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Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration (FTLD). Postmortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportionate to symptom severity and rate of progression. However, evidence for corresponding blood markers of inflammation and their relationship with central inflammation and clinical outcome are limited. There is a pressing need for such scalable, accessible and mechanistically relevant blood markers as these will reduce the time, risk, and costs of experimental medicine trials. We therefore assessed inflammatory patterns of serum cytokines from 214 patients with clinical syndromes associated with FTLD as compared to healthy controls, including their correlation with brain regional microglial activation and disease progression. Serum assays used the MesoScale Discovery V-Plex-Human Cytokine 36 plex panel plus five additional cytokine assays. A sub-group of patients underwent 11C-PK11195 TSPO PET imaging, as an index of microglial activation. A Principal Component Analysis (PCA) was used to reduce the dimensionality of cytokine data, excluding cytokines that were undetectable in >50% of participants. Frequentist and Bayesian analyses were performed on the principal components, to compare each patient cohort to controls, and test for associations with central inflammation, neurodegeneration-related plasma markers and survival. The first component identified by the PCA (explaining 21.5% variance) was strongly loaded by pro-inflammatory cytokines, including TNF-α, TNF-R1, M-CSF, IL-17A, IL-12, IP-10 and IL-6. Individual scores of the component showed significant differences between each patient cohort and controls. The degree to which a patient expressed this peripheral inflammatory profile at baseline correlated negatively with survival (higher inflammation, shorter survival), even when correcting for baseline clinical severity. Higher pro-inflammatory profile scores were associated with higher microglial activation in frontal and brainstem regions, as quantified with 11C-PK11195 TSPO PET. A permutation-based Canonical Correlation Analysis confirmed the association between the same cytokine-derived pattern and central inflammation across brain regions in a fully data-based manner. This data-driven approach identified a pro-inflammatory profile across the FTLD clinical spectrum, which is associated with central neuroinflammation and worse clinical outcome. Blood-based markers of inflammation could increase the scalability and access to neuroinflammatory assessment of people with dementia, to facilitate clinical trials and experimental medicine studies.
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BACKGROUND: Preclinical, postmortem, and positron emission tomography (PET) imaging studies have pointed to neuroinflammation as a key pathophysiological hallmark in primary 4-repeat (4R) tauopathies and its role in accelerating disease progression. OBJECTIVE: We tested whether microglial activation (1) progresses in similar spatial patterns as the primary pathology tau spreads across interconnected brain regions, and (2) whether the degree of microglial activation parallels tau pathology spreading. METHODS: We examined in vivo associations between tau aggregation and microglial activation in 31 patients with clinically diagnosed 4R tauopathies, using 18F-PI-2620 PET and 18F-GE180 (translocator protein [TSPO]) PET. We determined tau epicenters, defined as subcortical brain regions with highest tau PET signal, and assessed the connectivity of tau epicenters to cortical regions of interest using a 3-T resting-state functional magnetic resonance imaging template derived from age-matched healthy elderly controls. RESULTS: In 4R tauopathy patients, we found that higher regional tau PET covaries with elevated TSPO-PET across brain regions that are functionally connected to each other (ß = 0.414, P < 0.001). Microglial activation follows similar distribution patterns as tau and distributes primarily across brain regions strongly connected to patient-specific tau epicenters (ß = -0.594, P < 0.001). In these regions, microglial activation spatially parallels tau distribution detectable with 18F-PI-2620 PET. CONCLUSIONS: Our findings indicate that the spatial expansion of microglial activation parallels tau distribution across brain regions that are functionally connected to each other, suggesting that tau and inflammation are closely interrelated in patients with 4R tauopathies. The combination of in vivo tau and inflammatory biomarkers could therefore support the development of immunomodulatory strategies for disease-modifying treatments in these conditions. