Histaminergic tuberomammillary neuron loss in multiple system atrophy and dementia with Lewy bodies

Benarroch, Eduardo E.; Schmeichel, Ann M.; Parisi, Joseph E.; Low, Phillip A.

doi:10.1002/mds.26287

Cited by 15 publications

(9 citation statements)

References 28 publications

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“…However, we noticed a subsignificant signal within the HRH1 gene, encoding the histamine receptor H1 that is widely expressed within the central nervous system. Histaminergic dysregulation is a crucial feature of Alzheimer's disease and DLB, 26,27 making HRH1 a plausible risk gene. However, additional genetic association studies will be required to determine the importance of this observation.…”

Section: Discussionmentioning

confidence: 99%

Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups

Kaivola

Shah

Chia

et al. 2021

Brain

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The APOE locus is strongly associated with risk for developing Alzheimer’s disease and dementia with Lewy bodies. In particular, the role of the APOE ε4 allele as a putative driver of α-synuclein pathology is a topic of intense debate. Here, we performed a comprehensive evaluation in 2466 dementia with Lewy bodies cases versus 2928 neurologically healthy, aged controls. Using an APOE-stratified genome-wide association study approach, we found that GBA is associated with risk for dementia with Lewy bodies in patients without APOE ε4 (P = 6.58 × 10−9, OR = 3.41, 95% CI = 2.25–5.17), but not with dementia with Lewy bodies with APOE ε4 (P = 0.034, OR = 1.87, 95%, 95% CI = 1.05–3.37). We then divided 495 neuropathologically examined dementia with Lewy bodies cases into three groups based on the extent of concomitant Alzheimer’s disease co-pathology: pure dementia with Lewy bodies (n = 88), dementia with Lewy bodies with intermediate Alzheimer’s disease co-pathology (n = 66) and dementia with Lewy bodies with high Alzheimer’s disease co-pathology (n = 341). In each group, we tested the association of the APOE ε4 against the 2928 neurologically healthy controls. Our examination found that APOE ε4 was associated with dementia with Lewy bodies + Alzheimer’s disease (P = 1.29 × 10−32, OR = 4.25, 95% CI = 3.35–5.39) and dementia with Lewy bodies + intermediate Alzheimer’s disease (P = 0.0011, OR = 2.31, 95% CI = 1.40–3.83), but not with pure dementia with Lewy bodies (P = 0.31, OR = 0.75, 95% CI = 0.43–1.30). In conclusion, although deep clinical data were not available for these samples, our findings do not support the notion that APOE ε4 is an independent driver of α-synuclein pathology in pure dementia with Lewy bodies, but rather implicate GBA as the main risk gene for the pure dementia with Lewy bodies subgroup.

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Section: Discussionmentioning

confidence: 99%

Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups

Kaivola

Shah

Chia

et al. 2021

Brain

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“…This effect is also associated with OT anxiolytic, anti-depression and sedating effects as well as its increasing emotional stability as shown in postpartum women ( Comasco et al, 2016 ). In addition, OT fibers also innervate the mammillary body complex as shown in mice ( Liao et al, 2020 ) that participates in sleep regulation, memory and many other functions ( Benarroch et al, 2015 ). Thus, OT could modulate sleep by modulating the activity of mammillary body cells.…”

Section: Instinctive Behaviorsmentioning

confidence: 99%

Neural Functions of Hypothalamic Oxytocin and its Regulation

Wang

Liu

et al. 2022

ASN Neuro

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Oxytocin (OT), a nonapeptide, has a variety of functions. Despite extensive studies on OT over past decades, our understanding of its neural functions and their regulation remains incomplete. OT is mainly produced in OT neurons in the supraoptic nucleus (SON), paraventricular nucleus (PVN) and accessory nuclei between the SON and PVN. OT exerts neuromodulatory effects in the brain and spinal cord. While magnocellular OT neurons in the SON and PVN mainly innervate the pituitary and forebrain regions, and parvocellular OT neurons in the PVN innervate brainstem and spinal cord, the two sets of OT neurons have close interactions histologically and functionally. OT expression occurs at early life to promote mental and physical development, while its subsequent decrease in expression in later life stage accompanies aging and diseases. Adaptive changes in this OT system, however, take place under different conditions and upon the maturation of OT release machinery. OT can modulate social recognition and behaviors, learning and memory, emotion, reward, and other higher brain functions. OT also regulates eating and drinking, sleep and wakefulness, nociception and analgesia, sexual behavior, parturition, lactation and other instinctive behaviors. OT regulates the autonomic nervous system, and somatic and specialized senses. Notably, OT can have different modulatory effects on the same function under different conditions. Such divergence may derive from different neural connections, OT receptor gene dimorphism and methylation, and complex interactions with other hormones. In this review, brain functions of OT and their underlying neural mechanisms as well as the perspectives of their clinical usage are presented.

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“…The medullary catecholaminergic and serotonergic systems are involved even in the early stages of MSA, and dysfunction of the medullary serotonergic system could be responsible for sudden death [ 278 ]. Further involved areas are the dorsal vagal nucleus [ 267 ], the periaqueductal gray [ 150, 279 ], the Edinger-Westphal nucleus and posterior hypothalamus [ 280 ] including the histaminergic tuberomamillary neurons [ 281 ], the tuberomammillary nucleus [ 280, 282 ], and suprachiasmatic nucleus [ 267 ]. Affected is also the ponto-medullary reticular formation [ 160, 283 ], while the branchimotor neurons of the nucleus ambiguus are preserved [ 284 ].…”

Section: Neuropathologymentioning

confidence: 99%

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

Jellinger¹

2018

JAD

151

142

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Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein in both glia (mainly oligodendroglia) and neurons forming glial and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded α-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a “prion-like” manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.

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Histaminergic tuberomammillary neuron loss in multiple system atrophy and dementia with Lewy bodies

Abstract: Loss of tuberomammillary histaminergic neurons could potentially contribute to motor, sleep, and autonomic manifestations of both multiple system atrophy and dementia with Lewy bodies.

Cited by 15 publications

References 28 publications

Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups

Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups

Neural Functions of Hypothalamic Oxytocin and its Regulation

Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy1

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