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![CalbindinD28k immunohistochemistry on 100-μm cerebellar neocortex sections across diagnoses. Several categories of morphologic changes in Purkinje cells are identified, including cell body loss, heterotopia (white arrow, b, c, f, g, n, p), dendrite swelling (white caret, b–f, h, p), and axonal changes including torpedoes (large black arrow, b–h, n–p), thickened axons (arrowhead, b, c [inset], d–h, n, o) and recurrent collaterals on torpedo bearing axons (black caret, h, j–o). a Normal appearance of Purkinje cell dendrites and cell bodies and thin axon profiles in the granule cell layer of a control. b, c SCA3 and Friedreich’s ataxia (FA) with intermediate axonal changes including torpedoes, thickened axons and recurrent collaterals. Heterotopic Purkinje cells and dendrite swellings are present. In FA, a focus with multiple torpedoes associated with recurrent collaterals is shown (inset, c). d Axonal changes and Purkinje cell loss are more prominent in essential tremor (ET). A dendrite swelling is present. e–i Spectrum of changes in SCA1/2/6/7/8 with moderate to severe Purkinje cell body and dendrite loss, abundant torpedoes, thickened axons and torpedo associated recurrent collaterals. J–m Foci in ET (j), SCA1 (k), SCA2 (l) and SCA7 (m) where there are clusters of torpedo bearing axons with recurrent collaterals. n–o Spectrum of change in MSA, being mild in cases with predominant striatonigral degeneration (MSA-SND, n) and severe in cases with predominant olivopontocerebellar atrophy (MSA-OPCA, p). In MSA with mixed striatonigral and olivopontocerebellar atrophy (MSA-SNA-OPCA, o), there are numerous torpedoes that predominantly have recurrent collaterals. SCA spinocerebellar ataxia, MSA multiple system atrophy. Scale bar, 100 μm in m, p, inset in c](profile/Phyllis-Faust/publication/366927056/figure/fig3/AS:11431281120012431@1676343820991/CalbindinD28k-immunohistochemistry-on-100-mm-cerebellar-neocortex-sections-across.jpg)
CalbindinD28k immunohistochemistry on 100-μm cerebellar neocortex sections across diagnoses. Several categories of morphologic changes in Purkinje cells are identified, including cell body loss, heterotopia (white arrow, b, c, f, g, n, p), dendrite swelling (white caret, b–f, h, p), and axonal changes including torpedoes (large black arrow, b–h, n–p), thickened axons (arrowhead, b, c [inset], d–h, n, o) and recurrent collaterals on torpedo bearing axons (black caret, h, j–o). a Normal appearance of Purkinje cell dendrites and cell bodies and thin axon profiles in the granule cell layer of a control. b, c SCA3 and Friedreich’s ataxia (FA) with intermediate axonal changes including torpedoes, thickened axons and recurrent collaterals. Heterotopic Purkinje cells and dendrite swellings are present. In FA, a focus with multiple torpedoes associated with recurrent collaterals is shown (inset, c). d Axonal changes and Purkinje cell loss are more prominent in essential tremor (ET). A dendrite swelling is present. e–i Spectrum of changes in SCA1/2/6/7/8 with moderate to severe Purkinje cell body and dendrite loss, abundant torpedoes, thickened axons and torpedo associated recurrent collaterals. J–m Foci in ET (j), SCA1 (k), SCA2 (l) and SCA7 (m) where there are clusters of torpedo bearing axons with recurrent collaterals. n–o Spectrum of change in MSA, being mild in cases with predominant striatonigral degeneration (MSA-SND, n) and severe in cases with predominant olivopontocerebellar atrophy (MSA-OPCA, p). In MSA with mixed striatonigral and olivopontocerebellar atrophy (MSA-SNA-OPCA, o), there are numerous torpedoes that predominantly have recurrent collaterals. SCA spinocerebellar ataxia, MSA multiple system atrophy. Scale bar, 100 μm in m, p, inset in c
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In recent years, numerous morphologic changes have been identified in the essential tremor (ET) cerebellar cortex, distinguishing ET from control brains. These findings have not been fully contextualized within a broader degenerative disease spectrum, thus limiting their interpretability. Building off our prior study and now doubling the sample siz...
