Sex differences in alpha-synucleinopathies: a systematic review

Raheel, Kausar; Deegan, Gemma; Di Giulio, Irene; Cash, Diana; Ilic, Katarina; Gnoni, Valentina; Chaudhuri, K. Ray; Drakatos, Panagis; Moran, Rosalyn; Rosenzweig, Ivana

doi:10.3389/fneur.2023.1204104

Cited by 8 publications

(5 citation statements)

References 281 publications

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“…While differential genetic risk factors for PD in men vs women have not been demonstrated, sex-specific effects of genotype may exist 31,41 . 11 genomic loci have jointly been associated…”

Section: Female Predominance Among Lrrk2 Parkinsonism Cases Without E...mentioning

confidence: 99%

“…We found a female predominance among the LRRK2 parkinsonism cases without evidence for pathologic asyn. There is extensive literature that demonstrates that in individuals diagnosed with PD, sex differences exist for clinical, biomarker, neuropathological, or genetic endpoints 31 . Sex differences in LRRK2-parkinsonism cases are particularly notable.…”

Section: Female Predominance Among Lrrk2 Parkinsonism Cases Without E...mentioning

confidence: 99%

“…A relationship between sex hormones and neuroinflammation is another possible mechanism that may explain sex differences 39 , which is of particular relevance given the role of LRRK2 in the immune system. Sex differences in immune activation and microglial function may also play a role 31,39 .. Indeed, a study examining the serum profile of 23 immune-associated markers in sporadic and LRRK2-associated PD demonstrated sex differences in immune profile but without differences in the LRRK2 and sporadic group 40 .…”

Section: Female Predominance Among Lrrk2 Parkinsonism Cases Without E...mentioning

confidence: 99%

“…Charles Adler, PhD 49 ; Roy Alcalay, MD 35 ; Amy Amara, PhD 50 ; Paolo Barone, PhD 30 ; Bastiaan Bloem, PhD 58 Susan Bressman, MD 14 ; Kathrin Brockmann, MD 26 ; Norbert Brüggemann, MD 57 ; Lana Chahine, MD 39 ; Kelvin Chou, MD 42 ; Nabila Dahodwala, MD 12 ; Alberto Espay, MD 32 ; Stewart Factor, DO 16 ; Hubert Fernandez, MD 25 ; Michelle Fullard, MD 50 ; Douglas Galasko, MD 27 ; Robert Hauser, MD 19 ; Penelope Hogarth, MD 17 ; Shu-Ching Hu, PhD 21 ; Michele Hu, PhD 56 ; Stuart Isaacson, MD 31 ; Christine Klein, MD 57 ; Rejko Krueger, MD 2 ; Mark Lew, MD 47 ; Zoltan Mari, MD 54 ; Connie Marras, PhD 43 ; Maria Jose Martí, PhD 33 ; Nikolaus McFarland, PhD 52 ; Tiago Mestre, PhD 44 ; Brit Mollenhauer, MD 8 ; Emile Moukheiber, MD 28 ; Alastair Noyce, PhD 61 Wolfgang Oertel, PhD 62 ; Njideka Okubadejo, MD 63 ; Sarah O'Shea, MD 37 ; Rajesh Pahwa, MD 46 ; Nicola Pavese, PhD 55 ; Werner Poewe, MD 7 ; Ron Postuma, MD 53 ; Giulietta Riboldi, MD 51 ; Lauren Ruffrage, MS 18 ; Javier Ruiz Martinez, PhD 34 ; David Russell, PhD 1 ; Marie H Saint-Hilaire, MD 22 ; Neil Santos, BS 49 ; Wesley Schlett 45 ; Ruth Schneider, MD 23 ; Holly Shill, MD 48 ; David Shprecher, DO 24 ; Tanya Simuni, MD 3 ; David Standaert, PhD 18 ; Leonidas Stefanis, PhD 36 ; Yen Tai, PhD 29 ; Caroline Tanner, PhD 9 ; Arjun Tarakad, MD 20 ; Eduardo Tolosa PhD 33 and Aleksandar Videnovic, MD…”

