Initial non-amnestic symptoms relate to faster rate of functional and cognitive decline compared to amnestic symptoms in neuropathologically confirmed dementias.

INTRODUCTION: The relationship between initial cognitive symptoms and subsequent rate of clinical decline is important in clinical care and the design of dementia clinical trials. METHODS: This retrospective longitudinal, autopsy-confirmed, cohort study among 2426 participants in the National Alzheimer's Coordinating Center database included Alzheimer's disease (AD) pathology, n = 1187; Lewy body pathology (LBP), n = 331; and mixed pathology (AD-LBP), n = 904. The predominant initial cognitive symptom was assessed clinically. Linear mixed models evaluated the longitudinal outcome of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score. RESULTS: Non-amnestic initial symptoms had a faster rate of decline than amnestic symptoms in all three groups. Language symptoms had a faster rate of decline in all three groups. Executive symptoms had a faster rate of decline than amnestic in AD and AD-LBP. There was a similar trend for visuospatial symptoms in AD-LBP. DISCUSSION: Initial cognitive symptoms, despite varied underlying pathology, are a predictor of longitudinal functional outcomes among dementias. HIGHLIGHTS: Initial non-amnestic symptoms had a faster rate of longitudinal cognitive and functional decline on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores than amnestic symptoms among Alzheimer's disease, Lewy body pathology, and mixed neuropathology. Given the relative size of CDR-SB changes in Alzheimer's disease clinical trials, clarifying the nature of initial symptoms could be an important variable in ensuring appropriately designed clinical trials.

Insulin sensing by astrocytes is critical for normal thermogenesis and body temperature regulation.

The important role of astrocytes in the central control of energy balance and glucose homeostasis has recently been recognized. Changes in thermoregulation can lead to metabolic dysregulation, but the role of astrocytes in this process is not yet clear. Therefore, we generated mice congenitally lacking insulin receptors (Ir) in astrocytes (IrKOGFAP mice) to investigate the involvement of astrocyte insulin signaling. IrKOGFAP mice displayed significantly lower energy expenditure and a strikingly lower basal and fasting body temperature. When exposed to cold, however, they were able to mount a thermogenic response. IrKOGFAP mice displayed sex differences in metabolic function and thermogenesis that may contribute to the development of obesity and type II diabetes as early as 2 months of age. While brown adipose tissue exhibited higher adipocyte size in both sexes, more apoptosis was seen in IrKOGFAP males. Less innervation and lower BAR3 expression levels were also observed in IrKOGFAP brown adipose tissue. These effects have not been reported in models of astrocyte Ir deletion in adulthood. In contrast, body weight and glucose regulatory defects phenocopied such models. These findings identify a novel role for astrocyte insulin signaling in the development of normal body temperature control and sympathetic activation of BAT. Targeting insulin signaling in astrocytes has the potential to serve as a novel target for increasing energy expenditure.

Migraine and Ischemic Stroke in Women. A Narrative Review.

OBJECTIVE/BACKGROUND: Migraine is associated with ischemic stroke. Women are 3-fold as likely as men to have migraine, and high estrogen states increase the risk of migraine with aura (MWA), venous thromboembolism (VTE), and of stroke. We review the epidemiological and mechanistic evidence of the migraine-stroke relationship and its risk factors, with a focus on women and conditions that exclusively or predominantly affect them.  METHODS: We performed a search of MEDLINE/PubMed database, then a narrative review of the epidemiological evidence of the migraine-stroke relationship as well as the evidence for arterial, thrombophilic, and cardiac mechanisms to explain this connection. We examine the implications of this evidence for the diagnostic evaluation and treatment of MWA. RESULTS: MWA is associated with multiple stroke risk factors, such as hypertension, hyperlipidemia, diabetes mellitus, cigarette smoking, atrial fibrillation, and patent foramen ovale. In women, MWA is also associated with biomarkers of endothelial activation, hormonal contraceptive use, pregnancy, and VTE. This suggests that a subset of auras may be secondary, that is, induced by ischemia related to microemboli or in situ thrombosis. MWA-associated ischemic stroke is more common in young (<45 years old) women with high frequency of migraine attacks, hormonal contraception use, and with pregnancy and preeclampsia. There is increasing evidence that cardioembolism, often in conjunction with thrombophilia, plays a prominent role in MWA-associated cerebral infarction. CONCLUSION: The commonality of factors associated with MWA and with MWA-associated stroke suggest that persons with secondary, ischemia-induced aura may be at elevated risk of stroke. Although further research is needed, we recommend consideration of a diagnostic evaluation of MWA that mirrors the evaluation of transient ischemic attack, given that prophylactic treatment targeting the ischemic origin of secondary aura may prevent migraine as well as stroke.