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BACKGROUND: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer's disease (AD). OBJECTIVES: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could add additional support for detecting anosognosia. METHODS: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects' estimation of their performances in a computerized experiment. RESULTS: The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods. CONCLUSIONS: The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis.

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BACKGROUND: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare genetic disease due to a TUBB4A mutation, with motor features including dystonia. Deep brain stimulation (DBS) can be used to treat dystonia in pediatric populations, although the response is highly variable and preferential toward specific etiologies. OBSERVATIONS: A single pediatric subject with H-ABC received DBS using a staged procedure involving temporary depth electrode placement, identification of optimal stimulation targets, and permanent electrode implantation. After surgery, the patient significantly improved on both the Burke-Fahn-Marsden Dystonia Rating Scale and the Barry-Albright Dystonia Scale. The patient's response suggests that DBS can have potential benefit in H-ABC. LESSONS: TUBB4A mutations are associated with a variety of clinical phenotypes, and there is a lack of clearly identified targets for DBS, with this case being the second reported instance of DBS in this condition. The staged procedure with temporary depth electrode testing is recommended to identify optimal stimulation targets. The response seen in this patient implies that such a staged procedure may provide benefit in other conditions where DBS targets are currently unknown, including rare genetic or metabolic conditions associated with movement disorders.

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Mountains are renowned for their bountiful biodiversity. Explanations on the origin of such abundant life are usually regarded to their orogenic history. However, ancient mountain systems with geological stability also exhibit astounding levels of number of species and endemism, as illustrated by the Brazilian Quartzitic Mountains (BQM) in Eastern South America. Thus, cycles of climatic changes over the last couple million years are usually assumed to play an important role in the origin of mountainous biota. These climatic oscillations potentially isolated and reconnected adjacent populations, a phenomenon known as flickering connectivity, accelerating speciation events due to range fragmentation, dispersion, secondary contact, and hybridization. To evaluate the role of the climatic fluctuations on the diversification of the BQM biota, we estimated the ancient demography of distinct endemic species of animals and plants using hierarchical approximate Bayesian computation analysis and Ecological Niche Modelling. Additionally, we evaluated if climatic oscillations have driven a genetic spatial congruence in the genetic structure of codistributed species from the Espinhaço Range, one of the main BQM areas. Our results show that the majority of plant lineages underwent a synchronous expansion over the Last Glacial Maximum (LGM, c. 21 thousand years ago), although we could not obtain a clear demographic pattern for the animal lineages. We also obtained a signal of a congruent phylogeographic break between lineages endemic to the Espinhaço Range, suggesting how ancient climatic oscillations might have driven the evolutionary history of the Espinhaço's biota.

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BACKGROUND: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a neurodegenerative disease with neurodevelopmental delay, motor, and speech regression, pronounced extrapyramidal syndrome, and sensory deficits due to TUBB4A mutation. In 2017, a severe variant was described in 16 Roma infants due to mutation in UFM1. OBJECTIVE: The objective of this study is to expand the clinical manifestations of H-ABC due to UFM1 mutation and suggest clues for clinical diagnosis. METHODOLOGY: Retrospective analysis of all 9 cases with H-ABC due to c.-273_-271delTCA mutation in UFM1 treated during 2013-2020 in a Neuropediatric Ward in Plovdiv, Bulgaria. RESULTS: Presentation is no later than 2 months with inspiratory stridor, impaired sucking, swallowing, vision and hearing, and reduced active movements. By the age of 10 months, a monomorphic disease was observed: microcephaly (6/9), malnutrition (5/9), muscle hypertonia (9/9) and axial hypotonia (4/9), progressing to opisthotonus (6/9), dystonic posturing (5/9), nystagmoid ocular movements (6/9), epileptic seizures (4/9), non-epileptic spells (3/9). Dysphagia (7/9), inspiratory stridor (9/9), dyspnea (5/9), bradypnea (5/9), apnea (2/9) were major signs. Vision and hearing were never achieved or lost by 4-8 mo. Neurodevelopment was absent or minimal with subsequent regression after 2-5 mo. Brain imaging revealed cortical atrophy (7/9), atrophic ventricular dilatation (4/9), macrocisterna magna (5/9), reduced myelination (6/6), corpus callosum atrophy (3/6) and abnormal putamen and caput nuclei caudati. The age at death was between 8 and 18 mo. CONCLUSION: Roma patients with severe encephalopathy in early infancy with stridor, opisthotonus, bradypnea, severe hearing and visual impairment should be tested for the Roma founder mutation of H-ABC in UFM1.

