Faculty Bibliography

Background:Neuromodulation of the cerebello-thalamo-cortical (CTC) circuit via thalamic stimulation is an effective therapy for essential tremor (ET). In order to develop non-invasive neuromodulation approaches, clinically relevant thalamo-cortical connections must be elucidated. Methods:-tests were performed to compare groups, and associations with tremor severity were determined by Pearson correlations. All p-values were adjusted for multiple comparisons using Bonferroni correction. Results:= 0.438, p = 0.045) for the Vim-SMA tract, and no significant correlation for the Vim-pre-SMA or Vim-M1 tracts was found. Discussion:Patients with ET demonstrated a reinforcement of Vim-cortical connectivity, with higher Vim-SMA connectivity being associated with greater tremor severity. This finding suggests that the Vim-SMA connection is relevant to the underlying pathophysiology of ET, and inhibition of the SMA may be an effective therapeutic approach.

Programmed cell death protein 1 (PD-1) checkpoint blockade with an antibody has been shown to reduce amyloid-β plaques, associated pathologies and cognitive impairment in mouse models. More recently, this approach has shown effectiveness in a tauopathy mouse model to improve cognition and reduce tau lesions. Follow-up studies by other laboratories did not see similar benefits of this type of therapy in other amyloid-β plaque models. Here, we report a modest increase in locomotor activity but no effect on cognition or tau pathology, in a different more commonly used tauopathy model following a weekly treatment for 12 weeks with the same PD-1 antibody and isotype control as in the original Aβ- and tau-targeting studies. These findings indicate that further research is needed before clinical trials based on PD-1 checkpoint immune blockage are devised for tauopathies.

Different strategies for treatment and prevention of Alzheimer's disease (AD) are currently under investigation, including passive immunization with anti-amyloid β (anti-Aβ) monoclonal antibodies (mAbs). Here, we investigate the therapeutic potential of a novel type of Aβ-targeting agent based on an affibody molecule with fundamentally different properties to mAbs. We generated a therapeutic candidate, denoted Z_SYM73-albumin-binding domain (ABD; 16.8 kDa), by genetic linkage of the dimeric Z_SYM73 affibody for sequestering of monomeric Aβ-peptides and an ABD for extension of its in vivo half-life. Amyloid precursor protein (APP)/PS1 transgenic AD mice were administered with Z_SYM73-ABD, followed by behavioral examination and immunohistochemistry. Results demonstrated rescued cognitive functions and significantly lower amyloid burden in the treated animals compared to controls. No toxicological symptoms or immunology-related side-effects were observed. To our knowledge, this is the first reported in vivo investigation of a systemically delivered scaffold protein against monomeric Aβ, demonstrating a therapeutic potential for prevention of AD.

With respect to behavior, the term memory "consolidation" has canonically been used to describe increased fidelity during testing to a learned behavior shaped during training. While the sleeping brain appears to certainly aid in consolidation by this definition for a variety of memories, including motor memories, growing evidence suggests that sleep allows for much more flexible use of the information encountered during prior wakefulness. Sleep has been shown to augment the extraction of gist or patterns from wake experience in human subjects, but this has been difficult to recapitulate in animal models owing to the semantic requirements in many such tasks. Here we establish a model of motor gist learning in mice in which two bouts of exclusive forward running on the rotarod significantly augments the first experience of exclusive backward running. This augmentation does not occur if sleep is disrupted following the forward running template behavior or if a period of natural wakefulness follows one of the two bouts of exclusive forward running. This suggests that sleep is required for the extraction of the motor gist of forward running to apply to backward running.

