Systematic Review and Meta-Analysis of Automated Methods for Quantifying Enlarged Perivascular Spaces in the Brain.

Research into magnetic resonance imaging (MRI)- visible perivascular spaces (PVS) has recently increased, as results from studies in different diseases and populations are cementing their association with sleep, disease phenotypes, and overall health indicators. With the establishment of worldwide consortia and the availability of large databases, computational methods that allow to automatically process all this wealth of information are becoming increasingly relevant. Several computational approaches have been proposed to assess PVS from MRI, and efforts have been made to summarise and appraise the most widely applied ones. We systematically reviewed and meta-analysed all publications available up to September 2023 describing the development, improvement, or application of computational PVS quantification methods from MRI. We analysed 67 approaches and 60 applications of their implementation, from 112 publications. The two most widely applied were the use of a morphological filter to enhance PVS-like structures, with Frangi being the choice preferred by most, and the use of a U-Net configuration with or without residual connections. Older adults or population studies comprising adults from 18 years old onwards were, overall, more frequent than studies using clinical samples. PVS were mainly assessed from T2-weighted MRI acquired in 1.5T and/or 3T scanners, although combinations using it with T1-weighted and FLAIR images were also abundant. Common associations researched included age, sex, hypertension, diabetes, white matter hyperintensities, sleep and cognition, with occupation-related, ethnicity, and genetic/hereditable traits being also explored. Despite promising improvements to overcome barriers such as noise and differentiation from other confounds, a need for joined efforts for a wider testing and increasing availability of the most promising methods is now paramount.

Cerebrovascular Reactivity in Patients With Small Vessel Disease: A Cross-Sectional Study.

BACKGROUND: Cerebrovascular reactivity (CVR) is inversely related to white matter hyperintensity severity, a marker of cerebral small vessel disease (SVD). Less is known about the relationship between CVR and other SVD imaging features or cognition. We aimed to investigate these cross-sectional relationships. METHODS: Between 2018 and 2021 in Edinburgh, we recruited patients presenting with lacunar or cortical ischemic stroke, whom we characterized for SVD features. We measured CVR in subcortical gray matter, normal-appearing white matter, and white matter hyperintensity using 3T magnetic resonance imaging. We assessed cognition using Montreal Cognitive Assessment. Statistical analyses included linear regression models with CVR as outcome, adjusted for age, sex, and vascular risk factors. We reported regression coefficients with 95% CIs. RESULTS: Of 208 patients, 182 had processable CVR data sets (median age, 68.2 years; 68% men). Although the strength of association depended on tissue type, lower CVR in normal-appearing tissues and white matter hyperintensity was associated with larger white matter hyperintensity volume (BNAWM=-0.0073 [95% CI, -0.0133 to -0.0014] %/mm Hg per 10-fold increase in percentage intracranial volume), more lacunes (BNAWM=-0.00129 [95% CI, -0.00215 to -0.00043] %/mm Hg per lacune), more microbleeds (BNAWM=-0.00083 [95% CI, -0.00130 to -0.00036] %/mm Hg per microbleed), higher deep atrophy score (BNAWM=-0.00218 [95% CI, -0.00417 to -0.00020] %/mm Hg per score point increase), higher perivascular space score (BNAWM=-0.0034 [95% CI, -0.0066 to -0.0002] %/mm Hg per score point increase in basal ganglia), and higher SVD score (BNAWM=-0.0048 [95% CI, -0.0075 to -0.0021] %/mm Hg per score point increase). Lower CVR in normal-appearing tissues was related to lower Montreal Cognitive Assessment without reaching convention statistical significance (BNAWM=0.00065 [95% CI, -0.00007 to 0.00137] %/mm Hg per score point increase). CONCLUSIONS: Lower CVR in patients with SVD was related to more severe SVD burden and worse cognition in this cross-sectional analysis. Longitudinal analysis will help determine whether lower CVR predicts worsening SVD severity or vice versa. REGISTRATION: URL: https://www.isrctn.com; Unique identifier: ISRCTN12113543.

Relationship Between Venules and Perivascular Spaces in Sporadic Small Vessel Diseases.

Background and Purpose- Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain magnetic resonance imaging. Methods- We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility. Results- Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%-18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (ß=0.468 [95% CI, 0.187-0.750]) and transverse sinus pulsatility (ß=0.547 [95% CI, 0.309-0.786]) and adjusting for age, sex, and systolic blood pressure. Conclusions- Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular.

Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology.

Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There is a critical need to provide mechanistic insight and improve translation between pre-clinical research and the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. These proceedings provide a summary of key talks at the workshop with a particular focus on animal models of cerebral vascular disease and dementia, mechanisms and approaches to improve translation. The outcomes of discussion groups on related themes to identify the gaps in knowledge and requirements to advance knowledge are summarized.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects.

The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Liothyronine Improves Biochemical Control of Congenital Hypothyroidism in Patients with Central Resistance to Thyroid Hormone.

OBJECTIVE: To assess whether adding liothyronine (LT3) to levothyroxine (LT4) monotherapy normalizes serum thyrotropin (TSH) and thyroxine (T4) concentrations in children with congenital hypothyroidism and central resistance to thyroid hormone. STUDY DESIGN: We retrospectively studied 12 patients with congenital hypothyroidism and central resistance to thyroid hormone (6 treated with LT3+LT4 combined therapy and 6 treated with LT4 monotherapy). In patients receiving combined therapy, we compared serum concentrations of TSH, T4, and triiodothyronine before and after addition of LT3. We used repeated measures analysis to compare thyroid function in participants receiving combined therapy vs monotherapy, while accounting for age and intrasubject correlation. RESULTS: In patients receiving combined therapy, the addition of LT3 was associated with normalization of mean TSH (9.2 vs 4.5 mIU/L, P = .002), a lower proportion of TSH values greater than 10 mIU/L (35% vs 8%, P = .03), and a decrease in mean serum T4 by 23 ± 9% (P < .001). Compared with patients receiving LT4 monotherapy, patients receiving combined therapy had lower mean TSH (8.5 ± 0.9 vs 4.3 ± 0.4, P < .001), lower odds of TSH elevation greater than 10 mIU/L (OR 0.20, 95% CI 0.10-0.41, P < .001), and lower odds of T4 elevation (OR 0.21, 95% CI 0.04-1.09, P = .06). LT3 treatment did not increase serum T3 levels significantly. CONCLUSION: The addition of LT3 to LT4 monotherapy facilitates normalization of both serum TSH and T4 in patients with congenital hypothyroidism and central resistance to thyroid hormone. Larger prospective studies are needed to confirm these findings and to determine the effect of combined therapy on neurodevelopmental outcomes.

Detectability and accuracy of computational measurements of in-silico and physical representations of enlarged perivascular spaces from magnetic resonance images.

BACKGROUND: Magnetic Resonance Imaging (MRI) visible perivascular spaces (PVS) have been associated with age, decline in cognitive abilities, interrupted sleep, and markers of small vessel disease. But the limits of validity of their quantification have not been established. NEW METHOD: We use a purpose-built digital reference object to construct an in-silico phantom for addressing this need, and validate it using a physical phantom. We use cylinders of different sizes as models for PVS. We also evaluate the influence of 'PVS' orientation, and different sets of parameters of the two vesselness filters that have been used for enhancing tubular structures, namely Frangi and RORPO filters, in the measurements' accuracy. RESULTS: PVS measurements in MRI are only a proxy of their true dimensions, as the boundaries of their representation are consistently overestimated. The success in the use of the Frangi filter relies on a careful tuning of several parameters. Alpha= 0.5, beta= 0.5 and c= 500 yielded the best results. RORPO does not have these requirements and allows detecting smaller cylinders in their entirety more consistently in the absence of noise and confounding artefacts. The Frangi filter seems to be best suited for voxel sizes equal or larger than 0.4 mm-isotropic and cylinders larger than 1 mm diameter and 2 mm length. 'PVS' orientation did not affect measurements in data with isotropic voxels. COMPARISON WITH EXISTENT METHODS: Does not apply. CONCLUSIONS: The in-silico and physical phantoms presented are useful for establishing the validity of quantification methods of tubular small structures.

Influence of threshold selection and image sequence in in-vivo segmentation of enlarged perivascular spaces.

BACKGROUND: Growing interest surrounds perivascular spaces (PVS) as a clinical biomarker of brain dysfunction given their association with cerebrovascular risk factors and disease. Neuroimaging techniques allowing quick and reliable quantification are being developed, but, in practice, they require optimisation as their limits of validity are usually unspecified. NEW METHOD: We evaluate modifications and alternatives to a state-of-the-art (SOTA) PVS segmentation method that uses a vesselness filter to enhance PVS discrimination, followed by thresholding of its response, applied to brain magnetic resonance images (MRI) from patients with sporadic small vessel disease acquired at 3 T. RESULTS: The method is robust against inter-observer differences in threshold selection, but separate thresholds for each region of interest (i.e., basal ganglia, centrum semiovale, and midbrain) are required. Noise needs to be assessed prior to selecting these thresholds, as effect of noise and imaging artefacts can be mitigated with a careful optimisation of these thresholds. PVS segmentation from T1-weighted images alone, misses small PVS, therefore, underestimates PVS count, may overestimate individual PVS volume especially in the basal ganglia, and is susceptible to the inclusion of calcified vessels and mineral deposits. Visual analyses indicated the incomplete and fragmented detection of long and thin PVS as the primary cause of errors, with the Frangi filter coping better than the Jerman filter. COMPARISON WITH EXISTING METHODS: Limits of validity to a SOTA PVS segmentation method applied to 3 T MRI with confounding pathology are given. CONCLUSIONS: Evidence presented reinforces the STRIVE-2 recommendation of using T2-weighted images for PVS assessment wherever possible. The Frangi filter is recommended for PVS segmentation from MRI, offering robust output against variations in threshold selection and pathology presentation.

