C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia affecting the elderly. The GGGGCC hexanucleotide expansion mutation at the C9orf72 locus has been identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia, raising the question of whether this mutation is a factor in DLB. Furthermore, a small number of clinically diagnosed DLB patients have previously been reported to carry the pathologic C9orf72 hexanucleotide repeat expansion. OBJECTIVE: To explore whether the C9orf72 mutation is present in pathologically confirmed DLB patients. METHODS: We screened a cohort of 111 definite DLB cases with extensive Lewy body pathology for the C9orf72 hexanucleotide repeat expansion using the repeat-primed polymerase chain reaction assay. RESULTS: No pathogenic expansions of the C9orf72 hexanucleotide repeat were found, suggesting that there is no causal relationship between C9orf72 and DLB. CONCLUSION: Our data illustrate that C9orf72 screening of clinically diagnosed DLB patients should only be considered in cases with a family history of motor neuron disease or frontotemporal dementia to distinguish between mimic diseases.

Case Report: Successful Anterior Circulation Thrombectomy After 24 Hours in an Adolescent.

BACKGROUND: Arterial ischemic stroke in children comes with the potential for morbidity and mortality and can result in high cost of care and decreased quality of life among survivors. Children with arterial ischemic stroke are increasingly being treated with mechanical thrombectomy, but little is known about the risks and benefits 24 hours after a patient's last known well (LKW) time. METHODS: A 16-year-old female presented with acute onset of dysarthria and right hemiparesis with LKW time 22 hours prior. Pediatric National Institutes of Health Stroke Scale score was 12. Magnetic resonance imaging showed diffusion restriction and T2 hyperintensity primarily in the left basal ganglia. Magnetic resonance angiography revealed left M1 occlusion. Arterial spin labeling showed a large apparent perfusion deficit. She underwent thrombectomy with TICI3 recanalization 29.5 hours after LKW time. RESULTS: At 2-month follow-up, her examination showed moderate right-hand weakness and mild diminished sensation of the right arm. CONCLUSIONS: Adult thrombectomy trials include patients up to 24 hours from their LKW time and suggest that some patients maintain a favorable perfusion profile for over 24 hours. Without intervention many go on to experience infarct expansion. The persistence of a favorable perfusion profile likely reflects robust collateral circulation. We hypothesized our patient was relying on collateral circulation to maintain the noninfarcted areas of her left middle cerebral artery territory. Owing to concern for eventual collateral failure, thrombectomy outside of the 24-hour window was performed. This case serves as a call to action to better understand the impact of collateral circulation on cerebral perfusion in children with large vessel occlusions and delineate which children may benefit from thrombectomy in a delayed time window.

Assessing the Relationship between LAMS and CT Perfusion Parameters in Acute Ischemic Stroke Secondary to Large Vessel Occlusion.

BACKGROUND: The Los Angeles Motor Scale (LAMS) is a rapid pre-hospital scale used to predict stroke severity which has also been shown to accurately predict large vessel occlusions (LVOs). However, to date there is no study exploring whether LAMS correlates with the computed tomography perfusion (CTP) parameters in LVOs. METHODS: Patients with LVO between September 2019 and October 2021 were retrospectively reviewed and included if the CTP data and admission neurologic exams were available. The LAMS was documented based on emergency personnel exams or scored retrospectively using an admission neurologic exam. The CTP data was processed by RAPID (IschemaView, Menlo Park, CA, USA) with an ischemic core volume (relative cerebral blood flow [rCBF] < 30%), time-to-maximum (Tmax) volume (Tmax > 6 s delay), hypoperfusion index (HI), and cerebral blood volume (CBV) index. Spearman's correlations were performed between the LAMS and CTP parameters. RESULTS: A total of 85 patients were included, of which there were 9 intracranial internal carotid artery (ICA), 53 proximal M1 branch middle cerebral artery M1, and 23 proximal M2 branch occlusions. Overall, 26 patients had LAMS 0-3, and 59 had LAMS 4-5. In total, LAMS positively correlated with CBF < 30% (Correlation Coefficient (CC): 0.32, p < 0.01), Tmax > 6 s (CC:0.23, p < 0.04), HI (CC:0.27, p < 0.01), and negatively correlated with the CBV index (CC:-0.24, p < 0.05). The relationships between LAMS and CBF were < 30% and the HI was more pronounced in M1 occlusions (CC:0.42, p < 0.01; 0.34, p < 0.01 respectively) and proximal M2 occlusions (CC:0.53, p < 0.01; 0.48, p < 0.03 respectively). The LAMS also correlated with a Tmax > 6 s in M1 occlusions (CC:0.42, p < 0.01), and negatively correlated with the CBV index in M2 occlusions (CC:-0.69, p < 0.01). There were no significant correlations between the LAMS and intracranial ICA occlusions. CONCLUSIONS: The results of our preliminary study indicate that the LAMS is positively correlated with the estimated ischemic core, perfusion deficit, and HI, and negatively correlated with the CBV index in patients with anterior circulation LVO, with stronger relationships in the M1 and M2 occlusions. This is the first study showing that the LAMS may be correlated with the collateral status and estimated ischemic core in patients with LVO.

