CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)

Craig Ritchie; Nadja Smailagic<sup>a</sup>; Anna H Noel‐Storr; Obioha Ukoumunne; Emma C Ladds; Steven Martin

doi:10.1002/14651858.CD010803.pub2

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Figure 1

Study flow diagram

Note: a top‐up search performed in December 2015 revealed 6134 records

85 records retained after de‐duplication and assessment by one experienced reviewer

81 records excluded after further assessment performed by two review authors

4 studies identified for possible inclusion (Characteristics of studies awaiting classification)

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Figure 2

Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study

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Figure 3

Risk of bias and applicability concerns graph: review authors' judgements about each domain presented as percentages across included studies

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Figure 4

Forest plot of 1 CSF t‐tau conversion to AD dementia.

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Figure 5

Summary ROC Plot of 1 CSF t‐tau conversion to AD dementia.

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Figure 6

Post‐test probability plots (Analysis 1): Conversion from MCI to Alzheimer’s disease for CSF t‐tau as a diagnostic test

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Figure 7

Forest plot of 2 CSF p‐tau conversion to AD dementia.

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Figure 8

Summary ROC Plot of 2 CSF p‐tau conversion to AD dementia.

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Figure 9

Post‐test probability plots (Analysis 2): Conversion from MCI to Alzheimer’s disease for CSF p‐tau as a diagnostic test

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Figure 10

Forest plot of 3 CSF p‐tau/ABeta ratio to AD dementia.

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Figure 11

Summary ROC Plot of 3 CSF p‐tau/ABeta ratio to AD dementia.

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Figure 12

Forest plot of 4 CSF t‐tau conversion to all forms of dementia.

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Figure 13

Summary ROC Plot of 4 CSF t‐tau conversion to All dementias.

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Test 1

CSF t‐tau conversion to AD dementia.

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Test 2

CSF p‐tau conversion to AD dementia.

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Test 3

CSF p‐tau/ABeta ratio to AD dementia.

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Test 4

CSF t‐tau conversion to All dementias.

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Summary of findings Performance of CSF biomarkers in early diagnosis of dementia

What is the diagnostic accuracy of CSF biomarker levels for detecting Alzheimer's disease pathology in people with mild cognitive impairment (MCI), and identifying those MCI participants who would convert to Alzheimer’s disease dementia or other forms of dementia over time
Descriptive
Patient population	Participants diagnosed with MCI at baseline using any of the Petersen criteria or CDR = 0.5 or any 16 definitions included by Matthews (Matthews 2008)
Sampling procedure	Consecutive or random (n = 5) Not consecutive or random (n = 3) Unclear (n = 7)
Sources of recruitment	University memory clinic (n = 8); European multicentre memory clinics (n = 2); inpatients (n = 2); General Hospital memory clinic (n = 1); Research centre outpatient memory clinic (n = 1); not reported (n = 1)
Prior testing	The only testing prior to performing the plasma and CSF biomarkers was the application of diagnostic criteria for identifying participants with MCI.
MCI criteria	Petersen criteria (n = 14) Global Deterioration Scale (GDS) (n = 1)
Index tests	CSF t‐tau or CSF p‐tau or CSF p‐tau/ABeta ratio or CSF t‐tau/ABeta ratio
Reference standard	NINCDS‐ADRDA and/or DSM and/or ICD criteria for Alzheimer's disease dementia (n = 12); Global Dementia Scale (GDS) & Research criteria (n = 1); CDR = 1 criteria (n = 1); not specified (n = 1) McKeith criteria for Lewy body dementia; Lund criteria for frontotemporal dementia; and NINDS AIREN criteria for vascular dementia
Target condition	Alzheimer’s disease dementia or any other types of dementia
Included studies	Prospectively well‐defined cohorts of MCI participants (n = 7), nested case‐control studies with a prospectively defined MCI group (n = 6) and studies with a retrospectively defined MCI group with longitudinal data (n = 2). Fifteen studies (N = 1282 participants) were included. Number included in analysis: 1172
Quality concerns	Patient selection and conduct of the reference standard were poorly reported. Applicability concerns were generally low. Regarding the inclusion criteria set in the review, the majority of included studies did match the review question: 'Could CSF t‐tau and CSF t‐tau/ABetaratio biomarkers identify those MCI participants with Alzheimer’s disease pathology at baseline who would convert clinically to dementia at follow up?' However, due to a limited number of included studies and levels of heterogeneity, it is difficult to determine to what extent the findings from a meta‐analysis can be applied to clinical practice.
Limitations	Limited investigation of heterogeneity due to insufficient number of studies. There was a lack of common thresholds.
Test Median percentage converting (range) ²	Studies	Cases/participants	Median specificity from included studies	Sensitivity (95% CI)¹ at median specificity	Consequences in a cohort of 100
					Median percentage converting²	Missed cases	Overdiagnosed
Alzheimer's disease dementia
CSF t‐tau	7	436/709	72	77 (67, 85)	37	9	18
Alzheimer's disease dementia
CSF p‐tau	6	164/492	47.5	81 (64, 91.5)	37	7	33
Alzheimer's disease dementia
CSF p‐tau/ ABeta ratio	5	140/433	No meta‐analysis	No meta‐analysis
All types of dementia
CSF t‐tau	4	166/319	No meta‐analysis	No meta‐analysis
Investigation of heterogeneity: the planned investigations were not possible due to the limited number of studies available for each analysis. We were unable to investigate the effect of duration of follow‐up due to substantial variation in length and reporting.
Conclusions: Given the insufficient evidence to evaluate the diagnostic value in MCI of CSF t‐tau, CSF p‐tau, CSF t‐tau/ABeta ratio and CSF p‐tau/ABeta ratio for Alzheimer's disease dementia and other forms of dementias examined in this review, particular attention should be paid to the risk of misdiagnosis and overdiagnosis of dementia (and therefore overtreatment) in clinical practice. Future studies with more uniform approaches to thresholds, analysis and study conduct may provide a more homogenous estimate than the one that has been available from the included studies we have identified.
¹Meta‐analytic estimate of sensitivity derived from the HSROC model at a fixed value of specificity. Summary estimates of sensitivity and specificity were not computed because the studies that contributed to the estimation of the summary ROC curve used different thresholds. ²The median percentage converting was calculated using all the studies that reported 'conversion from MCI to Alzheimers' disease dementia' (Table 2)

