Anterior insula degeneration in frontotemporal dementia

The human anterior insula is anatomically and functionally heterogeneous, containing key nodes within distributed speech–language and viscero-autonomic/social–emotional networks. The frontotemporal dementias selectively target these large-scale systems, leading to at least three distinct clinical syndromes. Examining these disorders, researchers have begun to dissect functions which rely on specific insular nodes and networks. In the behavioral variant of frontotemporal dementia, early-stage frontoinsular degeneration begets progressive “Salience Network” breakdown that leaves patients unable to model the emotional impact of their own actions or inactions. Ongoing studies seek to clarify local microcircuit- and cellular-level factors that confer selective frontoinsular vulnerability. The search for frontotemporal dementia treatments will depend on a rich understanding of insular biology and could help clarify specialized human language, social, and emotional functions

Distinct Lysosomal Network Protein Profiles in Parkinsonian Syndrome Cerebrospinal Fluid.

BackgroundClinical diagnosis of parkinsonian syndromes like Parkinson's disease (PD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is hampered by overlapping symptomatology and lack of diagnostic biomarkers, and definitive diagnosis is only possible post-mortem.ObjectiveSince impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that profiles of select lysosomal network proteins in cerebrospinal fluid could be differentially expressed in these parkinsonian syndromes.MethodsCerebrospinal fluid samples were collected from PD patients (n = 18), clinically diagnosed 4-repeat tauopathy patients; corticobasal syndrome (CBS) (n = 3) and PSP (n = 8); and pathologically diagnosed PSP (n = 8) and CBD patients (n = 7). Each patient set was compared to its appropriate control group consisting of age and gender matched individuals. Select lysosomal network protein levels were detected via Western blotting. Factor analysis was used to test the diagnostic sensitivity, specificity and accuracy of the select lysosomal network protein expression profiles.ResultsPD, CBD and PSP were markedly different in their cerebrospinal fluid lysosomal network protein profiles. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in PD; early endosomal antigen 1 was decreased and lysozyme increased in PSP; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in CBD. A panel of lysosomal-associated membrane protein 2, lysozyme and microtubule-associated protein 1 light chain discriminated between controls, PD and 4-repeat tauopathies.ConclusionsThis study offers proof of concept that select lysosomal network proteins are differentially expressed in cerebrospinal fluid of Parkinson's disease, corticobasal syndrome and progressive supranuclear palsy. Lysosomal network protein analysis could be further developed as a diagnostic fluid biomarker in parkinsonian syndromes

Subcellular organization of UBE3A in human cerebral cortex.

BackgroundLoss of UBE3A causes Angelman syndrome, whereas excess UBE3A activity appears to increase the risk for autism. Despite this powerful association with neurodevelopmental disorders, there is still much to be learned about UBE3A, including its cellular and subcellular organization in the human brain. The issue is important, since UBE3A's localization is integral to its function.MethodsWe used light and electron microscopic immunohistochemistry to study the cellular and subcellular distribution of UBE3A in the adult human cerebral cortex. Experiments were performed on multiple tissue sources, but our results focused on optimally preserved material, using surgically resected human temporal cortex of high ultrastructural quality from nine individuals.ResultsWe demonstrate that UBE3A is expressed in both glutamatergic and GABAergic neurons, and to a lesser extent in glial cells. We find that UBE3A in neurons has a non-uniform subcellular distribution. In somata, UBE3A preferentially concentrates in euchromatin-rich domains within the nucleus. Electron microscopy reveals that labeling concentrates in the head and neck of dendritic spines and is excluded from the PSD. Strongest labeling within the neuropil was found in axon terminals.ConclusionsBy highlighting the subcellular compartments in which UBE3A is likely to function in the human neocortex, our data provide insight into the diverse functional capacities of this E3 ligase. These anatomical data may help to elucidate the role of UBE3A in Angelman syndrome and autism spectrum disorder

Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease.

The maintenance of genomic integrity is essential for normal cellular functions. However, it is difficult to maintain over a lifetime in postmitotic cells such as neurons, in which DNA damage increases with age and is exacerbated by multiple neurological disorders, including Alzheimer's disease (AD). Here we used immunohistochemical staining to detect DNA double strand breaks (DSBs), the most severe form of DNA damage, in postmortem brain tissues from patients with mild cognitive impairment (MCI) or AD and from cognitively unimpaired controls. Immunostaining for γH2AX-a post-translational histone modification that is widely used as a marker of DSBs-revealed increased proportions of γH2AX-labeled neurons and astrocytes in the hippocampus and frontal cortex of MCI and AD patients, as compared to age-matched controls. In contrast to the focal pattern associated with DSBs, some neurons and glia in humans and mice showed diffuse pan-nuclear patterns of γH2AX immunoreactivity. In mouse brains and primary neuronal cultures, such pan-nuclear γH2AX labeling could be elicited by increasing neuronal activity. To assess whether pan-nuclear γH2AX represents DSBs, we used a recently developed technology, DNA damage in situ ligation followed by proximity ligation assay, to detect close associations between γH2AX sites and free DSB ends. This assay revealed no evidence of DSBs in neurons or astrocytes with prominent pan-nuclear γH2AX labeling. These findings suggest that focal, but not pan-nuclear, increases in γH2AX immunoreactivity are associated with DSBs in brain tissue and that these distinct patterns of γH2AX formation may have different causes and consequences. We conclude that AD is associated with an accumulation of DSBs in vulnerable neuronal and glial cell populations from early stages onward. Because of the severe adverse effects this type of DNA damage can have on gene expression, chromatin stability and cellular functions, DSBs could be an important causal driver of neurodegeneration and cognitive decline in this disease

Distinctive Structural and Molecular Features of Myelinated Inhibitory Axons in Human Neocortex.