Association of midlife vascular risk and AD biomarkers with subsequent cognitive decline.

OBJECTIVE: To determine whether vascular risk and Alzheimer disease (AD) biomarkers have independent or synergistic effects on cognitive decline and whether vascular risk is associated with the accumulation of AD pathology as measured by change in biomarkers over time. METHODS: At baseline, participants (n = 168) were cognitively normal and primarily middle-aged (mean 56.4 years, SD 10.9 years) and had both vascular risk factor status and proximal CSF biomarkers available. Baseline vascular risk was quantified with a composite vascular risk score reflecting the presence or absence of hypertension, hypercholesterolemia, diabetes, current smoking, and obesity. CSF biomarkers of ß-amyloid (Aß)1-42, total tau (t-tau), and phosphorylated tau (p-tau) were used to create dichotomous high and low AD biomarker groups (based on Aß1-42 and tau). Linear mixed-effects models were used to examine change in a cognitive composite score (mean follow-up 13.9 years) and change in CSF biomarkers (mean follow-up 4.2 years). RESULTS: There was no evidence of a synergistic relationship between the vascular risk score and CSF AD biomarkers and cognitive decline. Instead, the vascular risk score (estimate -0.022, 95% confidence interval [CI] -0.043 to -0.002, p = 0.03) and AD biomarkers (estimate -0.060, 95% CI -0.096 to -0.024, p = 0.001) were independently and additively associated with cognitive decline. In addition, the vascular risk score was unrelated to levels of or rate of change in CSF Aß1-42, t-tau, or p-tau. CONCLUSIONS: The results of this observational cohort study suggest that vascular risk and biomarkers of AD pathology, when measured in midlife, act along independent pathways and underscore the importance of accounting for multiple risk factors for identifying cognitively normal individuals at the greatest risk of cognitive decline.

Age-related penetrance of the C9orf72 repeat expansion.

A pathogenic hexanucleotide repeat expansion within the C9orf72 gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among C9orf72 carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.

C9orf72 hexanucleotide repeat expansions are not a common cause of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a polygenic neuropsychiatric disorder characterized by repetitive thoughts and behaviors that cause distress. The pathogenic repeat expansion [GGGGCC]n found at the C9orf72 locus is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and has also been documented in patients with psychosis and schizophrenia. Furthermore, obsessions and compulsions have been identified in patients diagnosed with ALS and/or FTD and carrying the pathogenic repeat expansion. Here, we performed genetic screening for the C9orf72 repeat expansion on 573 patients diagnosed with OCD. None of the patients were found to carry the expansion. The results show that patients with OCD do not commonly carry the pathogenic repeat expansion and therefore should not be routinely screened. OCD and psychotic patients who do test positive for the C9orf72, however, should be closely observed for the later development of FTD and ALS.

Projected increase in amyotrophic lateral sclerosis from 2015 to 2040.

Although amyotrophic lateral sclerosis (ALS) is relatively rare, the socioeconomic significance of the disease is extensive. It is therefore vital to project the epidemiologic trend of ALS. To date, there have been few published studies attempting to estimate the number and distribution of ALS cases in the upcoming years. Here we show that the number of ALS cases across the globe will increase from 222,801 in 2015 to 376,674 in 2040, representing an increase of 69%. This increase is predominantly due to ageing of the population, particularly among developing nations. This projection is likely an underestimate due to improving healthcare and economic conditions. The results should be used to inform healthcare policy to more efficiently allocate healthcare resources.