Luca Passamonti

Biogen · Department of Neurology

Apathy and impulsivity are common and often coexistent consequences of frontotemporal lobar degeneration (FTLD). They increase patient morbidity and carer distress, but remain underestimated and poorly treated. Recent trans-diagnostic approaches that span the spectrum of clinical presentations of FTLD and parkinsonism, indicate that apathy and impu...

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease (AD). We tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [¹¹C]PK11195 positron emission tomography (PET) and resting-state functional...

Objective We tested whether in vivo neuroinflammation relates to the distinctive distributions of pathology in Alzheimer disease (AD) and progressive supranuclear palsy (PSP). Methods Sixteen patients with symptomatic AD (including amnestic mild cognitive impairment with amyloid-positive PET scan), 16 patients with PSP–Richardson syndrome, and 13...

The five-factor model (FFM) is a widely used taxonomy of human personality; yet its neuro anatomical basis remains unclear. This is partly because past associations between gray-matter volume and FFM were driven by different surface-based morphometry (SBM) indices (i.e. cortical thickness, surface area, cortical folding or any combination of them)....

The ability to assess the distribution and extent of tau pathology in Alzheimer’s disease and progressive supranuclear palsy in vivo would help to develop biomarkers for these tauopathies and clinical trials of disease-modifying therapies. New radioligands for positron emission tomography have generated considerable interest, and controversy, in th...

Noradrenaline is a powerful modulator of cognitive processes, including action-decisions underlying saccadic control. Changes in saccadic eye movements are common across neurodegenerative diseases of ageing, including Parkinson’s disease. With growing interest in noradrenergic treatment potential for non-motor symptoms in Parkinson’s disease, the t...

Noradrenaline plays an integral role in learning, by optimising behavioural strategies and facilitating choice execution. Testing the noradrenergic framework of learning in the context of human diseases offers a test bed for current normative neuroscience theories and may also indicate therapeutic potential. Parkinson's disease is often considered...

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 c...

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, a...

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant primary progressive aphasia [nfvPPA])....

Introduction: The functional connectivity patterns in the brain are highly heritable; however, it is unclear how genetic factors influence the directionality of such "information flows." Studying the "directionality" of the brain functional connectivity and assessing how heritability modulates it can improve our understanding of the human connecto...

Recently, it has become progressively more evident that classic diagnostic labels are unable to reliably describe the complexity and variability of several clinical phenotypes. This is particularly true for a broad range of neuropsychiatric illnesses (e.g., depression, anxiety disorders, behavioral phenotypes). Patient heterogeneity can be better d...

Background Depressed individuals show attentional biases in the processing of emotional stimuli, such as negative face expressions. Some of these biases persist in previously depressed individuals, but their mechanisms remain largely unknown. Methods A population-derived cohort (n = 134, 68 females; 21 - 92 years) was recruited by Cam-CAN. Function...

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...

The locus coeruleus–noradrenaline system plays an extensive role in cognition and behaviour. It is among the earliest and most prominent sites of pathology in neurodegenerative diseases of ageing, including Alzheimer’s and Parkinson’s disease. Improving our ability to detect changes in this system in vivo has implications for early diagnosis and fo...

Synaptic loss occurs early in many neurodegenerative diseases and contributes to cognitive impairment even in the absence of gross atrophy. Currently, for human disease there are few formal models to explain how cortical networks underlying cognition are affected by synaptic loss. We advocate that biophysical models of neurophysiology offer both a...

Personality neuroscience is the study of persistent psychological individual differences, typically in the general population, using neuroscientific methods. It has the potential to shed light on the neurobiological mechanisms underlying individual differences and their manifestation in ongoing behavior and experience. The field was inaugurated man...

Functional connectivity (FC) between regions of the brain is commonly estimated through statistical dependency measures applied to functional magnetic resonance imaging (fMRI) data. The resulting functional connectivity matrix (FCM) is often taken to represent the adjacency matrix of a brain graph. Recently, graph neural networks (GNNs) have been s...

