multimodal MRI.•Integrity of cholinergic pathways and age are strong contributors to cognition.•New opportunities emerge to re-evaluate the cholinergic hypothesis of aging.
Tau and amyloid beta (Aβ) proteins accumulate along neuronal circuits in Alzheimer's disease. Unraveling the genetic background for the regional vulnerability of these proteinopathies can help in ...understanding the mechanisms of pathology progression. To that end, we developed a novel graph theory approach and used it to investigate the intersection of longitudinal Aβ and tau positron emission tomography imaging of healthy adult individuals and the genetic transcriptome of the Allen Human Brain Atlas. We identified distinctive pathways for tau and Aβ accumulation, of which the tau pathways correlated with cognitive levels. We found that tau propagation and Aβ propagation patterns were associated with a common genetic profile related to lipid metabolism, in which APOE played a central role, whereas the tau-specific genetic profile was classified as 'axon related' and the Aβ profile as 'dendrite related'. This study reveals distinct genetic profiles that may confer vulnerability to tau and Aβ in vivo propagation in the human brain.
Cholinergic dysfunction plays a prominent role in cognitive impairment in Parkinson's disease (PD). The aim of this study was to assess the relationship of baseline and longitudinal basal forebrain ...atrophy with cognitive decline and dementia in PD.
We included 106 non-demented PD patients, 19 PD dementia (PDD) patients and 42 controls with longitudinal structural MRI and cognitive testing. After 4.2 ± 1.8 years, 20 non-demented PD patients were diagnosed with dementia (PD-dementia converters), whereas the rest of PD patients remained non-demented (stable-PD). We compared MRI volumes of the medial septum/diagonal band (Ch1/Ch2) and nucleus basalis of Meynert (Ch4) between groups. Cox regression analyses were applied to test whether Ch1/Ch2 or Ch4 atrophy could predict future dementia and linear mixed models assessed their association with cognitive decline.
Compared to controls, we found reduced Ch4 baseline volumes in PD-dementia converters (p = .003) and those who already had PDD (p < .001) but not in stable-PD. Over time, there was a greater loss in Ch1/Ch2 volumes in PD-dementia converters and PDD compared to the other groups (p = .004). Baseline and longitudinal Ch4 volumes were associated with cognition (p < .002) and longitudinal Ch4 atrophy predicted future dementia (p = .009).
Atrophy of Ch4 precedes and predicts future dementia in PD and is followed by changes in Ch1/Ch2, reflecting a posterior-anterior pattern of basal forebrain atrophy. This pattern could be used to track the spread of cholinergic degeneration and identify patients at risk of developing dementia.
•Ch4 atrophy precedes and predicts future dementia in PD.•These changes are followed by Ch1/Ch2 longitudinal atrophy.•The basal forebrain shows an anterior-posterior pattern of atrophy over time in PD.
The functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems. We show that the ...location of human tissue samples extracted along the longitudinal axis of the adult human hippocampus can be predicted within 2mm using the expression pattern of less than 100 genes. Futhermore, this model generalizes to an external set of tissue samples from prenatal human hippocampi. We examine variation in this specific gene expression pattern across the whole brain, finding a distinct anterioventral-posteriodorsal gradient. We find frontal and anterior temporal regions involved in social and motivational behaviors, and more functionally connected to the anterior hippocampus, to be clearly differentiated from posterior parieto-occipital regions involved in visuospatial cognition and more functionally connected to the posterior hippocampus. These findings place the human hippocampus at the interface of two major brain systems defined by a single molecular gradient.
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