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An uncertain year: looking back, moving forwards
Masud Husain
doi : 10.1093/brain/awaa439
Brain, Volume 144, Issue 1, January 2021, Page 1
It is a precarious moment. When people look back at this time they might not view it this way, but as we who are living through it know, we begin the new year on the edge of an extremely uncertain future. Are we on the verge of a way out of the stranglehold that the pandemic had over us in 2020? Will science and the remarkable vaccination programmes that were initiated only months ago provide a decisive solution? Or are we being falsely optimistic about the months ahead? Let us hope not. Let’s also hope that the spurious claims of the lamentable anti-vaccine movement do...
Bird watching on the asphalt
A J Lees
doi : 10.1093/brain/awaa437
Brain, Volume 144, Issue 1, January 2021, Pages 2–5
Attempting to make a diagnosis from a collection of baffling symptoms is comparable to the challenge of identifying an unusual bird that refuses to stay still. Many neurologists take up birding as a hobby where they can apply their observation and listening skills and be free to celebrate the thrill of accurate diagnosis without censure1. A few also become ornithologists, writing in scientific publications on avian anatomy, physiology and behaviour, and even on the neurological disorders of birds. In this essay I describe how bird watching and a love of natural history turned me not only into a noticer but also influenced my...
Neuregulin therapy for multiple sclerosis: an each-way bet?
Trevor J Kilpatrick, Michele D Binder
doi : 10.1093/brain/awaa434
Brain, Volume 144, Issue 1, January 2021, Pages 6–8
The past 35 years have seen significant advances in the understanding and treatment of inflammatory conditions that affect the CNS, not least multiple sclerosis. The field has been well served by a swathe of immunomodulatory and immunosuppressive agents for the treatment of multiple sclerosis, but none of these therapies have been shown to directly modulate endogenous pathogenic mechanisms (Rommer et al., 2019). The most overt example of the current approach is autologous haemopoietic stem cell transplantation, which is predicated on...
Pathological brain ageing in epilepsy and dementia: two sides of the same coin?
Arjune Sen, Michele Romoli
doi : 10.1093/brain/awaa441
Brain, Volume 144, Issue 1, January 2021, Pages 9–11
As the global population ages, the intersection between ageing, epilepsy and dementia has become an increasingly pressing concern. Both the incidence and prevalence of epilepsy are greatest in older individuals (Sen et al., 2020). Patients with epilepsy have long reported that memory impairment can be of greater concern to them than the seizures themselves. Only recently, however, has systematic, well-controlled work begun to evaluate the role that epilepsy may play in the pathogenesis...
Integrating events in the disintegration of Alzheimer’s disease
William Jagust
doi : 10.1093/brain/awaa402
Brain, Volume 144, Issue 1, January 2021, Pages 11–14
Alzheimer’s disease pathology is extraordinarily complex, evolving over decades and manifesting as aggregation of the amyloid-? and tau proteins as plaques and neurofibrillary tangles. Human research has been facilitated by the use of biomarkers for amyloid-? and pathological tau, initially through CSF measurement and more recently with PET ligands that bind to the protein aggregates. Detection of these pathological proteins, while transformative for Alzheimer’s disease research, has not provided a mechanistic understanding of events occurring at the cellular...
Concatenating plasma p-tau to Alzheimer’s disease
Betty M Tijms, Charlotte E Teunissen
doi : 10.1093/brain/awaa422
Brain, Volume 144, Issue 1, January 2021, Pages 14–17
Amyloid plaques and tau tangles are the pathological hallmarks of Alzheimer’s disease, and the capacity to detect amyloid and tau on PET and in CSF has greatly improved the disease diagnostic process (Jack et al., 2018). Now amyloid and tau can also be measured in blood, and since blood is easier to obtain than PET images or CSF, this could enable biomarkers to become part...
The synapse in traumatic brain injury
Aimun A B Jamjoom, Jonathan Rhodes, Peter J D Andrews, Seth G N Grant
doi : 10.1093/brain/awaa321
Brain, Volume 144, Issue 1, January 2021, Pages 18–31
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide and is a risk factor for dementia later in life. Research into the pathophysiology of TBI has focused on the impact of injury on the neuron. However, recent advances have shown that TBI has a major impact on synapse structure and function through a combination of the immediate mechanical insult and the ensuing secondary injury processes, leading to synapse loss. In this review, we highlight the role of the synapse in TBI pathophysiology with a focus on the confluence of multiple secondary injury processes including excitotoxicity, inflammation and oxidative stress. The primary insult triggers a cascade of events in each of these secondary processes and we discuss the complex interplay that occurs at the synapse. We also examine how the synapse is impacted by traumatic axonal injury and the role it may play in the spread of tau after TBI. We propose that astrocytes play a crucial role by mediating both synapse loss and recovery. Finally, we highlight recent developments in the field including synapse molecular imaging, fluid biomarkers and therapeutics. In particular, we discuss advances in our understanding of synapse diversity and suggest that the new technology of synaptome mapping may prove useful in identifying synapses that are vulnerable or resistant to TBI.
Developmental and epileptic encephalopathies: what we do and do not know
Nicola Specchio, Paolo Curatolo
doi : 10.1093/brain/awaa371
Brain, Volume 144, Issue 1, January 2021, Pages 32–43
Developmental encephalopathies, including intellectual disability and autistic spectrum disorder, are frequently associated with infant epilepsy. Epileptic encephalopathy is used to describe an assumed causal relationship between epilepsy and developmental delay. Developmental encephalopathies pathogenesis more independent from epilepsy is supported by the identification of several gene variants associated with both developmental encephalopathies and epilepsy, the possibility for gene-associated developmental encephalopathies without epilepsy, and the continued development of developmental encephalopathies even when seizures are controlled. Hence, ‘developmental and epileptic encephalopathy’ may be a more appropriate term than epileptic encephalopathy. This update considers the best studied ‘developmental and epileptic encephalopathy’ gene variants for illustrative support for ‘developmental and epileptic encephalopathy’ over epileptic encephalopathy. Moreover, the interaction between epilepsy and developmental encephalopathies is considered with respect to influence on treatment decisions. Continued research in genetic testing will increase access to clinical tests, earlier diagnosis, better application of current treatments, and potentially provide new molecular-investigated treatments.
Subthalamic stimulation impairs stopping of ongoing movements
Roxanne Lofredi, Georg Cem Auernig, Friederike Irmen, Johanna Nieweler, Wolf-Julian Neumann ...
doi : 10.1093/brain/awaa341
Brain, Volume 144, Issue 1, January 2021, Pages 44–52
The subthalamic nucleus is part of a global stopping network that also includes the presupplementary motor area and inferior frontal gyrus of the right hemisphere. In Parkinson’s disease, subthalamic deep brain stimulation improves movement initiation and velocity, but its effect on stopping of ongoing movement is unknown. Here, we examine the relation between movement stopping and connectivity of stimulation volumes to the stopping network. Stop and go times were collected in 17 patients with Parkinson’s disease on and off subthalamic stimulation during visually cued initiation and termination of continuous, rotational movements. Deep brain stimulation contacts were localized; the stimulation volume computed and connectivity profiles estimated using an openly available, normative structural connectome. Subthalamic stimulation significantly increased stop times, which correlated with the connectivity of the stimulation volume to presupplementary motor area and inferior frontal gyrus of the right hemisphere. The robustness of this finding was validated using three separate analysis streams: voxel-wise whole-brain connectivity, region of interest connectivity and a tract-centred method. Our study sheds light on the role of the fronto-subthalamic inhibitory triangle in stopping of ongoing movements and may inspire circuit based adaptive stimulation strategies for control of stopping impairment, possibly reflected in stimulation-induced dyskinesia.
Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma
James L Ross, Zhihong Chen, Cameron J Herting, Yura Grabovska, Frank Szulzewsky ...
doi : 10.1093/brain/awaa382
Brain, Volume 144, Issue 1, January 2021, Pages 53–69
Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12–15 months. One promising avenue of research is the development of novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFR?, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.
From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury
Cornelius K Donat, Maria Yanez Lopez, Magdalena Sastre, Nicoleta Baxan, Marc Goldfinger ...
doi : 10.1093/brain/awaa336
Brain, Volume 144, Issue 1, January 2021, Pages 70–91
The relationship between biomechanical forces and neuropathology is key to understanding traumatic brain injury. White matter tracts are damaged by high shear forces during impact, resulting in axonal injury, a key determinant of long-term clinical outcomes. However, the relationship between biomechanical forces and patterns of white matter injuries, associated with persistent diffusion MRI abnormalities, is poorly understood. This limits the ability to predict the severity of head injuries and the design of appropriate protection. Our previously developed human finite element model of head injury predicted the location of post-traumatic neurodegeneration. A similar rat model now allows us to experimentally test whether strain patterns calculated by the model predicts in vivo MRI and histology changes. Using a controlled cortical impact, mild and moderate injuries (1 and 2 mm) were performed. Focal and axonal injuries were quantified with volumetric and diffusion 9.4 T MRI at 2 weeks post injury. Detailed analysis of the corpus callosum was conducted using multi-shell diffusion MRI and histopathology. Microglia and astrocyte density, including process parameters, along with white matter structural integrity and neurofilament expression were determined by quantitative immunohistochemistry. Linear mixed effects regression analyses for strain and strain rate with the employed outcome measures were used to ascertain how well immediate biomechanics could explain MRI and histology changes. The spatial pattern of mechanical strain and strain rate in the injured cortex shows good agreement with the probability maps of focal lesions derived from volumetric MRI. Diffusion metrics showed abnormalities in the corpus callosum, indicating white matter changes in the segments subjected to high strain, as predicted by the model. The same segments also exhibited a severity-dependent increase in glia cell density, white matter thinning and reduced neurofilament expression. Linear mixed effects regression analyses showed that mechanical strain and strain rate were significant predictors of in vivo MRI and histology changes. Specifically, strain and strain rate respectively explained 33% and 28% of the reduction in fractional anisotropy, 51% and 29% of the change in neurofilament expression and 51% and 30% of microglia density changes. The work provides evidence that strain and strain rate in the first milliseconds after injury are important factors in determining patterns of glial and axonal injury and serve as experimental validators of our computational model of traumatic brain injury. Our results provide support for the use of this model in understanding the relationship of biomechanics and neuropathology and can guide the development of head protection systems, such as airbags and helmets.
Detecting axonal injury in individual patients after traumatic brain injury
Amy E Jolly, Maria B?l?e?, Adriana Azor, Daniel Friedland, Stefano Sandrone ...
doi : 10.1093/brain/awaa372
Brain, Volume 144, Issue 1, January 2021, Pages 92–113
Poor outcomes after traumatic brain injury (TBI) are common yet remain difficult to predict. Diffuse axonal injury is important for outcomes, but its assessment remains limited in the clinical setting. Currently, axonal injury is diagnosed based on clinical presentation, visible damage to the white matter or via surrogate markers of axonal injury such as microbleeds. These do not accurately quantify axonal injury leading to misdiagnosis in a proportion of patients. Diffusion tensor imaging provides a quantitative measure of axonal injury in vivo, with fractional anisotropy often used as a proxy for white matter damage. Diffusion imaging has been widely used in TBI but is not routinely applied clinically. This is in part because robust analysis methods to diagnose axonal injury at the individual level have not yet been developed. Here, we present a pipeline for diffusion imaging analysis designed to accurately assess the presence of axonal injury in large white matter tracts in individuals. Average fractional anisotropy is calculated from tracts selected on the basis of high test-retest reliability, good anatomical coverage and their association to cognitive and clinical impairments after TBI. We test our pipeline for common methodological issues such as the impact of varying control sample sizes, focal lesions and age-related changes to demonstrate high specificity, sensitivity and test-retest reliability. We assess 92 patients with moderate-severe TBI in the chronic phase (?6 months post-injury), 25 patients in the subacute phase (10 days to 6 weeks post-injury) with 6-month follow-up and a large control cohort (n?=?103). Evidence of axonal injury is identified in 52% of chronic and 28% of subacute patients. Those classified with axonal injury had significantly poorer cognitive and functional outcomes than those without, a difference not seen for focal lesions or microbleeds. Almost a third of patients with unremarkable standard MRIs had evidence of axonal injury, whilst 40% of patients with visible microbleeds had no diffusion evidence of axonal injury. More diffusion abnormality was seen with greater time since injury, across individuals at various chronic injury times and within individuals between subacute and 6-month scans. We provide evidence that this pipeline can be used to diagnose axonal injury in individual patients at subacute and chronic time points, and that diffusion MRI provides a sensitive and complementary measure when compared to susceptibility weighted imaging, which measures diffuse vascular injury. Guidelines for the implementation of this pipeline in a clinical setting are discussed.
Abnormal dorsal attention network activation in memory impairment after traumatic brain injury
Emma-Jane Mallas, Sara De Simoni, Gregory Scott, Amy E Jolly, Adam Hampshire ...
doi : 10.1093/brain/awaa380
Brain, Volume 144, Issue 1, January 2021, Pages 114–127
Memory impairment is a common, disabling effect of traumatic brain injury. In healthy individuals, successful memory encoding is associated with activation of the dorsal attention network as well as suppression of the default mode network. Here, in traumatic brain injury patients we examined whether: (i) impairments in memory encoding are associated with abnormal brain activation in these networks; (ii) whether changes in this brain activity predict subsequent memory retrieval; and (iii) whether abnormal white matter integrity underpinning functional networks is associated with impaired subsequent memory. Thirty-five patients with moderate-severe traumatic brain injury aged 23–65 years (74% males) in the post-acute/chronic phase after injury and 16 healthy control subjects underwent functional MRI during performance of an abstract image memory encoding task. Diffusion tensor imaging was used to assess structural abnormalities across patient groups compared to 28 age-matched healthy controls. Successful memory encoding across all participants was associated with activation of the dorsal attention network, the ventral visual stream and medial temporal lobes. Decreased activation was seen in the default mode network. Patients with preserved episodic memory demonstrated increased activation in areas of the dorsal attention network. Patients with impaired memory showed increased left anterior prefrontal activity. White matter microstructure underpinning connectivity between core nodes of the encoding networks was significantly reduced in patients with memory impairment. Our results show for the first time that patients with impaired episodic memory show abnormal activation of key nodes within the dorsal attention network and regions regulating default mode network activity during encoding. Successful encoding was associated with an opposite direction of signal change between patients with and without memory impairment, suggesting that memory encoding mechanisms could be fundamentally altered in this population. We demonstrate a clear relationship between functional networks activated during encoding and underlying abnormalities within the structural connectome in patients with memory impairment. We suggest that encoding failures in this group are likely due to failed control of goal-directed attentional resources.