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Background: Cerebellar atrophy is the neuropathological hallmark of most ataxias. Hence, quantifying the volume of the cerebellar grey and white matter is of great interest. In this study, we aim to identify volume differences in the cerebellum between spinocerebellar ataxia type 1 (SCA1), SCA3 and SCA6 as well as multiple system atrophy of cerebel...
Citations
... The ETCBR, which was established in 2003 and serves ET cases throughout the United States, is a longstanding, joint collaboration between investigators at University Texas Southwestern Medical Center and Columbia Universities. 7,11,18,28 ET diagnoses were assigned by a senior movement disorders neurologist specializing in tremor (E.D.L.), using three sequential methods, as has been our practice for 20 years, and as employed in over 50 publications. 7,8,11,14,18,28 First, the clinical diagnosis of ET was initially assigned by treating neurologist(s), and second, confirmed by E.D.L. who reviewed semi-structured clinical questionnaires, medical records, and Archimedes spirals and who used the following criteria: (i) moderate or greater amplitude kinetic tremor (i.e., a severity rating ≥2 29 ) in at least one of the submitted Archimedes spirals; (ii) no history of PD or dystonia; and (iii) no other etiology for tremor (e.g., medication-induced tremor and hyperthyroidism). ...
... 7,11,18,28 ET diagnoses were assigned by a senior movement disorders neurologist specializing in tremor (E.D.L.), using three sequential methods, as has been our practice for 20 years, and as employed in over 50 publications. 7,8,11,14,18,28 First, the clinical diagnosis of ET was initially assigned by treating neurologist(s), and second, confirmed by E.D.L. who reviewed semi-structured clinical questionnaires, medical records, and Archimedes spirals and who used the following criteria: (i) moderate or greater amplitude kinetic tremor (i.e., a severity rating ≥2 29 ) in at least one of the submitted Archimedes spirals; (ii) no history of PD or dystonia; and (iii) no other etiology for tremor (e.g., medication-induced tremor and hyperthyroidism). 7,11,18,28 Third, a detailed, videotaped, neurological examination was performed, from which action tremor was rated on numerous tasks (e.g., pouring, drinking, using a spoon, finger-nose-finger maneuver, and spiral drawing) and a total tremor score assigned (range = 0-36 [maximum]). ...
... 7,8,11,14,18,28 First, the clinical diagnosis of ET was initially assigned by treating neurologist(s), and second, confirmed by E.D.L. who reviewed semi-structured clinical questionnaires, medical records, and Archimedes spirals and who used the following criteria: (i) moderate or greater amplitude kinetic tremor (i.e., a severity rating ≥2 29 ) in at least one of the submitted Archimedes spirals; (ii) no history of PD or dystonia; and (iii) no other etiology for tremor (e.g., medication-induced tremor and hyperthyroidism). 7,11,18,28 Third, a detailed, videotaped, neurological examination was performed, from which action tremor was rated on numerous tasks (e.g., pouring, drinking, using a spoon, finger-nose-finger maneuver, and spiral drawing) and a total tremor score assigned (range = 0-36 [maximum]). 7,11,18,28 These ratings and clinical questionnaire data were used to assign a final diagnosis of ET, 7,11,18,28 using previously published diagnostic criteria (moderate or greater amplitude kinetic tremor [tremor rating ≥2] during three or more activities or a head tremor in the absence of PD or other known causes), 29 which have been shown to be both reliable and valid. ...
Objective
Essential tremor is among the most prevalent neurological diseases. Diagnosis is based entirely on neurological evaluation. Historically, there were few postmortem brain studies, hindering attempts to develop pathologically based criteria to distinguish essential tremor from control brains. However, an intensive effort to bank essential tremor brains over recent years has resulted in postmortem studies involving >200 brains, which have identified numerous degenerative changes in the essential tremor cerebellar cortex. Although essential tremor and controls have been compared with respect to individual metrics of pathology, there has been no overarching analysis to derive a combination of metrics to distinguish essential tremor from controls. We asked whether there is a constellation of pathological findings that separates essential tremor from controls, and how well that constellation performs.
Methods
Analyses included 100 essential tremor brains from the essential tremor centralized brain repository and 50 control brains. A standard tissue block from the cerebellar cortex was used to quantify 11 metrics of pathological change. Three supervised classification algorithms were investigated, with data divided into training and validation samples.
