Association between the degree of vertebrobasilar stenosis, location, infarction pattern, and QMRA flow state.

BACKGROUND AND PURPOSE: We aimed to investigate the relationship between the degree and location of vertebrobasilar stenosis and quantitative magnetic resonance angiography (QMRA) distal flow. METHODS: We retrospectively reviewed patients who presented with acute ischemic stroke with ≥50% stenosis of the extracranial or intracranial vertebral or basilar arteries, and QMRA performed within 1 year of stroke. Standardized techniques were used to measure stenosis and to dichotomize vertebrobasilar distal flow status. Patients were grouped based on the involved artery and the severity of disease. All p-values were calculated using chi-squared analysis and Fisher exact test with statistical significance defined as p < .05. RESULTS: Sixty-nine patients met study inclusion, consisting of 31 with low distal flow and 38 with normal distal flow. The presence of severe stenosis or occlusion was 100% sensitive, but only 47% predictive and 26% specific of a low distal flow state. Bilateral vertebral disease was only 55% sensitive but was 71% predictive and 82% specific of a low-flow state and was five times and nearly three times more likely to result in a low-flow state compared to unilateral vertebral disease (14%) and isolated basilar disease (28%), respectively. CONCLUSIONS: Severe stenosis of ≥70% may mark the minimal threshold required to cause hemodynamic insufficiency in the posterior circulation, but nearly half of these patients may remain hemodynamically sufficient. Bilateral vertebral stenosis resulted in a fivefold increase in QMRA low distal flow status compared to unilateral vertebral disease. These results may have implications in the design of future treatment trials of intracranial atherosclerotic disease.

Ghost infarct core: A systematic review of the frequency, magnitude, and variables of CT perfusion overestimation.

BACKGROUND AND PURPOSE: CT perfusion (CTP) imaging is now widely used to select patients with large vessel occlusions for mechanical thrombectomy. Ghost infarct core (GIC) phenomenon has been coined to describe CTP core overestimation and has been investigated in several retrospective studies. Our aim is to review the frequency, magnitude, and variables associated with this phenomenon. METHODS: A primary literature search resulted in eight studies documenting median time from symptom onset to CTP, median estimated core size, median final infarct volume, median core overestimation of the GIC population, recanalization rates, good outcomes, and collateral status for this systematic review. RESULTS: All the studies investigated patients who underwent CTP within 6 hours of symptom onset, ranging from median times of 105 to 309 minutes. The frequency of core overestimation varied from 6% to 58.4%, while the median estimated ischemic core and final infarction volume ranged from 7 to 27 mL and 12 to 31 mL, respectively. The median core overestimation ranged from 3.6 to 30 mL with upper quartile ranges up to 58 mL. GIC was found to be a highly time-and-collateral-dependent process that increases in frequency and magnitude as the time from symptom onset to imaging decreases and in the presence of poor collaterals. CONCLUSIONS: CTP ischemic core overestimation appears to be a relatively common phenomenon that is most frequent in patients with poor collaterals imaged within the acute time window. Early perfusion imaging should be interpreted with caution to prevent the inadvertent exclusion of patients from highly effective reperfusion therapies.

Stroke mechanisms in adult moyamoya disease: The association between infarction patterns and quantitative magnetic resonance angiography flow state.

INTRODUCTION: Flow augmentation is the mainstay treatment for moyamoya disease as hemodynamic failure is believed to be the dominant mechanism. We aimed to investigate the mechanisms of stroke in moyamoya disease by assessing the relationship between infarction patterns and quantitative magnetic resonance angiography flow state. METHODS: A retrospective study of adult patients with suspected MMD who presented with MRI confirmed acute ischemic stroke predating or following QMRA by a maximum of six months between 2009 and 2021 was conducted. Of the 177 consecutive patients with MMD who received QMRA, 35 patients, consisting of 41 hemispheres, met inclusion criteria. Flow-status was dichotomized into low-flow and normal-flow state based on previously established criteria. RESULTS: Mixed infarction pattern was the most frequent finding (70.7 %), followed by embolic (17.1 %), perforator (7.3 %), and internal borderzone (IBZ) (4.9 %). Infarction patterns were further dichotomized into IBZ+ (internal borderzone alone or mixed) and IBZ- (no internal borderzone constituent). Low-flow states were not significantly more frequent in the IBZ+ compared to IBZ- population (48.4 % vs. 20.0 %, p = 0.14). Ipsilateral posterior cerebral artery fractional flow was significantly higher with IBZ+ compared to IBZ- (345.0 % vs. 214.7 %, p = 0.04). CONCLUSION: Mixed infarction pattern was the most common pattern of infarction in patients with moyamoya disease, implying hypoperfusion and thromboembolism are codominant stroke mechanisms. An association between ICA flow status and infarction pattern was not found, although QMRA evidence of more robust posterior cerebral artery leptomeningeal collaterals was found in patients with a hypoperfusion contribution to their stroke mechanism.