Section: Data Availabilitymentioning

confidence: 99%

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LRRK2-Associated Parkinsonism With and WithoutIn VivoEvidence of Alpha-Synuclein Aggregates

Chahine,

Lafontant,

Choi

et al. 2024

Preprint

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Background: Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates. Methods: Data were from the Parkinson's Progression Markers Initiative, a multicenter prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient- reported outcome assessments were administered. Biomarkers included dopamine transporter SPECT scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups. Results: 148 LRRK2-parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay were included. At baseline, the negative group were older than the positive group (median [interquartile range] 69.1 [65.2-72.3] vs 61.5 [55.6-66.9] years, p<0.001) and a greater proportion were female (28 (61%) vs 43 (42%), p=0.035). Despite being older, the negative group had similar duration since diagnosis, and similar motor rating scale (16 [11-23] vs 16 [10-22], p=0.480) though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared to 75 (77%) of the positive group. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (0.36 [0.29-0.45] vs 0.26 [0.22-0.37], p<0.001). Serum neurofilament light chain was higher in the negative group compared to the positive group (17.10 [13.60-22.10] vs 10.50 [8.43-14.70]; age-adjusted p-value=0.013). In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (p=0.037), but no other differences in trajectory were found. Conclusion: Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline may have more significant cognitive dysfunction. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation. Key words: Parkinsonism, LRRK2, alpha-synuclein

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“…While differential genetic risk factors for PD in men vs women have not been demonstrated, sex-specific effects of genotype may exist 31,41 . 11 genomic loci have jointly been associated…”

Section: Female Predominance Among Lrrk2 Parkinsonism Cases Without E...mentioning

confidence: 99%

Section: Female Predominance Among Lrrk2 Parkinsonism Cases Without E...mentioning

confidence: 99%

Section: Female Predominance Among Lrrk2 Parkinsonism Cases Without E...mentioning

confidence: 99%

Section: Data Availabilitymentioning

confidence: 99%

See 2 more Smart Citations

LRRK2-Associated Parkinsonism With and WithoutIn VivoEvidence of Alpha-Synuclein Aggregates

Chahine,

Lafontant,

Choi

et al. 2024

Preprint

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“…22 Most of abnormal motor events likely arise during phasic REM, which in RBD can vacillate from elementary movements to vivid dream enactments. 8,23 Historically, RBD was predominantly linked with male sex, [24][25][26][27] but that has been increasingly disputed with recognition that women tend to have a significantly later age of onset of RBD 28,29 and that they less frequently report dream-enacting behaviours. [29][30][31] Fernández-Arcos et al reported significantly more aggressive behavior in male RBD, and less so in women, who dreamt more about children in life-threatening contexts.…”

Section: Introductionmentioning

confidence: 99%

Dreaming Characteristics in Non-Rapid Eye Movement Parasomnia and Idiopathic Rapid Eye Movement Sleep Behaviour Disorder: Similarities and Differences