Vestibular agnosia in traumatic brain injury and its link to imbalance
Elena Calzolari, Mariya Chepisheva, Rebecca M Smith, Mohammad Mahmud, Peter J Hellyer ...
doi : 10.1093/brain/awaa386
Brain, Volume 144, Issue 1, January 2021, Pages 128–143
Vestibular dysfunction, causing dizziness and imbalance, is a common yet poorly understood feature in patients with TBI. Damage to the inner ear, nerve, brainstem, cerebellum and cerebral hemispheres may all affect vestibular functioning, hence, a multi-level assessment—from reflex to perception—is required. In a previous report, postural instability was the commonest neurological feature in ambulating acute patients with TBI. During ward assessment, we also frequently observe a loss of vertigo sensation in patients with acute TBI, common inner ear conditions and a related vigorous vestibular-ocular reflex nystagmus, suggesting a ‘vestibular agnosia’. Patients with vestibular agnosia were also more unbalanced; however, the link between vestibular agnosia and imbalance was confounded by the presence of inner ear conditions. We investigated the brain mechanisms of imbalance in acute TBI, its link with vestibular agnosia, and potential clinical impact, by prospective laboratory assessment of vestibular function, from reflex to perception, in patients with preserved peripheral vestibular function. Assessment included: vestibular reflex function, vestibular perception by participants’ report of their passive yaw rotations in the dark, objective balance via posturography, subjective symptoms via questionnaires, and structural neuroimaging. We prospectively screened 918 acute admissions, assessed 146 and recruited 37. Compared to 37 matched controls, patients showed elevated vestibular-perceptual thresholds (patients 12.92°/s versus 3.87°/s) but normal vestibular-ocular reflex thresholds (patients 2.52°/s versus 1.78°/s). Patients with elevated vestibular-perceptual thresholds [3 standard deviations (SD) above controls’ average], were designated as having vestibular agnosia, and displayed worse posturography than non-vestibular-agnosia patients, despite no difference in vestibular symptom scores. Only in patients with impaired postural control (3 SD above controls’ mean), whole brain diffusion tensor voxel-wise analysis showed elevated mean diffusivity (and trend lower fractional anisotropy) in the inferior longitudinal fasciculus in the right temporal lobe that correlated with vestibular agnosia severity. Thus, impaired balance and vestibular agnosia are co-localized to the inferior longitudinal fasciculus in the right temporal lobe. Finally, a clinical audit showed a sevenfold reduction in clinician recognition of a common peripheral vestibular condition (benign paroxysmal positional vertigo) in acute patients with clinically apparent vestibular agnosia. That vestibular agnosia patients show worse balance, but without increased dizziness symptoms, explains why clinicians may miss treatable vestibular diagnoses in these patients. In conclusion, vestibular agnosia mediates imbalance in traumatic brain injury both directly via white matter tract damage in the right temporal lobe, and indirectly via reduced clinical recognition of common, treatable vestibular diagnoses.
Acute and non-resolving inflammation associate with oxidative injury after human spinal cord injury
Tobias Zrzavy, Carmen Schwaiger, Isabella Wimmer, Thomas Berger, Jan Bauer ...
doi : 10.1093/brain/awaa360
Brain, Volume 144, Issue 1, January 2021, Pages 144–161
Traumatic spinal cord injury is a devastating insult followed by progressive cord atrophy and neurodegeneration. Dysregulated or non-resolving inflammatory processes can disturb neuronal homeostasis and drive neurodegeneration. Here, we provide an in-depth characterization of innate and adaptive inflammatory responses as well as oxidative tissue injury in human traumatic spinal cord injury lesions compared to non-traumatic control cords. In the lesion core, microglia were rapidly lost while intermediate (co-expressing pro- as well as anti-inflammatory molecules) blood-borne macrophages dominated. In contrast, in the surrounding rim, TMEM119+ microglia numbers were maintained through local proliferation and demonstrated a predominantly pro-inflammatory phenotype. Lymphocyte numbers were low and mainly consisted of CD8+ T cells. Only in a subpopulation of patients, CD138+/IgG+ plasma cells were detected, which could serve as candidate cellular sources for a developing humoral immunity. Oxidative neuronal cell body and axonal injury was visualized by intracellular accumulation of amyloid precursor protein (APP) and oxidized phospholipids (e06) and occurred early within the lesion core and declined over time. In contrast, within the surrounding rim, pronounced APP+/e06+ axon-dendritic injury of neurons was detected, which remained significantly elevated up to months/years, thus providing mechanistic evidence for ongoing neuronal damage long after initial trauma. Dynamic and sustained neurotoxicity after human spinal cord injury might be a substantial contributor to (i) an impaired response to rehabilitation; (ii) overall failure of recovery; or (iii) late loss of recovered function (neuro-worsening/degeneration).
Neuregulin-1 beta 1 is implicated in pathogenesis of multiple sclerosis
Hardeep Kataria, Christopher G Hart, Arsalan Alizadeh, Michael Cossoy, Deepak K Kaushik ...
doi : 10.1093/brain/awaa385
Brain, Volume 144, Issue 1, January 2021, Pages 162–185
Multiple sclerosis is characterized by immune mediated neurodegeneration that results in progressive, life-long neurological and cognitive impairments. Yet, the endogenous mechanisms underlying multiple sclerosis pathophysiology are not fully understood. Here, we provide compelling evidence that associates dysregulation of neuregulin-1 beta 1 (Nrg-1?1) with multiple sclerosis pathogenesis and progression. In the experimental autoimmune encephalomyelitis model of multiple sclerosis, we demonstrate that Nrg-1?1 levels are abated within spinal cord lesions and peripherally in the plasma and spleen during presymptomatic, onset and progressive course of the disease. We demonstrate that plasma levels of Nrg-1?1 are also significantly reduced in individuals with early multiple sclerosis and is positively associated with progression to relapsing-remitting multiple sclerosis. The functional impact of Nrg-1?1 downregulation preceded disease onset and progression, and its systemic restoration was sufficient to delay experimental autoimmune encephalomyelitis symptoms and alleviate disease burden. Intriguingly, Nrg-1?1 therapy exhibited a desirable and extended therapeutic time window of efficacy when administered prophylactically, symptomatically, acutely or chronically. Using in vivo and in vitro assessments, we identified that Nrg-1?1 treatment mediates its beneficial effects in EAE by providing a more balanced immune response. Mechanistically, Nrg-1?1 moderated monocyte infiltration at the blood-CNS interface by attenuating chondroitin sulphate proteoglycans and MMP9. Moreover, Nrg-1?1 fostered a regulatory and reparative phenotype in macrophages, T helper type 1 (Th1) cells and microglia in the spinal cord lesions of EAE mice. Taken together, our new findings in multiple sclerosis and experimental autoimmune encephalomyelitis have uncovered a novel regulatory role for Nrg-1?1 early in the disease course and suggest its potential as a specific therapeutic target to ameliorate disease progression and severity.