Numerous types of inhibitory neurons sculpt the performance of human neocortical circuits, with each type exhibiting a constellation of subcellular phenotypic features in support of its specialized functions. Axonal myelination has been absent among the characteristics used to distinguish inhibitory neuron types; in fact, very little is known about myelinated inhibitory axons in human neocortex. Here, using array tomography to analyze samples of neurosurgically excised human neocortex, we show that inhibitory myelinated axons originate predominantly from parvalbumin-containing interneurons. Compared to myelinated excitatory axons, they have higher neurofilament and lower microtubule content, shorter nodes of Ranvier, and more myelin basic protein (MBP) in their myelin sheath. Furthermore, these inhibitory axons have more mitochondria, likely to sustain the high energy demands of parvalbumin interneurons, as well as more 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a protein enriched in the myelin cytoplasmic channels that are thought to facilitate the delivery of nutrients from ensheathing oligodendrocytes. Our results demonstrate that myelinated axons of parvalbumin inhibitory interneurons exhibit distinctive features that may support the specialized functions of this neuron type in human neocortical circuits

Damage to left frontal regulatory circuits produces greater positive emotional reactivity in frontotemporal dementia.

Positive emotions foster social relationships and motivate thought and action. Dysregulation of positive emotion may give rise to debilitating clinical symptomatology such as mania, risk-taking, and disinhibition. Neuroanatomically, there is extensive evidence that the left hemisphere of the brain, and the left frontal lobe in particular, plays an important role in positive emotion generation. Although prior studies have found that left frontal injury decreases positive emotion, it is not clear whether selective damage to left frontal emotion regulatory systems can actually increase positive emotion. We measured happiness reactivity in 96 patients with frontotemporal dementia (FTD), a neurodegenerative disease that targets emotion-relevant neural systems and causes alterations in positive emotion (i.e., euphoria and jocularity), and in 34 healthy controls. Participants watched a film clip designed to elicit happiness and a comparison film clip designed to elicit sadness while their facial behavior, physiological reactivity, and self-reported emotional experience were monitored. Whole-brain voxel-based morphometry (VBM) analyses revealed that atrophy in predominantly left hemisphere fronto-striatal emotion regulation systems including left ventrolateral prefrontal cortex, orbitofrontal cortex, anterior insula, and striatum was associated with greater happiness facial behavior during the film (pFWE < .05). Atrophy in left anterior insula and bilateral frontopolar cortex was also associated with higher cardiovascular reactivity (i.e., heart rate and blood pressure) but not self-reported positive emotional experience during the happy film (p < .005, uncorrected). No regions emerged as being associated with greater sadness reactivity, which suggests that left-lateralized fronto-striatal atrophy is selectively associated with happiness dysregulation. Whereas previous models have proposed that left frontal injury decreases positive emotional responding, we argue that selective disruption of left hemisphere emotion regulating systems can impair the ability to suppress positive emotions such as happiness

Early frontotemporal dementia targets neurons unique to apes and humans

Objective: Frontotemporal dementia (FTD) is a neurodegenerative disease that erodes uniquely human aspects of social behavior and emotion. The illness features a characteristic pattern of early injury to anterior cingulate and frontoinsular cortex. These regions, though often considered ancient in phylogeny, are the exclusive homes to the von Economo neuron (VEN), a large bipolar projection neuron found only in great apes and humans. Despite progress toward understanding the genetic and molecular bases of FTD, no class of selectively vulnerable neurons has been identified. Methods: Using unbiased stereology, we quantified anterior cingulate VENs and neighboring Layer 5 neurons in FTD (n = 7), Alzheimer's disease (n = 5), and age‐matched nonneurological control subjects (n = 7). Neuronal morphology and immunohistochemical staining patterns provided further information about VEN susceptibility. Results: FTD was associated with early, severe, and selective VEN losses, including a 74% reduction in VENs per section compared with control subjects. VEN dropout was not attributable to general neuronal loss and was seen across FTD pathological subtypes. Surviving VENs were often dysmorphic, with pathological tau protein accumulation in Pick's disease. In contrast, patients with Alzheimer's disease showed normal VEN counts and morphology despite extensive local neurofibrillary pathology. Interpretation: VEN loss links FTD to its signature regional pattern. The findings suggest a new framework for understanding how evolution may have rendered the human brain vulnerable to specific forms of degenerative illness

Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing