David J Brooks

Newcastle upon Tyne University · Translational and Clinical Research Institute

Background Cognitive dysfunction is increasingly recognized in multiple system atrophy (MSA). Locus coeruleus (LC) integrity is associated with cognitive performance both in healthy controls (HC) and neurodegenerative conditions such as Parkinson’s disease (PD). Furthermore, cortical glucose hypometabolism is associated with impaired cognitive perf...

Substantia nigra (SN) and locus coeruleus (LC) are two catecholaminergic, neuromelanin-rich nuclei that are affected in Parkinson’s Disease and may show neuroimaging abnormalities before the onset of motor manifestations. The simultaneous, multimodal investigation of their microstructural abnormalities may provide useful insights on the spatial dif...

Background Microglial reactivity and neuroinflammation are crucial pathological processes in Alzheimer’s Disease (AD). Several attempts to develop a treatment by supressing the immune response in AD have been made, yet these yielded very limited results. Recent studies suggest contrasting effects of microglial reactivity, indicating a biphasic resp...

Background Microglial reactivity and neuroinflammation are crucial pathological processes in Alzheimer’s Disease (AD). Several attempts to develop a treatment by supressing the immune response in AD have been made, yet these yielded very limited results. Recent studies suggest contrasting effects of microglial reactivity, indicating a biphasic resp...

Isolated rapid-eye-movement sleep behavior disorder (iRBD) is a strong predictor of Parkinson’s disease and Dementia with Lewy bodies. Previous studies indicate that cortical atrophy in iRBD patients may be linked to cognitive impairment, but the pattern of atrophy is inconsistently reported. This study aimed to elucidate cortical atrophy patterns...

Vagus nerve stimulation (VNS) is the subject of exploration as an adjunct treatment for neurological disorders such as epilepsy, chronic migraine, pain, and depression. A non‐invasive form of VNS is transcutaneous auricular VNS (taVNS). Combining animal models and positron emission tomography (PET) may lead to a better understanding of the elusive...

INTRODUCTION Microglial responses are an integral part of Alzheimer's disease (AD) pathology and are associated with amyloid beta (Aβ) deposition. This study aimed to investigate the effects of Aβ and microglial responses on global cognitive impairment. METHODS In this longitudinal study, 28 patients with mild cognitive impairment and 11 healthy c...

Background and purpose Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) progress to a parkinsonian alpha‐synucleinopathy. However, time to phenoconversion shows great variation. The aim of this study was to investigate whether cholinergic and dopaminergic dysfunction in iRBD patients was associated with impending pheno...

REM sleep behaviour disorder (RBD) is a parasomnia characterised by dream-enacting behaviour with loss of muscle atonia during REM sleep and is a prodromal feature of α-synucleinopathies like Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Although cortical-to-subcortical connectivity is well-studied in RBD, cerebellar...

Background: Neuroinflammation in Alzheimer's disease is known as an important process in the disease, yet how microglial activation affects disease progression remains unclear. Objective: The current study aims to interrogate the predictive value of neuroinflammation biomarker (11C-PBR28 PET), together with A/T/N imaging markers on disease deter...

The effects of subthalamic nucleus deep brain stimulation (STN-DBS) on anxiety in Parkinson’s disease (PD) are understudied. We identified clinical predictors of STN-DBS effects on anxiety in this study. In this prospective, open-label, multicentre study, we assessed patients with anxiety undergoing STN-DBS for PD preoperatively and at 6-month foll...

Major depressive disorder is one of the most prevalent mental health disorders, posing a global socioeconomic burden. Conventional antidepressant treatments have a slow onset of action, and 30% of patients show no clinically significant treatment response. The recently approved fast‐acting antidepressant S‐ketamine, an N‐methyl‐D‐aspartate receptor...

Background: Using 11C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. Objectives: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. Methods: Fifteen iRBD patients previously s...

The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer’s Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aβ aggregates in plasma from patients with mild cognitive impairment (n = 38). The ag...

Gait is an excellent indicator of physical, emotional, and mental health. Previous studies have shown that gait impairments in ageing are common, but the neural basis of these impairments are unclear. Existing methodologies are suboptimal and novel paradigms capable of capturing neural activation related to real walking are needed. In this study, w...

To revalidate the Freezing of Gait Questionnaire (FOG-Q), patients with Parkinson's disease (PD) were randomly assigned to receive rasagiline (1 mg/day) (n ϭ 150), entacapone (200 mg with each dose of levodopa) (n ϭ 150), or placebo (n ϭ 154). Patients were assessed at baseline and after 10 weeks using the FOG-Q, Unified Parkinson's Disease Rating...

