Dx of MSA
Diagnosis of MSA – three levels — (Gilman et al., 2008, PMID: 18725592) Second consensus statement on the diagnosis of MSA
| level | criteria | |
|---|---|---|
| Possible |
Table 2 — Criteria for possible MSA A sporadic, progressive, adult (>30 y)-onset disease characterized by:
|
Table 3 — Additional features of possible MSA Possible MSA-P or MSA-C
|
| Probable |
Table 1 — Criteria for the diagnosis of probable MSA A sporadic, progressive, adult (>30 y)-onset disease characterized by:
| |
| Definite | Autopsy findings of widespread and abundant CNS aSyn–positive glial cytoplasmic inclusions in association with neurodegenerative changes in striatonigral or olivopontocerebellar structures |
Criteria for the Diagnosis of Probable MSA
A sporadic, progressive, adult (>30 years)–onset disease characterized by the following:
- Autonomic failure involving urinary incontinence (inability to control the release of urine from the bladder, with erectile dysfunction in male subjects) or an orthostatic decrease of blood pressure within 3 minutes of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic, and
- Poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or postural instability), or
- A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction).
Criteria for Possible MSA
A sporadic, progressive, adult (>30 years)–onset disease characterized by the following:
- Parkinsonism (bradykinesia with rigidity, tremor, or postural instability), or
- A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction), and
- At least 1 feature suggesting autonomic dysfunction (otherwise unexplained urinary urgency, frequency or incomplete bladder emptying, erectile dysfunction in male subjects, or significant orthostatic blood pressure decline that does not meet the level required for improbable MSA), and
At least 1 of the following additional features:
Possible MSA with predominant parkinsonism (MSA-P) or MSA with predominant cerebellar ataxia (MSA-C):
- Babinski sign with hyperreflexia.
- Stridor.
Possible MSA with predominant parkinsonism (MSA-P):
- Rapidly progressive parkinsonism.
- Poor response to levodopa.
- Postural instability within 3 years of motor onset.
- Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction.
- Dysphagia within 5 years of motor onset.
- Atrophy on MRI of the putamen, middle cerebellar peduncle, pons, or cerebellum.
- Hypometabolism on fluorodeoxyglucose (FDG)–positron emission tomography (PET) in the putamen, brainstem, or cerebellum.
Possible with predominant cerebellar ataxia (MSA-C):
- Parkinsonism (bradykinesia and rigidity).
- Atrophy on MRI of the putamen, middle cerebellar peduncle, or pons.
- Hypometabolism on FDG-PET in the putamen.
- Presynaptic nigrostriatal dopaminergic …
Genetics
| {Stankovic, 2019 #1649} | Causative loss-of-function mutations in the COQ2 gene were found in 2 siblings diagnosed with definite and probable MSA from a consanguineous family and in 2 siblings with probable MSA-C from another family in Japan.27 |
| Stankovic, 2019 #1649} | heritability of MSA as a result of common genetic variance using Genome-Wide Complex Trait Analysis is 2.09% to 6.65%, and |
| - {Wernick, 2020 #2585} |
on 167 pathologically confirmed MSA patients collected at Mayo Clinic Florida Brain Bank, and data were extracted from whole-genome sequencing of 834 clinical controls. When collapsing across all GBA variants, the presence of any GBA variant was significantly more frequent in MSA patients than in controls (OR = 1.90, P = 0.031). However, this association was driven by p.T408M, which had a significantly higher frequency in MSA patients compared to controls (OR = 4.21, P = 0.002). There was no significant association with risk of MSA for the p.E365K variant (OR = 0.79, P = 0.72). Conclusions: Other than the specific GBA p.T408M variant, coding GBA variants are not associated with risk of MSA. |
| {Sklerov, 2017 #2586} |
17 patients with autopsy-proven MSA Of 17 MSA brains, 4 carried GBA variants (23.5%), including 1 that was homozygous for N370S and 1 each that carried heterozygous N370S, T369M, and R496H variants. Among the comparator brains with pure AD, 3 of 82 (3.7%) carried GBA variants (P = 0.0127; Fisher exact test), including 1 each with an N370S homozygous variant, an R496H heterozygous variant, and a T369M heterozygous variant. |
In vitro systems
below {Abati 2018 #2279}
| Authors | Starting cells | Main findings |
|---|---|---|
