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ABSTRACT- Horseradish peroxidase (HRP) and lanthanum chloride (LaCl3) are useful tools for, respectively, the study of vesicular transport through the hepatocyte and the study of the permeability of junctional complexes. These tracers have been used to detect the changes associated with the choleresis independent of bile acids induced by valproic acid (VPA) in rats. The animals were given a single dose of VPA (600 mg/kg, ip). HRP (100 mg/kg) or 5 mM LaCl3 were given intraportally after 1 h, when bile flow had increased twofold. The excretion of HRP in bile was measured colorimetrically up to 2 h after HRP. Ultrastructural morphometry was conducted on liver of intact rats taken from 1 to 40 min after HRP. The volume density (VD) of HRP-containing vesicles and of HRP-containing multivesicular bodies (MVB) was counted. In VPA-treated rats, HRP appeared in bile with a peak showing at 5 min against 20 min in controls, but the total amount of HRP excreted was less than in controls. The intrahepatocytic vesicular transport of HRP was also modified, showing a peak at 3 min in VPA-treated rats compared to 10 min in controls, together with a decreased VD of pericanalicular vesicles. This was accompanied by an increase of HRP-containing MVB, already evident at 5 min. VPA-induced changes in HRP transport through the hepatocytes appeared twofold: 1) during VPA-induced stimulation of bile flow, there was an early and short-lived increase of transcellular transport and biliary elimination of HRP: 2) a diversion of HRP towards the indirect, lysosomal pathway apparently occurred, in agreement with previous findings concerning the formation of numerous cytolysomes induced by VPA ( Hepatology 1984: 4: 1159-1166). The decreased amount of HRP excreted in bile could be accounted for by a diversion of HRP towards the degradation pathway. The pattern of distribution of LaCl3 was similar in VPA-treated animals and in controls, suggesting that gross structural alterations of the junctional complexes are unlikely to occur during VPA-induced choleresis. [ABSTRACT FROM AUTHOR]

ABSTRACT- The study reports functional and morphological findings in eight male subjects undergoing anticonvulsant therapy for periods from 20 days up to 15 years. All subjects showed an increased activity of the hepatic microsomal NADPH cytochrome c reductase and an increased amount of smooth membranes in hepatocytes. The enzymatic activity was higher in the first years of treatment. Quantitative ultrastructural analysis showed that a twofold increase of the smooth membranes of hepatocytes had already been reached after 20 days of therapy, with a modest additional increase occurring thereafter. Both enzymatic and structural changes appear to be related to therapy. In addition, abnormal lipofuscin-related cytoplasmic formations were present in the hepatocytes of five subjects. Such formations are thought to represent an accumulation of abnormal degradation products, possibly related to an interaction of the drug(s) metabolites with cellular components. [ABSTRACT FROM AUTHOR]

Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT., Competing Interests: Declaration of interests B.J.T. holds patents on clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72., (Published by Elsevier Inc.)