Results
Using three different algorithms, we illustrate the ability to correctly predict a diagnosis of essential tremor, with sensitivity and specificity >87%, and in the majority of situations, >90%. We also provide a web‐based application that uses these metric values, and based on specified cutoffs, determines the likely diagnosis.
Interpretation
These analyses set the stage for use of pathologically based criteria to distinguish clinically diagnosed essential tremor cases from controls, at the time of postmortem.
... [7][8][9][10] Neuropathological observations further suggest involvement of the cerebellum in ET's pathophysiology, as demonstrated by a loss of Purkinje cells, swelling of Purkinje cell bodies, 11 and abnormal synaptic connection formation of climbing fibers with Purkinje cells. [12][13][14][15] Ethanol has been reported to improve tremor severity in two-thirds to three-fourths of patients with ET who report that they drink alcohol. 8,16,17 However, this metric relies on self-reported response data and may imply that ethanol response-or consequently also the lack thereofin ET represents a specific phenotype within ET. ...
... drinks, with 26.5 (10-75) drinking days in the past 90 days. Nonresponders reported a median 18 (6-31) drinks, with 18 (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) drinking days in the past 90 days (Table 1). ...
Background and Objectives
Ethanol has been reported to improve tremor severity in approximately two thirds of patients with essential tremor (ET), but the accuracy of that proportion is not certain and the mechanism of action is unknown. The goal of this study was to investigate alcohol response on tremor by applying an a priori objective response definition and subsequently to describe the responder rate to a standardized ethanol dose in a cohort of 85 ET patients. A secondary analysis evaluated other tremor and nontremor features, including demographics, tremor intensity, breath alcohol concentration, nontremor effects of alcohol, self-reported responder status to ethanol, and prior ethanol exposure.
Methods
This was a prospective, open-label, single-dose challenge of oral ethanol during which motor and nonmotor measurements were obtained starting immediately prior to ethanol administration and subsequently every 20 min for 120 min. We defined tremor reduction as a 35% decline in power in the patient's tremor frequency recorded during spiral drawing 60 min after ethanol administration.
Results
In total, 80% of patients were considered alcohol responsive using our objective definition. Responder status and change in the objective tremor metrics were significantly correlated with the change in breath alcohol concentration levels after ethanol administration, but no other relationships to nontremor metrics were found.
Discussion
A high percentage of patients actually respond to acute ethanol. However, their self-reported response does not correlate well with their objective response. Objective response correlates with breath alcohol level but not with sedation, indicating a specific effect of ethanol on tremor.
... Cerebellar pathophysiology is also strongly associated with movement disorders that have different motor disturbances, namely tremor [31][32][33][34] and ataxia [35][36][37]. Even though these three movement disorders can often occur together, they can also occur as independent conditions, which suggests that there may be overlapping features as well as unique pathophysiological signatures for dystonia, tremor, and ataxia [38,39]. Yet, it remains unclear how dysfunction in one brain region, the cerebellum, can cause these three distinct motor disorders. ...
Dystonia is a movement disorder characterized by involuntary co- or over-contractions of the muscles, which results in abnormal postures and movements. These symptoms arise from the pathophysiology of a brain-wide dystonia network. There is mounting evidence suggesting that the cerebellum is a central node in this network. For example, manipulations that target the cerebellum cause dystonic symptoms in mice, and cerebellar neuromodulation reduces these symptoms. Although numerous findings provide insight into dystonia pathophysiology, they also raise further questions. Namely, how does cerebellar pathophysiology cause the diverse motor abnormalities in dystonia, tremor, and ataxia? Here, we describe recent work in rodents showing that distinct cerebellar circuit abnormalities could define different disorders and we discuss potential mechanisms that determine the behavioral presentation of cerebellar diseases.
... We added one additional metric that assesses climbing fiber synaptic density, which was also found to provide good disease distinction. These eleven metrics are: [55,63]. PC axons with a torpedo are more likely to have a recurrent collateral. ...