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Four-repeat (4R) tauopathies are neurodegenerative diseases characterized by cerebral accumulation of 4R tau pathology. The most prominent 4R tauopathies are progressive supranuclear palsy (PSP) and corticobasal degeneration characterized by subcortical tau accumulation and cortical neuronal dysfunction, as shown by PET-assessed hypoperfusion and glucose hypometabolism. Yet, there is a spatial mismatch between subcortical tau deposition patterns and cortical neuronal dysfunction, and it is unclear how these two pathological brain changes are interrelated. Here, we hypothesized that subcortical tau pathology induces remote neuronal dysfunction in functionally connected cortical regions to test a pathophysiological model that mechanistically links subcortical tau accumulation to cortical neuronal dysfunction in 4R tauopathies. We included 51 Aß-negative patients with clinically diagnosed PSP variants (n = 26) or corticobasal syndrome (n = 25) who underwent structural MRI and 18F-PI-2620 tau-PET. 18F-PI-2620 tau-PET was recorded using a dynamic one-stop-shop acquisition protocol to determine an early 0.5-2.5 min post tracer-injection perfusion window for assessing cortical neuronal dysfunction, as well as a 20-40 min post tracer-injection window to determine 4R-tau load. Perfusion-PET (i.e. early window) was assessed in 200 cortical regions, and tau-PET was assessed in 32 subcortical regions of established functional brain atlases. We determined tau epicentres as subcortical regions with the highest 18F-PI-2620 tau-PET signal and assessed the connectivity of tau epicentres to cortical regions of interest using a resting-state functional MRI-based functional connectivity template derived from 69 healthy elderly controls from the ADNI cohort. Using linear regression, we assessed whether: (i) higher subcortical tau-PET was associated with reduced cortical perfusion; and (ii) cortical perfusion reductions were observed preferentially in regions closely connected to subcortical tau epicentres. As hypothesized, higher subcortical tau-PET was associated with overall lower cortical perfusion, which remained consistent when controlling for cortical tau-PET. Using group-average and subject-level PET data, we found that the seed-based connectivity pattern of subcortical tau epicentres aligned with cortical perfusion patterns, where cortical regions that were more closely connected to the tau epicentre showed lower perfusion. Together, subcortical tau-accumulation is associated with remote perfusion reductions indicative of neuronal dysfunction in functionally connected cortical regions in 4R-tauopathies. This suggests that subcortical tau pathology may induce cortical dysfunction, which may contribute to clinical disease manifestation and clinical heterogeneity.
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Corteza Cerebral , Tomografía de Emisión de Positrones , Parálisis Supranuclear Progresiva , Tauopatías , Proteínas tau , Humanos , Masculino , Femenino , Tomografía de Emisión de Positrones/métodos , Anciano , Tauopatías/diagnóstico por imagen , Tauopatías/metabolismo , Tauopatías/patología , Proteínas tau/metabolismo , Persona de Mediana Edad , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/metabolismo , Parálisis Supranuclear Progresiva/patología , Parálisis Supranuclear Progresiva/fisiopatología , Imagen por Resonancia Magnética/métodosRESUMEN
Deep brain stimulation (DBS) holds promise for neuropsychiatric conditions where imbalance in network activity contributes to symptoms. Treatment-resistant Combat post-traumatic stress disorder (TR-PTSD) is a highly morbid condition and 50% of PTSD sufferers fail to recover despite psychotherapy or pharmacotherapy. Reminder-triggered symptoms may arise from inadequate top-down ventromedial prefrontal cortex (vmPFC) control of amygdala reactivity. Here, we report long-term data on two TR-PTSD participants from an investigation utilizing high-frequency amygdala DBS. The two combat veterans were implanted bilaterally with quadripolar electrodes targeting the basolateral amygdala. Following a randomized staggered onset, patients received stimulation with adjustments based on PTSD symptom severity for four years while psychiatric and neuropsychiatric symptoms, neuropsychological performance, and electroencephalography were systematically monitored. Evaluation of vmPFC-Amygdala network engagement was assessed with 18FDG positron emission tomography (PET). CAPS-IV scores varied over time, but improved 55% from 119 at baseline to 53 at 4-year study endpoint in participant 1; and 44%, from 68 to 38 in participant 2. Thereafter, during 5 and 1.5 years of subsequent clinical care respectively, long-term bilateral amygdala DBS was associated with additional, clinically significant symptomatic and functional improvement. There were no serious stimulation-related adverse psychiatric, neuropsychiatric, neuropsychological, neurological, or neurosurgical effects. In one subject, symptomatic improvement was associated with an intensity-dependent reduction in amygdala theta frequency power. In our two participants, FDG-PET findings were inconclusive regarding the hypothesized mechanism of suppression of amygdala hyperactivity. Our findings encourage further research to confirm and extend our preliminary observations.