The olfactory bulb is involved early in the pathophysiology of Parkinson's disease (PD), which is consistent with the early onset of olfactory dysfunction. Identifying the molecular mechanisms through which PD affects the olfactory bulb could lead to a better understanding of the pathophysiology and etiology of olfactory dysfunction in PD. We specifically aimed to assess gene expression changes, affected pathways and co-expression network by whole transcriptomic profiling of the olfactory bulb in subjects with clinicopathologically defined PD. Bulk RNA sequencing was performed on frozen human olfactory bulbs of 20 PD and 20 controls without dementia or any other neurodegenerative disorder, from the Arizona Study of Aging and Neurodegenerative disorders and the Brain and Body Donation Program. Differential expression analysis (19 PD vs 19 controls) revealed 2164 significantly differentially expressed genes (1090 upregulated and 1074 downregulated) in PD. Pathways enriched in downregulated genes included oxidative phosphorylation, olfactory transduction, metabolic pathways, and neurotransmitters synapses while immune and inflammatory responses as well as cellular death related pathways were enriched within upregulated genes. An overrepresentation of microglial and astrocyte-related genes was observed amongst upregulated genes, and excitatory neuron-related genes were overrepresented amongst downregulated genes. Co-expression network analysis revealed significant modules highly correlated with PD and olfactory dysfunction that were found to be involved in the MAPK signaling pathway, cytokine-cytokine receptor interaction, cholinergic synapse, and metabolic pathways. LAIR1 (leukocyte associated immunoglobulin like receptor 1) and PPARA (peroxisome proliferator activated receptor alpha) were identified as hub genes with a high discriminative power between PD and controls reinforcing an important role of neuroinflammation in the olfactory bulb of PD subjects. Olfactory identification test score positively correlated with expression of genes coding for G-coupled protein, glutamatergic, GABAergic, and cholinergic receptor proteins and negatively correlated with genes for proteins expressed in glial olfactory ensheathing cells. In conclusion, this study reveals gene alterations associated with neuroinflammation, neurotransmitter dysfunction, and disruptions of factors involved in the initiation of olfactory transduction signaling that may be involved in PD-related olfactory dysfunction., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Auditory detection of the Amplitude Modulation (AM) of sounds, crucial for speech perception, improves until 10 years of age. This protracted development may not only be explained by sensory maturation, but also by improvements in processing efficiency: the ability to make efficient use of available sensory information. This hypothesis was tested behaviorally on 86 6-to-9-year-olds and 15 adults using AM-detection tasks assessing absolute sensitivity, masking, and response consistency in the AM domain. Absolute sensitivity was estimated by the detection thresholds of a sinusoidal AM applied to a pure-tone carrier; AM masking was estimated as the elevation of AM-detection thresholds produced when replacing the pure-tone carrier by a narrowband noise; response consistency was estimated using a double-pass paradigm where the same set of stimuli was presented twice. Results showed that AM sensitivity improved from childhood to adulthood, but did not change between 6 and 9 years. AM masking did not change with age, suggesting that the selectivity of perceptual AM filters was adult-like by 6 years. However, response consistency increased developmentally, supporting the hypothesis of reduced processing efficiency in early childhood. At the group level, double-pass data of children and adults were well simulated by a model of the human auditory system assuming a higher level of internal noise for children. At the individual level, for both children and adults, double-pass data were better simulated when assuming a sub-optimal decision strategy in addition to differences in internal noise. In conclusion, processing efficiency for AM detection is reduced in childhood. Moreover, worse AM detection was linked to both systematic and stochastic inefficiencies, in both children and adults., Competing Interests: Declaration of competing interest The authors declare no financial or non-financial conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The determination of RNA integrity is a critical quality assessment tool for gene expression studies where the experiment's success is highly dependent on the sample quality. Since its introduction in 1999, the gold standard in the scientific community has been the Agilent 2100 Bioanalyzer's RNA integrity number (RIN), which uses a 1-10 value system, from 1 being the most degraded, to 10 being the most intact. In 2015, Agilent launched 4200 TapeStation's RIN equivalent, and reported a strong correlation of r 2 of 0.936 and a median error < ±0.4 RIN units. To evaluate this claim, we compared the Agilent 4200 TapeStation's RIN equivalent (RINe) and DV200 to the Agilent 2100 Bioanalyzer's RIN for 183 parallel RNA samples. In our study, using RNA from a total of 183 human postmortem brain samples, we found that the RIN and RINe values only weakly correlate, with an r 2 of 0.393 and an average difference of 3.2 RIN units. DV200 also only weakly correlated with RIN (r 2 of 0.182) and RINe (r 2 of 0.347). Finally, when applying a cut-off value of 6.5 for both metrics, we found that 95.6% of samples passed with RIN, while only 23.5% passed with RINe. Our results suggest that even though RIN (Bioanalyzer) and RINe (TapeStation) use the same 1-10 value system, they should not be used interchangeably, and cut-off values should be calculated independently.