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Phylogeography investigates historical drivers of the geographical distribution of intraspecific lineages. Particular attention has been given to ecological, climatic and geological processes in the diversification of the Neotropical biota. Several species sampled across the South American diagonal of open formations (DOF), comprising the Caatinga, Cerrado and Chaco biomes, experienced range shifts coincident with Quaternary climatic changes. However, comparative studies across different spatial, temporal and biological scales on DOF species are still meagre. Here, we combine phylogeographical model selection and machine learning predictive frameworks to investigate the influence of Pleistocene climatic changes on several plant and animal species from the DOF. We assembled mitochondrial/chloroplastic DNA sequences in public repositories and inferred the demographic responses of 44 species, comprising 70 intraspecific lineages of plants, lizards, frogs, spiders and insects. We then built a random forest model using biotic and abiotic information to identify the best predictors of demographic responses in the Pleistocene. Finally, we assessed the temporal synchrony of species demographic responses with hierarchical approximate Bayesian computation. Biotic variables related to population connectivity, gene flow and habitat preferences largely predicted how species responded to Pleistocene climatic changes, and demographic changes were synchronous primarily during the Middle Pleistocene. Although 22 (~31%) lineages underwent demographic expansion, presumably associated with the spread of aridity during the glacial Pleistocene periods, our findings suggest that nine lineages (~13%) exhibited the opposite response due to taxon-specific attributes.

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Syntaxin-1 (STX1) and Munc18-1 are two requisite components of synaptic vesicular release machinery, so much so synaptic transmission cannot proceed in their absence. They form a tight complex through two major binding modes: through STX1's N-peptide and through STX1's closed conformation driven by its Habc- domain. However, physiological roles of these two reportedly different binding modes in synapses are still controversial. Here we characterized the roles of STX1's N-peptide, Habc-domain, and open conformation with and without N-peptide deletion using our STX1-null mouse model system and exogenous reintroduction of STX1A mutants. We show, on the contrary to the general view, that the Habc-domain is absolutely required and N-peptide is dispensable for synaptic transmission. However, STX1A's N-peptide plays a regulatory role, particularly in the Ca2+-sensitivity and the short-term plasticity of vesicular release, whereas STX1's open conformation governs the vesicle fusogenicity. Strikingly, we also show neurotransmitter release still proceeds when the two interaction modes between STX1A and Munc18-1 are presumably intervened, necessitating a refinement of the conceptualization of STX1A-Munc18-1 interaction.

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Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a central neurodegenerative disease due to mutations in the tubulin beta-4A (TUBB4A) gene, characterized by motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. Diagnosis is made by integrating clinical data and radiological signs. Differences in MRIs have been reported in patients that carry the same mutation; however, a quantitative study has not been performed so far. Our study aimed to provide a longitudinal analysis of the changes in the cerebellum (Cb), corpus callosum (CC), ventricular system, and striatum in a patient suffering from H-ABC and in the taiep rat. We correlated the MRI signs of the patient with the results of immunofluorescence, gait analysis, segmentation of cerebellum, CC, and ventricular system, performed in the taiep rat. We found that cerebellar and callosal changes, suggesting a potential hypomyelination, worsened with age, in concomitance with the emergence of ataxic gait. We also observed a progressive lateral ventriculomegaly in both patient and taiep, possibly secondary to the atrophy of the white matter. These white matter changes are progressive and can be involved in the clinical deterioration. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) gives rise to a spectrum of clinical signs whose pathophysiology still needs to be understood.