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BACKGROUND/OBJECTIVE: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to ß-amyloid status. METHODS: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had ß-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. RESULTS: Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the ß-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. DISCUSSION: Distinct patterns of [11C]UCB-J and [18F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Péptidos beta-Amiloides , Tomografía de Emisión de Positrones , Sinapsis , Humanos , Masculino , Femenino , Anciano , Péptidos beta-Amiloides/metabolismo , Persona de Mediana Edad , Sinapsis/patología , Sinapsis/metabolismo , Degeneración Corticobasal/patología , Degeneración Corticobasal/metabolismo , Degeneración Corticobasal/diagnóstico por imagen , Proteínas tau/metabolismo , Imagen por Resonancia Magnética , Sustancia Gris/patología , Sustancia Gris/metabolismo , Sustancia Gris/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/patología , Disfunción Cognitiva/diagnóstico por imagen , CarbolinasRESUMEN
This paper provides an overview of the role of neuroinflammation in Alzheimer's disease and other neurodegenerative diseases, highlighting the potential of anti-inflammatory treatments to slow or prevent decline. This research focuses on the use of positron emission tomography (PET) imaging to visualize and quantify molecular brain changes in patients, specifically microglial activation and reactive astrogliosis. We discuss the development and application of several PET radioligands, including first-generation ligands like PK11195 and Ro5-4864, as well as second- and third-generation ligands such as [11C]PBR28, [18F]DPA-714, [18F]GE-180, and [11C]ER176. These ligands target the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia and upregulated in astrocytes. We also address the limitations of these ligands, such as low brain uptake, poor penetration of the blood-brain barrier, short half-life, and variable kinetic behavior. Furthermore, we demonstrate the impact of genetic polymorphisms on ligand binding.
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Enfermedad de Alzheimer , Enfermedades Neuroinflamatorias , Humanos , Receptores de GABA/metabolismo , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Enfermedad de Alzheimer/metabolismo , Ligandos , Microglía/metabolismoRESUMEN
The development of dementia is a devastating aspect of Parkinson's disease (PD), affecting nearly half of patients within 10â years post-diagnosis. For effective therapies to prevent and slow progression to PD dementia (PDD), the key mechanisms that determine why some people with PD develop early dementia, while others remain cognitively unaffected, need to be understood. Neuroinflammation and tau protein accumulation have been demonstrated in post-mortem PD brains, and in many other neurodegenerative disorders leading to dementia. However, whether these processes mediate dementia risk early on in the PD disease course is not established. To this end, we used PET neuroimaging with 11C-PK11195 to index neuroinflammation and 18F-AV-1451 for misfolded tau in early PD patients, stratified according to dementia risk in our 'Neuroinflammation and Tau Accumulation in Parkinson's Disease Dementia' (NET-PDD) study. The NET-PDD study longitudinally assesses newly-diagnosed PD patients in two subgroups at low and high dementia risk (stratified based on pentagon copying, semantic fluency, MAPT genotype), with comparison to age- and sex-matched controls. Non-displaceable binding potential (BPND) in 43 brain regions (Hammers' parcellation) was compared between groups (pairwise t-tests), and associations between BPND of the tracers tested (linear-mixed-effect models). We hypothesized that people with higher dementia risk have greater inflammation and/or tau accumulation in advance of significant cognitive decline. We found significantly elevated neuroinflammation (11C-PK11195 BPND) in multiple subcortical and restricted cortical regions in the high dementia risk group compared with controls, while in the low-risk group this was limited to two cortical areas. The high dementia risk group also showed significantly greater neuroinflammation than the low-risk group concentrated on subcortical and basal ganglia regions. Neuroinflammation in most of these regions was associated with worse cognitive performance (Addenbrooke's Cognitive Examination-III score). Overall neuroinflammation