Background

Half of the population of non-small cell lung cancer (NSCLC) patients are older than 70 years and have limited therapeutic options due to poor tolerance and being excluded in most clinical trials. Anlotinib hydrochloride, a novel oral multi-target tyrosine kinase inhibitor, has been approved for the standard third-line treatment for NSCLC in China. Herein we report an elderly NSCLC patient without any driver gene mutations who was undergoing anlotinib as a front-line treatment and who achieved long-term survival.

Case summary

The 77-year-old male patient was admitted to the hospital for chest tightness after engaging in physical activity for a week. The patient has been diagnosed with stage IIIB driver gene-negative squamous cell lung carcinoma. After that, he was treated with anlotinib for 2 years and 10 months from the first diagnosis until the last disease progression. Briefly, anlotinib combined with platinum-based chemotherapy was performed as the first-line therapy over six cycles. After 6 more cycles of anlotinib monotherapy maintenance, disease progression occurred. Then, anlotinib combined with tegafur was administered as a salvage treatment, and the disease was controlled again. After 29 cycles of anlotinib combined with tegafur regimens, the disease progressed finally. The patient achieved a total of 34 months of progression-free survival after anlotinib was used as the front-line treatment. He is still alive with a good performance status now (performance status score: 1).

Conclusion

This patient achieved long-term survival using anlotinib as a front-line regimen combined with chemotherapy.

Structural MRI (sMRI)-identified tissue "growth" after neuropsychological training has been reported in many studies but the origins of those apparent tissue changes (ATC) still remain elusive. One possible contributor to ATC is brain perfusion since T1-weighted MRI, the tool used to identify ATC, is sensitive to perfusion-change induced tissue T1 alterations. To test the hypothetical perfusion contribution to ATC, sMRI data were acquired before and after short-term global and regional perfusion manipulations via intaking a 200 mg caffeine pill and performing a sensorimotor task. Caffeine intake caused a global CBF reduction and apparent tissue density reduction in temporal cortex, anterior cingulate cortex, and the limbic area; sensorimotor task induced CBF increase and apparent tissue increase in spatially overlapped brain regions. After compensating CBF alterations through a voxel-wise regression, the ATC patterns demonstrated in both experiments were substantially suppressed. These data clearly proved existence of the perfusion contribution to short-term ATC, and suggested a need for correcting perfusion changes in longitudinal T1-weighted structural MRI analysis if a short-term design is used.

We examined whether the effect of the apolipoprotein E (APOE) genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared with ε3 homozygotes. More important, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared with either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer's disease, i.e., spinal fluid levels of tau, provided corresponding evidence for this gender-by-APOE interaction. Together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer's disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.

The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic-sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone. Here, we show that bvFTD is associated with reduced baseline cardiac vagal tone and that this reduction correlates with left-lateralized functional and structural frontoinsular and cingulate cortex deficits and with reduced agreeableness. Our results suggest that networked brain regions in the dominant hemisphere are critical for maintaining an adaptive level of baseline parasympathetic outflow.

The salience network is a distributed neural system that maintains homeostasis by regulating autonomic nervous system activity and social-emotional function. Here we examined how within-network connectivity relates to individual differences in human (including males and females) baseline parasympathetic and sympathetic nervous activity. We measured resting autonomic nervous system physiology in 24 healthy controls and 23 patients with behavioral variant frontotemporal dementia (bvFTD), a neurodegenerative disease characterized by baseline autonomic deficits. Participants also underwent structural and task-free fMRI. First, we used voxel-based morphometry to determine whether salience network atrophy was associated with lower baseline respiratory sinus arrhythmia (a parasympathetic measure) and skin conductance level (a sympathetic measure) in bvFTD. Next, we examined whether functional connectivity deficits in 21 autonomic-relevant, salience network node-pairs related to baseline autonomic dysfunction. Lower baseline respiratory sinus arrhythmia was associated with smaller volume in left ventral anterior insula (vAI), weaker connectivity between bilateral vAI and bilateral anterior cingulate cortex (ACC), and stronger connectivity between bilateral ACC and bilateral hypothalamus/amygdala. Lower baseline skin conductance level, in contrast, was associated with smaller volume in inferior temporal gyrus, dorsal mid-insula, and hypothalamus; weaker connectivity between bilateral ACC and right hypothalamus/amygdala; and stronger connectivity between bilateral dorsal anterior insula and periaqueductal gray. Our results suggest that baseline parasympathetic and sympathetic tone depends on the integrity of lateralized salience network hubs (left vAI for parasympathetic and right hypothalamus/amygdala for sympathetic) and highly calibrated ipsilateral and contralateral network connections. In bvFTD, deficits in this system may underlie resting parasympathetic and sympathetic disruption.SIGNIFICANCE STATEMENT The salience network maintains homeostasis and regulates autonomic nervous system activity. Whether within-network connectivity patterns underlie individual differences in resting parasympathetic and sympathetic nervous system activity, however, is not well understood. We measured baseline autonomic nervous system activity in healthy controls and patients with behavioral variant frontotemporal dementia, a neurodegenerative disease characterized by resting autonomic deficits, and probed how salience network dysfunction relates to diminished parasympathetic and sympathetic outflow. Our results indicate that baseline parasympathetic and sympathetic tone are the product of complex, opposing intranetwork nodal interactions and depend on the integrity of highly tuned, lateralized salience network hubs (i.e., left ventral anterior insula for parasympathetic activity and right hypothalamus/amygdala for sympathetic activity).