In vivo gradients of thalamic damage in paediatric multiple sclerosis: a window into pathology
Ermelinda De Meo, Loredana Storelli, Lucia Moiola, Angelo Ghezzi, Pierangelo Veggiotti ...
doi : 10.1093/brain/awaa379
Brain, Volume 144, Issue 1, January 2021, Pages 186–197
The thalamus represents one of the first structures affected by neurodegenerative processes in multiple sclerosis. A greater thalamic volume reduction over time, on its CSF side, has been described in paediatric multiple sclerosis patients. However, its determinants and the underlying pathological changes, likely occurring before this phenomenon becomes measurable, have never been explored. Using a multiparametric magnetic resonance approach, we quantified, in vivo, the different processes that can involve the thalamus in terms of focal lesions, microstructural damage and atrophy in paediatric multiple sclerosis patients and their distribution according to the distance from CSF/thalamus interface and thalamus/white matter interface. In 70 paediatric multiple sclerosis patients and 26 age- and sex-matched healthy controls, we tested for differences in thalamic volume and quantitative MRI metrics—including fractional anisotropy, mean diffusivity and T1/T2-weighted ratio—in the whole thalamus and in thalamic white matter, globally and within concentric bands originating from CSF/thalamus interface. In paediatric multiple sclerosis patients, the relationship of thalamic abnormalities with cortical thickness and white matter lesions was also investigated. Compared to healthy controls, patients had significantly increased fractional anisotropy in whole thalamus (f2 = 0.145; P?=?0.03), reduced fractional anisotropy (f2 = 0.219; P?=?0.006) and increased mean diffusivity (f2 = 0.178; P?=?0.009) in thalamic white matter and a trend towards a reduced thalamic volume (f2 = 0.027; P?=?0.058). By segmenting the whole thalamus and thalamic white matter into concentric bands, in paediatric multiple sclerosis we detected significant fractional anisotropy abnormalities in bands nearest to CSF (f2 = 0.208; P?=?0.002) and in those closest to white matter (f2 range = 0.183–0.369; P range = 0.010–0.046), while we found significant mean diffusivity (f2 range = 0.101–0.369; P range = 0.018–0.042) and T1/T2-weighted ratio (f2 = 0.773; P?=?0.001) abnormalities in thalamic bands closest to CSF. The increase in fractional anisotropy and decrease in mean diffusivity detected at the CSF/thalamus interface correlated with cortical thickness reduction (r range = ?0.27–0.34; P range = 0.004–0.028), whereas the increase in fractional anisotropy detected at the thalamus/white matter interface correlated with white matter lesion volumes (r range = 0.24–0.27; P range = 0.006–0.050). Globally, our results support the hypothesis of heterogeneous pathological processes, including retrograde degeneration from white matter lesions and CSF-mediated damage, leading to thalamic microstructural abnormalities, likely preceding macroscopic tissue loss. Assessing thalamic microstructural changes using a multiparametric magnetic resonance approach may represent a target to monitor the efficacy of neuroprotective strategies early in the disease course.
Quantitative spinal cord MRI in MOG-antibody disease, neuromyelitis optica and multiple sclerosis
Romina Mariano, Silvia Messina, Adriana Roca-Fernandez, Maria I Leite, Yazhuo Kong ...
doi : 10.1093/brain/awaa347
Brain, Volume 144, Issue 1, January 2021, Pages 198–212
Spinal cord involvement is a hallmark feature of multiple sclerosis, neuromyelitis optica with AQP4 antibodies and MOG-antibody disease. In this cross-sectional study we use quantitative spinal cord MRI to better understand these conditions, differentiate them and associate with relevant clinical outcomes. Eighty participants (20 in each disease group and 20 matched healthy volunteers) underwent spinal cord MRI (cervical cord: 3D T1, 3D T2, diffusion tensor imaging and magnetization transfer ratio; thoracic cord: 3D T2), together with disability, pain and fatigue scoring. All participants had documented spinal cord involvement and were at least 6 months post an acute event. MRI scans were analysed using publicly available software. Those with AQP4-antibody disease showed a significant reduction in cervical cord cross-sectional area (P?=?0.038), thoracic cord cross-sectional area (P?=?0.043), cervical cord grey matter (P?=?0.011), magnetization transfer ratio (P???0.001), fractional anisotropy (P?=?0.004) and increased mean diffusivity (P?=?0.008). Those with multiple sclerosis showed significantly increased mean diffusivity (P?=?0.001) and reduced fractional anisotropy (P?=?0.013), grey matter volume (P?=?0.002) and magnetization transfer ratio (P?=?0.011). In AQP4-antibody disease the damage was localized to areas of the cord involved in the acute attack. In multiple sclerosis this relationship with lesions was absent. MOG-antibody disease did not show significant differences to healthy volunteers in any modality. However, when considering only areas involved at the time of the acute attack, a reduction in grey matter volume was found (P?=?0.023). This suggests a predominant central grey matter component to MOG-antibody myelitis, which we hypothesize could be partially responsible for the significant residual sphincter dysfunction. Those with relapsing MOG-antibody disease showed a reduction in cord cross-sectional area compared to those with monophasic disease, even when relapses occurred elsewhere (P?=?0.012). This suggests that relapsing MOG-antibody disease is a more severe phenotype. We then applied a principal component analysis, followed by an orthogonal partial least squares analysis. MOG-antibody disease was discriminated from both AQP4-antibody disease and multiple sclerosis with moderate predictive values. Finally, we assessed the clinical relevance of these metrics using a multiple regression model. Cervical cord cross-sectional area associated with disability scores (B = ?0.07, P?=?0.0440, R2 = 0.20) and cervical cord spinothalamic tract fractional anisotropy associated with pain scores (B = ?19.57, P?=?0.016, R2 = 0.55). No spinal cord metric captured fatigue. This work contributes to our understanding of myelitis in these conditions and highlights the clinical relevance of quantitative spinal cord MRI.
Non-invasive quantification of inflammation, axonal and myelin injury in multiple sclerosis
Simona Schiavi, Maria Petracca, Peng Sun, Lazar Fleysher, Sirio Cocozza ...
doi : 10.1093/brain/awaa381
Brain, Volume 144, Issue 1, January 2021, Pages 213–223
The aim of this study was to determine the feasibility of diffusion basis spectrum imaging in multiple sclerosis at 7 T and to investigate the pathological substrates of tissue damage in lesions and normal-appearing white matter. To this end, 43 patients with multiple sclerosis (24 relapsing-remitting, 19 progressive), and 21 healthy control subjects were enrolled. White matter lesions were classified in T1-isointense, T1-hypointense and black holes. Mean values of diffusion basis spectrum imaging metrics (fibres, restricted and non-restricted fractions, axial and radial diffusivities and fractional anisotropy) were measured from whole brain white matter lesions and from both lesions and normal appearing white matter of the corpus callosum. Significant differences were found between T1-isointense and black holes (P ranging from 0.005 to <0.001) and between lesions’ centre and rim (P?<?0.001) for all the metrics. When comparing the three subject groups in terms of metrics derived from corpus callosum normal appearing white matter and T2-hyperintense lesions, a significant difference was found between healthy controls and relapsing-remitting patients for all metrics except restricted fraction and fractional anisotropy; between healthy controls and progressive patients for all metrics except restricted fraction and between relapsing-remitting and progressive multiple sclerosis patients for all metrics except fibres and restricted fractions (P ranging from 0.05 to <0.001 for all). Significant associations were found between corpus callosum normal-appearing white matter fibres fraction/non-restricted fraction and the Symbol Digit Modality Test (respectively, r?=?0.35, P?=?0.043; r = ?0.35, P?=?0.046), and between black holes radial diffusivity and Expanded Disability Status Score (r?=?0.59, P?=?0.002). We showed the feasibility of diffusion basis spectrum imaging metrics at 7 T, confirmed the role of the derived metrics in the characterization of lesions and normal appearing white matter tissue in different stages of the disease and demonstrated their clinical relevance. Thus, suggesting that diffusion basis spectrum imaging is a promising tool to investigate multiple sclerosis pathophysiology, monitor disease progression and treatment response.