burden also correlated with serum levels of pro-inflammatory cytokines. In contrast, increases in 18F-AV-1451 (tau) BPND in PD versus controls were restricted to subcortical regions where off-target binding is typically seen, with no relationship to cognition found. Whole-brain 18F-AV-1451 burden correlated with serum phosphorylated tau181 levels. Although there was minimal regional tau accumulation in PD, regional neuroinflammation and tau burden correlated in PD participants, with the strongest association in the high dementia risk group, suggesting possible co-localization of these pathologies. In conclusion, our findings suggest that significant regional neuroinflammation in early PD might underpin higher risk for PDD development, indicating neuroinflammation as a putative early modifiable aetiopathological disease factor to prevent or slow dementia development using immunomodulatory strategies.
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Demencia , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedades Neuroinflamatorias , Demencia/diagnóstico por imagen , Ganglios Basales , Inflamación/complicaciones , Progresión de la EnfermedadRESUMEN
There is extensive synaptic loss from frontotemporal lobar degeneration, in preclinical models and human in vivo and post mortem studies. Understanding the consequences of synaptic loss for network function is important to support translational models and guide future therapeutic strategies. To examine this relationship, we recruited 55 participants with syndromes associated with frontotemporal lobar degeneration and 24 healthy controls. We measured synaptic density with positron emission tomography using the radioligand [11C]UCB-J, which binds to the presynaptic vesicle glycoprotein SV2A, neurite dispersion with diffusion magnetic resonance imaging, and network function with task-free magnetic resonance imaging functional connectivity. Synaptic density and neurite dispersion in patients was associated with reduced connectivity beyond atrophy. Functional connectivity moderated the relationship between synaptic density and clinical severity. Our findings confirm the importance of synaptic loss in frontotemporal lobar degeneration syndromes, and the resulting effect on behaviour as a function of abnormal connectivity.
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Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Humanos , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/diagnóstico por imagen , Degeneración Lobar Frontotemporal/patología , Imagen por Resonancia Magnética/métodos , Imagen de Difusión por Resonancia Magnética , Síndrome , Tomografía de Emisión de Positrones , Encéfalo/patologíaRESUMEN
INTRODUCTION: Many studies of the Richardson's syndrome phenotype of progressive supranuclear palsy (PSP) have elucidated regions of progressive atrophy and neural correlates of clinical severity. However, the neural correlates of survival and how these differ according to variant phenotypes are poorly understood. We set out to identify structural changes that predict severity and survival from scanning date to death. METHODS: Structural magnetic resonance imaging data from 112 deceased people with clinically defined 'probable' or 'possible' PSP were analysed. Neuroanatomical regions of interest volumes, thickness and area were correlated with 'temporal stage', defined as the ratio of time from symptom onset to death, time from scan to death ('survival from scan'), and in a subset of patients, clinical severity, adjusting for age and total intracranial volume. Forty-nine participants had post mortem confirmation of the diagnosis. RESULTS: Using T1-weighted magnetic resonance imaging, we confirmed the midbrain, and bilateral cortical structural correlates of contemporary disease severity. Atrophy of the striatum, cerebellum and frontotemporal cortex correlate with temporal stage and survival from scan, even after adjusting for severity. Subcortical structure-survival relationships were stronger in Richardson's syndrome than variant phenotypes. CONCLUSIONS: Although the duration of PSP varies widely between people, an individual's progress from disease onset to death (their temporal stage) reflects atrophy in striatal, cerebellar and frontotemporal cortical regions. Our findings suggest magnetic resonance imaging may contribute to prognostication and stratification of patients with heterogenous clinical trajectories and clarify the processes that confer mortality risk in PSP.