Objective
Despite being one of the most prevalent neurological diseases, the pathophysiology of essential tremor (ET) is not fully understood. Neuropathological studies have identified numerous degenerative changes in the cerebellum of ET patients, however. These data align with considerable clinical and neurophysiological data linking ET to the cerebellum. While neuroimaging studies have variably shown mild atrophy in the cerebellum, marked atrophy is not a clear feature of the cerebellum in ET and a search for a more suitable neuroimaging signature of neurodegeneration is in order. Postmortem studies in ET have examined different neuropathological alterations in the cerebellum, but as of yet have not focused on measures of generalized synaptic markers. This pilot study focuses on synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in practically all synapses in the brain, as a measure of synaptic density in postmortem ET cases.
Methods
The current study utilized autoradiography with the SV2A radioligand [¹⁸F]SDM-16 to assess synaptic density in the cerebellar cortex and dentate nucleus in three ET cases and three age-matched controls.
Results
Using [¹⁸F]SDM-16, SV2A was 53% and 46% lower in the cerebellar cortex and dentate nucleus, respectively, in ET cases compared to age-matched controls.
Conclusion
In this pilot study, using in vitro SV2A autoradiography, we have observed significantly lower synaptic density in the cerebellar cortex and dentate nucleus of ET cases. Future research could expand on our sample size and focus on in vivo imaging in ET to explore whether SV2A imaging could serve as a much-needed disease biomarker.
... The cardinal symptom of ET is an action tremor that mainly affects the upper limbs but can also involve the head, voice, and other body regions (2,3). Pathological studies, disease course, and age-related prevalence provide evidence that ET is a cerebellar neurodegenerative disease associated with morphologic changes centered around the Purkinje cells (PC) of the cerebellar cortex with heterotopic PC, PC loss, PC axonal swelling, and redistribution of climbing fiber synapses to the outer PC dendritic arbor (4). Conventional structural imaging does not disclose a specific pattern of atrophy neither in the cerebellum nor in the hemispheric cortices, but diffusion tensor imaging (DTI) consistently shows across studies of microstructural alterations of the . ...
Background
Essential tremor (ET) is a movement disorder characterized by cerebellar neurodegenerative changes. ET is also associated with non-motor symptoms including cognitive impairment. The neuropsychologic profile of a patient with ET could relate to cerebellar cognitive affective syndrome (CCAS).
Objective
This study aimed to assess the prevalence of cognitive impairment in patients with ET and identify whether the cognitive impairment in ET corresponds to a CCAS.
Methods
Cognitive functions were evaluated with the CCAS-Scale (CCAS-S) in 20 patients with ET and 20 controls matched for age, sex, and level of education. The results of the CCAS-S were compared between patients and controls. The underlying determinant of CCAS inpatients with ET was identified through the correlation between the results of the CCAS-S and age at onset of symptoms, disease duration, and the Essential Tremor Rating Assessment Scale (TETRAS).
Results
On a group level, ET patients performed significantly worse than matched controls. In total, 13 individuals with ET had a definite CCAS (CCAS-S failed items ≥ 3). ASO and TETRAS scores significantly correlated with CCAS-S performances in ET patients.
Conclusion
CCAS is highly prevalent in patients with ET which supports the cerebellar pathophysiology of associated cognitive impairment and supports a more systematic use of the CCAS-S to cognitively assessed patients with ET.
... A broad range of clinical and imaging studies link ET to the cerebellum [1][2][3][4][5]. Furthermore, in recent years, a spectrum of degenerative changes has been identified in the ET cerebellar cortex, aligning ET with numerous other disorders of cerebellar degeneration [6]. As such, ET may be the most common form of cerebellar degeneration [7]. ...
... In recent years, neurofilament light chain (NfL) has emerged as a novel biomarker of axonal loss and a surrogate indicator of disease activity in diverse disorders of the central nervous system that involve neuronal compromise, breakdown and/or degeneration, including amyotrophic lateral sclerosis (ALS), Parkinson Disease (PD), Alzheimer's disease, multiple sclerosis (MS) and stroke [8,9]. Following histological evidence of Purkinje cell loss and other degenerative changes [6,10], biochemical data showing neurofilament protein accumulation in brain samples [11], a leading hypothesis characterizes ET as a neurodegenerative disorder, and the potential for the discovery of a bona fide disease biomarker underlies the efforts described herein to quantify serum NfL concentrations in ET patients. ...