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The taiep rat undergoes hypomyelination and progressive demyelination caused by an abnormal microtubule accumulation in oligodendrocytes, which elicits neuroinflammation and motor behavior dysfunction. Based on taurine antioxidant and proliferative actions, this work explored whether its sustained administration from the embryonic age to adulthood could prevent neuroinflammation, stimulate cell proliferation, promote myelination, and relieve motor impairment. Taurine (50 mg/L of drinking water = 50 ppm) was given to taiep pregnant rats on gestational day 15 and afterward to the male offspring until eight months of age. We measured the levels of nitric oxide (NO), malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA), CXCL1, CXCR2 receptor, growth factors (BNDF and FGF2), cell proliferation, and myelin content over time. Integral motor behavior was also evaluated. Our results showed that taurine administration significantly decreased NO and MDA + 4-HDA levels, increased cell proliferation, and promoted myelination in an age- and brain region-dependent fashion compared with untreated taiep rats. Taurine effect on chemokines and growth factors was also variable. Taurine improved vestibular reflexes and limb muscular strength in perinatal rats and fine movements and immobility episodes in adult rats. These results show that chronic taurine administration partially alleviates the taiep neuropathology.

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Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a neurodegenerative disease due to mutations in TUBB4A. Patients suffer from extrapyramidal movements, spasticity, ataxia, and cognitive deficits. Magnetic resonance imaging features are hypomyelination and atrophy of the striatum and cerebellum. A correlation between the mutations and their cellular, tissue and organic effects is largely missing. The effects of these mutations on sensory functions have not been described so far. We have previously reported a rat carrying a TUBB4A (A302T) mutation and sharing most of the clinical and radiological signs with H-ABC patients. Here, for the first time, we did a comparative study of the hearing function in an H-ABC patient and in this mutant model. By analyzing hearing function, we found that there are no significant differences in the auditory brainstem response (ABR) thresholds between mutant rats and WT controls. Nevertheless, ABRs show longer latencies in central waves (II-IV) that in some cases disappear when compared to WT. The patient also shows abnormal AEPs presenting only Waves I and II. Distortion product of otoacoustic emissions and immunohistochemistry in the rat show that the peripheral hearing function and morphology of the organ of Corti are normal. We conclude that the tubulin mutation severely impairs the central hearing pathway most probably by progressive central white matter degeneration. Hearing function might be affected in a significant fraction of patients with H-ABC; therefore, screening for auditory function should be done on patients with tubulinopathies to evaluate hearing support therapies.

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Tubulinopathies are a group of recently described diseases characterized by mutations in the tubulin genes. Mutations in TUBB4A produce diseases such as dystonia type 4 (DYT4) and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), which are clinically diagnosed by magnetic resonance imaging (MRI). We propose the taiep rat as the first animal model for tubulinopathies. The spontaneous mutant suffers from a syndrome related to a central leukodystrophy and characterized by tremor, ataxia, immobility, epilepsy, and paralysis. The pathological signs presented by these rats and the morphological changes we found by our longitudinal MRI study are similar to those of patients with mutations in TUBB4A. The diffuse atrophy we found in brain, cerebellum and spinal cord is related to the changes detectable in many human tubulinopathies and in particular in H-ABC patients, where myelin degeneration at the level of putamen and cerebellum is a clinical trademark of the disease. We performed Tubb4a exon analysis to corroborate the genetic defect and formulated hypotheses about the effect of amino acid 302 change on protein physiology. Optical microscopy of taiep rat cerebella and spinal cord confirmed the optical density loss in white matter associated with myelin loss, despite the persistence of neural fibers.