Background Reduced cortical acetylcholinesterase activity, as measured by ¹¹C‐donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship betwe...

INTRODUCTION Capillary dysfunction, characterized by disturbances in capillary blood flow distribution, might be an overlooked factor in the development of Alzheimer's disease (AD). This study investigated microvascular blood flow in preclinical and prodromal AD individuals. METHODS Using dynamic susceptibility contrast magnetic resonance imaging...

There is evidence of early pathological changes in cholinergic neurons of patients with Alzheimer’s disease and Lewy body disease. This makes cholinergic molecular imaging one of the most important tools for studying prodromal and preclinical disease states of dementia. Various tracers have been developed for visualizing the cholinergic system. The...

Physical exercise benefits Parkinson's disease (PD) patients but the mechanism is unclear. Cannabinoid receptor type 1 (CB1R) is known to be reduced in PD patients and animal models. We test the hypothesis that binding of the CB1R inverse agonist, [3H]SR141716A, is normalized by treadmill exercise in the toxin-induced 6-hydroxdopamine (6-OHDA) mode...

Many advances in understanding the pathophysiology of Parkinson disease (PD) have been based on research addressing its motor symptoms and phenotypes. Various data-driven clinical phenotyping studies supported by neuropathological and in vivo neuroimaging data suggest the existence of distinct non-motor endophenotypes of PD even at diagnosis, a con...

Background: Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor. Objective: The objective of this study was to investigate whether local cortical s...

Background Cholinergic degeneration is strongly associated with cognitive decline in patients with Parkinson’s disease (PD) but may also cause motor symptoms and olfactory dysfunction. Regional differences are striking and may reflect different PD related symptoms and disease progression patterns. Objective To map and quantify the regional cerebra...

Brain network dysfunction is increasingly recognised in Alzheimer’s disease (AD). However, the causes of brain connectivity disruption are still poorly understood. Recently, neuroinflammation has been identified as an important factor in AD pathogenesis. Microglia participate in the construction and maintenance of healthy neuronal networks, but pro...

Alterations in cerebral perfusion is increasingly considered to play a crucial role in Alzheimer's disease (AD) and together with accumulated β-amyloid, deficiencies in the brain microvascular circulation may result in local hypoxia. Here, we studied alterations in cerebral circulation and the correlation between β-amyloid load and cerebral perfusi...

There is growing evidence that microglial activation plays a crucial role in the early pathological changes reported in Alzheimer’s disease (AD). Multimodal neuroimaging can be used to detect micro‐ and macrostructural alterations together with molecular imaging to quantify metabolism and proteins expression. Diffusivity map, reflecting neuronal in...

There is growing evidence that pathological changes in Alzheimer’s disease (AD) begin several years before the symptom onset. Neuroimaging approaches can be used to detect microstructural alterations in the early stages of neurodegeneration using diffusion‐weighted MRI. Cortical grey matter mean diffusivity (cMD) is thought to be increased in AD fo...

Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson’s disease dementia) apart from cholinesteras...

Background The average human lifespan has increased dramatically over the past century. However, molecular and physiological alterations of the healthy brain during aging remain incompletely understood. Generalized synaptic restructuring may contribute to healthy aging and the reduced metabolism observed in the aged brain. The aim of this study was...

The established causal genes in Alzheimer’s disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease’s initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%–3% of individuals with early-onset AD, and SORL1 haploi...

Introduction The peripheral autonomic nervous system may be involved years before onset of motor symptoms in some patients with Parkinson's disease (PD). Specific imaging techniques to quantify the cholinergic nervous system in peripheral organs are an unmet need. We tested the hypothesis that patients with PD display decreased [¹⁸F]FEOBV uptake in...

Introduction The typical spatial pattern of amyloid-β (Aβ) in diagnosed Alzheimer’s disease (AD) is that of a symmetrical hemispheric distribution. However, Aβ may be asymmetrically distributed in early stages of AD. Aβ distribution on PET has previously been explored in MCI and AD, but it has yet to be directly investigated in preclinical AD (pAD)...

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimer’s disease (AD). In this study, we quantified the in vivo expression of the endoplasmic reticulum stress marker, sigma 1 receptor (S1R), using [ ¹¹ C]SA4503 positron emission tomography (PET), the...

Background: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. Methods: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2...

The Göttingen minipig is a large animal with a gyrencephalic brain that expresses complex behaviour, making it an attractive model for Parkinson’s disease research. Here, we investigate the temporal evolution of presynaptic dopaminergic function for 14 months after injections of 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into the minipig u...