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Parálisis Supranuclear Progresiva , Humanos , Parálisis Supranuclear Progresiva/diagnóstico , Imagen por Resonancia Magnética/métodos , Mesencéfalo/patología , Cerebelo/patología , Atrofia/patologíaRESUMEN
Parkinson's disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system. Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson's syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetization-transfer-weighted imaging of the LC. Parameters of "race models" of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer nondecision times, and more lapses of attention. The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioral modeling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioral changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimization of noradrenergic treatment is likely to benefit from stratification according to LC integrity.SIGNIFICANCE STATEMENT Response inhibition deficits contribute to clinical symptoms and poor outcomes in people with Parkinson's disease and progressive supranuclear palsy. We used cognitive modeling of performance of a response inhibition task to identify disease-specific mechanisms of abnormal inhibitory control. Response inhibition in both patient groups was associated with the integrity of the noradrenergic locus coeruleus, which we measured in vivo using ultra-high field MRI. We propose that the imaging biomarker of locus coeruleus integrity provides a trans-diagnostic tool to explain individual differences in response inhibition ability beyond the classic nosological borders and diagnostic criteria. Our data suggest a potential new stratified treatment approach for Parkinson's disease and progressive supranuclear palsy.
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Enfermedad de Parkinson , Trastornos Parkinsonianos , Parálisis Supranuclear Progresiva , Humanos , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Parálisis Supranuclear Progresiva/psicología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/diagnóstico por imagen , Locus Coeruleus , Teorema de BayesRESUMEN
INTRODUCTION: Artificial intelligence (AI) and neuroimaging offer new opportunities for diagnosis and prognosis of dementia. METHODS: We systematically reviewed studies reporting AI for neuroimaging in diagnosis and/or prognosis of cognitive neurodegenerative diseases. RESULTS: A total of 255 studies were identified. Most studies relied on the Alzheimer's Disease Neuroimaging Initiative dataset. Algorithmic classifiers were the most commonly used AI method (48%) and discriminative models performed best for differentiating Alzheimer's disease from controls. The accuracy of algorithms varied with the patient cohort, imaging modalities, and stratifiers used. Few studies performed validation in an independent cohort. DISCUSSION: The literature has several methodological limitations including lack of sufficient algorithm development descriptions and standard definitions. We make recommendations to improve model validation including addressing key clinical questions, providing sufficient description of AI methods and validating findings in independent datasets. Collaborative approaches between experts in AI and medicine will help achieve the promising potential of AI tools in practice. HIGHLIGHTS: There has been a rapid expansion in the use of machine learning for diagnosis and prognosis in neurodegenerative disease Most studies (71%) relied on the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset with no other individual dataset used more than five times There has been a recent rise in the use of more complex discriminative models (e.g., neural networks) that performed better than other classifiers for classification of AD vs healthy controls We make recommendations to address methodological considerations, addressing key clinical questions, and validation We also make recommendations for the field more broadly to standardize outcome measures, address gaps in the literature, and monitor sources of bias.