Recently, it has become progressively more evident that classic diagnostic labels are unable to accurately and reliably describe the complexity and variability of several clinical phenotypes. This is particularly true for a broad range of neuropsychiatric illnesses such as depression and anxiety disorders or behavioural phenotypes such as aggressio...

Marek et al. analyzed three very large magnetic resonance imaging (MRI) datasets and concluded that thousands of participants are necessary to ensure replicable results in “brain-wide associations studies,” which they defined as “studies of the associations between common inter-individual variability in human brain structure/function and cognition...

Apathy is a debilitating feature of many neuropsychiatric diseases, that is typically described as a reduction of goal-directed behaviour. Despite its prevalence and prognostic importance, the mechanisms underlying apathy remain controversial. Degeneration of the locus coeruleus-noradrenaline system is known to contribute to motivational deficits,...

Resting-state functional magnetic resonance imaging (rs-fMRI) has been successfully employed to understand the organisation of the human brain. Typically, the brain is parcellated into regions of interest (ROIs) and modelled as a graph where each ROI represents a node and association measures between ROI-specific blood-oxygen-level-dependent (BOLD)...

Background: Neurodegeneration in the locus coeruleus (LC) contributes to neuropsychiatric symptoms in both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Spatial precision of LC imaging is improved with ultrahigh field 7 T magnetic resonance imaging. Objectives: This study aimed to characterize the spatial patterns of LC path...

Background: Although disabling fatigue is common in Parkinson's disease (PD), available consensus-based diagnostic criteria have not yet been empirically validated. The aim of the study was to evaluate the clinimetric properties of the criteria. Methods: A sample of outpatients with PD was evaluated for demographic, clinical, behavioural, and co...

Background Magnetoencephalography (MEG) is a promising tool for experimental medicine in dementia, and a core technology for the Dementias Platform UK. It quantifies in vivo human network and synaptic physiology, with high‐dimensional data at a millisecond time‐scale. Its proven sensitivity to neurodegenerative disease has applications in diagnosti...

Background Neuroinflammation is implicated in the pathogenesis of neurodegenerative disorders including dementia with Lewy bodies (DLB), but its relationship with disease progression, including cognitive decline, is less well understood. We investigated the predictive value of microglial activation, assessed in vivo using positron emission tomograp...

Background Apathy is a common neuropsychiatric feature of both Parkinson’s disease and progressive supranuclear palsy (PSP) (Aarsland, et al., 2001). Early neuropathology in the locus coeruleus (LC) and consequent noradrenergic deficiency are proposed to be key contributors to the pathogenesis of apathy (Passamonti et al., 2018). Here we test the h...

Background Frontotemporal lobar degeneration (FTLD) is associated with deficits to GABA and glutamatergic neurotransmitters, particularly in the frontal cortex. While targeting GABAergic systems has shown to restore frontotemporal deficits in FTLD, little is known whether pharmacological probes of glutamatergic functioning have similar effects in t...

Background Frontotemporal dementia is clinically and neuropathologically heterogeneous, but atrophy, neuroinflammation, and executive dysfunction occur in each of the principal variants. Across the clinical spectrum of frontotemporal dementia, we assessed the predictive value of in vivo neuroimaging measures of grey‐matter volume (from structural M...

Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by neuro-glial tau pathology. A new staging system for PSP pathology at post-mortem has been described and validated. We used a data-driven approach to test whether post-mortem pathological staging in PSP can be reproduced in vivo with 18F-flortaucipir PET. Methods:...

Parkinson's disease and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals, and have been linked with worse prognosis and lack of improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the corte...

Background. Previous studies have reported brain structure abnormalities in conduct disorder (CD), but it is unclear whether these neuroanatomical alterations mediate the effects of familial (genetic and environmental) risk for CD. We investigated brain structure in adolescents with CD and their unaffected relatives (URs) to identify neuroanatomica...

Persistent postural-perceptual dizziness (PPPD), defined in 2017, is a vestibular disorder characterized by chronic dizziness that is exacerbated by upright posture and exposure to complex visual stimuli. This review focused on recent neuroimaging studies that explored the pathophysiological mechanisms underlying PPPD and three conditions that pred...