Essential tremor (ET) is a common neurological disorder, with clinical and pathophysiological links to the cerebellum. Inquiries into the etiology, pathophysiology, and nosology of ET stand to benefit from the identification of disease biomarkers. Serum neurofilament light chain (NfL) has emerged as a novel signature of conditions in which neuronal injury reflects an outcome of the ongoing disease process. We sought to investigate the concentrations of NfL in ET patients and healthy controls. In this case–control study, our powered study population of 41 ET patients and 40 age-matched healthy controls underwent clinical assessments and measurement of serum NfL concentration using Simoa technology. Serum NfL was elevated in ET patients - mean log-transformed serum NfL concentration = 1.23 ± 0.19 (95% confidence interval [CI] = 1.17–1.29) vs. 1.08 ± 0.15 (95% CI = 1.03–1.13), p = 0.0002. This difference persisted after accounting for age, sex and Montreal Cognitive Assessment score in a multiple linear regression model (p = 0.002) and in an age-matched sample subset of 35 ET cases and 35 controls (p = 0.006). There was no association between tremor severity and serum NfL levels (p = 0.73). In this sample of ET patients and controls, serum NfL concentrations were significantly higher in ET. Studies in additional cohorts of ET cases would be of value in attempting to replicate these results and assessing diagnostic utility.
... Evidence that the cerebellum is involved in disease pathophysiology comes from extensive clinical [6], physiological [21], neuroimaging [10] and neuropathologic studies [46,57]. With respect to the latter, neuropathological studies have identified numerous degenerative changes centered in and around Purkinje Cells (PCs), including the cell body (PC loss [11,52], heterotopic PCs [34,55], empty PC basket plexus [40]), dendrites (dendritic swellings [82], spine loss [56]), axons (axonal swellings [torpedoes] [51,60], axon branching [4], recurrent axon collaterals [4], thickened axon profiles [4]), and synaptic connections with adjacent neuronal populations including basket cells ("hairy" baskets [18]) and climbing fibers (decreased climbing fiber synaptic density [39], increased climbing fiber extension into parallel fiber territory [42]). ...
... ± 2.81 nM) (p < 0.0001; Fig. 2a), indicating that the binding affinity of calstabin1 for the RyR1 channel is much lower in ET (i.e., higher K d = lower binding affinity). We then chose four metrics of cerebellar pathology that provide the greatest distinction between ET and controls [57] to correlate with the calstabin1-RyR1 Kd values in this initial set of ET cases (Supplemental Table 1). We identified a strong negative correlation between the calstabin1-RyR1 K d values and the linear density of PCs in ET cerebellar cortex (PC/mm) (r = − 0.8760, p = 0.0004; Fig. 2b), indicating that as PC loss increases the affinity of calstabin1 binding for the RyR1 channel decreases in ET. ...
... Thus, long-term cerebellar ER Ca 2+ leak and resulting cellular excitotoxic damage could be a risk factor for neuronal death, leading to PC loss. PC loss has been observed in several, although not all [50], studies of ET pathology [11,30], and alterations in CF synapses on PCs are also a pathological feature of ET [42,57]. In this study, we directly demonstrated that the K d values for calstabin1-RyR1 channel binding were significantly increased in ET vs. controls (Fig. 2a), consistent with increased dissociation of calstabin1 from RyR1 that would lead to increased ER Ca 2+ leak in ET. ...