Summary of findings Performance of CSF biomarkers in early diagnosis of dementia

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Table 1. Studies awaiting classification

Conversion from MCI to Alzheimer’s disease dementia
Study	Participants n/N (included in analysis)	Index test (number and % of positive tests)	Threshold (test abnormal) (prespecified Yes/No)	Number of converters (%) FP and FN	Test accuracy at study level		Duration of follow‐up
					Sensitivity	Specificity
*Balasa 2014	51/51	CSF ABeta42/p‐tau ratio 25/51 (49%)	< 6.43 (Yes)	24/51 (47%) FP =1; FN =0	100%	96%	41 months for MCI‐AD; 30 months for MCI‐MCI
*Ewers 2012	130/130	CSF t‐tau 65/130 (50%)	Not reported	58/130 (45%) FP = 30; FN = 23	60.7%	58.9%	24 months
		CSF p‐tau 67/130 (51.5%)	Not reported	58/130 (45%) FP = 30; FN = 21	63.9%	58.9%
*Leuzy 2015	33/33	CSF t‐tau 15/33 (45%)	˃ 400 pg/mL(Yes)	12/33 (36%) FP = 7; FN = 4	67%	67%	Not reported
		CSF t‐tau/ABeta ratio 12/33 (36%)	< 1.14 (Yes)	12/33 (36%) FP = 6; FN = 6	50%	71%
Conversion from MCI to all dementias
*Eckerstrom 2015	73/73	CSF p‐tau 15/73 (20.5%)	73 pg/mL (No)	27/73 (36.9%) FP = 3; FN = 15	75%	92%	43.1 ± 23 months MCI‐stable; 33.7 ± 24 months MCI converters
Study awaiting translation
Urakami 2004
^{AD: Alzheimer's disease; FN: false negative; FP: false positive; MCI: mild cognitive impairment} ^{*Authors need to be contacted in order to obtain missing data/relevant information. Data presented are provisional.}

Table 1. Studies awaiting classification

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Table 2. Conversion from MCI to Alzheimer's disease dementia