Neuroimaging standards for research into small vessel disease-advances since 2013.

Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. Since then, new information on these established SVD markers and novel MRI sequences and imaging features have emerged. As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2.

A multi-disciplinary commentary on preclinical research to investigate vascular contributions to dementia.

Although dementia research has been dominated by Alzheimer's disease (AD), most dementia in older people is now recognised to be due to mixed pathologies, usually combining vascular and AD brain pathology. Vascular cognitive impairment (VCI), which encompasses vascular dementia (VaD) is the second most common type of dementia. Models of VCI have been delayed by limited understanding of the underlying aetiology and pathogenesis. This review by a multidisciplinary, diverse (in terms of sex, geography and career stage), cross-institute team provides a perspective on limitations to current VCI models and recommendations for improving translation and reproducibility. We discuss reproducibility, clinical features of VCI and corresponding assessments in models, human pathology, bioinformatics approaches, and data sharing. We offer recommendations for future research, particularly focusing on small vessel disease as a main underpinning disorder.

Topological relationships between perivascular spaces and progression of white matter hyperintensities: A pilot study in a sample of the Lothian Birth Cohort 1936.

Enlarged perivascular spaces (PVS) and white matter hyperintensities (WMH) are features of cerebral small vessel disease which can be seen in brain magnetic resonance imaging (MRI). Given the associations and proposed mechanistic link between PVS and WMH, they are hypothesized to also have topological proximity. However, this and the influence of their spatial proximity on WMH progression are unknown. We analyzed longitudinal MRI data from 29 out of 32 participants (mean age at baseline = 71.9 years) in a longitudinal study of cognitive aging, from three waves of data collection at 3-year intervals, alongside semi-automatic segmentation masks for PVS and WMH, to assess relationships. The majority of deep WMH clusters were found adjacent to or enclosing PVS (waves-1: 77%; 2: 76%; 3: 69%), especially in frontal, parietal, and temporal regions. Of the WMH clusters in the deep white matter that increased between waves, most increased around PVS (waves-1-2: 73%; 2-3: 72%). Formal statistical comparisons of severity of each of these two SVD markers yielded no associations between deep WMH progression and PVS proximity. These findings may suggest some deep WMH clusters may form and grow around PVS, possibly reflecting the consequences of impaired interstitial fluid drainage via PVS. The utility of these relationships as predictors of WMH progression remains unclear.

Targeting NMNAT1 to axons and synapses transforms its neuroprotective potency in vivo.

Axon and synapse degeneration are common components of many neurodegenerative diseases, and their rescue is essential for effective neuroprotection. The chimeric Wallerian degeneration slow protein (Wld(S)) protects axons dose dependently, but its mechanism is still elusive. We recently showed that Wld(S) acts at a non-nuclear location and is present in axons. This and other recent reports support a model in which Wld(S) protects by extranuclear redistribution of its nuclear NMNAT1 portion. However, it remains unclear whether cytoplasmic NMNAT1 acts locally in axons and synapses or at a non-nuclear site within cell bodies. The potency of axon protection by non-nuclear NMNAT1 relative to Wld(S) also needs to be established in vivo. Because the N-terminal portion of Wld(S) (N70) localized to axons, we hypothesized that it mediates the trafficking of the NMNAT1 portion. To test this, we substituted N70 with an axonal targeting peptide derived from amyloid precursor protein, and fused this to NMNAT1 with disrupted nuclear targeting. In transgenic mice, this transformed NMNAT1 from a molecule unable to inhibit Wallerian degeneration, even at high expression levels, into a protein more potent than Wld(S), able to preserve injured axons for several weeks at undetectable expression levels. Preventing NMNAT1 axonal delivery abolished its protective effect. Axonally targeted NMNAT1 localized to vesicular structures, colocalizing with extranuclear Wld(S), and was cotransported at least partially with mitochondria. We conclude that axonal targeting of NMNAT activity is both necessary and sufficient to delay Wallerian degeneration, and that promoting axonal and synaptic delivery greatly enhances the effectiveness.