Retinal asymmetry in multiple sclerosis
Axel Petzold, Sharon Y L Chua, Anthony P Khawaja, Pearse A Keane, Peng T Khaw ...
doi : 10.1093/brain/awaa361
Brain, Volume 144, Issue 1, January 2021, Pages 224–235
The diagnosis of multiple sclerosis is based on a combination of clinical and paraclinical tests. The potential contribution of retinal optical coherence tomography (OCT) has been recognized. We tested the feasibility of OCT measures of retinal asymmetry as a diagnostic test for multiple sclerosis at the community level. In this community-based study of 72?120 subjects, we examined the diagnostic potential of the inter-eye difference of inner retinal OCT data for multiple sclerosis using the UK Biobank data collected at 22 sites between 2007 and 2010. OCT reporting and quality control guidelines were followed. The inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD) were calculated for the macular retinal nerve fibre layer (RNFL), ganglion cell inner plexiform layer (GCIPL) complex and ganglion cell complex. Area under the receiver operating characteristic curve (AUROC) comparisons were followed by univariate and multivariable comparisons accounting for a large range of diseases and co-morbidities. Cut-off levels were optimized by ROC and the Youden index. The prevalence of multiple sclerosis was 0.0023 [95% confidence interval (CI) 0.00229–0.00231]. Overall the discriminatory power of diagnosing multiple sclerosis with the IEPD AUROC curve (0.71, 95% CI 0.67–0.76) and IEAD (0.71, 95% CI 0.67–0.75) for the macular GCIPL complex were significantly higher if compared to the macular ganglion cell complex IEPD AUROC curve (0.64, 95% CI 0.59–0.69, P?=?0.0017); IEAD AUROC curve (0.63, 95% CI 0.58–0.68, P?<?0.0001) and macular RNFL IEPD AUROC curve (0.59, 95% CI 0.54–0.63, P?<?0.0001); IEAD AUROC curve (0.55, 95% CI 0.50–0.59, P?<?0.0001). Screening sensitivity levels for the macular GCIPL complex IEPD (4% cut-off) were 51.7% and for the IEAD (4 ?m cut-off) 43.5%. Specificity levels were 82.8% and 86.8%, respectively. The number of co-morbidities was important. There was a stepwise decrease of the AUROC curve from 0.72 in control subjects to 0.66 in more than nine co-morbidities or presence of neuromyelitis optica spectrum disease. In the multivariable analyses greater age, diabetes mellitus, other eye disease and a non-white ethnic background were relevant confounders. For most interactions, the effect sizes were large (partial ?2 > 0.14) with narrow confidence intervals. In conclusion, the OCT macular GCIPL complex IEPD and IEAD may be considered as supportive measurements for multiple sclerosis diagnostic criteria in a young patient without relevant co-morbidity. The metric does not allow separation of multiple sclerosis from neuromyelitis optica. Retinal OCT imaging is accurate, rapid, non-invasive, widely available and may therefore help to reduce need for invasive and more costly procedures. To be viable, higher sensitivity and specificity levels are needed.
Atrophy and cognitive profiles in older adults with temporal lobe epilepsy are similar to mild cognitive impairment
Erik Kaestner, Anny Reyes, Austin Chen, Jun Rao, Anna Christina Macari ...
doi : 10.1093/brain/awaa397
Brain, Volume 144, Issue 1, January 2021, Pages 236–250
Epilepsy incidence and prevalence peaks in older adults yet systematic studies of brain ageing and cognition in older adults with epilepsy remain limited. Here, we characterize patterns of cortical atrophy and cognitive impairment in 73 older adults with temporal lobe epilepsy (>55 years) and compare these patterns to those observed in 70 healthy controls and 79 patients with amnestic mild cognitive impairment, the prodromal stage of Alzheimer’s disease. Patients with temporal lobe epilepsy were recruited from four tertiary epilepsy surgical centres; amnestic mild cognitive impairment and control subjects were obtained from the Alzheimer’s Disease Neuroimaging Initiative database. Whole brain and region of interest analyses were conducted between patient groups and controls, as well as between temporal lobe epilepsy patients with early-onset (age of onset <50 years) and late-onset (>50 years) seizures. Older adults with temporal lobe epilepsy demonstrated a similar pattern and magnitude of medial temporal lobe atrophy to amnestic mild cognitive impairment. Region of interest analyses revealed pronounced medial temporal lobe thinning in both patient groups in bilateral entorhinal, temporal pole, and fusiform regions (all P?<?0.05). Patients with temporal lobe epilepsy demonstrated thinner left entorhinal cortex compared to amnestic mild cognitive impairment (P?=?0.02). Patients with late-onset temporal lobe epilepsy had a more consistent pattern of cortical thinning than patients with early-onset epilepsy, demonstrating decreased cortical thickness extending into the bilateral fusiform (both P?<?0.01). Both temporal lobe epilepsy and amnestic mild cognitive impairment groups showed significant memory and language impairment relative to healthy control subjects. However, despite similar performances in language and memory encoding, patients with amnestic mild cognitive impairment demonstrated poorer delayed memory performances relative to both early and late-onset temporal lobe epilepsy. Medial temporal lobe atrophy and cognitive impairment overlap between older adults with temporal lobe epilepsy and amnestic mild cognitive impairment highlights the risks of growing old with epilepsy. Concerns regarding accelerated ageing and Alzheimer’s disease co-morbidity in older adults with temporal lobe epilepsy suggests an urgent need for translational research aimed at identifying common mechanisms and/or targeting symptoms shared across a broad neurological disease spectrum.
Dendritic pathology, spine loss and synaptic reorganization in human cortex from epilepsy patients
Laura Rossini, Dalia De Santis, Roberta Rosa Mauceri, Chiara Tesoriero, Marina Bentivoglio ...
doi : 10.1093/brain/awaa387
Brain, Volume 144, Issue 1, January 2021, Pages 251–265
Neuronal dendritic arborizations and dendritic spines are crucial for a normal synaptic transmission and may be critically involved in the pathophysiology of epilepsy. Alterations in dendritic morphology and spine loss mainly in hippocampal neurons have been reported both in epilepsy animal models and in human brain tissues from patients with epilepsy. However, it is still unclear whether these dendritic abnormalities relate to the cause of epilepsy or are generated by seizure recurrence. We investigated fine neuronal structures at the level of dendritic and spine organization using Golgi impregnation, and analysed synaptic networks with immunohistochemical markers of glutamatergic (vGLUT1) and GABAergic (vGAT) axon terminals in human cerebral cortices derived from epilepsy surgery. Specimens were obtained from 28 patients with different neuropathologically defined aetiologies: type Ia and type II focal cortical dysplasia, cryptogenic (no lesion) and temporal lobe epilepsy with hippocampal sclerosis. Autoptic tissues were used for comparison. Three-dimensional reconstructions of Golgi-impregnated neurons revealed severe dendritic reshaping and spine alteration in the core of the type II focal cortical dysplasia. Dysmorphic neurons showed increased dendritic complexity, reduction of dendritic spines and occasional filopodia-like protrusions emerging from the soma. Surprisingly, the intermingled normal-looking pyramidal neurons also showed severe spine loss and simplified dendritic arborization. No changes were observed outside the dysplasia (perilesional tissue) or in neocortical postsurgical tissue obtained in the other patient groups. Immunoreactivities of vGLUT1 and vGAT showed synaptic reorganization in the core of type II dysplasia characterized by the presence of abnormal perisomatic baskets around dysmorphic neurons, in particular those with filopodia-like protrusions, and changes in vGLUT1/vGAT expression. Ultrastructural data in type II dysplasia highlighted the presence of altered neuropil engulfed by glial processes. Our data indicate that the fine morphological aspect of neurons and dendritic spines are normal in epileptogenic neocortex, with the exception of type II dysplastic lesions. The findings suggest that the mechanisms leading to this severe form of cortical malformation interfere with the normal dendritic arborization and synaptic network organization. The data argue against the concept that long-lasting epilepsy and seizure recurrence per se unavoidably produce a dendritic pathology.
