Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration.

BACKGROUND AND OBJECTIVES: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106Bs effect on divergent pathophysiologic changes before the appearance of clinical symptoms

Comorbid Neurological Illness

Abstract Cerebrovascular disease, movement disorders, epilepsy, and other neurological diseases disproportionately affect the elderly. Prevalence rates of mood disorders, particularly depression, exceed 20% in most neurological disorders. Thus, many mood disturbances in the elderly are comorbid with neurological illness. Furthermore, elderly individuals and neurological patients have high rates of mood-related morbidity and mortality. Unfortunately, mood disorders in neurological conditions are poorly recognized and under-treated. This chapter discusses the problem of mood disorders in specific neurological conditions in the elderly, and provides a general framework for approaching and treating these problems.</jats:p

Does Informant-Based Reporting of Cognitive Decline Correlate with Age-Adjusted Hippocampal Volume in Mild Cognitive Impairment and Alzheimer’s Disease?

Background: Informant-based measures are effective screening tools for cognitive impairment. The Alzheimer’s Questionnaire (AQ) is a subjective, informant-based measure that detects amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) with high sensitivity and specificity and has been shown to predict amyloid burden. Objective: To determine whether informant-based report of cognitive decline correlates with hippocampal volume changes in MCI and AD. Methods: Retrospective chart review of 139 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ-Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ-Total. The AQ was used to assign diagnostic status. Thus, the relationship between the AQ and diagnostic status was excluded. Results: The sample include 88 female and 51 male participants. The mean age was 74.37±9.45, mean MOCA was 22.65±4.18, mean education was 14.80±3.35, and mean AQ score was 10.54±5.22. Hippocampal volume and the AQ correlation was r = –0.33 [95%CI –0.47 to –0.17], p &lt; 0.0001. Conclusion: In a mixed-clinical sample of patients presenting to an outpatient memory disorders center, higher endorseme-nts of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision-making and demonstrate an additional relationship between clinical measures and volumetric MRI.</jats:p

Stab wounds to the back and flank in the hemodynamically stable patient: A decision algorithm based on contrast-enhanced computed tomography with colonic opacification

The authors wanted to determine whether contrast-enhanced computed tomography (CE-CT) with colonic opacification is an accurate tool to triage hemodynamically stable victims of stab wounds to the flank and back. One hundred forty-five consecutive patients were categorized as low-risk (penetration superficial to the deep fascia) or high-risk (penetration beyond the deep fascia) based on CE-CT findings. There were no significant differences in admission vital signs, Glasgow Coma Scale, or complete blood counts between low- and high-risk groups. None of the 92 low-risk patients required surgery or had sequelae. Six of the 53 high-risk patients underwent surgery, 2 based on initial CE-CT, 4 due to evolving clinical signs. The CE-CT correctly predicted surgical findings in all cases. Hemodynamically stable patients with stab wounds to the back and/or flank can be successfully triaged based on CE-CT findings. Low-risk patients may be discharged immediately. High-risk patients may have a discharge decision implemented at 24 hours

Does Informant-Based Reporting of Cognitive Decline Correlate with Age-Adjusted Hippocampal Volume in Mild Cognitive Impairment and Alzheimer\u27s Disease?

Background: Informant-based measures are effective screening tools for cognitive impairment. The Alzheimer\u27s Questionnaire (AQ) is a subjective, informant-based measure that detects amnestic mild cognitive impairment (aMCI) and Alzheimer\u27s disease (AD) with high sensitivity and specificity and has been shown to predict amyloid burden. Objective: To determine whether informant-based report of cognitive decline correlates with hippocampal volume changes in MCI and AD. Methods: Retrospective chart review of 139 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ-Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ-Total. The AQ was used to assign diagnostic status. Thus, the relationship between the AQ and diagnostic status was excluded. Results: The sample include 88 female and 51 male participants. The mean age was 74.37±9.45, mean MOCA was 22.65±4.18, mean education was 14.80±3.35, and mean AQ score was 10.54±5.22. Hippocampal volume and the AQ correlation was r = -0.33 [95%CI -0.47 to -0.17], p \u3c 0.0001. Conclusion: In a mixed-clinical sample of patients presenting to an outpatient memory disorders center, higher endorseme-nts of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision-making and demonstrate an additional relationship between clinical measures and volumetric MRI