Objective: To describe an unusual case of a young girl of Jewish Ashkenazi descent with two rare genetic disorders: familial dysautonomia and congenital adrenal hyperplasia.
Method(s): Case report.
Result(s): Female patient presenting with hypotonia, failure to thrive, recurrent vomiting and frequent lower respiratory tract infections during the first year of life. Her physical exam disclosed genital ambiguity and, because an older sister had a diagnosis of congenital adrenal hyperplasia, the diagnosis was suspected in this case, and confirmed by low levels of cortisol and aldosterone. Targeted genetic testing showed homozygosis for a pathogenic variant in the CYP21A2 gene (c.293-13C[G, aka I2G, well-described in Jewish Ashkenazi patients) and heterozygosis for 7 other variants in the same gene. She was started on fludrocortisone for mineralocorticoid replacement therapy. Additional signs and symptoms were identified including frequent aspiration pneumonias prompting a gastrostomy tube placement at 6 months of age, emotionally-induced episodes of face, hand and feet blotching, frequent falls, impaired sensitivity to pain, and lack of tears. Additional genetic testing at age 2 disclosed homozygous copies of the founder mutation variant of familial dysautonomia (variant IVS20?6 T[C) in the IKBKAP gene.
Conclusion(s): The presence of one rare genetic disorder does not preclude the presence of another rare genetic disorder. Signs and symptoms not consistent with one diagnosed genetic disorder should prompt suspicion of additional causes

Background: We have shown previously that PH has better HRQoL compared to cystine stone formers and the US Standard Population. Now we show the first crosssectional HRQoL profiles of PH patients.
Method(s): PH participants were enrolled from the Rare Kidney Stone Consortium (RKSC) registry. The group of PH participants consist of PH 1, 2, 3, and PH-NMD (no mutation detected). PH-NMD met clinical criteria for PH. HRQoL was measured with the generic non-disease specific instrument (SF-36v2). Results were calculated as norm-based scores (NBS) based on US Standard Population (mean domain score = 50). We created three stone event groups (<= 30 days, 31-365 days, >=366 days). We compared HRQoL by last stone event for PH participants without a liver and/or kidney transplant. Group means < 47 indicate the presence of impaired functioning in associated dimensions.
Result(s): We used 184 surveys of adults with PH at different time points, adjusted for the last stone event, and compared SF-36 domain profiles. 56 participants were included with multiple surveys (PH1 26, PH2 8, PH3 13, PH-NMD 9; 30 males, 26 females; 42 years old, males 42 years, females 41 years). Lowest domain results were found in participants that experienced a stone event <= 30 days before the survey. Participants with no stone event within a year had the best HRQoL with domain scores above the US Standard Population. PH-NMD compared to PH1, PH2 and PH3 had the highest stone event rate within one year of the survey (58.1 vs 35 vs 3 vs 29.5%). All PH patients with a stone event within 30 days of the survey trended towards higher urine oxalate excretion and lower eGFR (underpowered, not significant). Figure 1 shows that time since the last stone significantly affected HRQoL.
Conclusion(s): PH participants as a group are not homogeneous and experience different HRQoL based on proximity to stone event. PH type is a covariate. Overall PH2 has fewer stone events compared to other PH participants, with an expected direct impact on HRQoL

Autism Spectrum Disorder (ASD) is an increasingly common developmental disorder that affects 1 in 59 children. Despite this high prevalence of ASD, knowledge regarding the biological basis of its associated cognitive difficulties remains scant. In this study, we aimed to identify altered neurophysiological responses underlying inhibitory control and emotion processing difficulties in ASD, together with their associations with age and various domains of cognitive and social function. This was accomplished by assessing electroencephalographic recordings during an emotional go/nogo task alongside parent rating scales of behavior. Event related potential (ERP) N200 component amplitudes were reduced in children with ASD compared to typically developing (TD) children. No group differences were found, however, for task performance, P300 amplitude or latency, or N170 amplitude or latency, suggesting that individuals with ASD may only present conflict monitoring abnormalities, as reflected by the reduced N200 component, compared to TD individuals. Consistent with previous findings, increased age correlated with improved task performance scores and reduced N200 amplitude in the TD group, indicating that as these children develop, their neural systems become more efficient. These associations were not identified in the ASD group. Results also showed significant associations between increased N200 amplitudes and improved executive control abilities and decreased autism traits in TD children only. The newly discovered findings of decreased brain activation in children with ASD, alongside differences in correlations with age compared to TD children, provide a potential neurophysiological indicator of atypical development of inhibitory control mechanisms in these individuals.