18F-AV-1451 positron emission tomography in neuropathological substrates of corticobasal syndrome
Anna E Goodheart, Joseph J Locascio, Wesley R Samore, Jessica A Collins, Michael Brickhouse ...
doi : 10.1093/brain/awaa383
Brain, Volume 144, Issue 1, January 2021, Pages 266–277
Multiple neuropathological processes can manifest in life as a corticobasal syndrome. We sought to relate retention of the tau-PET tracer 18F-AV-1451 and structural magnetic resonance measures of regional atrophy to clinical features in clinically diagnosed and neuropathologically confirmed cases of corticobasal syndrome and to determine whether these vary with the underlying neuropathological changes. In this observational, cross-sectional study, 11 subjects (eight female and three male, median age 72 years) with corticobasal syndrome underwent structural MRI, tau-PET with 18F-AV-1451, amyloid-PET with 11C-Pittsburgh compound B, detailed clinical examinations and neuropsychological testing. Of the 11, three had evidence of high amyloid burden consistent with Alzheimer’s disease while eight did not. Neuropathological evaluations were acquired in six cases. Mixed effects general linear models were used to compare 18F-AV-1451 retention and atrophy in amyloid-negative corticobasal syndrome cases to 32 age-matched healthy control subjects and to relate cortical and subcortical 18F-AV-1451 retention and atrophy to clinical features. Subjects without amyloid, including three with pathologically confirmed corticobasal degeneration, showed greater regional 18F-AV-1451 retention and associated regional atrophy in areas commonly associated with corticobasal degeneration pathology than healthy control subjects [retention was higher compared to healthy controls (P?=?0.0011), driven especially by the precentral gyrus (P?=?0.011) and pallidum (P?<?0.0001), and greater atrophy was seen in subjects compared to control subjects (P?=?0.0004)]. Both 18F-AV-1451 retention and atrophy were greater in the clinically more affected hemisphere [on average, retention was 0.173 standardized uptake value ratio units higher on the more affected side (95% confidence interval, CI 0.11–0.24, P?<?0.0001), and volume was 0.719 lower on the more affected side (95% CI 0.35–1.08, P?=?0.0001)]. 18F-AV-1451 retention was greater in subcortical than in cortical regions, P?<?0.0001. In contrast to these findings, subjects with amyloid-positive corticobasal syndrome, including two neuropathologically confirmed cases of Alzheimer’s disease, demonstrated greater and more widespread 18F-AV-1451 retention and regional atrophy than observed in the amyloid-negative cases. There was thalamic 18F-AV-1451 retention but minimal cortical and basal ganglia uptake in a single corticobasal syndrome subject without neuropathological evidence of tau pathology, likely representing non-specific signal. Asymmetric cortical and basal ganglia 18F-AV-1451 retention consonant with the clinical manifestations characterize corticobasal syndrome due to corticobasal degeneration, whereas the cortical retention in cases associated with Alzheimer’s disease is greater and more diffuse.
Dopaminergic imaging and clinical predictors for phenoconversion of REM sleep behaviour disorder
Dario Arnaldi, Andrea Chincarini, Michele T Hu, Karel Sonka, Bradley Boeve ...
doi : 10.1093/brain/awaa365
Brain, Volume 144, Issue 1, January 2021, Pages 278–287
This is an international multicentre study aimed at evaluating the combined value of dopaminergic neuroimaging and clinical features in predicting future phenoconversion of idiopathic REM sleep behaviour (iRBD) subjects to overt synucleinopathy. Nine centres sent 123I-FP-CIT-SPECT data of 344 iRBD patients and 256 controls for centralized analysis. 123I-FP-CIT-SPECT images were semiquantified using DaTQUANTTM, obtaining putamen and caudate specific to non-displaceable binding ratios (SBRs). The following clinical variables were also analysed: (i) Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale, motor section score; (ii) Mini-Mental State Examination score; (iii) constipation; and (iv) hyposmia. Kaplan-Meier survival analysis was performed to estimate conversion risk. Hazard ratios for each variable were calculated with Cox regression. A generalized logistic regression model was applied to identify the best combination of risk factors. Bayesian classifier was used to identify the baseline features predicting phenoconversion to parkinsonism or dementia. After quality check of the data, 263 iRBD patients (67.6?±?7.3 years, 229 males) and 243 control subjects (67.2?±?10.1 years, 110 males) were analysed. Fifty-two (20%) patients developed a synucleinopathy after average follow-up of 2 years. The best combination of risk factors was putamen dopaminergic dysfunction of the most affected hemisphere on imaging, defined as the lower value between either putamina (P?<?0.000001), constipation, (P?<?0.000001) and age over 70 years (P?=?0.0002). Combined features obtained from the generalized logistic regression achieved a hazard ratio of 5.71 (95% confidence interval 2.85–11.43). Bayesian classifier suggested that patients with higher Mini-Mental State Examination score and lower caudate SBR asymmetry were more likely to develop parkinsonism, while patients with the opposite pattern were more likely to develop dementia. This study shows that iRBD patients older than 70 with constipation and reduced nigro-putaminal dopaminergic function are at high risk of short-term phenoconversion to an overt synucleinopathy, providing an effective stratification approach for future neuroprotective trials. Moreover, we provide cut-off values for the significant predictors of phenoconversion to be used in single subjects.
Alzheimer’s disease brain-derived extracellular vesicles spread tau pathology in interneurons
Zhi Ruan, Dhruba Pathak, Srinidhi Venkatesan Kalavai, Asuka Yoshii-Kitahara, Satoshi Muraoka ...
doi : 10.1093/brain/awaa376
Brain, Volume 144, Issue 1, January 2021, Pages 288–309
Extracellular vesicles are highly transmissible and play critical roles in the propagation of tau pathology, although the underlying mechanism remains elusive. Here, for the first time, we comprehensively characterized the physicochemical structure and pathogenic function of human brain-derived extracellular vesicles isolated from Alzheimer’s disease, prodromal Alzheimer’s disease, and non-demented control cases. Alzheimer’s disease extracellular vesicles were significantly enriched in epitope-specific tau oligomers in comparison to prodromal Alzheimer’s disease or control extracellular vesicles as determined by dot blot and atomic force microscopy. Alzheimer’s disease extracellular vesicles were more efficiently internalized by murine cortical neurons, as well as more efficient in transferring and misfolding tau, than prodromal Alzheimer’s disease and control extracellular vesicles in vitro. Strikingly, the inoculation of Alzheimer’s disease or prodromal Alzheimer’s disease extracellular vesicles containing only 300 pg of tau into the outer molecular layer of the dentate gyrus of 18-month-old C57BL/6 mice resulted in the accumulation of abnormally phosphorylated tau throughout the hippocampus by 4.5 months, whereas inoculation of an equal amount of tau from control extracellular vesicles, isolated tau oligomers, or fibrils from the same Alzheimer’s disease donor showed little tau pathology. Furthermore, Alzheimer’s disease extracellular vesicles induced misfolding of endogenous tau in both oligomeric and sarkosyl-insoluble forms in the hippocampal region. Unexpectedly, phosphorylated tau was primarily accumulated in glutamic acid decarboxylase 67 (GAD67) GABAergic interneurons and, to a lesser extent, glutamate receptor 2/3-positive excitatory mossy cells, showing preferential extracellular vesicle-mediated GABAergic interneuronal tau propagation. Whole-cell patch clamp recordings of CA1 pyramidal cells showed significant reduction in the amplitude of spontaneous inhibitory post-synaptic currents. This was accompanied by reductions in c-fos+ GAD67+ neurons and GAD67+ neuronal puncta surrounding pyramidal neurons in the CA1 region, confirming reduced GABAergic transmission in this region. Our study posits a novel mechanism for the spread of tau in hippocampal GABAergic interneurons via brain-derived extracellular vesicles and their subsequent neuronal dysfunction.
Untangling the association of amyloid-? and tau with synaptic and axonal loss in Alzheimer’s disease
Joana B Pereira, Shorena Janelidze, Rik Ossenkoppele, Hlin Kvartsberg, Ann Brinkmalm ...
doi : 10.1093/brain/awaa395
Brain, Volume 144, Issue 1, January 2021, Pages 310–324
It is currently unclear how amyloid-? and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer’s disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-? and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer’s disease i.e. in amyloid-?-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-? pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-? and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-? and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.
Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum
Alexis Moscoso, Michel J Grothe, Nicholas J Ashton, Thomas K Karikari, Juan Lantero Rodriguez ...
doi : 10.1093/brain/awaa399
Brain, Volume 144, Issue 1, January 2021, Pages 325–339
Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer’s disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer’s disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer’s disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer’s disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n?=?1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-? PET scan at baseline. A subset of participants (n?=?864) also had measures of amyloid-?1–42 and p-tau181 levels in CSF, and another subset (n?=?298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-? pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer’s disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-? markers reached abnormal levels, with greater rates of change correlating with increased amyloid-? pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-? pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-? were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer’s disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ?6.5 and 5.7 years after CSF and PET measures of amyloid-?, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-? pathology and with prospective Alzheimer’s disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer’s disease.
How do the blind ‘see’? The role of spontaneous brain activity in self-generated perception
Avital Hahamy, Meytal Wilf, Boris Rosin, Marlene Behrmann, Rafael Malach
doi : 10.1093/brain/awaa384
Brain, Volume 144, Issue 1, January 2021, Pages 340–353
Spontaneous activity of the human brain has been well documented, but little is known about the functional role of this ubiquitous neural phenomenon. It has previously been hypothesized that spontaneous brain activity underlies unprompted (internally generated) behaviour. We tested whether spontaneous brain activity might underlie internally-generated vision by studying the cortical visual system of five blind/visually-impaired individuals who experience vivid visual hallucinations (Charles Bonnet syndrome). Neural populations in the visual system of these individuals are deprived of external input, which may lead to their hyper-sensitization to spontaneous activity fluctuations. To test whether these spontaneous fluctuations can subserve visual hallucinations, the functional MRI brain activity of participants with Charles Bonnet syndrome obtained while they reported their hallucinations (spontaneous internally-generated vision) was compared to the: (i) brain activity evoked by veridical vision (externally-triggered vision) in sighted controls who were presented with a visual simulation of the hallucinatory streams; and (ii) brain activity of non-hallucinating blind controls during visual imagery (cued internally-generated vision). All conditions showed activity spanning large portions of the visual system. However, only the hallucination condition in the Charles Bonnet syndrome participants demonstrated unique temporal dynamics, characterized by a slow build-up of neural activity prior to the reported onset of hallucinations. This build-up was most pronounced in early visual cortex and then decayed along the visual hierarchy. These results suggest that, in the absence of external visual input, a build-up of spontaneous fluctuations in early visual cortex may activate the visual hierarchy, thereby triggering the experience of vision.
Assessing the NOTCH2NLC GGC expansion in essential tremor patients from eastern China
Yaping Yan, Lanxiao Cao, Luyan Gu, Bo Zhang, Congying Xu ...
doi : 10.1093/brain/awaa348
Brain, Volume 144, Issue 1, January 2021, Page e1
We read the recent paper by Sun et al. (2020) which showed that abnormal GGC repeat expansion in the NOTCH2NLC gene with a detection rate of 5.58% was found in a cohort of essential tremor patients from China. Expanded GGC repeats within human-specific NOTCH2NLC was initially identified as the probable pathogenic genetic cause of neuronal intranuclear inclusion disease (NIID), a rare multisystem neurodegenerative disease characterized by eosinophilic intranuclear inclusions existing in the nervous system and multiple visceral organs (Sone et al., 2019). Interestingly, the expanded GGC repeats in NOTCH2NLC were also detected in affected individuals with other neurodegenerative phenotypes, like parkinsonism, Alzheimer’s...
Reply: Assessing the NOTCH2NLC GGC expansion in essential tremor patients from eastern China
Qi-Ying Sun, Ji-Feng Guo, Bei-Sha Tang
doi : 10.1093/brain/awaa349
Brain, Volume 144, Issue 1, January 2021, Page e2
We read with great interest the letter of Yan et al. (2020), and we are thankful for their attention dedicated to our recently published work (Sun et al., 2020), in which we identified that abnormal GGC repeat expansions in the 5? region of NOTCH2NLC gene were co-segregated with disease in 11 essential tremor families from 197 Chinese pedigrees clinically diagnosed with essential tremor, by using a comprehensive strategy combining linkage analysis, whole-exome sequencing, long-read whole-genome sequencing, repeat-primed PCR (RP-PCR) and GC-rich PCR (GC-PCR). To evaluate the association between NOTCH2NLC GGC repeat expansion and essential tremor further, Yan et al. screened...
PSAP intronic variants around saposin D domain and Parkinson’s disease
Zhi-Hao Lin, Yang Ruan, Nai-Jia Xue, Yi Fang, Jia-Li Pu ...
doi : 10.1093/brain/awaa354
Brain, Volume 144, Issue 1, January 2021, Page e3
We read with great interest the article by Yutaka Oji and colleagues published in Brain (Oji et al., 2020), in which they identified three pathogenic mutations in the saposin D domain of prosaposin (PSAP) in three families with autosomal dominant Parkinson’s disease. Subsequently, they sequenced the saposin D domain and all adjacent introns of PSAP in patients with sporadic Parkinson’s disease from Japan and Taiwan. There were no exonic variants in their population; however, they detected six intronic variants (rs3747860, rs11000016, rs4747203, rs142614739, rs749823, rs885828) in the Japanese cohort, which had statistically significant differences compared to the east Asian population...
Reply: PSAP intronic variants around saposin D domain and Parkinson’s disease
Yutaka Oji, Taku Hatano, Manabu Funayama, Nobutaka Hattori
doi : 10.1093/brain/awaa356
Brain, Volume 144, Issue 1, January 2021, Page e4
We thank Lin et al. (2020) for their interest in our article and their analysis of PSAP intronic variants using an eastern Chinese cohort study of sporadic Parkinson’s disease and sex-, age-, and ethnicity-matched healthy controls.
Lesion network mapping: where do we go from here?