See,

Raheel,

Duncan

et al. 2024

NSS

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Background Speech graph analysis (SGA) of dreams has recently shown promise as an objective and language-invariant diagnostic tool that can aid neuropsychiatric diagnosis. Whilst the notion that dreaming mentations reflect distinct physiologic processes is not new, such studies in patients with sleep disorders remain exceptionally scarce. Here, using SGA and other dream content analyses, we set to investigate structural and thematic differences in morning dream recalls of patients diagnosed with Non-Rapid Eye Movement Parasomnia (NREMP) and Idiopathic REM Sleep Behavior Disorder (iRBD). Methods A retrospective cross-sectional study of morning dream recalls of iRBD and NREMP patients was undertaken. Traditional dream content analyses, such as Orlinsky and Hall and Van de Castle analyses, were initially conducted. Subsequently, SGA was performed in order to objectively quantify structural speech differences between the dream recalls of the two patient groups. Results Comparable rate of morning recall of dreams in the sleep laboratory was recorded; 25% of iRBD and 18.35% of NREMP patients. Aggression in dreams was recorded by 28.57% iRBD versus 20.00% in NREMP group. iRBD patients were more likely to recall dreams (iRBD vs NREMP; P = 0.007), but they also had more white dreams, ie having a feeling of having dreamt, but with no memory of it. Visual and quantitative graph speech analyses of iRBD dreams suggested stable sequential structure, reflecting the linearity of the chronological narrative. Conversely, NREMP dream reports displayed more recursive, less stable systems, with significantly higher scores of graph connectivity measures. Conclusion The findings of our exploratory study suggest that iRBD and NREMP patients may not only differ on what is recalled in their dreams but also, perhaps more strikingly, on how dreams are recalled. It is hoped that future SGA-led dream investigations of larger groups of patients will help discern distinct mechanistic underpinnings and any associated clinical implications.

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Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review

Raheel,

See,

Munday

et al. 2024

Curr Neurol Neurosci Rep

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Purpose of Review Sleep disturbances are amongst most frequent non-motor symptoms of Parkinson’s Disease (PD), and they are similarly frequently reported in other alpha-syncleinopathies, such as Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA). More recently, the orexin system has been implicated in control of arousal based on salient environmental set points, and its dysregulation in sleep issues in alpha-synucleinopathies suggested by the findings from the translational animal models. However, its role in the patients with alpha-synucleinopathies remains unclear. We thus set to systematically review, and to critically assess, contemporary evidence on the association of the orexinergic system and sleep disturbances in alpha-synucleinopathies. In this systematic review, studies investigating orexin and sleep in alpha-synucleinopathies (Rapid Eye Movement (REM) Behaviour Disorder (RBD), Parkinson's Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) were identified using electronic database searches of PubMed, Web of Science and PsychINFO using MeSH terms, keywords, and title words such as “Alpha-synucleinopathies” AND “Orexin” AND “Sleep Disturbances”. Recent findings 17 studies were included in this systemic review, of which 2 studies on RBD, 10 on PD, 4 on DLB, and 1 on MSA patients. Taken together, RBD and PD studies suggest a potential adaptive increase in orexin levels in early stages of the neurodegenerative process, with reduced levels more often reported for later, more advanced stages of illness. To date, no differences in orexin levels were demonstrated between MSA patients and healthy controls. Summary There is a dearth of studies on the role of orexin levels in alpha-synucleinopathies. Moreover, significant methodologic limitations in the current body of work, including use of non-standardised research protocols and lack of prospective, multi-centre studies, disallow for any finite conclusion in regards to underlying pathomechanisms. Nonetheless, a picture of a complex, multifaceted relationship between the dysregulation of the orexinergic pathway and sleep disturbances in alpha-synucleinopathies is emerging. Hence, future studies disentangling orexinergic pathomechanisms of alpha-syncleinopathies are urgently needed to obtain a more comprehensive account of the role of orexinergic pathway in alpha-synucleinopathies. Pharmacological manipulations of orexins may have multiple therapeutic applications in treatment strategies, disease diagnosis, and might be effective for treating both motor and non-motor symptoms.

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Sex differences in alpha-synucleinopathies: a systematic review

Cited by 8 publications

References 281 publications

LRRK2-Associated Parkinsonism With and WithoutIn VivoEvidence of Alpha-Synuclein Aggregates

LRRK2-Associated Parkinsonism With and WithoutIn VivoEvidence of Alpha-Synuclein Aggregates

Dreaming Characteristics in Non-Rapid Eye Movement Parasomnia and Idiopathic Rapid Eye Movement Sleep Behaviour Disorder: Similarities and Differences

Orexin and Sleep Disturbances in Alpha-Synucleinopathies: a Systematic Review

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