The association of patient education level with outcomes after elective lumbar surgery: a Michigan Spine Surgery Improvement Collaborative study.

OBJECTIVE: Socioeconomic factors have been shown to impact a host of healthcare-related outcomes. Level of education is a marker of socioeconomic status. This study aimed to investigate the relationship between patient education level and outcomes after elective lumbar surgery and to characterize any education-related disparities. METHODS: The Michigan Spine Surgery Improvement Collaborative registry was queried for all lumbar spine operations. Primary outcomes included patient satisfaction determined by the North American Spine Society patient satisfaction index, and reaching the minimum clinically important difference of Patient-Reported Outcomes Measurement Information System Physical Function score and return to work up to 2 years after surgery. Multivariate Poisson generalized estimating equation models reported adjusted risk ratios. RESULTS: A total of 26,229 lumbar spine patients had data available for inclusion in this study. On multivariate generalized estimating equation analysis all comparisons were done versus the high school (HS)/general equivalency development (GED)-level cohort. For North American Spine Society satisfaction scores after surgery the authors observed the following: at 90 days the likelihood of satisfaction significantly decreased by 11% (p < 0.001) among < HS, but increased by 1% (p = 0.52) among college-educated and 3% (p = 0.011) among postcollege-educated cohorts compared to the HS/GED cohort; at 1 year there was a decrease of 9% (p = 0.02) among < HS and increases of 3% (p = 0.02) among college-educated and 9% (p < 0.001) among postcollege-educated patients; and at 2 years, there was an increase of 5% (p = 0.001) among postcollege-educated patients compared to the < HS group. The likelihood of reaching a minimum clinically important difference of Patient-Reported Outcomes Measurement Information System Physical Function score at 90 days increased by 5% (p = 0.005) among college-educated and 9% (p < 0.001) among postcollege-educated cohorts; at 1 year, all comparison cohorts demonstrated significance, with a decrease of 12% (p = 0.007) among < HS, but an increase by 6% (p < 0.001) among college-educated patients and 14% (p < 0.001) among postcollege-educated compared to the HS/GED cohort; at 2 years, there was a significant decrease by 19% (p = 0.003) among the < HS cohort, an increase by 8% (p = 0.001) among the college-educated group, and an increase by 16% (p < 0.001) among the postcollege-educated group. For return to work, a significant increase was demonstrated at 90 days and 1 year when comparing the HS or less group with college or postcollege cohorts. CONCLUSIONS: This study demonstrated negative associations on all primary outcomes with lower levels of education. This finding suggests a potential disparity linked to education in elective spine surgery.

A retrospective comparison of radiographic and clinical outcomes in single-level degenerative lumbar disease undergoing anterior versus transforaminal lumbar interbody fusion.