Aaron D Boes
doi : 10.1093/brain/awaa350
Brain, Volume 144, Issue 1, January 2021, Page e5
I read with great interest the recent article by Salvalaggio and colleagues in Brain, ‘Post- stroke deficit prediction from lesion and indirect structural and functional disconnection’ (Salvalaggio et al., 2020). In this article, the authors evaluated the relative value of lesion location and lesion-associated networks in predicting behavioural deficits in a sample of 132 individuals with new-onset stroke. The authors compared three different approaches for estimating the impact of the lesion in disrupting a broader network of structures that extend beyond the anatomical boundaries of the lesion: one relying on each subject’s own functional connectivity MRI data, a second that relied...
Reply: Lesion network mapping: where do we go from here?
Alessandro Salvalaggio, Lorenzo Pini, Michele De Filippo De Grazia, Michel Thiebaut De Schotten, Marco Zorzi ...
doi : 10.1093/brain/awaa351
Brain, Volume 144, Issue 1, January 2021, Page e6
In a letter to the editor, Dr Aaron Boes (2020) commented on our study (Salvalaggio et al., 2020) in which we compared different structural and functional MRI methods to predict behavioural deficits in a large cohort of subacute stroke patients (Corbetta et al., 2015). Specifically, we used lesion symptom mapping, i.e. the behavioural prediction based on lesion location and volume, as a baseline for three methods measuring brain network(s) disconnection. Two methods assessed disconnection ‘indirectly’ using the lesion to generate maps of altered connectivity based on healthy control datasets (7 T ‘Human Connectome Project’ datasets: http://www.humanconnectome.org/study/hcp-young-adult/; Vu et...
Tissue-resident CD8+ memory T cells in multiple sclerosis
Reinhard Hohlfeld, Eduardo Beltran, Lisa Ann Gerdes, Klaus Dornmair
doi : 10.1093/brain/awaa352
Brain, Volume 144, Issue 1, January 2021, Page e7
We read with interest the article by Fransen et al. (2020) in Brain. The authors studied the role of CD8+ T cells in a large cohort of chronic multiple sclerosis autopsy cases from the Netherlands Brain Bank. In all white matter samples, CD8+ T cells were conspicuous in the perivascular space (PVS; Virchow-Robin space). At the level of postcapillary venules where lymphocyte extravasation takes place, this specialized compartment is bordered by the endothelial basement membrane on the vascular side, and the glia limitans on the brain parenchymal side (Engelhardt et al., 2017). A large proportion of the...
Reply: Tissue-resident CD8+ memory T cells in multiple sclerosis
Joost Smolders, Nina L Fransen, Inge Huitinga, J?rg Hamann
doi : 10.1093/brain/awaa353
Brain, Volume 144, Issue 1, January 2021, Page e8
We thank Hohlfield et al. (2020) for their appreciation and discussion of our work. Our data provide an extension of the data earlier reported by Machado-Santos et al. (2018). We showed that white matter perivascular CD8+ T cells of multiple sclerosis donors co-expressed CD69 with variable levels of CD103 and CD49a, PD-1, and CXCR6 (Fransen et al., 2020), characterizing them as tissue-resident memory T (TRM) cells (Kumar et al., 2017).
Association analysis of PSAP variants in Parkinson’s disease patients
Yin Xia Chao, Bernett Lee, Ebonne Yulin Ng, Michelle Mulan Lian, Elaine Guo Yan Chew ...
doi : 10.1093/brain/awaa358
Brain, Volume 144, Issue 1, January 2021, Page e9
We read with interest the recent report by Oji and colleagues who identified three exonic mutations in the prosaposin (PSAP) gene from three families with Parkinson’s disease. In addition, a case control study involving 440 Japanese and 705 patients with sporadic Parkinson’s disease from Taiwan demonstrated that that intronic variants (rs4747203 and rs885828) located in the PSAP saposin D domain increased the risk of Parkinson’s disease (Oji et al., 2020). Since the sample size for the association study was relatively small, and independent replication is a litmus test for the reproducibility of the findings, we investigated for exome and intronic...
Reply: Association analysis of PSAP variants in Parkinson’s disease patients
Yutaka Oji, Taku Hatano, Manabu Funayama, Nobutaka Hattori
doi : 10.1093/brain/awaa359
Brain, Volume 144, Issue 1, January 2021, Page e10
Chao and colleagues (2020) analysed 1714 Parkinson’s disease patients with 2048 age- and gender-matched healthy controls, which was much larger than the cohorts in the article by Oji et al. (2020). In their analysis, the two intronic variants (rs4747203 and rs885828), which were considered to be the risk variants in the Parkinson’s disease cohort in the analysis by Oji et al., were not identified as having any significant association with Parkinson's disease. Additionally, the authors found four novel and nine known PSAP variants but no significant differences existed in the genotype distribution between patients with Parkinson’s disease and control subjects. The three PSAP...
A novel de novo SPTAN1 nonsense variant causes hereditary motor neuropathy in a Chinese family
Hai-Lin Dong, Lei Chen, Zhi-Ying Wu
doi : 10.1093/brain/awaa357
Brain, Volume 144, Issue 1, January 2021, Page e11
It was with great interest that we read the article published by Beijer et al. (2019) about autosomal dominant distal hereditary motor neuropathy (dHMN) caused by pathogenic variants in the ?II-spectrin gene (SPTAN1; OMIM 182810). Using whole exome sequencing (WES) or whole genome sequencing (WGS), the authors identified three nonsense heterozygous mutations, c.415C>T (p.Arg139*), c.4615C>T (p.Gln1539*) and c.6460C>T (p.Gln2154*), in three dHMN families. Although the penetrance and severity of the disease were highly variable, most affected patients had juvenile onset of axonal motor neuropathy characterized by lower limb weakness and muscle atrophy. Nerve conduction studies supported a distal axonal motor predominant neuropathy.
Corrigendum to: MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14?468 individuals worldwide
doi : 10.1093/brain/awaa328
Brain, Volume 144, Issue 1, January 2021, Page e12
Vishnu M. Bashyam, Guray Erus, Jimit Doshi, Mohamad Habes, Ilya Nasralah, Monica Truelove-Hill, Dhivya Srinivasan, Liz Mamourian, Raymond Pomponio, Yong Fan, Lenore J. Launer, Colin L. Masters, Paul Maruff, Chuanjun Zhuo, Henry V?lzke, Sterling C. Johnson, Jurgen Fripp, Nikolaos Koutsouleris, Theodore D. Satterthwaite, Daniel Wolf, Raquel E. Gur, Ruben C. Gur, John Morris, Marilyn S. Albert, Hans J. Grabe, Susan Resnick, R. Nick Bryan, David A. Wolk, Haochang Shou, Christos Davatzikos on behalf of the ISTAGING Consortium, the Preclinical Alzheimer’s disease Consortium, ADNI, and CARDIA studies. MRI signatures of brain age and disease over the lifespan based on a deep brain network and 14 468...
Erratum to: Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders
doi : 10.1093/brain/awaa366
Brain, Volume 144, Issue 1, January 2021, Page e13
Niccol? E. Mencacci, Regina Reynolds, Sonia Garcia Ruiz, Jana Vandrovcova, Paola Forabosco, Alvaro S?nchez-Ferrer, Viola Volpato, UK Brain Expression Consortium, International Parkinson’s Disease Genomics Consortium, Michael E. Weale, Kailash P. Bhatia, Caleb Webber, John Hardy, Juan A. Bot?a, Mina Ryten. Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders. Brain 2020; 143: 2771–2787. doi:10.1093/brain/awaa217.