The amplitude modulation following response (AMFR) is the steady-state auditory response signaling phase-locking to slow variations in the amplitude (AM) of auditory stimuli that provide fundamental acoustic information. From a developmental perspective, the AMFR has been recorded in sleeping infants, compared to sleeping or awake adults. The lack of AMFR recordings in awake infants limits conclusions on the development of phase-locking to AM. Moreover, previous studies assessing phase-locking to AM using non-speech carriers have not included slow AM rates (<20 Hz), which are particularly important for speech processing. This study aimed at disentangling these issues by recording the AMFR with electroencephalography: in awake infants (3- and 10-month-olds) and awake young adults and for both slow and faster modulation rates (8 and 40 Hz). The AMFR was observable at 8 Hz at all ages (40%, 60%, and 33% of significant AMFR at 3 months, 10 months, and adults, respectively), but only adults showed reliable responses at 40 Hz (6% of significant AMFR at both 3 and 10 months, 100% in adults), thus, ruling out the possibility that sleep has a suppressing effect on the response. This pattern might be explained by developmental differences in the sources of neural processing of faster AM rates., (© 2023 Acoustical Society of America.)

This study is a validation of the LENA system for the Italian language. In Study 1, to test LENA's accuracy, seventy-two 10-minute samples extracted from daylong LENA recordings were manually transcribed for 12 children longitudinally observed at 1;0 and 2;0. We found strong correlations between LENA and human estimates in the number of Adult Word Count (AWC) and Child Vocalisations Count (CVC) and a weak correlation between LENA and human estimates in Conversational Turns Count (CTC). In Study 2, to test the concurrent validity, direct and indirect language measures were considered on a sample of 54 recordings (19 children). Correlational analyses showed that LENA's CVC and CTC were significantly related to the children's vocal production, a parent report measure of prelexical vocalizations and the vocal reactivity scores. These results confirm that the automatic analyses performed by the LENA device are reliable and powerful for studying language development in Italian-speaking infants.

While motor and cortical neurons are affected in C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), it remains largely unknown if and how non-neuronal cells induce or exacerbate neuronal damage. We differentiated C9orf72 ALS/FTD patient-derived induced pluripotent stem cells into microglia (iPSC-MG) and examined their intrinsic phenotypes. Similar to iPSC motor neurons, C9orf72 ALS/FTD iPSC-MG mono-cultures form G 4 C 2 repeat RNA foci, exhibit reduced C9orf72 protein levels, and generate dipeptide repeat proteins. Healthy control and C9orf72 ALS/FTD iPSC-MG equally express microglial specific genes and perform microglial functions, including inflammatory cytokine release and phagocytosis of extracellular cargos, such as synthetic amyloid beta peptides and healthy human brain synaptoneurosomes. RNA sequencing analysis revealed select transcriptional changes of genes associated with neuroinflammation or neurodegeneration in diseased microglia yet no significant differentially expressed microglial-enriched genes. Moderate molecular and functional differences were observed in C9orf72 iPSC-MG mono-cultures despite the presence of C9orf72 pathological features suggesting that a diseased microenvironment may be required to induce phenotypic changes in microglial cells and the associated neuronal dysfunction seen in C9orf72 ALS/FTD neurodegeneration., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lorenzini, Alsop, Levy, Gittings, Lall, Rabichow, Moore, Pevey, Bustos, Burciu, Bhatia, Singer, Saul, McQuade, Tzioras, Mota, Logemann, Rose, Almeida, Gao, Marks, Donnelly, Hutchins, Hung, Ichida, Bowser, Spires-Jones, Blurton-Jones, Gendron, Baloh, Van Keuren-Jensen and Sattler.)

