artical presentation on lipid control in stroke and role of csf biomarkers in NPH...

1. JOURNAL CLUB
Dr Bhavin J Patel
SR Neurology
GMC Kota.

2. Trial 1

3. Background
• The use of intensive lipid-lowering therapy by means of statin
medications is recommended after transient ischemic attack (TIA) and
ischemic stroke of atherosclerotic origin .
• Stroke Prevention by Aggressive Reduction in Cholesterol Level
(SPARCL) trial
• The risk of stroke was 20% lower for every reduction of 39 mg per
deciliter (1.0 mmol per liter) in the LDL cholesterol level

4. Purpose of study
• A target level of LDL cholesterol of less than 70 mg per deciliter
would be superior to a target range of 90 mg to 110 mg in reducing
recurrent cardiovascular event.
• The target level for low-density lipoprotein (LDL) cholesterol to
reduce cardiovascular events after stroke has not been well studied.

5. Methodology
• Randomized, parallel-group, event-driven trial
• Conducted at 61 sites in France and 16 sites in South Korea
• From March 2010 through December 2018
• Eligible patients were randomly assigned in a 1:1 ratio to a target LDL
cholesterol level of less than 70 mg per deciliter (lower-target group) or a
target range of 90 mg to 110 mg per deciliter (higher-target group)

6. Methodology
• Investigators were allowed to prescribe any type and any dose of statin to reach
these targets
• Determine the LDL cholesterol level 3 weeks after randomization in order to
adjust the statin dose or to add other lipid-lowering agents
• Patients were followed every 6 months after randomization with measurement
of LDL cholesterol
• Data regarding levels of triglycerides, high-density lipoprotein cholesterol,
blood pressure in the sitting position, fasting glucose, and glycated hemoglobin
were collected at the 6-month visits .

7. Patient selection
• 18 years of age or older (>20 years of age in South Korea)
• An ischemic stroke within the past 3 months, which was followed by a
MRS of 0 to 3
• TIA within the previous 15 days
• All the patients were screened with the use of noninvasive imaging of the
cervical vessels (carotid duplex, CT angiography, and MR angiography)

8. Patient selection
• In addition, CT angiography or MR angiography of the intracranial
vasculature was performed
• Transesophageal echocardiography or CT angiography of the aorta to detect
aortic atheroma
• Patients had to have atherosclerotic disease that included
1. Stenosis of an extracranial or intracranial cerebral artery
2. Ipsilateral or contralateral to the region of imputed brain ischemia
3. Atherosclerotic plaques of the aortic arch measuring at least 4 mm in
thickness
4. A known history of coronary artery disease

9. Outcome
• Composite primary end point of major cardiovascular events
included
1. Nonfatal cerebral infarction or stroke of undetermined origin
2. Nonfatal myocardial infarction
3. Hospitalization for unstable angina followed by urgent
coronary-artery revascularization,
4. TIA treated with urgent carotid revascularization
5. Cardiovascular death, including unexplained sudden death

10. Outcome
• The secondary end points :-
1. Myocardial infarction or urgent coronary revascularization after the onset of
new symptoms
2. Cerebral infarction or urgent revascularization of a carotid or cerebral artery
after TIA
3. Cerebral infarction or TIA
4. Any revascularization of a coronary, cerebral, or peripheral artery
5. Cardiovascular death; death from any cause
6. Cerebral infarction or intracranial hemorrhage
7. Newly diagnosed diabetes

11. Statistical analysis
• We estimated that the enrollment of 3786 patients would result in 385 primary end-
point events and provide a power of approximately 80% to detect a 25% lower relative
risk of major cardiovascular events.
• Kaplan–Meier method to estimate the cumulative incidence of the primary end point
• Cox proportional-hazards regression model to perform the primary efficacy analysis
• The data were analyzed with the use of SAS software, version 9.3

12. Patient characteristics

14. Results
• Median follow-up was 3.5 years in the lower-target group and 3.6 years in
the higher-target group
• 65.9% of the patients in the lower-target group and 94.0% of those in the
higher-target group received only a statin
• 33.8% and 5.8% of the patients, respectively, received ezetimibe plus a
statin
• At a median of 2.7 years in the two groups, discontinuation rates were 30.3%
and 28.5%, respectively
• the mean LDL cholesterol level was 65 mg per deciliter in the lower-target
group and 96 mg per deciliter in the higher-target group

16. Results

17. Results

20. Discussion
• A target LDL cholesterol level of less than 70 mg per deciliter
could provide a further risk reduction.
• Whether reducing the LDL cholesterol level to a target below 50
mg per deciliter is beneficial is not known and could be
tested in other studies.
• A numerically higher number of intracranial hemorrhages in the
lower-target group than in the higher-target group

21. Limitations
• Median follow up of 2 years in Korean population produced lack
of power to detect significant effect.
• Premature cessation of trial due to stoppage of funding.