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Enfermedad de Alzheimer , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Pronóstico , Inteligencia Artificial , Encéfalo/diagnóstico por imagen , Neuroimagen/métodosRESUMEN
INTRODUCTION: Although many cognitive measures have been developed to assess cognitive decline due to Alzheimer's disease (AD), there is little consensus on optimal measures, leading to varied assessments across research cohorts and clinical trials making it difficult to pool cognitive measures across studies. METHODS: We used a two-stage approach to harmonize cognitive data across cohorts and derive a cross-cohort score of cognitive impairment due to AD. First, we pool and harmonize cognitive data from international cohorts of varying size and ethnic diversity. Next, we derived cognitive composites that leverage maximal data from the harmonized dataset. RESULTS: We show that our cognitive composites are robust across cohorts and achieve greater or comparable sensitivity to AD-related cognitive decline compared to the Mini-Mental State Examination and Preclinical Alzheimer Cognitive Composite. Finally, we used an independent cohort validating both our harmonization approach and composite measures. DISCUSSION: Our easy to implement and readily available pipeline offers an approach for researchers to harmonize their cognitive data with large publicly available cohorts, providing a simple way to pool data for the development or validation of findings related to cognitive decline due to AD.
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There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.
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Degeneración Corticobasal , Enfermedades Neurodegenerativas , Parálisis Supranuclear Progresiva , Humanos , Parálisis Supranuclear Progresiva/diagnóstico por imagen , Pronóstico , Enfermedades Neurodegenerativas/diagnóstico por imagenRESUMEN
BACKGROUND: Synaptic loss is characteristic of many neurodegenerative diseases; it occurs early and is strongly related to functional deficits. OBJECTIVE: In this longitudinal observational study, we determine the rate at which synaptic density is reduced in the primary tauopathies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and we test the relationship with disease progression. METHODS: Our cross-sectional cohort included 32 participants with probable PSP and 16 with probable CBD (all amyloid-negative corticobasal syndrome), recruited from tertiary care centers in the United Kingdom, and 33 sex- and age-matched healthy control subjects. Synaptic density was estimated by positron emission tomography imaging with the radioligand [11 C]UCB-J that binds synaptic vesicle 2A. Clinical severity and cognition were assessed by the PSP Rating Scale and the Addenbrooke's cognitive examination. Regional [11 C]UCB-J nondisplaceable binding potential was estimated in Hammersmith Atlas regions of interest. Twenty-two participants with PSP/CBD had a follow-up [11 C]UCB-J positron emission tomography scan after 1 year. We calculated the annualized change in [11 C]UCB-J nondisplaceable binding potential and correlated this with the change in clinical severity. RESULTS: We found significant annual synaptic loss within the frontal lobe (-3.5%, P = 0.03) and the right caudate (-3.9%, P = 0.046). The degree of longitudinal synaptic loss within the frontal lobe correlated with the rate of change in the PSP Rating Scale (R = 0.47, P = 0.03) and cognition (Addenbrooke's Cognitive Examination-Revised, R = -0.62, P = 0.003). CONCLUSIONS: We provide in vivo evidence for rapid progressive synaptic loss, correlating with clinical progression in primary tauopathies. Synaptic loss may be an important therapeutic target and outcome variable for early-phase clinical trials of disease-modifying treatments. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Trastornos del Movimiento , Parálisis Supranuclear Progresiva , Tauopatías , Humanos , Estudios Transversales , Tomografía de Emisión de Positrones/métodos , Tauopatías/diagnóstico por imagen , Tauopatías/metabolismo , Parálisis Supranuclear Progresiva/diagnóstico , Trastornos del Movimiento/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismoRESUMEN
Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-ß (Aß; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOEε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aß and tau deposition. Furthermore, microglial activation mediated the Aß-independent effects of APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aß-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.
