Heterogeneity of neuroanatomical patterns in prodromal Alzheimer’s disease: links to cognition, progression and biomarkers
See Coulthard and Knight (doi:10.1093/aww335) for a scientific commentary on this article.
Individuals with clinical diagnoses of mild cognitive impairment and Alzheimer’s disease display phenotypic heterogeneity. Using a state-of-the-art neuroanatomical dimensional clustering approach, Dong and Toledo et al. identify four different subgroups of patients. These delineated groups are associated with distinct cognitive profiles, CSF biomarkers, and patterns of atrophy and progression.
Bauer et al. show that seizures self-terminate through a mechanism that also determines the length of the postictal period. Using a computational model validated with EEG data, they show that the slowing of clonic movements at the end of seizures is related to the duration of postictal generalised EEG suppression.
See King et al. (doi:10.1093/aww348) for a scientific commentary on this article.
Mapping the symptoms of cerebellar disease to specific cerebellar lobules may clarify structure-function relationships. Kansal et al. link the anterior lobe of the cerebellum to motor skills and memory, and the posterior lobules to language, memory and executive function, facilitating future studies of mechanisms underlying clinical dysfunction in cerebellar disease.
Interleukin-2 stimulates regulatory T cells (Treg). Alves et al. report that IL-2 levels are decreased in Alzheimer's disease, and that treatment with AAV-IL2 induces systemic/brain Treg expansion in an Alzheimer's disease mouse model. The mice show reduced hippocampal pathology and improved synaptic plasticity and memory, suggesting therapeutic benefits of IL-2.
Does resting tremor in Parkinson's disease reflect dopaminergic dysfunction? Using fMRI network analyses, Dirkx et al. report that dopamine reduces tremor by selectively inhibiting the cerebellar thalamus and that this effect correlates with the clinical dopamine response. Dopaminergic projections to the cerebellar thalamus may control tremulous activity in this region.
Relationships between flortaucipir PET tau binding and amyloid burden, clinical diagnosis, age and cognition
The relation between tau, amyloid and cognition has yet to be fully defined. Using flortaucipir (18F-AV-1451) PET tau imaging in patients with varying amyloid and cognitive status, Pontecorvo et al. suggest that development of tau beyond the mesial temporal lobe is associated with, and may be dependent on, amyloid accumulation.
Network analysis is increasingly used to study the human brain. Chapeton et al. use intracranial EEG to identify effective connections in the brain that exhibit consistent timing across multiple temporal scales. Functional networks constructed from these connections are stable and exhibit a preferred direction for information propagation.
See Saver (doi:10.1093/awx020) for a scientific commentary on this article.
The extent to which CT perfusion imaging variables before and after reperfusion therapy for stroke predict the length of subsequent disability-free life is unclear. Kawano et al. show that saving a millilitre of penumbra translates into benefits equivalent to more than a week of disability-free life.
Distinct binding of PET ligands PBB3 and AV-1451 to tau fibril strains in neurodegenerative tauopathies
Tau proteins form diverse conformers known as strains in Alzheimer's disease and allied disorders. Ono et al. report differential selectivity of two tau PET radioligands, [11C]PBB3 and [18F]AV-1451, for these fibril subspecies, supporting the utility of these imaging agents for pursuing roles of tau strains in the pathogenesis of tauopathies.
The extent to which the tau tracer [18F]AV-1451 can differentiate between tauopathies is unknown. By comparing patients with Alzheimer’s disease and progressive supranuclear palsy (PSP), Passamonti et al. show that [18F]AV-1451 displays greater specificity for Alzheimer-related tau pathology than PSP-related pathology. A machine learning algorithm correctly diagnosed 94% of cases.
Using clinical-pathological data from more than 1,000 individuals, Boyle et al. show that age-related neuropathologies are differentially related to late-life cognitive trajectories. Whereas some contribute to progressive cognitive deterioration, others impair cognition but exert relatively stable effects over time. The findings have implications for preventing and treating late-life cognitive decline.
Dravet syndrome is a catastrophic intractable childhood epilepsy. Using a zebrafish Dravet syndrome model, Griffin et al. reveal that serotonergic signalling is likely to mediate the antiepileptic activity of clemizole. The serotonergic drugs trazodone and lorcaserin are also antiepileptic in this model, with the latter showing promising results in patients.