Cerebral white matter rarefaction (CWMR) was considered by Binswanger and Alzheimer to be due to cerebral arteriolosclerosis. Renewed attention came with CT and MR brain imaging, and neuropathological studies finding a high rate of CWMR in Alzheimer disease (AD). The relative contributions of cerebrovascular disease and AD to CWMR are still uncertain. In 1181 autopsies by the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), large-format brain sections were used to grade CWMR and determine its vascular and neurodegenerative correlates. Almost all neurodegenerative diseases had more severe CWMR than the normal control group. Multivariable logistic regression models indicated that Braak neurofibrillary stage was the strongest predictor of CWMR, with additional independently significant predictors including age, cortical and diencephalic lacunar and microinfarcts, body mass index, and female sex. It appears that while AD and cerebrovascular pathology may be additive in causing CWMR, both may be solely capable of this. The typical periventricular pattern suggests that CWMR is primarily a distal axonopathy caused by dysfunction of the cell bodies of long-association corticocortical projection neurons. A consequence of these findings is that CWMR should not be viewed simply as "small vessel disease" or as a pathognomonic indicator of vascular cognitive impairment or vascular dementia., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Sex differences in Alzheimer's disease (AD) may contribute to disease heterogeneity and affect prevalence, risk factors, disease trajectories and outcomes. Depression impacts a large number of patients with AD and has been reported to be more prevalent in women. We aimed to better understand the interaction between sex, depression and AD neuropathology, which could have implications for detection of symptoms, earlier diagnosis, therapeutic management, and enhanced quality of life., Methods: We compared 338 cases with clinicopathologically confirmed AD (46% women) to 258 control cases (50% women), without dementia, parkinsonism or a significant pathological diagnosis. Depression was assessed both, using the Hamilton Depression Scale (HAM-D), and as being reported in their medical history combined with treatment with antidepressant medication., Results: In the control group, women showed a higher depression severity, and a higher proportion of women were found to meet the cut-off score for depression on the HAM-D (32 vs. 16%) and having an history of depression (33 vs. 21%), while these sex differences were not observed in AD. Further, in both groups, female sex independently predicted the presence of depression, with covariates for age and cognitive status. AD subjects had higher mean HAM-D scores, were more likely to meet cutoff scores for depression (41 vs. 24%) and have a history of depression than controls (47 vs. 27%). When comparing the increase in frequency of depression in controls versus AD, the difference was significantly greater in men (AD men - control men: 24%) than in women (AD women - control women: 9%). Although subjects with depression were more likely to have higher levels of AD neuropathology, these differences were not observed when investigating the control or AD group separately., Discussion: Control women had a higher likelihood and severity of depression than control men, but this sex difference was not noted when considering only those with pathologically defined AD, emphasizing the importance of considering sex in aging studies. AD was associated with higher rates of depression and men may be more likely to report or be diagnosed with depression once they develop AD indicating the importance of more frequent depression screenings in men., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tremblay, Choudhury, Belden, Goldfarb, Lorenzini, Beach and Serrano.)

Growing evidence shows that early speech processing relies on information extracted from speech production. In particular, production skills are linked to word-form processing, as more advanced producers prefer listening to pseudowords containing consonants they do not yet produce. However, it is unclear whether production affects word-form encoding (the translation of perceived phonological information into a memory trace) and/or recognition (the automatic retrieval of a stored item). Distinguishing recognition from encoding makes it possible to explore whether sensorimotor information is stored in long-term phonological representations (and thus, retrieved during recognition) or is processed when encoding a new item, but not necessarily when retrieving a stored item. In this study, we asked whether speech-related sensorimotor information is retained in long-term representations of word-forms. To this aim, we tested the effect of production on the recognition of ecologically learned, real familiar word-forms. Testing these items allowed to assess the effect of sensorimotor information in a context in which encoding did not happen during testing itself. Two groups of French-learning monolinguals (11- and 14-month-olds) participated in the study. Using the Headturn Preference Procedure, each group heard two lists, each containing 10 familiar word-forms composed of either early-learned consonants (commonly produced by French-learners at these ages) or late-learned consonants (more rarely produced at these ages). We hypothesized differences in listening preferences as a function of word-list and/or production skills. At both 11 and 14 months, babbling skills modulated orientation times to the word-lists containing late-learned consonants. This specific effect establishes that speech production impacts familiar word-form recognition by 11 months, suggesting that sensorimotor information is retained in long-term word-form representations and accessed during word-form processing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor CP declared a shared parent affiliation with the authors at the time of review., (Copyright © 2022 Lorenzini and Nazzi.)