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The role that vitamin D plays in pulmonary function remains uncertain. Epidemiological studies reported mixed findings for serum 25-hydroxyvitamin D (25(OH)D)-pulmonary function association. We conducted the largest cross-sectional meta-analysis of the 25(OH)D-pulmonary function association to date, based on nine European ancestry (EA) cohorts (n 22 838) and five African ancestry (AA) cohorts (n 4290) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Data were analysed using linear models by cohort and ancestry. Effect modification by smoking status (current/former/never) was tested. Results were combined using fixed-effects meta-analysis. Mean serum 25(OH)D was 68 (sd 29) nmol/l for EA and 49 (sd 21) nmol/l for AA. For each 1 nmol/l higher 25(OH)D, forced expiratory volume in the 1st second (FEV1) was higher by 1·1 ml in EA (95 % CI 0·9, 1·3; P<0·0001) and 1·8 ml (95 % CI 1·1, 2·5; P<0·0001) in AA (P race difference=0·06), and forced vital capacity (FVC) was higher by 1·3 ml in EA (95 % CI 1·0, 1·6; P<0·0001) and 1·5 ml (95 % CI 0·8, 2·3; P=0·0001) in AA (P race difference=0·56). Among EA, the 25(OH)D-FVC association was stronger in smokers: per 1 nmol/l higher 25(OH)D, FVC was higher by 1·7 ml (95 % CI 1·1, 2·3) for current smokers and 1·7 ml (95 % CI 1·2, 2·1) for former smokers, compared with 0·8 ml (95 % CI 0·4, 1·2) for never smokers. In summary, the 25(OH)D associations with FEV1 and FVC were positive in both ancestries. In EA, a stronger association was observed for smokers compared with never smokers, which supports the importance of vitamin D in vulnerable populations.

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Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum of diseases ranging from hereditary generalized dystonia with whispering dysphonia (DYT-TUBB4A) and hereditary spastic paraplegia (HSP) to leukodystrophy hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). TUBB4A encodes the brain-specific ß-tubulin isotype, ß-tubulin 4A. To elucidate the pathogenic mechanisms conferred by TUBB4A mutations leading to the different phenotypes, we functionally characterized three pathogenic TUBB4A variants (c.4C>G,p.R2G; c.745G>A,p.D249N; c.811G>A, p.A271T) as representatives of the mutational and disease spectrum) in human neuroblastoma cells and human induced pluripotent stem cell (iPSC)-derived neurons. We showed that mRNA stability was not affected by any of the TUBB4A variants. Although two mutations (p.R2G and p.D249N) are located at the α/ß-tubulin interdimer interface, we confirmed incorporation of all TUBB4A mutants into the microtubule network. However, we showed that the mutations p.D249N and p.A271T interfered with motor protein binding to microtubules and impaired neurite outgrowth and microtubule dynamics. Finally, TUBB4A mutations, as well as heterozygous knockout of TUBB4A, disrupted mitochondrial transport in iPSC-derived neurons. Taken together, our findings suggest that functional impairment of microtubule-associated transport is a shared pathogenic mechanism by which the TUBB4A mutations studied here cause a spectrum of diseases.

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Many studies propose that Quaternary climatic cycles contracted and/or expanded the ranges of species and biomes. Strong expansion-contraction dynamics of biomes presume concerted demographic changes of associated fauna. The analysis of temporal concordance of demographic changes can be used to test the influence of Quaternary climate on diversification processes. Hierarchical approximate Bayesian computation (hABC) is a powerful and flexible approach that models genetic data from multiple species, and can be used to estimate the temporal concordance of demographic processes. Using available single-locus data, we can now perform large-scale analyses, both in terms of number of species and geographic scope. Here, we first compared the power of four alternative hABC models for a collection of single-locus data. We found that the model incorporating an a priori hypothesis about the timing of simultaneous demographic change had the best performance. Second, we applied the hABC models to a data set of seven squamate and four amphibian species occurring in the Seasonally Dry Tropical Forests (Caatinga) in northeastern Brazil, which, according to paleoclimatic evidence, experienced an increase in aridity during the Pleistocene. If this increase was important for the diversification of associated xeric-adapted species, simultaneous population expansions should be evident at the community level. We found a strong signal of synchronous population expansion in the Late Pleistocene, supporting the increase of the Caatinga during this time. This expansion likely enhanced the formation of communities adapted to high aridity and seasonality and caused regional extirpation of taxa adapted to wet forest.