Chronic idiopathic itch is often diagnosed as a psychogenic disorder. Martinelli-Boneschi et al. discover an association between COL6A5 and idiopathic chronic itch in eight patients from three kindreds, plus one unrelated patient, with small fibre neuropathy. The findings add to knowledge of itch pathogenesis and suggest a new therapeutic target.
Mild traumatic brain injury is associated with reduced cortical thickness in those at risk for Alzheimer’s disease
Whether mild traumatic brain injury (mTBI) confers increased risk of Alzheimer's disease is unknown. Hayes et al. report that mTBI in war veterans is associated with reduced cortical thickness among those at high genetic risk for Alzheimer's disease, which in turn is associated with reduced memory recall.
Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli
Transplantation of stem cells can ameliorate impairments in animal models of stroke. Tornero et al. demonstrate that intracortical grafts of human skin-derived cortical neurons restore specific connections in stroke-injured cortex and respond to tactile stimulation of nose and paw. Thus, these neurons can participate in reconstruction of injured brain circuitries.
The longitudinal course of microglial activation in the trajectory of Alzheimer’s disease is unclear. Fan et al. demonstrate two peaks: one in early MCI and another in late Alzheimer’s disease. Activated microglia in MCI may initially adopt a protective anti-inflammatory phenotype, changing to a pro-inflammatory phenotype as the disease progresses.
Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis
It is unclear whether brain MRI characteristics of MOG-antibody(Ab) disease differ from those of multiple sclerosis and AQP4-Ab disease. Jurynczyk et al. show that MOG-Ab disease can be clearly separated from multiple sclerosis but overlaps with AQP4-Ab. Best classifiers are identified to aid diagnostic decisions and classify undetermined patients.
Gene delivery to oligodendrocytes will be necessary to treat leukodystrophies resulting from mutations in myelin-related genes. Georgiou et al. report that intracerebral delivery of an AAV.MBP vector achieves widespread oligodendrocyte-specific expression of GJC2/Cx47, a gene associated with hypomyelinating leukodystrophy, and rescues the phenotype of a mouse model of the disease.
Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome
Fragile X Syndrome (FXS) often also presents with autism spectrum disorder (ASD). Boland et al. reveal consistent disease-associated phenotypes during neuronal differentiation of induced pluripotent stem cells from multiple patients diagnosed with FXS. FMR1- cells showed altered expression and epigenetic regulation of genes associated with ASD, suggesting common disease mechanisms.
Trafficking kinesin proteins (TRAKs) support mitochondrial trafficking in neurons. Barel, Malicdan, Ben-zeev et al. report the first cases of fatal encephalopathy caused by pathogenic TRAK1 variants, in which aberrant mitochondrial movement and distribution led to abnormal uncoupled respiration. This study provides new understanding of how mitochondrial dynamics relate to disease.
See Lytton (doi:10.1093/awx018) for a scientific commentary on this article.
Patients with drug-resistant epilepsy show different seizure propagation patterns and postsurgical outcomes. Proix et al. merge structural information from brain imaging with mathematical modelling to generate personalized brain network models. Validation of the models against presurgical stereotactic EEGs and clinical data shows that they can account for the variability observed.
Progressive multiple sclerosis can be challenging to diagnose and difficult to treat. Correale et al. review the mechanisms of disease pathogenesis, the difficulties surrounding diagnosis, and the correlation between histopathology and MRI studies. Finally, they consider new therapeutic approaches with the potential to slow down disease progression.
This scientific commentary refers to ‘Perfusion computed tomography in patients with stroke thrombolysis’, by Kawano et al. (doi:10.1093/brain/aww338).
This scientific commentary refers to ‘Structural cerebellar correlates of cognitive and motor dysfunctions in cerebellar degeneration’, by Kansal et al. (doi:10.1093/aww327).
This scientific commentary refers to ‘Heterogeneity of neuroanatomical patterns in prodromal Alzheimer’s disease: links to cognition, progression and biomarkers’, by Dong et al. (doi:10.1093/brain/aww319).
Cover image: Schematic image depicting how drugs, identified from a genetic zebrafish model of Dravet syndrome, and shown to be effective in erasing (zebrafish) or reducing (patients) seizures, could lead to clinical application for the personalized treatment of epilepsy. From Griffin et al. Clemizole and modulators of serotonin signaling suppress seizures in Dravet syndrome. Pp. 669–683.
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