Background The autonomic nervous system is frequently affected in some neurodegenerative diseases, including Parkinson’s disease and Dementia with Lewy bodies. In vivo imaging methods to visualize and quantify the peripheral cholinergic nervous system are lacking. By using [ ¹⁸ F]FEOBV PET, we here describe the peripheral distribution of the specif...

Non-motor Parkinson's Disease is a burgeoning area of the movement disorders field, as patients increasingly live longer and encounter more late-stage symptoms. The spectrum of non-motor manifestations spans much of the body, with non-motor features occurring in all stages of the disease. Identification of symptoms is key for preserving quality of...

Background: Gait impairments are characteristic motor manifestations and significant predictors of poor quality of life in Parkinson's disease (PD). Neuroimaging biomarkers for gait impairments in PD could facilitate effective interventions to improve these symptoms and are highly warranted. Objective: The aim of this study was to identify neura...

Cardiovascular risk factors are associated with the development of Alzheimer’s disease (AD), and increasing evidence suggests that cerebral microvascular dysfunction plays a vital role in the disease progression. Using magnetic resonance imaging, we investigated the two-year changes of the cerebral microvascular blood flow in 11 mild cognitively im...

Importance: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. Objective:...

To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperati...

Background Liraglutide is a glucagon‐like peptide‐1 (GLP‐1) analogue licensed for the treatment of type 2 diabetes. Preclinical evidence in transgenic models of Alzheimer’s disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the p...

Background Neuroinflammation has been established as a key component of Alzheimer’s pathology. Numerous cross‐sectional studies have found associations between neuroinflammatory markers and neuronal damage in AD, suggesting neuroinflammation as a potential drive force of disease progression. However, there have been debate on whether neuroinflammat...

Background Microglial activation plays a significant role in neuroinflammation in the neurodegenerative process. Microglial activation is characterised by the over‐expression of a mitochondrial protein (TSPO), that can be targeted by PET Tracers. This study aims to evaluate the relationship between [ ¹⁸ F]GE180 PET uptake and grey matter atrophy....

Background: To investigate whether neuroinflammation and β-amyloid (Aβ) deposition influence brain structural and functional connectivity in Alzheimer's spectrum, we conducted a cross-sectional multimodal imaging study and interrogated the associations between imaging biomarkers of neuroinflammation, Aβ deposition, brain connectivity and cognition...

Background Synaptic loss and neurite dystrophy are early events in Alzheimers Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo. Methods MRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloi...

Background We have hypothesized that Parkinson’s disease (PD) comprises two subtypes. Brain-first, where pathogenic α-synuclein initially forms unilaterally in one hemisphere leading to asymmetric nigrostriatal degeneration, and body-first with initial enteric pathology, which spreads through overlapping vagal innervation leading to more symmetric...

Objective Imaging activated glutamate N‐methyl‐D‐aspartate receptor ion channels (NMDAR‐ICs) using positron emission tomography (PET) has proved challenging due to low brain uptake, poor affinity and selectivity, and high metabolism and dissociation rates of candidate radioligands. The radioligand [¹⁸F]GE‐179 is a known use‐dependent marker of NMDA...

Cell stress and impaired oxidative phosphorylation are central to mechanisms of synaptic loss and neurodegeneration in the cellular pathology of Alzheimers disease (AD). We quantified the in vivo density of the endoplasmic reticulum stress marker, the sigma 1 receptor (S1R) using [11C]SA4503 PET, as well as that of mitochondrial complex I (MC1) wit...

The central cholinergic system includes the basal forebrain nuclei, mainly projecting to the cortex, the mesopontine tegmental nuclei, mainly projecting to the thalamus and subcortical structures, and other groups of projecting‐ and inter‐neurons. This system regulates many functions of human behaviour such as cognition, locomotion and sleep. In Pa...

The few established causal genes in Alzheimer's disease (AD), mutations in APP and PSENs, have been functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. SORL1, a gene encoding the endosome recycling receptor SORLA, epidemiologically behaves as a causal gene when truncating mut...

Previous studies have reported substantial involvement of the noradrenergic system in Parkinson’s disease. Neuromelanin-sensitive MRI sequences and PET tracers have become available to visualize the cell bodies in the locus coeruleus and the density of noradrenergic terminal transporters. Combining these methods, we investigated the relationship of...

The gold standard animal model of Parkinson’s disease is the non-human primate rendered parkinsonian with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin. Low availability, ethical issues, and primate-specific biohazards make alternative large animal models necessary. Here, we investigate the temporal evolution of presynaptic dopamine...