The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic-sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone. Here, we show that bvFTD is associated with reduced baseline cardiac vagal tone and that this reduction correlates with left-lateralized functional and structural frontoinsular and cingulate cortex deficits and with reduced agreeableness. Our results suggest that networked brain regions in the dominant hemisphere are critical for maintaining an adaptive level of baseline parasympathetic outflow.

Objective

Progressive supranuclear palsy (PSP) has been conceptualized as a large-scale network disruption, but the specific network targeted has not been fully characterized. We sought to delineate the affected network in patients with clinical PSP.

Methods

Using task-free functional magnetic resonance imaging, we mapped intrinsic connectivity to the dorsal midbrain tegmentum (dMT), a region that shows focal atrophy in PSP. Two healthy control groups (1 young, 1 older) were used to define and replicate the normal connectivity pattern, and patients with PSP were compared to an independent matched healthy control group on measures of network connectivity.

Results

Healthy young and older subjects showed a convergent pattern of connectivity to the dMT, including brainstem, cerebellar, diencephalic, basal ganglia, and cortical regions involved in skeletomotor, oculomotor, and executive control. Patients with PSP showed significant connectivity disruptions within this network, particularly within corticosubcortical and cortico-brainstem interactions. Patients with more severe functional impairment showed lower mean dMT network connectivity scores.

Interpretation

This study defines a PSP-related intrinsic connectivity network in the healthy brain and demonstrates the sensitivity of network-based imaging methods to PSP-related physiological and clinical changes.

The salience network is a distributed neural system that maintains homeostasis by regulating autonomic nervous system activity and social-emotional function. Here we examined how within-network connectivity relates to individual differences in human (including males and females) baseline parasympathetic and sympathetic nervous activity. We measured resting autonomic nervous system physiology in 24 healthy controls and 23 patients with behavioral variant frontotemporal dementia (bvFTD), a neurodegenerative disease characterized by baseline autonomic deficits. Participants also underwent structural and task-free fMRI. First, we used voxel-based morphometry to determine whether salience network atrophy was associated with lower baseline respiratory sinus arrhythmia (a parasympathetic measure) and skin conductance level (a sympathetic measure) in bvFTD. Next, we examined whether functional connectivity deficits in 21 autonomic-relevant, salience network node-pairs related to baseline autonomic dysfunction. Lower baseline respiratory sinus arrhythmia was associated with smaller volume in left ventral anterior insula (vAI), weaker connectivity between bilateral vAI and bilateral anterior cingulate cortex (ACC), and stronger connectivity between bilateral ACC and bilateral hypothalamus/amygdala. Lower baseline skin conductance level, in contrast, was associated with smaller volume in inferior temporal gyrus, dorsal mid-insula, and hypothalamus; weaker connectivity between bilateral ACC and right hypothalamus/amygdala; and stronger connectivity between bilateral dorsal anterior insula and periaqueductal gray. Our results suggest that baseline parasympathetic and sympathetic tone depends on the integrity of lateralized salience network hubs (left vAI for parasympathetic and right hypothalamus/amygdala for sympathetic) and highly calibrated ipsilateral and contralateral network connections. In bvFTD, deficits in this system may underlie resting parasympathetic and sympathetic disruption.SIGNIFICANCE STATEMENT The salience network maintains homeostasis and regulates autonomic nervous system activity. Whether within-network connectivity patterns underlie individual differences in resting parasympathetic and sympathetic nervous system activity, however, is not well understood. We measured baseline autonomic nervous system activity in healthy controls and patients with behavioral variant frontotemporal dementia, a neurodegenerative disease characterized by resting autonomic deficits, and probed how salience network dysfunction relates to diminished parasympathetic and sympathetic outflow. Our results indicate that baseline parasympathetic and sympathetic tone are the product of complex, opposing intranetwork nodal interactions and depend on the integrity of highly tuned, lateralized salience network hubs (i.e., left ventral anterior insula for parasympathetic activity and right hypothalamus/amygdala for sympathetic activity).

Background

In Alzheimer's disease (AD), the gradual accumulation of amyloid-β (Aβ) and tau proteins may underlie alterations in empathy.

Objective

To assess whether tau aggregation in the medial temporal lobes related to differences in cognitive empathy (the ability to take others' perspectives) and emotional empathy (the ability to experience others' feelings) in AD.

Methods

Older adults (n = 105) completed molecular Aβ positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aβ positive and symptomatic with diagnoses of mild cognitive impairment, dementia of the Alzheimer's type, logopenic variant primary progressive aphasia, or posterior cortical atrophy. The remaining 37 (22 women) were asymptomatic Aβ negative healthy older controls. Using the Interpersonal Reactivity Index, we compared current levels of informant-rated cognitive empathy (Perspective-Taking subscale) and emotional empathy (Empathic Concern subscale) in the Aβ positive and negative participants. The Aβ positive participants also underwent molecular tau-PET scans, which were used to investigate whether regional tau burden in the bilateral medial temporal lobes related to empathy.

Results

Aβ positive participants had lower perspective-taking and higher empathic concern than Aβ negative healthy controls. Medial temporal tau aggregation in the Aβ positive participants had divergent associations with cognitive and emotional empathy. Whereas greater tau burden in the amygdala predicted lower perspective-taking, greater tau burden in the entorhinal cortex predicted greater empathic concern. Tau burden in the parahippocampal cortex did not predict either form of empathy.

Conclusions

Across AD clinical syndromes, medial temporal lobe tau aggregation is associated with lower perspective-taking yet higher empathic concern.