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20240722_184219

8 min read

Outcome Measures

  • Original
    • (Schrag, 2007 #1503) , 그런데 questionnaire 자체는 안 구해지네, MDS site 에도 안 보이는 듯?
  • Example
    • (Matsushima, 2021 #1389)

ICLEMSA (Items That Change Largely in Early-Stage Multiple System Atrophy)

  • 8 items
    • handwriting, finger taps, transfers, standing with feet together, turning the trunk, turning 360°, gait and body sway;
ICLEMSAFrom(Palma, 2021 #1633) NHSS cohort, 1 y f/u
GaitSARA 1
TransfersBBS (Berg Balance Scale) 5
Finger tappingUMSARS PART 2-8poor ability to detect longitudinal change (standardized effect < 0.20)
HandwritingUMSARS PART 1-3excellent ability to detect change (standardized effect > 0.30)
Standing unsupported with feet togetherBBS 7
Turning to look behind over left and right shoulders while standingBBS 10
Turning 360°BBS 11
Body swayUMSARS PART 2-13poor ability to detect longitudinal change (standardized effect < 0.20)

위 에서 handwriting 은 Palma에서도 고순위인데, finger tapping & body sway 는 Palma 에서 X.

  • 개발과정
    • 여러 tool 에서 가장 SRM 큰 것들만 모음.
    • 모집단은 MSA-C가 많았음 (60명 VS 25명 of MSA-P)

(Matsushima, 2016 #1447) : 위 그림은 6m & 12m, 12m에서 가장 큰 SRM항목들은 Finger tapping, transfers, standing unsupported with feet together, gait, 등. 전반적으로 cerebellar sign 들이네, MSA-C가 많아서 그럴 듯 ( 29.4 % had MSA-P and 70.6 % had MSA cerebellar ataxia dominant subtype.)

  • total score=36).
  • original
    • (Matsushima, 2017 #1446)
  • Example
    • (Matsushima, 2021 #1389)

Table 4 — The eight items with the largest standardized response mean

Cerebellum (2016) 15:190-200, p.196.

  1. Gait (from SARA 1)

    Proband is asked (1) to walk at a safe distance parallel to a wall including a half-turn (turn around to face the opposite direction of gait) and (2) to walk in tandem (heel-to-toe) without support.

    • 0. Normal, no difficulties in walking, turning, or walking tandem (up to one misstep allowed)
      1. Slight difficulties, only visible when walking 10 consecutive steps in tandem
      1. Clearly abnormal, tandem walking >10 steps not possible
      1. Considerable staggering, difficulties in half-turn, but without support
      1. Marked staggering, intermittent support of the wall required
      1. Severe staggering, permanent support of one stick or light support by one arm required
      1. Walking >10 m only with strong support (two special sticks or stroller or accompanying person)
      1. Walking <10 m only with strong support (two special sticks or stroller or accompanying person)
      1. Unable to walk, even if supported

  2. Transfers (from BBS 5)

    Arrange chair(s) for a pivot transfer. Ask subject to transfer one way toward a seat with armrests and one way toward a seat without armrests. Two chairs (one with and one without armrests) or a bed and a chair may be used.

    • 0. Able to transfer safely with minor use of hands
      1. Able to transfer safely definite need of hands
      1. Able to transfer with verbal cueing and/or supervision
      1. Needs one person to assist
      1. Needs two people to assist or supervise to be safe

  3. Finger tapping (from UMSARS Part 2-8)

    Patient taps thumb with index finger in rapid succession with widest amplitude possible, with each hand for at least 15 to 20 s. Rate the worst affected limb. Note that impaired performance on this task can be caused by bradykinesia and/or cerebellar incoordination. Rate functional performance regardless of underlying motor disorder.

    • 0. Normal.
      1. Mildly impaired.
      1. Moderately impaired.
      1. Severely impaired.
      1. Can barely perform the task.

  4. Handwriting (from UMSARS Part 1-3)

      1. Normal.
      1. Mildly impaired (all words are legible).
      1. Moderately impaired (up to half of the words are illegible).
      1. Markedly impaired (the majority of words are illegible).
      1. Unable to write.

  5. Standing unsupported with feet together (from BBS 7)

    Place your feet together and stand without holding.

    • 0. Able to place feet together independently and stand 1 min safely
      1. Able to place feet together independently and stand for 1 min with supervision
      1. Able to place feet together independently but unable to hold for 30 s
      1. Needs help to attain position but able to stand 15 s feet together
      1. Needs help to attain position and unable to hold for 15 s

  6. Turning to look behind over left and right shoulders while standing (from BBS 10)

    Turn to look directly behind you over toward left shoulder. Repeat to the right. Examiner may pick an object to look at directly behind the subject to encourage a better twist turn.