Background Subjective complaints of cognitive deficits are not necessarily consistent with objective evidence of cognitive impairment in Parkinson’s disease (PD). Here we examined the factors associated with the objective-subjective cognitive discrepancy. Methods We consecutively enrolled 90 non-demented patients with PD who completed the Parkinso...

Introduction Psychological factors can underlie fatigue in neurological disorders, but its relationship to fatigue in Parkinson’s disease (PD) has not been explored. We assessed the association between maladaptive metacognitive beliefs and presence of fatigue in PD. Methods Ninety-eight consecutive outpatients with PD (61% male; median age: 66.50...

Background: Apathy and impulsivity are common consequences of progressive supranuclear palsy (PSP) and can worsen its prognosis. They can co-exist in the same patients although their concomitant prevalence remains unclear. Their relationship to emotional lability is unknown. Objectives: To estimate the co-occurrence of apathy and impulsivity and...

The relationship between in vivo synaptic density and molecular pathology in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology...

A bstract Apathy is a debilitating feature of many diseases, including Parkinson’s disease. We tested the hypothesis that degeneration of the locus coeruleus-noradrenaline system contributes to apathy by modulating the relative weighting of prior beliefs about action outcomes. Participants with mild-to-moderate idiopathic Parkinson’s disease ( N =1...

Progressive supranuclear palsy causes diverse clinical presentations, including classical Richardson’s syndrome and several variant phenotypes. Clinical trials of disease-modifying therapies have recently been completed, with more planned for the next 2 years. However, many people with progressive supranuclear palsy do not meet eligibility criteria...

Synaptic loss is an early and clinically relevant feature of many neurodegenera-tive diseases. Here we assess three adults at risk of frontotemporal dementia from C9orf72 mutation, using [ 11 C]UCB-J PET to quantify synaptic density in comparison with 19 healthy controls and one symptomatic patient with beha-vioural variant frontotemporal dementia....

Objective The loss of noradrenergic neurons in the locus coeruleus contributes to neuropsychiatric symptoms in both Parkinson’s disease (PD) and progressive supranuclear palsy (PSP). This study aimed to characterise the spatial patterns of locus coeruleus pathological change in PD and PSP, and its relationship to cognitive and psychiatric symptoms....

Background: Vulnerability of the substantia nigra dopaminergic neurons in Parkinson's disease is associated with ferric overload, leading to neurodegeneration with cognitive and motor decline. Here, we quantify iron and neuromelanin-related markers in vivo using ultra-high field 7-Tesla MRI, and examine the clinical correlates of these imaging asse...

Background: Neuroticism is linked to mood disorders and Alzheimer's disease, but fewer studies have tested the prospective association with Parkinson's disease (PD). Objectives: To examine the association between neuroticism and risk of PD in a large cohort and a meta‐analysis of prospective cohort studies. Methods: Participants from the UK Biobank...

Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition defi...

This study examines whether neuroticism is differentially associated with risk of incident Alzheimer’s disease (AD), vascular dementia (VD), and frontotemporal dementia (FTD) using a prospective study design. Participants from the UK Biobank (N = 401,422) completed a self-report neuroticism scale in 2006-2010 and incident all-cause dementia, AD, VD...

Introduction In addition to tau pathology and neuronal loss, neuroinflammation occurs in progressive supranuclear palsy (PSP). However, the prognostic value of the in vivo imaging markers for these processes in PSP remains unclear. We test the primary hypothesis that baseline in vivo imaging assessment of neuroinflammation in subcortical regions pr...

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy (PSP). Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major n...

Recently, it has become progressively more evident that classic diagnostic labels are unable to accurately and reliably describe the complexity and variability of several clinical phenotypes. This is particularly true for a broad range of neuropsychiatric illnesses such as depression and anxiety disorders or behavioural phenotypes such as aggressio...

The relationship between in vivo synaptic density and tau burden in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology, in the p...

In addition to beta-amyloid accumulation, misfolded tau and activated microglia are also present in Alzheimer's disease (AD). It is important to study the relationship amongst these pathologies in vivo and their effects on the cognitive deficits for developing effective trails and future therapeutic or preventive strategies for AD. To investigate t...