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Enfermedad de Alzheimer , Microglía , Animales , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Encéfalo/metabolismo , Microglía/metabolismo , Placa Amiloide/patología , Tomografía de Emisión de Positrones , Proteínas tau/metabolismo , Lóbulo Temporal/metabolismo , Apolipoproteínas E/metabolismoRESUMEN
Frontotemporal dementia is clinically and neuropathologically heterogeneous, but neuroinflammation, atrophy and cognitive impairment occur in all of its principal syndromes. Across the clinical spectrum of frontotemporal dementia, we assess the predictive value of in vivo neuroimaging measures of microglial activation and grey-matter volume on the rate of future cognitive decline. We hypothesized that inflammation is detrimental to cognitive performance, in addition to the effect of atrophy. Thirty patients with a clinical diagnosis of frontotemporal dementia underwent a baseline multimodal imaging assessment, including [11C]PK11195 PET to index microglial activation and structural MRI to quantify grey-matter volume. Ten people had behavioural variant frontotemporal dementia, 10 had the semantic variant of primary progressive aphasia and 10 had the non-fluent agrammatic variant of primary progressive aphasia. Cognition was assessed at baseline and longitudinally with the revised Addenbrooke's Cognitive Examination, at an average of 7-month intervals (for an average of â¼2 years, up to â¼5 years). Regional [11C]PK11195 binding potential and grey-matter volume were determined, and these were averaged within four hypothesis-driven regions of interest: bilateral frontal and temporal lobes. Linear mixed-effect models were applied to the longitudinal cognitive test scores, with [11C]PK11195 binding potentials and grey-matter volumes as predictors of cognitive performance, with age, education and baseline cognitive performance as covariates. Faster cognitive decline was associated with reduced baseline grey-matter volume and increased microglial activation in frontal regions, bilaterally. In frontal regions, microglial activation and grey-matter volume were negatively correlated, but provided independent information, with inflammation the stronger predictor of the rate of cognitive decline. When clinical diagnosis was included as a factor in the models, a significant predictive effect was found for [11C]PK11195 BPND in the left frontal lobe (-0.70, P = 0.01), but not for grey-matter volumes (P > 0.05), suggesting that inflammation severity in this region relates to cognitive decline regardless of clinical variant. The main results were validated by two-step prediction frequentist and Bayesian estimation of correlations, showing significant associations between the estimated rate of cognitive change (slope) and baseline microglial activation in the frontal lobe. These findings support preclinical models in which neuroinflammation (by microglial activation) accelerates the neurodegenerative disease trajectory. We highlight the potential for immunomodulatory treatment strategies in frontotemporal dementia, in which measures of microglial activation may also improve stratification for clinical trials.
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Afasia Progresiva Primaria , Disfunción Cognitiva , Demencia Frontotemporal , Enfermedades Neurodegenerativas , Enfermedad de Pick , Humanos , Demencia Frontotemporal/metabolismo , Enfermedades Neuroinflamatorias , Enfermedades Neurodegenerativas/patología , Microglía/metabolismo , Teorema de Bayes , Lóbulo Frontal/patología , Enfermedad de Pick/patología , Disfunción Cognitiva/metabolismo , Imagen por Resonancia Magnética/métodos , Inflamación/patología , Atrofia/patología , Afasia Progresiva Primaria/patologíaRESUMEN
INTRODUCTION: We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). METHODS: For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. RESULTS: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. DISCUSSION: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. HIGHLIGHTS: We investigated brain network predictors of dementia symptom onset Frontotemporal dementia results in characteristic dynamic network patterns Alterations in network dynamics are associated with neuropsychological impairment Network dynamic changes predict symptomatic conversion in presymptomatic carriers Network dynamic changes are associated with longitudinal cognitive decline.
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Disfunción Cognitiva , Demencia Frontotemporal , Humanos , Demencia Frontotemporal/diagnóstico , Mutación/genética , Encéfalo , Disfunción Cognitiva/genética , Imagen por Resonancia MagnéticaRESUMEN
OBJECTIVE: Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. METHODS: Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). RESULTS: Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. INTERPRETATION: In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.
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Demencia Frontotemporal , Enfermedades Neurodegenerativas , Enfermedad de Pick , Humanos , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/metabolismo , Tomografía de Emisión de Positrones/métodos , Lóbulo Frontal , Encéfalo/metabolismoRESUMEN
Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer's disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer's disease across the broad spectrum of ages and clinical phenotypes in Alzheimer's disease.