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Mutations in TUBB4A have been identified to cause a wide phenotypic spectrum ranging from hereditary generalized dystonia with whispering dysphonia (DYT4) to the leukodystrophy hypomyelination syndrome with atrophy of the basal ganglia and cerebellum (H-ABC). To test for the contribution of TUBB4A mutations in different ethnicities (Spanish, Italian, Korean, Japanese), we screened 492 isolated dystonia cases for mutations in this gene and for the first time determined TUBB4A copy number variations in 336 dystonia patients. A potentially pathogenic rare 3bp-in-frame deletion was found in a patient with cervical dystonia but no copy number variations were detected in this study, suggesting that TUBB4A mutations exceedingly rarely contribute to the etiology of isolated dystonia.

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Pleistocene climatic cycles altered species distributions in the Eastern Nearctic of North America, yet the degree of congruent demographic response to the Pleistocene among codistributed taxa remains unknown. We use a hierarchical approximate Bayesian computational approach to test if population sizes across lineages of snakes, lizards, turtles, mammals, birds, salamanders and frogs in this region expanded synchronously to Late Pleistocene climate changes. Expansion occurred in 75% of 74 lineages, and of these, population size trajectories across the community were partially synchronous, with coexpansion found in at least 50% of lineages in each taxonomic group. For those taxa expanding outside of these synchronous pulses, factors related to when they entered the community, ecological thresholds or biotic interactions likely condition their timing of response to Pleistocene climate change. Unified timing of population size change across communities in response to Pleistocene climate cycles is likely rare in North America.

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BACKGROUND: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases. PATIENTS AND METHODS: The study included patients referred to us for an unclassified hypomyelinating leukodystrophy. We selected patients with deleterious heterozygous TUBB4A mutations. Molecular analysis of TUBB4A was performed on genomic DNA extracted from peripheral blood. RESULTS: The series included 12 patients (5 females and 7 males). Five patients carried the common mutation c.745G > A (p.Asp249Asn), while the remaining harbored different mutations. Three new mutations were found in 5 patients. Clinical and neuroimaging observations are described. A clear correlation between the clinical presentation and the genotype seems to be absent in our group of 12 patients. CONCLUSIONS: TUBB4A-mutated patients manifest a comparable clinical and neuroimaging picture but they can differ from each other in terms of rate of disease progression. Extrapyramidal signs can be absent in the first stages of the disease, and a careful evaluation of MRI is fundamental to obtain the final diagnosis. From a therapeutic perspective a trial with l-dopa should be considered in all patients presenting extrapyramidal symptoms.

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The contribution of Pleistocene sea level changes to diversification patterns in archipelagos around the world, and specifically whether the repeated cycles of island connectivity and isolation acted as a 'species pump' is debated. The debate has been perpetuated in part because of the type of evidence used to evaluate the species-pump hypothesis. Specifically, existing tests of the 'Pleistocene Aggregate Island Complex' (PAIC) model of diversification interpret the lack of concordant divergence times among multiple codistributed taxa as a rejection of the PAIC model. However, the null expectation of concordance disregards taxon-specific ecological traits and geographic characteristics that may affect population persistence and gene flow among islands. Here, we study the factors affecting population divergence in thirteen flightless darkling beetle species (Coleoptera: Tenebrionidae) across the PAIC system of the Cycladic plateau in the Aegean archipelago. Based on isolation-by-resistance analyses, hierarchical amova and the degree of genealogical sorting on individual islands, we identify a major effect of bathymetry and habitat stability on the levels of genetic divergence across the PAIC, with island size and body size playing a secondary role as well. We subsequently use bathymetric maps and habitat association to generate predictions about the set of islands and group of taxa expected to show phylogeographic concordance. We test these predictions using hierarchical approximate Bayesian computation and show how our interpretations regarding the role of PAICs as drivers of divergence change when relying on a null expectation of concordance compared to a refined model that takes geography and ecological traits into account.

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