Rates, risks and routes to reduce vascular dementia (R4vad), a UK-wide multicentre prospective observational cohort study of cognition after stroke: Protocol.

BACKGROUND: Stroke commonly affects cognition and, by definition, much vascular dementia follows stroke. However, there are fundamental limitations in our understanding of vascular cognitive impairment, restricting understanding of prevalence, trajectories, mechanisms, prevention, treatment and patient-service needs. AIMS: Rates, Risks and Routes to Reduce Vascular Dementia (R4VaD) is an observational cohort study of post-stroke cognition. We aim to recruit a wide range of patients with stroke, presenting to geographically diverse UK hospitals, into a longitudinal study to determine rates of, and risk factors for, cognitive and related impairments after stroke, to assess potential mechanisms and improve prediction models. METHODS: We will recruit at least 2000 patients within six weeks of stroke with or without capacity to consent and collect baseline demographic, clinical, socioeconomic, lifestyle, cognitive, neuropsychiatric and informant data using streamlined patient-centred methods appropriate to the stage after stroke. We will obtain more detailed assessments at four to eight weeks after the baseline assessment and follow-up by phone and post yearly to at least two years. We will assess diagnostic neuroimaging in all and high-sensitivity inflammatory markers, genetics, blood pressure and diffusion tensor imaging in mechanistic sub-studies.Planned outputs: R4VaD will provide reliable data on long-term cognitive function after stroke, stratified by prior cognition, stroke- and patient-related variables and improved risk prediction. It will create a platform enabling sharing of data, imaging and samples. Participants will be consented for re-contact, facilitating future clinical trials and providing a resource for the stroke and dementia research communities.

A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease.

Cerebral small vessel disease (SVD) is a major health burden, yet the pathophysiology remains poorly understood with no effective treatment. Since much of SVD develops silently and insidiously, non-invasive neuroimaging such as MRI is fundamental to detecting and understanding SVD in humans. Several relevant SVD rodent models are established for which MRI can monitor in vivo changes over time prior to histological examination. Here, we critically review the MRI methods pertaining to salient rodent models and evaluate synergies with human SVD MRI methods. We found few relevant publications, but argue there is considerable scope for greater use of MRI in rodent models, and opportunities for harmonisation of the rodent-human methods to increase the translational potential of models to understand SVD in humans. We summarise current MR techniques used in SVD research, provide recommendations and examples and highlight practicalities for use of MRI SVD imaging protocols in pre-selected, relevant rodent models.

Rationale and design of a longitudinal study of cerebral small vessel diseases, clinical and imaging outcomes in patients presenting with mild ischaemic stroke: Mild Stroke Study 3.

BACKGROUND: Cerebral small vessel disease is a major cause of dementia and stroke, visible on brain magnetic resonance imaging. Recent data suggest that small vessel disease lesions may be dynamic, damage extends into normal-appearing brain and microvascular dysfunctions include abnormal blood-brain barrier leakage, vasoreactivity and pulsatility, but much remains unknown regarding underlying pathophysiology, symptoms, clinical features and risk factors of small vessel disease.Patients and Methods: The Mild Stroke Study 3 is a prospective observational cohort study to identify risk factors for and clinical implications of small vessel disease progression and regression among up to 300 adults with non-disabling stroke. We perform detailed serial clinical, cognitive, lifestyle, physiological, retinal and brain magnetic resonance imaging assessments over one year; we assess cerebrovascular reactivity, blood flow, pulsatility and blood-brain barrier leakage on magnetic resonance imaging at baseline; we follow up to four years by post and phone. The study is registered ISRCTN 12113543. SUMMARY: Factors which influence direction and rate of change of small vessel disease lesions are poorly understood. We investigate the role of small vessel dysfunction using advanced serial neuroimaging in a deeply phenotyped cohort to increase understanding of the natural history of small vessel disease, identify those at highest risk of early disease progression or regression and uncover novel targets for small vessel disease prevention and therapy.

Axonal and neuromuscular synaptic phenotypes in Wld(S), SOD1(G93A) and ostes mutant mice identified by fiber-optic confocal microendoscopy.

We used live imaging by fiber-optic confocal microendoscopy (CME) of yellow fluorescent protein (YFP) expression in motor neurons to observe and monitor axonal and neuromuscular synaptic phenotypes in mutant mice. First, we visualized slow degeneration of axons and motor nerve terminals at neuromuscular junctions following sciatic nerve injury in Wld(S) mice with slow Wallerian degeneration. Protection of axotomized motor nerve terminals was much weaker in Wld(S) heterozygotes than in homozygotes. We then induced covert modifiers of axonal and synaptic degeneration in heterozygous Wld(S) mice, by N-ethyl-N-nitrosourea (ENU) mutagenesis, and used CME to identify candidate mutants that either enhanced or suppressed axonal or synaptic degeneration. From 219 of the F1 progeny of ENU-mutagenized BALB/c mice and thy1.2-YFP16/Wld(S) mice, CME revealed six phenodeviants with suppression of synaptic degeneration. Inheritance of synaptic protection was confirmed in three of these founders, with evidence of Mendelian inheritance of a dominant mutation in one of them (designated CEMOP_S5). We next applied CME repeatedly to living Wld(S) mice and to SOD1(G93A) mice, an animal model of motor neuron disease, and observed degeneration of identified neuromuscular synapses over a 1-4day period in both of these mutant lines. Finally, we used CME to observe slow axonal regeneration in the ENU-mutant ostes mouse strain. The data show that CME can be used to monitor covert axonal and neuromuscular synaptic pathology and, when combined with mutagenesis, to identify genetic modifiers of its progression in vivo.

Organotypic Culture Assay for Neuromuscular Synaptic Degeneration and Function.

We describe here an organotypic culture system we have used to investigate mechanisms that maintain structure and function of axon terminals at the neuromuscular junction (NMJ). We developed this by taking advantage of the slow Wallerian degeneration phenotype in mutant Wlds mice, using these to compare preservation of NMJs with degeneration in nerve-muscle preparations from wild-type mice. We take hind limb tibial nerve/flexor digitorum brevis and lumbrical muscles and incubate them in mammalian physiological saline at 32 °C for 24-48 h. Integrity of NMJs can then be compared using a combination of electrophysiological and morphological techniques. We illustrate our method with data showing synaptic preservation ex vivo in nerve-muscle explants from Sarm-1 null-mutant mice. The ex vivo assays of NMJ integrity we describe here may therefore be useful for detailed investigation of synaptic maintenance and degeneration.

Perivascular spaces in the brain: anatomy, physiology and pathology.

Perivascular spaces include a variety of passageways around arterioles, capillaries and venules in the brain, along which a range of substances can move. Although perivascular spaces were first identified over 150 years ago, they have come to prominence recently owing to advances in knowledge of their roles in clearance of interstitial fluid and waste from the brain, particularly during sleep, and in the pathogenesis of small vessel disease, Alzheimer disease and other neurodegenerative and inflammatory disorders. Experimental advances have facilitated in vivo studies of perivascular space function in intact rodent models during wakefulness and sleep, and MRI in humans has enabled perivascular space morphology to be related to cognitive function, vascular risk factors, vascular and neurodegenerative brain lesions, sleep patterns and cerebral haemodynamics. Many questions about perivascular spaces remain, but what is now clear is that normal perivascular space function is important for maintaining brain health. Here, we review perivascular space anatomy, physiology and pathology, particularly as seen with MRI in humans, and consider translation from models to humans to highlight knowns, unknowns, controversies and clinical relevance.

Autoimmune thyroid disease: unlocking a complex puzzle.

PURPOSE OF REVIEW: The autoimmune thyroid diseases (AITD), Graves' disease and chronic lymphocytic thyroiditis (CLT) are amongst the most common endocrine diseases in childhood and adolescence. The application of molecular biology has permitted an unparalleled insight into susceptibility genes that predispose to their development and has allowed enhanced understanding of their complex immune pathophysiology. RECENT FINDINGS: The susceptibility genes that predispose to AITD can be subdivided into those that affect the immune response in general and thyroid-specific antigens. Both known and new susceptibility genes have been the focus of recent attention. Although there is no known human leukocyte antigen (HLA) association in CLT, recent work has demonstrated an association with a specific amino acid pocket signature irrespective of the HLA-DR class. In Graves' disease a specific combination of polymorphisms for thyroglobulin and HLA-DR markedly increases the odds ratio for developing disease. The availability of recombinant antigen [particularly thyroid peroxidase and thyrotropin (TSH) receptor] and of high affinity monoclonal antibodies has provided insight into the specific epitopes recognized by antibodies in AITD and has confirmed the increased affinity of stimulating TSH receptor antibodies for the shed A subunit rather than the holoreceptor. SUMMARY: Powerful molecular tools have been developed that have shed light on the nature of the susceptibility genes for and the pathophysiology of AITD. These have already led to improved diagnostic tools and, hopefully, will permit the development of more specific immune therapy in the future.