Although autism can be diagnosed at any age, it is described as a “developmental disorder” because symptoms generally appear in the first 2 years of life. https://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-asd
zeitgeber とは、ドイツ語で英語でいうとtime giverだそうです。time giver timeというとますますわからないですね。zeitgeberのzeitはtimeというよりも時間周期を与えるキュー（刺激）みたいに捉えたほうがしっくりきます。
“Zeitgeber” in German is “Time giver” in English and refers to the “agent of entrainment”. https://ruo.mbl.co.jp/bio/e/product/circadian/exuse/per1-2.html
下の説明が非常にわかりやすく、徹底的です。
A zeitgeber is any environmental cue that can be used by an organism to align its endogenous rhythm with the external day-night cycle. So far we have focused mainly on light as it is the most common zeitgeber, but there are other zeitgebers as well.
the experimental manipulations that chronobiologists impose lead to two new ways of talking about time. When an organism is free-running, we speak of circadian time (CT). When an organism is entrained to an artificially-imposed, environmental daily cycle, we speak of zeitgeber time (ZT).
the peak of mRNA abundance (phase) Peak times (phase) and amplitudes are summarized in circle plots. the peak times (also referred to as phases) of pre-mRNA accumulation for cycling genes https://www.pnas.org/doi/10.1073/pnas.1715225115 この論文では位相（遺伝子発現のピーク）をZT(zeitgeber time）で表示しています。
phase (the maximum peak of expression of a certain gene) https://stackoverflow.com/questions/30463959/circadian-phase-plot-in-r
Parkinson’s disease is characterized by the presence of abnormal, intraneuronal α-synuclein aggregates, which may propagate from cell-to-cell in a prion-like manner. However, it remains uncertain where the initial α-synuclein aggregates originate. We have hypothesized that Parkinson’s disease comprises two subtypes. A brain-first (top-down) type, where α-synuclein pathology initially arises in the brain with secondary spreading to the peripheral autonomic nervous system; and a body-first (bottom-up) type, where the pathology originates in the enteric or peripheral autonomic nervous system and then spreads to the brain. https://academic.oup.com/brain/article/143/10/3077/5896254
The hypothesis of body-first vs. brain-first subtype of PD has been proposed with REM-Sleep behavior disorder (RBD) defining the former. The body-first PD presumes an involvement of the brainstem in the pathogenic process with higher burden of autonomic dysfunction. https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd223511
Brain-first and body-first Parkinson’s disease: are there subgroups of prodromal patients? VJNeurology チャンネル登録者数 4480人
How valid is the brain-first vs body-first model of Parkinson’s disease? VJNeurology チャンネル登録者数 4480人 Alberto Espay, MD, FAAN, University of Cincinnati, Cincinnati, OH
Brain-first and body-first仮説に関するレビュー論文
Neurobiology of Disease Clinical and imaging evidence of brain-first and body-first Parkinson’s diseaseNeurobiology of Disease Volume 164, March 2022, 105626 Braak‘s hypothesis has been extremely influential over the last two decades. By using REM-sleep behavior disorder (RBD) as a clinical identifier to distinguish between body-first PD (RBD-positive at motor symptom onset) and brain-first PD (RBD-negative at motor symptom onset), we explored the literature to evaluate clinical and imaging differences between these proposed subtypes.
Braak’s Hypothesis: This theory suggests that Parkinson’s disease may start in the peripheral nervous system or the gut and then progress to the brain. According to this hypothesis, abnormal alpha-synuclein protein aggregates may initiate the disease process in the enteric nervous system and later spread to the brain through the vagus nerve. https://chat.openai.com/
It has been hypothesized that α-synucleininclusions initially form in nerve terminals of the enteric nervous system, and then subsequently spread via autonomic connections to the dorsal motor nucleus of the vagus and intermediolateral cell columns of the sympathetic system (Braak et al., 2003a, b; Borghammer, 2018).
(引用元：Brain-first versus body-first Parkinson’s disease: a multimodal imaging case-control study Brain, Volume 143, Issue 10, October 2020, Pages 3077–3088, https://doi.org/10.1093/brain/awaa238）PDF
The intermediolateral nucleus (IML) is a region of grey matter found in one of the three grey columns of the spinal cord, the lateral grey column. The intermediolateral cell column exists at vertebral levels T1 – L3. It mediates the entire sympathetic innervation of the body, but the nucleus resides in the grey matter of the spinal cord.
デュアルヒット仮説とは
the idea that PD pathology may in fact originate in synapses of the peripheral nervous system (PNS) and invade the brain from the olfactory epithelium and via retrograde axonal transport through the vagus, termed the dual-hit hypothesis [4]. https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd191721
The progressive, neurodegenerative process underlying idiopathic Parkinson’s disease is associated with the formation of proteinaceous inclusion bodies that involve a few susceptible neuronal types of the human nervous system. In the lower brain stem, the process begins in the dorsal motor nucleus of the vagus nerve and advances from there essentially upwards through susceptible regions of the medulla oblongata, pontine tegmentum, midbrain, and basal forebrain until it reaches the cerebral cortex. With time, multiple components of the autonomic, limbic, and motor systems become severely impaired. All of the vulnerable subcortical grays and cortical areas are closely interconnected. Incidental cases of idiopathic Parkinson’s disease may show involvement of both the enteric nervous system and the dorsal motor nucleus of the vagus nerve. This observation, combined with the working hypothesis that the stereotypic topographic expansion pattern of the lesions may resemble that of a falling row of dominos, prompts the question whether the disorder might originate outside of the central nervous system, caused by a yet unidentified pathogen that is capable of passing the mucosal barrier of the gastrointestinal tract and, via postganglionic enteric neurons, entering the central nervous system along unmyelinated praeganglionic fibers generated from the visceromotor projection cells of the vagus nerve.
J Neural Transm (Vienna) . 2003 May;110(5):517-36. doi: 10.1007/s00702-002-0808-2. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen H Braak 1, U Rüb, W P Gai, K Del Tredici Affiliations expand PMID: 12721813 DOI: 10.1007/s00702-002-0808-2
レビー小体とは
Lewy bodies (LBs) are complex, intracellular inclusions that are common pathological features of many neurodegenerative diseases. They consist largely of aggregated forms of the protein alpha-Synuclein (α-Syn), which misfolds to give rise to beta-sheet rich amyloid fibrils. The aggregation of monomers into fibrils occurs readily in vitro and pre-formed fibrils (PFFs) generated from recombinant α-Syn monomers are the basis of many models of LB diseases. https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01288-2
Metaiodobenzylguanidine (MIBG) とは
Metaiodobenzylguanidine (MIBG) was first developed in USA, in Michigan University Medical Centre, in early 1970, for imaging the adrenal medulla and its disease.1 MIBG, a guanithidine analog, is taken up by an active mechanism into the neuroendocrine cells due to its similarities with nor-epinephrine. It came into clinical practice in 1981 for localization of pheochromocytoma (pheo).2 In course of time, MIBG demonstrated its ability to concentrate in tumors of the neural crest origin such as neuroblastoma (NBL),3 carcinoids and medullary carcinoma of the thyroid.4, 5 Due to good selective uptake and retention of MIBG by these tumors, its potential was explored for therapy of neuroendocrine tumors (NETs) as well. MIBG is labeled with 123-Iodine (123I) which is exclusively used for imaging and also with 131-Iodine (131I); which can be used both for imaging and therapy of NBL or other MIBG avid neural crest tumors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6475939/