Background Apathy and impulsivity are common problems in progressive supranuclear palsy (PSP) and can worsen its prognosis. They can co-exist in the same patients although their concomitant prevalence remains unclear. Their relationship to emotional lability is also unknown. Objectives To estimate the co-occurrence of apathy and impulsivity and th...

Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborisation are characteristic and can be quantified in vivo, with [¹¹C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of progressive s...

Early and profound pathological changes are evident in the locus coeruleus (LC) in dementia and Parkinson's disease, with effects on arousal, attention, cognitive and motor control. The LC can be identified in vivo using non-invasive magnetic resonance imaging techniques which have potential as biomarkers for detecting and monitoring disease progre...

Introduction: Associations between cerebral small vessel disease (SVD) and inflammation have been largely examined using peripheral blood markers of inflammation, with few studies measuring inflammation within the brain. We investigated the cross-sectional relationship between SVD and in vivo neuroinflammation using [11C]PK11195 positron emission t...

Understanding the cellular underpinnings of neurodegeneration remains a challenge; loss of synapses and dendritic arborisation are characteristic and can be quantified i n vivo , with [ ¹¹ C]UCB-J PET and MRI-based Orientation Dispersion Imaging (ODI), respectively. We aimed to assess how both measures are correlated, in 4R-tauopathies of Progressi...

Cognitive dysfunction and dementia are a common consequence of several types of neurodegenerative disorders. Yet, there are numerous challenges in the differential diagnosis of neurodegenerative forms of dementia which have hampered the successful implementation of clinical trials and development of new disease-modifying therapies. One of the main...

Background Progressive Supranuclear Palsy (PSP) is associated with tau pathology and neurodegeneration, particularly in basal ganglia, diencephalon, and brainstem. Recently, neuroinflammation has been recognized as another key aspect in the pathophysiology of PSP. Understanding whether these three pathological features predict the clinical progress...

Background Neuroinflammation is part of the pathophysiology of Alzheimer’s disease (AD), in addition to amyloid‐β plaques and tau neurofibrillary tangles. PET markers of microglial activation have indicated inflammation of temporo‐parietal regions, in proportion to disease severity. Here we test the prognostic value of [11C]PK11195 PET on longitudi...

Resting-state functional magnetic resonance imaging (rs-fMRI) has been successfully employed to understand the organisation of the human brain. For rs-fMRI analysis, the brain is typically parcellated into regions of interest (ROIs) and modelled as a graph where each ROI is a node and pairwise correlation between ROI blood-oxygen-level-dependent (B...

Alzheimer’s disease (AD) pathology is frequently observed as a comorbidity in people with dementia with Lewy bodies (DLB). Here, we evaluated the in vivo distribution of tau burden and its influence on the clinical phenotype of DLB. Tau deposition was quantified using [¹⁸F]-AV1451 positron emission tomography in people with DLB (n = 11) and AD (n =...

Introduction We report in vivo patterns of neuroinflammation and abnormal protein aggregation in seven cases of familial frontotemporal dementia (FTD) with mutations in MAPT, GRN and C9orf72 genes. Methods Using positron emission tomography (PET), we explored the association of the distribution of activated microglia, as measured by the radioligan...

Primary open angle Glaucoma (POAG) is one of the most common causes of permanent blindness in the world. Recent studies have suggested the hypothesis that POAG is also a central nervous system disorder which may result in additional (i.e., extra-ocular) involvement. The aim of this study is to assess possible structural, whole-brain connectivity al...

Glaucoma is an optic neuropathy characterized by death of retinal ganglion cells and loss of their axons, progressively leading to blindness. Recently, glaucoma has been conceptualized as a more diffuse neurodegenerative disorder involving the optic nerve and also the entire brain. Consistently, previous studies have used a variety of magnetic reso...

Objective: We examined the relationship between tau pathology and neuroinflammation using [11 C]PK11195 and [18 F]AV-1451 PET in seventeen patients with progressive supranuclear palsy Richardson's syndrome (PSP). We tested the hypothesis that neuroinflammation and tau protein aggregation co-localize macroscopically, and correlate with clinical sev...

Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition defi...