BACKGROUND: Single-level lumbar degenerative disc disease (DDD) remains a significant cause of morbidity in adulthood. Anterior lumbar interbody fusion (ALIF) and Transforaminal lumbar interbody fusion (TLIF) are surgical techniques developed to treat this condition. With limited studies on intermediate term outcomes in a single cohort, we compare radiographic and clinical outcomes in patients undergoing ALIF and TLIF. METHODS: A retrospective chart review was performed on 164 patients (111 TLIF; 53 ALIF) over a 60-month period. X-ray radiographs obtained pre-operatively, prior to discharge, and at one year were utilized for radiographic assessment. Segmental lordosis, lumbar lordosis and HRQOL scores were measured preoperatively and at one-year timepoints. RESULTS: Changes in lumbar lordosis and segmental lordosis were significantly greater after ALIF (4.6° vs. -0.6°, P=0.05; 4.7° vs. -0.7°, P<0.05) at one year (mean time, 366±20 days). At one year or greater, there was a greater reduction in mean VAS-leg score in TLIF patients (3.4 vs. 0.6, P<0.05) and ODI score (16.2 vs. 5.4, P<0.05). Similar outcomes were seen for VAS-back, SF-12 Physical Health, and SRS-30 Function/Activity. SF-12 Mental Health scores were found to be lower in patients undergoing TLIF (-3.5 vs. 2.7, P<0.05). CONCLUSIONS: ALIF demonstrated a superior method of increasing lumbar and segmental lordosis. TLIF was utilized more in patients with higher pre-operative VAS-leg pain scores and therefore, showed a greater magnitude of VAS-leg pain improvement. TLIF also demonstrated a greater improvement in ODI scores despite similar baseline scores, suggesting a possible enhanced functional outcome.

The modified frailty index and patient outcomes following transforaminal lumbar interbody fusion surgery for single-level degenerative spine disease.

OBJECTIVE: The modified frailty index (mFI) is a simple tool that measures physiological reserve based on a thorough history and physical examination. Its use has been validated in several surgical specialties, including spinal deformity surgery. Prior research has suggested no significant differences in clinical outcomes between elderly and nonelderly patients undergoing posterior lumbar interbody fusion. The authors sought to investigate the use of the mFI in patients undergoing transforaminal lumbar interbody fusion (TLIF) and the relationship between frailty scores and clinical outcomes. METHODS: A retrospective chart review was conducted on 198 patients who underwent a single-level TLIF over a 60-month period at a single institution. For all patients, an mFI score was computed incorporating a set of 11 clinical factors to assess preexisting comorbidities and functional status. Clinical follow-up and health-related quality-of-life (HRQOL) scores were obtained at baseline and regular intervals of 6 weeks, 6 months, and 1 year following surgery. RESULTS: Patients were grouped according to their level of frailty: no frailty (mFI = 0), mild frailty (mFI = 0.09), moderate frailty (mFI = 0.18), and severe frailty (mFI ≥ 0.27). One-way ANOVA revealed increasing levels of frailty to be associated with an increased rate of complications, from 10.3% to 63.6%. In addition, increasing levels of frailty were associated with longer hospital length of stay (LOS), from 3.1 days to 6.5 days, and lower rates of disposition to home. At the 1-year follow-up, increased levels of frailty were associated with worse HRQOL measures. CONCLUSIONS: Increasing mFI score was associated with higher morbidity, longer inpatient LOS, and a lower probability of discharge to home in patients undergoing single-level TLIF. Consideration of the mFI may help surgeons improve decision-making across the spectrum of patients who are at risk from frailty.

Small Molecule Recognition and Tools to Study Modulation of r(CGG)(exp) in Fragile X-Associated Tremor Ataxia Syndrome.

RNA transcripts containing expanded nucleotide repeats cause many incurable diseases via various mechanisms. One such disorder, fragile X-associated tremor ataxia syndrome (FXTAS), is caused by a noncoding r(CGG) repeat expansion (r(CGG)(exp)) that (i) sequesters proteins involved in RNA metabolism in nuclear foci, causing dysregulation of alternative pre-mRNA splicing, and (ii) undergoes repeat associated non-ATG translation (RANT), which produces toxic homopolymeric proteins without using a start codon. Here, we describe the design of two small molecules that inhibit both modes of toxicity and the implementation of various tools to study perturbation of these cellular events. Competitive Chemical Cross Linking and Isolation by Pull Down (C-Chem-CLIP) established that compounds bind r(CGG)(exp) and defined small molecule occupancy of r(CGG)(exp) in cells, the first approach to do so. Using an RNA GFP mimic, r(CGG)(exp)-Spinach2, we observe that our optimal designed compound binds r(CGG)(exp) and affects RNA localization by disrupting preformed RNA foci. These events correlate with an improvement of pre-mRNA splicing defects caused by RNA gain of function. In addition, the compounds reduced levels of toxic homopolymeric proteins formed via RANT. Polysome profiling studies showed that small molecules decreased loading of polysomes onto r(CGG)(exp), explaining decreased translation.