| Stefanova et al (2005) | U373 astrocytoma cell line and primary mixed rat glial culture overexpressing human WT α-syn(1-140) or C-terminally truncated α-syn (1-111) under the CMV promotor. | Presence of widespread fibrillar α-syn aggregates, more numerous in cells expressing the C-terminally truncated form; increased cell death rates; increased susceptibility to treatment with TNFα. |
| ...ragh et al (2009) | Oligodendroglial cell line (OLN-93) derived from primary Wistar rat brain glial cultures expressing human WT α-syn or S129A or S129D mutant α-syn with human WT p25α. | Coexpression of α-syn and p25α causes microtubule relocalization to the perinuclear region; p25α-mediated microtubule retraction requires low levels of α-syn; α-syn-dependent microtubule retraction induces apoptotic markers with activation of caspase and nuclear chromatin condensation. |
| ...ay et al (2014) | Primary rodent oligodendroglial cell line (CG4) expressing human WT α-syn under the CMV promoter. | Intracellular α-syn impairs OPC maturation in vitro; BDNF partially rescues OPC maturation. |
| ...alera et al (2017) | Primary rodent oligodendroglial cell line (CG4) co-infected with Lentivirus expressing human α-syn or LV control and microRNA-101 (miR-101a-3p) or control vector. | Autophagy inhibition in CG4 cells compared to controls; Lentiviral delivery of an antimiR 101 construct reduces α-syn-induced autophagy deficits. |
| ...elloul et al (2015) | iPSCs obtained from donors' skin fibroblasts, differentiated into oligodendrocytes. | O4+, OLIG2+, PDGFRA+ oligodendrocyte progenitors express Snca and α-syn; this expression decreases in MBP+, CNPASE+ premyelinating oligodendrocytes, with significant differences among control and patient lines. |
Imaging
{Stankovic, 2019 #1649}
Conventional MRI and fluorodeoxyglucose PET indices of neurodegeneration in the putamen, middle cerebellar peduncle (MCP), pons, and cerebellum, presynaptic nigrostriatal denervation on single-photon emission computed tomography or 18F-fluorodopa PET are additional features of possible MSA in the second consensus criteria.6
Suboptimal accuracy of neuroradiological diagnosis, particularly in the early disease stages,29,30 may be improved by implementing diffusion-weighted sequences and advanced MRI techniques (see Table 1).
Patterns highly predictive for an early diagnosis of MSA-P include increased diffusivity in the posterior putamen and MCP with spared superior cerebellar peduncle on diffusion-weighted sequences31 and volume loss in the putamen and cerebellar gray matter in the absence of severe midbrain atrophy on automated independent volumetric MRI based on the segmentation of subcortical regions.32
Intact functional integrity of myocardial sympathetic fibers on 123I-metaiodobenzylguanidine–SPECT is a useful supporting feature for MSA diagnosis.3)
The diagnostic characteristics of cutaneous alpha-syn deposition in MSA patients are not definitively established.
DATscan
{Nocker, 2012 #1075} 8 MSA-P patients (age 60, disease duration 2.4 y, UPDRS-III 40), 11 sPd,
| Brainstem | Striatum | |||
|---|---|---|---|---|
| Cross sectional | 1.3y후 | Cross sectional | 1.3y후 | |
| MSA-P | ↓ than sPD | No further ↓ | sPD보다 아주약간만 ↓ | 17-30% ↓ |
| SPD | 약간 decline 9~5% | |||
above Nocker 2012,
Table 1: Calculated sample sizes, for the number of patients needed in …
| Effect size (%) | Striatum | Putamen | Caudate |
|---|---|---|---|
| 20 | 211 | 414 | 219 |
| 33 | 75 | 151 | 79 |
| 50 | 34 | 67 | 35 |
Uncertain Spans
- “…ragh et al (2009)”, “…ay et al (2014)”, “…alera et al (2017)”, “…elloul et al (2015)” — the Authors column for the lower four rows of the In vitro systems table is clipped at the left edge of the page; only the trailing characters of each surname are visible. The leading characters are not unambiguously readable from the photo and have not been guessed.
- “intact functional integrity of myocardial sympathetic fibers on 123I-metaiodobenzylguanidine–SPECT is a useful supporting feature for MSA diagnosis.3)” — the closing footnote glyph reads as
3)in the source; it may be a typesetting artifact for footnote 33 but the visible character is3)and not unambiguously a single number. - “Possible MSA-C … Presynaptic nigrostriatal dopaminergic …” — the prose form of the Possible MSA-C bullet ends mid-sentence at
Presynaptic nigrostriatal dopaminergicand is cut at the page boundary; the rest of the sentence (...denervation on SPECT or PET) is only visible inside the right-hand color panel above.