Introduction Reduced postsynaptic D3 dopaminergic receptor availability has been reported in the ventral striatum of pathological gamblers without Parkinson’s disease (PD) and in patients with PD and impulse control disorders (ICD). However, a direct relationship between ventral striatum D3 dopaminergic receptors and the severity of ICD in PD patie...

Background: Parkinson's disease (PD) is characterized by Lewy body and neurite pathology associated with dopamine terminal dysfunction. Clinically, it is associated with motor slowing, rigidity, and tremor. Postural instability and pain are also features. Physical exercise benefits PD patients - possibly by promoting neuroplasticity including syna...

During the prodromal period of Parkinson’s disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, b...

Background: Patients with Parkinson's disease (PD) often develop dementia, but the underlying substrate is incompletely understood. Generalized synaptic degeneration may contribute to dysfunction and cognitive decline in Lewy body dementias, but in vivo evidence is lacking. Objective: The objective of this study was to assess the density of syna...

Significance This study shows that the myeloid immune response in isolated rapid-eye-movement sleep behavior disorder (iRBD) patients involves both brain and periphery, and that these responses are related, supporting a cross-talk between the brain and the peripheral immune system. Furthermore, these immune events were correlated with dopaminergic...

Background Type 2 diabetes is a risk factor for Alzheimer’s disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter...

Background: Neuroimaging has been used to support a diagnosis of possible multiple system atrophy (MSA). Only blood pressure changes upon standing are included in the second consensus criteria but other autonomic function tests (AFT) are also useful to diagnose widespread and progressive autonomic failure typical of MSA. Additional diagnostic tool...

Noradrenergic neurotransmission may play an important role in tremor modulation through its innervation of key structures of the central tremor circuits. Here, Parkinson's disease (PD) patients with (PDT+) or without (PDT-) rest tremor had ¹¹C-methylreboxetine(¹¹C-MeNER) positron emission tomography (PET) to test the hypothesis that noradrenaline t...

In this paper, the structural and functional imaging changes associated with sporadic and genetic Parkinson’s disease and atypical Parkinsonian variants are reviewed. The role of imaging for supporting diagnosis and detecting subclinical disease is discussed, and the potential use and drawbacks of using imaging biomarkers for monitoring disease pro...

Background Sleep disorders can occur in early Parkinson’s disease (PD). However, the relationship between different sleep disturbances and their longitudinal evolution has not been fully explored.Objective To describe the frequency, coexistence, and longitudinal change in excessive daytime sleepiness (EDS), insomnia, and probable REM sleep behavior...

Background Glucocerebrosidase gene mutations are a common genetic risk factor for Parkinson's disease. They exhibit incomplete penetrance. The objective of the present study was to measure microglial activation and dopamine integrity in glucocerebrosidase gene mutation carriers without Parkinson's disease compared to controls. Methods We performed...

Background Microglial activation has been found surrounding amyloid plaques and neurofibrillary tangles in brains of Alzheimer’s subjects . In‐vivo imaging using 11C‐PBR28 (a marker of translocator protein over expressed in activated microglia) has demonstrated significant correlation between both amyloid (18F‐Flutematemol PET) and tau deposition (...

Background Cerebral metabolic rate of glucose (CMRglc) can be measured with fluorodeoxyglucose (FDG) positron emission tomography (PET) using arterial blood sampling. However, blood sampling is an invasive methodology for subjects. Standard uptake value (SUV) is a non‐invasive method to assess the cerebral glucose metabolism. Here we evaluate the r...

Background 18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) measures regional cerebral glucose metabolism –which is a biomarker of neuronal function in Alzheimer’s disease (AD) Neuropsychological measures such as the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS‐Cog) – a measure of memory, language and praxis has been...

Background Brain atrophy can be reliably measured through volumetric analysis of structural MRI and is a valid biomarker of neurodegeneration in Alzheimer’s disease (AD) pathology ¹ . The Alzheimer’s Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog12) is a neuropsychological test designed to assess the level of cognitive dysfunction in AD with...

Background Activated microglia is present in both Alzheimer’s subjects (AD) and mild cognitive impairment (MCI) subjects and can be visualised by both pathological evaluation and in‐vivo imaging studies. It has been established that neuroinflammation plays a vital role in Alzheimer’s trajectory and disruption in structural and functional connectivi...

Background Microglial activation plays a significant role, and could be quantified using PET tracers targeting TSPO. We evaluated the use of Flutriciclamide PET tracer in a cohort of subject diagnosed with Alzheimer’s Disease (AD) or Mild Cognitive Impairment (MCI), using spectral analysis Method Twenty‐three subjects with AD, fourteen with MCI an...