22. Trial 1
• Population :- patient with atherosclerotic disease who are at risk
of cardiovascular event.
• Exposure:- lipid lowering agent with target LDL level below <70
mg/dl.
• Comparator:- high target LDL level between 90-110 mg/dl
• Outcome:- reduced risk of cardiovascular event in low LDL target
population with hazard ratio of 0.78.

23. Trial 2

24. Background
• Idiopathic normal pressure hydrocephalus (iNPH) is one of few
neurodegenerative disorders that can be successfully treated
• Shunt surgery improves around 80% of the patients.
• The condition remains underdiagnosed and undertreated in part due
to lack of specific diagnostic tests.

25. Methodology
• 82 patients with iNPH were selected retrospectively
• All were diagnosed at the Hydrocephalus Research Unit, Sahlgrenska
University Hospital in Gothenburg, Sweden, according to international
guidelines.
• All patients received a ventriculo-peritoneal shunt with an adjustable
valve and were evaluated post-surgery at median 8 months

26. Methodology
• 70 patients with definite PD according to the UK Parkinson’s
Disease Society Brain Bank clinical diagnostic criteria.
• 34 with probable multiple system atrophy (MSA)
• 34 with probable or definite progressive supranuclear palsy
(PSP)
• 15 with probable corticobasal degeneration (CBD)

27. Methodology
• 50 patients with AD
• 19 patients with frontotemporal lobar degeneration (FTLD) were
diagnosed at the Department of Neurology at Kuopio University Hospital,
Kuopio, Finland.
• 75 patients with VAD were diagnosed at the Department of Geriatric
Medicine at Linköping University Hospital, Sweden using the International
Classification of Disease.

28. Methodology
• In total, 54 neurologically healthy individuals (HIs) were included in the analysis,
cognitively tested subjects with a mini mental state examination
(MMSE) score of 26 or, higher.
• 20 From Kuopio University Hospital
• 34 From the Linkoping University Hospital, Linköping, Sweden
• AD, FTLD, VAD, PD, PSP, MSA and CBD were together denoted non-iNPH disorders.
• AD, FTLD and VAD were named cognitive disorders, whereas PD, PSP, MSA and CBD
formed movement disorders.

29. Methodology
• Written informed consent was obtained from all participants or their next of kin in
agreement
• All CSF samples were collected via lumbar puncture with the patient in recumbent
position.
1. Neurofilament light concentration
2. Amyloid β
3. Isoforms (Aβ38, Aβ40 and Aβ42), sAPPα, sAPPβ
4. Monocyte chemoattractant protein 1 (MCP-1)
5. CSF T-tau and P-tau concentrations

30. Statistical analysis
• One-way analysis of covariance (ANCOVA) adjusted for age
and sex was used for post-hoc analysis
• Univariable logistic regression analysis was performed for each
individual CSF variable to separate iNPH versus non-iNPH disorders
• Statistical analyses were performed using SPSS Statistics for Windows
V.25

31. Result

34. • (a) iNph versus
hI (aUc = 0.8715),
• (B) iNph versus non-iNph
(aUc = 0.8581)
• (c) iNph versus cognitive
disorders (aUc = 0.9161)
• (D) iNph versus
movement disorders (aUc
= 0.8035)

35. Discussion
• The CSF biomarker profile in iNPH indicates that the pathophysiology is characterised
by changed metabolism of APP as well as astrocyte activation, but no major cortical
neural damage or tau pathology
• The changes in the APP-derived proteins normalise after surgical treatment of
patients with iNPH
• The low concentrations of CSF T-tau and P-tau, which are reversed after treatment
could signal a reduced cortical metabolism or neuronal activity

36. Discussion
• Pathological examinations of iNPH cases have revealed neurodegenerative
changes in the periventricular white matter with demyelination and astrogliosis
which might be the explanation for the increased MCP-1 concentration seen in
iNPH.
• The probability that a patient presenting with typical symptoms, signs and MR
changes is suffering from iNPH should be close to 1 if T-tau is 200 pg/mL or
lower, Aβ40 1000 pg/mL or lower and MCP-1 800 pg/mL or more.

37. Discussion
• There were several patients diagnosed as iNPH who had low estimated probability of
being diagnosed using the algorithm and thus it cannot be used for excluding iNPH.
I. The most important problem is the high comorbidity seen in patients with iNPH.
II. High frequency of vascular risk factors present in patients diagnosed with iNPH

38. Limitations
• This study was not dedicated to examine the prediction of outcome after surgery using
the biomarkers profile.
• We have aimed at analysing distinct disorders. However, the diagnoses are clinical
and are as such subject to possible false classification as we do not include post-mortem
diagnostic verification.
• We are lacking comparative clinical data to stage severity in the different disorders.
• The HIs were from two different cohorts.

39. Trial 2
• Population :- patient with cognitive disorder including iNPH and
non iNPH disorder.
• Exposure:- CSF analysis to differentiate between iNPH and non
iNPH disorder.
• Comparator:- iNPH patient with non iNPH disease patient
including cognitive and movement disorder.
• Outcome:- combination of low t-Tau, Ab 40 and high MCP-1
increase probability of iNPH disease.

40. Thank you