Accumulating evidence suggests brain network dysfunction in attention-deficit/hyperactivity disorder (ADHD). Whether large-scale brain network connectivity patterns reflect clinical heterogeneity in ADHD remains to be fully understood. This study aimed to characterize the differential within- and between-network functional connectivity (FC) changes in children with ADHD combined (ADHD-C) or inattentive (ADHD-I) subtypes and their associations with ADHD symptoms. We studied the task-free functional magnetic resonance imaging (fMRI) data of 58 boys with ADHD and 28 demographically matched healthy controls. We measured within- and between-network connectivity of both low-level (sensorimotor) and high-level (cognitive) large-scale intrinsic connectivity networks and network modularity. We found that children with ADHD-C but not those with ADHD-I exhibited hyper-connectivity within the anterior default mode network (DMN) compared with controls. Additionally, children with ADHD-C had higher inter-network FC between the left executive control (ECN) and the salience (SN) networks, between subcortical and visual networks, and between the DMN and left auditory networks than controls, while children with ADHD-I did not show differences compared with controls. Similarly, children with ADHD-C but not ADHD-I showed lower network modularity compared with controls. Importantly, these observed abnormal inter-network connectivity and network modularity metrics were associated with Child Behavioral Checklist (CBCL) attention-deficit/hyperactivity problems and internalizing problems in children with ADHD. This study revealed relatively greater loss of brain functional network segregation in childhood ADHD combined subtype compared to the inattentive subtype, suggesting differential large-scale functional brain network topology phenotype underlying childhood ADHD heterogeneity.

Background: Cystinuria is a disease of impaired absorption of cystine and dibasic amino acids (DAA) from the intestine and renal tubule leading to formation of cystine kidney stones. However, the metabolic impact of reduced amino acid absorption and excessive loss in the urine is poorly understood. We measured endogenous, gut microbial, and xenobiotic metabolites, providing insight into consequences of the disease and its treatment.
Method(s): Urinary biochemicals were assayed using LC-MS in 293 urine specimens from patients with cystinuria or control urinary phenotypes. Multivariate statistical analyses were conducted to reveal statistically significant biochemical signatures of the disease and products of cysteine-binding thiol drugs (CBTDs). 16s rRNA gene sequencing was performed on fecal samples from 12 wildtype (WT) and 12 cystinuric (Slc3a1 knockout; KO) mice to evaluate their gut microbial composition.
Result(s): Cystinuric urine samples had elevated levels of cysteine-gamma-glutamyl cystine disulfide (glutathione precursor), indole-3-acetic acid (microbial tryptophan metabolism), and novel conjugated forms of putrescine (microbial DAA decomposition). Conversely, taurine (sulfur metabolism), indole-3-acetic acid-glucuronide, and novel urinary metabolite N-methyl pipecolic acid (lysine metabolism) were reduced in cystinuric urine. Where cysteine-bound CBTDs were observed, substantial amounts of "wasted" drug were also detected as CBTD homodimers, non-cysteine disulfides, and mixed drug disulfides. The differentiation of gut microbially-derived metabolites led us to evaluate the gut microbiome diversity and composition in a mouse model of cystinuria revealing clear beta diversity and taxa differentiation between WT and KO mice.
Conclusion(s): Cystinuria is associated with unique urinary metabolic profiles beyond hyperexcretion of cystine and DAA, indicating perturbed metabolic processes and potential gut microbial effects. Study of the gut microbiome of WT and KO mice provides the first evidence for them having distinct taxa, perhaps due to poorly absorbed DAA present in the intestinal lumen. Urinary profiles allow us to characterize the excretion profiles of CBTDs, providing insight which may be helpful to tailor treatment