RAN translation at CGG repeats induces ubiquitin proteasome system impairment in models of fragile X-associated tremor ataxia syndrome.

Fragile X-associated tremor ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG trinucleotide repeat expansion in the 5' UTR of the Fragile X gene, FMR1. FXTAS is thought to arise primarily from an RNA gain-of-function toxicity mechanism. However, recent studies demonstrate that the repeat also elicits production of a toxic polyglycine protein, FMRpolyG, via repeat-associated non-AUG (RAN)-initiated translation. Pathologically, FXTAS is characterized by ubiquitin-positive intranuclear neuronal inclusions, raising the possibility that failure of protein quality control pathways could contribute to disease pathogenesis. To test this hypothesis, we used Drosophila- and cell-based models of CGG-repeat-associated toxicity. In Drosophila, ubiquitin proteasome system (UPS) impairment led to enhancement of CGG-repeat-induced degeneration, whereas overexpression of the chaperone protein HSP70 suppressed this toxicity. In transfected mammalian cells, CGG repeat expression triggered accumulation of a UPS reporter in a length-dependent fashion. To delineate the contributions from CGG repeats as RNA from RAN translation-associated toxicity, we enhanced or impaired the production of FMRpolyG in these models. Driving expression of FMRpolyG enhanced induction of UPS impairment in cell models, while prevention of RAN translation attenuated UPS impairment in cells and suppressed the genetic interaction with UPS manipulation in Drosophila. Taken together, these findings suggest that CGG repeats induce UPS impairment at least in part through activation of RAN translation.

Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS.

A repeat expansion in C9ORF72 causes frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). RNA of the expanded repeat (r(GGGGCC)exp) forms nuclear foci or undergoes repeat-associated non-ATG (RAN) translation, producing "c9RAN proteins." Since neutralizing r(GGGGCC)exp could inhibit these potentially toxic events, we sought to identify small-molecule binders of r(GGGGCC)exp. Chemical and enzymatic probing of r(GGGGCC)8 indicate that it adopts a hairpin structure in equilibrium with a quadruplex structure. Using this model, bioactive small molecules targeting r(GGGGCC)exp were designed and found to significantly inhibit RAN translation and foci formation in cultured cells expressing r(GGGGCC)66 and neurons transdifferentiated from fibroblasts of repeat expansion carriers. Finally, we show that poly(GP) c9RAN proteins are specifically detected in c9ALS patient cerebrospinal fluid. Our findings highlight r(GGGGCC)exp-binding small molecules as a possible c9FTD/ALS therapeutic and suggest that c9RAN proteins could potentially serve as a pharmacodynamic biomarker to assess efficacy of therapies that target r(GGGGCC)exp.

CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome.

Fragile X-associated tremor ataxia syndrome (FXTAS) results from a CGG repeat expansion in the 5' UTR of FMR1. This repeat is thought to elicit toxicity as RNA, yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of protein-mediated neurodegeneration. We explain this paradox by demonstrating that CGG repeats trigger repeat-associated non-AUG-initiated (RAN) translation of a cryptic polyglycine-containing protein, FMRpolyG. FMRpolyG accumulates in ubiquitin-positive inclusions in Drosophila, cell culture, mouse disease models, and FXTAS patient brains. CGG RAN translation occurs in at least two of three possible reading frames at repeat sizes ranging from normal (25) to pathogenic (90), but inclusion formation only occurs with expanded repeats. In Drosophila, CGG repeat toxicity is suppressed by eliminating RAN translation and enhanced by increased polyglycine protein production. These studies expand the growing list of nucleotide repeat disorders in which RAN translation occurs and provide evidence that RAN translation contributes to neurodegeneration.

Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome.

Fragile X Tremor Ataxia Syndrome (FXTAS) is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 5'UTR of the fragile X syndrome (FXS) gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11) suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT) inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.