    • 0. Looks behind from both sides and weight shifts well
      1. Looks behind one side only other side shows less weight shift
      1. Turns sideways only but maintains balance
      1. Needs supervision when turning
      1. Needs assist to keep from losing balance or falling

  7. Turning 360° (from BBS 11)

    Turn completely around in a full circle. Pause. Then turn a full circle in the other direction.

    • 0. Able to turn 360° safely in 4 s or less
      1. Able to turn 360° safely one side only in 4 s or less
      1. Able to turn 360° safely but slowly
      1. Needs close supervision or verbal cueing
      1. Needs assistance while turning

  8. Body sway (from UMSARS Part 2-13)

    Rate spontaneous body sway and response to sudden, strong posterior displacement produced by pull on shoulder while patient erect with eyes open and feet slightly apart. Patient has to be warned.

      1. Slight body sway and/or retropulsion with unaided recovery.
      1. Moderate body sway and/or deficient postural response; might fall if not caught by examiner.
      1. Severe body sway. Very unstable. Tends to lose balance spontaneously.
      1. Unable to stand without assistance.

UMSARS Unified Multiple System Atrophy Rating Scale, SARA Scale for the Assessment and Rating of Ataxia, BBS Berg Balance Scale

Table 5 — The required sample size to detect treatment effects for each scale

ScalesSample size (n)a
UMSARS Part 11002
UMSARS Part 2140
UMSARS Part 3 (systolic decrease)152,590
UMSARS Part 3 (diastolic decrease)13,900
UMSARS Part 4217
SARA136
BBS142
MSA-QoL532
SCOPA-AUT499,207
Barthel index249
provisional scaleb98
  • a in the case of 80 % power, 30 % treatment effect
  • b The provisional scale consists of selected eight items with the largest standardized response mean

UMSARS Unified Multiple System Atrophy Rating Scale, SARA Scale for the Assessment and Rating of Ataxia, BBS Berg Balance Scale, MSA-QoL Multiple System Atrophy Health-Related Quality of Life scale, SCOPA-AUT Scales for Outcomes in Parkinson’s Disease–Autonomic questionnaire

*2-sided, alpha=0.05, sample size is per group {Matsushima, 2016 #1447}

Pathology

Inclusions
  • GCI (hallmark, glial cytoplasmic inclusions, =Papp-Lantos bodies,) in oligodendrocytes, this is mandatory for 확진, this drives neuronal loss!, aSyn 이외에도 여러 protein 존재, pSer129-aSyn이 core에 존재. The origin of α-syn in GCI remains unclear, but might come from neuronal secretion because oligodendrocyte don't express SNCA [38].
  • The oligodendrocyte connectome is nearly identical to the neuronal connectome (discussed with Alain Dagher and others at the MJFF aSYN conference). 그래서 TAK-341 이 MSA에서도 유효할 것이다.
  • Glial nuclear inclusion: less frequent
  • neuronal nuclear inclusions,
  • neuronal cytoplasmic inclusion
  • neuronal threads, (also composed of aSyn [126])
  • astrocyte inclusions are also occasionally seen ((Radford, 2014 #1417)
  • P-αSyn is accumulated in subpial and periventricular astrocytes after long disease duration [140]. (this also occurs in DLB)
  • cf) wide distribution of aSyn oligomers not only in oligodendrocytes but also in neocortical neurons and Purkinje cells [Jellinger 2020]. In the MSA brain, αSyn 140 and 122 isoform levels are increased, whereas αSyn 126 is decreased, in the substantia nigra (SN), striatum, and cerebellum. In early disease states, diffuse αSyn staining in neuronal nuclei and cytoplasm occurs in many gray matter areas, [Jellinger 2020] 2nd, 1st is {Dickson, 2012 #1779 이것도 review} 아래가 Asyn 인지 neuronal loss 인지 불분명.
  • Consistently, severely affected areas: putamen, CN, SN, pontine and medullary tegmental nuclei, inferior olives, and cerebellar WM; -
  • moderately affected areas are the motor cortex and GP, and
  • mild lesions involve the cingular cortex, hypothalamus, nucleus basalis of Meynert, thalamus, subthalamus, and pontine tegmentum [158].
  • Another neuropathological study showed that the striatonigral region was most severely affected in 34% of SND and in 17% in OPCA cases, while in almost half of them both regions were equally affected [133].
  • {Kikuchi, 2010 #1078} GCI, high distribution volumes in the subcortical white matter, putamen and posterior cingulate cortex, GP, primary motor cortex and anterior cingulate cortex, and SN
Cell loss(row continues on 20240722_184233)

Uncertain Spans

  • “전반적으로 cerebellar sign 들이네” — “전반적으로”의 첫 글자가 작아 확신도 95% 수준 (image suggests 전반적, OCR suggests 선반석).
  • “MSA cerebellar ataxia dominant subtype” — 70.6 % 뒤 문장 끝이 줄바꿈되어 마침 마침표 확인 어려움.

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