Essential Tremor (ET) is a prevalent neurological disease characterized by an 8–10 Hz action tremor. Molecular mechanisms of ET remain poorly understood. Clinical data suggest the importance of the cerebellum in disease pathophysiology, and pathological studies indicate Purkinje Cells (PCs) incur damage. Our recent cerebellar cortex and PC-specific transcriptome studies identified alterations in calcium (Ca²⁺) signaling pathways that included ryanodine receptor type 1 (RyR1) in ET. RyR1 is an intracellular Ca²⁺ release channel located on the Endoplasmic Reticulum (ER), and in cerebellum is predominantly expressed in PCs. Under stress conditions, RyR1 undergoes several post-translational modifications (protein kinase A [PKA] phosphorylation, oxidation, nitrosylation), coupled with depletion of the channel-stabilizing binding partner calstabin1, which collectively characterize a “leaky channel” biochemical signature. In this study, we found markedly increased PKA phosphorylation at the RyR1-S2844 site, increased RyR1 oxidation and nitrosylation, and calstabin1 depletion from the RyR1 complex in postmortem ET cerebellum. Decreased calstabin1-RyR1-binding affinity correlated with loss of PCs and climbing fiber-PC synapses in ET. This ‘leaky’ RyR1 signature was not seen in control or Parkinson’s disease cerebellum. Microsomes from postmortem cerebellum demonstrated excessive ER Ca²⁺ leak in ET vs. controls, attenuated by channel stabilization. We further studied the role of RyR1 in tremor using a mouse model harboring a RyR1 point mutation that mimics constitutive site-specific PKA phosphorylation (RyR1-S2844D). RyR1-S2844D homozygous mice develop a 10 Hz action tremor and robust abnormal oscillatory activity in cerebellar physiological recordings. Intra-cerebellar microinfusion of RyR1 agonist or antagonist, respectively, increased or decreased tremor amplitude in RyR1-S2844D mice, supporting a direct role of cerebellar RyR1 leakiness for tremor generation. Treating RyR1-S2844D mice with a novel RyR1 channel-stabilizing compound, Rycal, effectively dampened cerebellar oscillatory activity, suppressed tremor, and normalized cerebellar RyR1-calstabin1 binding. These data collectively support that stress-associated ER Ca²⁺ leak via RyR1 may contribute to tremor pathophysiology.
... The neuropathology of ET primarily involves the cerebellar cortex, centered on Purkinje cells and surrounding neuronal populations. (Louis and Faust 2020;Louis et al. 2023). ...
This study utilized cervical vestibular-evoked myogenic potentials tests (cVEMP) and ocular vestibular-evoked myogenic potentials tests (oVEMP) to investigate the vestibulocollic and vestibuloocular reflex arcs and to evaluate cerebellar and brainstem involvement) in essential tremor (ET). Eighteen cases with ET and 16 age- and gender-matched healthy control subjects (HCS) were included in the present study. Otoscopic and neurologic examinations were performed on all participants, and both cervical and ocular VEMP tests were performed. Pathological cVEMP results were increased in the ET group (64.7%) compared to the HCS (41,2%; p > 0.05). The latencies of P1 and N1 waves were shorter in the ET group than in HCS (p = 0.01 and p = 0.001). Pathological oVEMP responses were significantly higher in the ET group (72.2%) compared to the HCS (37.5%; p = 0.01). There was no statistically significant difference in oVEMP N1-P1 latencies between groups (p > 0.05). Because the ET group had high pathological responses to the oVEMP, but not the cVEMP, the upper brainstem pathways may be more affected by ET.
Fatty acids play many critical roles in brain function but have not been investigated in essential tremor (ET), a frequent movement disorder suspected to involve cerebellar dysfunction. Here, we report a postmortem analysis of fatty acid profiles by gas chromatography in the cerebellar cortex from ET patients (n=15), Parkinson’s disease (PD) patients (n=15) and Controls (n=17). Phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI)/ phosphatidylserine (PS) were separated by thin-layer chromatography and analyzed separately. First, the total amounts of fatty acids retrieved from the cerebellar cortex were lower in ET patients, including monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA), such as docosahexaenoic (DHA) and arachidonic (ARA) acids. The diagnosis of ET was associated with lower cerebellar levels of saturated fatty acids (SFA) and PUFA (DHA and ARA) in the PE fraction specifically, but with a higher relative content of dihomo-γ-linolenic acid (DGLA; 20:3 ω-6) in the PC fraction. In contrast, a diagnosis of PD was associated with higher absolute concentrations of SFA, MUFA and ω-6 PUFA in the PI+PS fractions. However, relative PI+PS contents of ω-6 PUFA were lower in both PD and ET patients. Finally, linear regression analyses showed that the ω-3:ω-6 PUFA ratio was positively associated with age of death, but inversely associated with insoluble α-synuclein. Although it remains unclear how these FA changes in the cerebellum are implicated in ET or PD pathophysiology, they may be related to an ongoing neurodegenerative process or to dietary intake differences. The present findings provide a window of opportunity for lipid-based therapeutic nutritional intervention.
