Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal dementia (FTD) in 14% of ca... more Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal dementia (FTD) in 14% of cases. Five percent report a family history of ALS, and other ALS patients report a family history of other neurodegenerative diseases. The objective of this study was to conduct a family aggregation study of ALS, and neurodegenerative and neuropsychiatric conditions in ALS kindreds and matched healthy controls. The aim was to determine the true rate of familial ALS and the recurrence risk of ALS in family members, and to identify kindreds with increased aggregation of neurodegenerative and neuropsychiatric disease in the context of the recently described expanded hexanucleotide repeat in C9orf72. A prospective, population-based, case-control family aggregation study was conducted. Family history information was collected through questionnaires and interviews from ALS patients and matched controls. Cause of death was verified with death certification. The recurrence rate of ALS and the risk in family members of other neurodegenerative and neuropsychiatric disease was calculated using the relative risk (lambda) and cumulative risk using Kaplan-Meier analysis. Medical histories from 9,684 first- and second-degree relatives of 172 ALS probands and 192 controls were obtained. Cause of death was verified in 2,494 cases. Sixteen percent (n=27) of ALS patients had a family history of ALS. The lifetime hazard ratio (HR) of developing ALS among first- and second-degree relatives was 34.3 (p<0.0001) in relatives of ALS patients with the C9orf72 repeat expansion, and 2.3 (p=0.019) in relatives of ALS patients without the expansion. The relatives of ALS patients also had an increased HR of developing a psychotic illness (HR=4.7, p=0.004, 95% confidence interval [CI]=1.6-12.3) and of suicide (HR=5.6, p<0.0001, 95% CI=2.4-12.9) INTERPRETATION: The true rate of familial ALS in Ireland is 16%. There is an overlap between ALS, FTD, and neuropsychiatric disease that is pronounced in kindreds with the C9orf72 repeat expansion, but is also present in kindreds of those without the C9orf72 expanded repeat.
JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective ther... more JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established...
Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal dementia (FTD) in 14% of ca... more Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal dementia (FTD) in 14% of cases. Five percent report a family history of ALS, and other ALS patients report a family history of other neurodegenerative diseases. The objective of this study was to conduct a family aggregation study of ALS, and neurodegenerative and neuropsychiatric conditions in ALS kindreds and matched healthy controls. The aim was to determine the true rate of familial ALS and the recurrence risk of ALS in family members, and to identify kindreds with increased aggregation of neurodegenerative and neuropsychiatric disease in the context of the recently described expanded hexanucleotide repeat in C9orf72. A prospective, population-based, case-control family aggregation study was conducted. Family history information was collected through questionnaires and interviews from ALS patients and matched controls. Cause of death was verified with death certification. The recurrence rate of ALS and the risk in family members of other neurodegenerative and neuropsychiatric disease was calculated using the relative risk (lambda) and cumulative risk using Kaplan-Meier analysis. Medical histories from 9,684 first- and second-degree relatives of 172 ALS probands and 192 controls were obtained. Cause of death was verified in 2,494 cases. Sixteen percent (n=27) of ALS patients had a family history of ALS. The lifetime hazard ratio (HR) of developing ALS among first- and second-degree relatives was 34.3 (p<0.0001) in relatives of ALS patients with the C9orf72 repeat expansion, and 2.3 (p=0.019) in relatives of ALS patients without the expansion. The relatives of ALS patients also had an increased HR of developing a psychotic illness (HR=4.7, p=0.004, 95% confidence interval [CI]=1.6-12.3) and of suicide (HR=5.6, p<0.0001, 95% CI=2.4-12.9) INTERPRETATION: The true rate of familial ALS in Ireland is 16%. There is an overlap between ALS, FTD, and neuropsychiatric disease that is pronounced in kindreds with the C9orf72 repeat expansion, but is also present in kindreds of those without the C9orf72 expanded repeat.
JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective ther... more JAK4D, a first-in-class thyrotropin-releasing hormone (TRH)-based compound, is a prospective therapeutic candidate offering a multifaceted approach to treating neurodegeneration and other CNS conditions. The purpose of these studies was to determine the ability of JAK4D to bind to TRH receptors in human brain and to evaluate its neuropharmacological effects in neurodegenerative animal models. Additionally, JAK4D brain permeation was examined in mouse, and initial toxicology was assessed in vivo and in vitro. We report that JAK4D bound selectively with nanomolar affinity to native TRH receptors in human hippocampal tissue and showed for the first time that these receptors are pharmacologically distinct from TRH receptors in human pituitary, thus revealing a new TRH receptor subtype which represents a promising neurotherapeutic target in human brain. Systemic administration of JAK4D elicited statistically significant and clinically-relevant neuroprotective effects in three established...
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