It is still unclear whether the gradual improvement in amplitude-modulation (AM) sensitivity typically found in children up to 10 years of age reflects an improvement in "processing efficiency" (the central ability to use information extracted by sensory mechanisms). This hypothesis was tested by evaluating temporal integration for AM, a capacity relying on memory and decision factors. This was achieved by measuring the effect of increasing the number of AM cycles (2 vs 8) on AM-detection thresholds for three groups of children aged from 5 to 11 years and a group of young adults. AM-detection thresholds were measured using a forced-choice procedure and sinusoidal AM (4 or 32 Hz rate) applied to a 1024-Hz pure-tone carrier. All age groups demonstrated temporal integration for AM at both rates; that is, significant improvements in AM sensitivity with a higher number of AM cycles. However, an effect of age is observed as both 5-6 year olds and adults exhibited more temporal integration compared to 7-8 and 10-11 year olds at both rates. This difference is due to: (i) the 5-6 year olds displaying the worst thresholds with 2 AM cycles, but similar thresholds with 8 cycles compared to the 7-8 and 10-11 year olds, and, (ii) adults showing the best thresholds with 8 AM cycles but similar thresholds with 2 cycles compared to the 7-8 and 10-11 year olds. Computational modelling indicated that higher levels of internal noise combined with poorer short-term memory capacities in children accounted for the developmental trends. Improvement in processing efficiency may therefore account for the development of AM detection in childhood., (Copyright © 2021 Elsevier B.V. All rights reserved.)

C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities., Competing Interests: Declaration of interests R.H.B. is employed by Roche Pharmaceuticals. D.M.H. is listed as an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics, LLC. C2N Diagnostics, LLC, has licensed certain anti-tau antibodies to AbbVie for therapeutic development. D.M.H. is on the scientific advisory board of Denali and consults for Genentech, Merck, and Cajal Neurosciences. D.M.H. and J.D.U. are listed as inventors on a provisional patent from Washington University on TREM2 antibodies. R.S. is on the scientific advisory board of Spinogenix Inc., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson's disease and Menkes disease are neurodevelopmental disorders resulting from mutations in the copper transporters ATP7A and ATP7B, with ATP7A mutations also causing occipital horn syndrome, and distal motor neuropathy. A 65 year old male presenting with brachial amyotrophic diplegia and diagnosed with amyotrophic lateral sclerosis (ALS) was found to harbor a p.Met1311Val (M1311V) substitution variant in ATP7A. ALS is a fatal neurodegenerative disease associated with progressive muscle weakness, synaptic deficits and degeneration of upper and lower motor neurons. To investigate the potential contribution of the ATP7A M1311V variant to neurodegeneration, we obtained and characterized both patient-derived fibroblasts and patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs), and compared them to control cell lines. We found reduced localization of ATP7A M1311V to the trans-Golgi network (TGN) at basal copper levels in patient-derived fibroblasts and iPSC-MNs. In addition, redistribution of ATP7A M1311V out of the TGN in response to increased extracellular copper was defective in patient fibroblasts. This manifested in enhanced intracellular copper accumulation and reduced survival of ATP7A M1311V fibroblasts. iPSC-MNs harboring the ATP7A M1311V variant showed decreased dendritic complexity, aberrant spontaneous firing, and decreased survival. Finally, expression of the ATP7A M1311V variant in Drosophila motor neurons resulted in motor deficits. Apilimod, a drug that targets vesicular transport and recently shown to enhance survival of C9orf72-ALS/FTD iPSC-MNs, also increased survival of ATP7A M1311V iPSC-MNs and reduced motor deficits in Drosophila expressing ATP7A M1311V . Taken together, these observations suggest that ATP7A M1311V negatively impacts its role as a copper transporter and impairs several aspects of motor neuron function and morphology., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Fibroblasts from an amyotrophic lateral sclerosis patient with simultaneous mutations in the MATR3 gene and KIF5A gene were isolated and reprogrammed into induced pluripotent stem cells via a non-integrating Sendai viral vector. The generated iPSC clones demonstrated normal karyotype, expression of pluripotency markers, and the capacity to differentiate into three germ layers. The unique presence of two simultaneous mutations in ALS-associated genes represent a novel tool for the study of ALS disease mechanisms., (Copyright © 2020. Published by Elsevier B.V.)