Included studies, index test and test accuracy at study level for conversion from MCI to Alzheimer’s disease dementia
Study	Participants n/N (included in analysis)	Index test (number and % of positive tests)	Threshold (test abnormal) (prespecified Yes/No)	Number of converters (%) FP and FN	Test accuracy at study level		Duration of follow‐up
Study	Participants n/N (included in analysis)	Index test (number and % of positive tests)	Threshold (test abnormal) (prespecified Yes/No)	Number of converters (%) FP and FN	Sensitivity	Specificity	Duration of follow‐up
Amlien 2013	49/39	CSF t‐tau 9/39 (23%)	≥ 300 ng/L for age younger than 50 years; ≥ 450 ng/L for age 50 to 69 years; ≥ 500 ng/L for age older than 70 years (Sjogren 2001) (Yes)	9/39 (23%); FP = 4; FN = 4	56%	87%	mean 2.6 ± 0.5 years (range 1.6 to 4 years)
Buchhave 2012*	137/134	CSF p‐tau/ABeta ratio 69/134 (51%)	˂ 6.2 ng/L (No)	72/134 (54%) FP = 6; FN = 9	88%	90%	median: 9.2 years (range 4 to 12 years)
Fellgiebel 2007	16/16	CSF p‐tau 12/16 (75%)	≥ 50 pg/mL (No)	4/16 (25%) FP = 8; FN = 0	100%	33%	mean 19.6 ± 9.0 months
Hampel 2004	52/52	CSF t‐tau 38/52 (73%)	≥ 479 ng/L (No)	29/52 (56%); FP = 12; FN = 3	90%	48%	mean 8.4 ± 5.1 months (range 2 to 24 months)
Hansson 2006*	137/134	CSF t‐tau 38/134 (28%)	> 350 ng/L (No)	57/134 (42%); FP = 9; FN = 28	51%	88%	Total sample: median 5.2 years (range 4.0 to 6.8 years); MCI‐AD: median: 4.3 years (range 1.1 to 6.7 years) MCI‐other dementias: median 4.2 years (range 1.5 to 3 years)
		CSF p‐tau 50/134 (37%)	≥ 60 ng/L (No)	57/134 (42%); FP = 11; FN = 18	68%	86%
		CSF p‐tau/ABeta ratio 74/134 (55%)	˂ 6.5 ng/L (No)	57/134 (42%); FP = 19; FN = 2	96%	75%
Kester 2011	153/100	CSF t‐tau 64/100 (64%)	> 356 pg/mL (Yes)	42/100 (42%) FP = 29; FN = 7	83%	50%	median 18 months (IQR 13 ‐ 24)
Koivunen 2008	15/14	CSF p‐tau 9/14 (64%)	≥ 70 pg/mL (Yes)	5/14 (36%) FP = 7; FN = 3	40%	22%	2 years
Koivunen 2008	15/14	CSF p‐tau/ABeta ratio 9/14 (64%)	˂ 6.5 pg/mL (yes)	5/14 (36%) FP = 6; FN = 1	80%	33%	2 years
Monge‐Argiles 2011	37/37	CSF t‐tau 16/37 (43%)	≥ 77.5 pg/mL (No)	11/37 (28%) FP = 8; FN = 3	73%	69%	6 months
		CSF p‐tau 20/37 (54%)	≥ 54.5 pg/mL (No)	11/37 (28%) FP = 11; FN = 2	82%	58%
		CSF p‐tau/ABeta ratio 18/37 (49%)	0.17 (No)	11/37 (28%) FP = 9; FN = 2	82%	66%
		CSF t‐tau/ABeta ratio 23/37 (62%)	0.18 (No)	11/37 (28%) FP = 13; FN = 1	91%	50%
Palmqvist 2013	133/133	CSF t‐tau 65/133 (49%)	> 87 pg/mL (No)	52/133 (39%) FP = 23; FN = 10	81%	72%	mean 5.9 years (range 3.2 to 8.8 years)
Palmqvist 2013	133/133	CSF p‐tau 46/133 (34%)	> 39 pg/mL (No)	52/133 (39%) FP = 11; FN = 17	67%	86%	mean 5.9 years (range 3.2 to 8.8 years)
Parnetti 2012	90/90	CSF p‐tau/ABeta ratio 29/90 (32%)	1074.0 (No)	32/90 (35%) FP = 3; FN = 6	81%	95%	maximum: 4 years; mean 3.40 ± 1.01 years
Visser 2009	168/158	CSF p‐tau 108/158 (68%)	≥ 51 pg/mL (used in clinical practice) (No)	35/158 (22%) FP = 77; FN = 4	88%	37%	range 1 to 3 for MCI
		CSF p‐tau 45/158 (28%)	≥ 85pg/mL (> 90th percentile of controls after correction for age) (No)	35/158 (22%) FP = 25; FN = 15	57%	80%
		CSF p‐tau/ABeta ratio 77/158 (49%)	˂ 9.92 (< 10th percentile of reference group after correction for age) (No)	35/158 (22%); FP = 49; FN = 7	80%	60%
Vos 2013	231/214	CSF t‐tau 93/214 (43%)	> 450 pg/mL for age less than 70 years; > 500 pg/mL for age older than 70 years (Yes)	91/214 (42%) FP = 28; FN = 26	71%	77%	mean 2.5 ± 1.0 years
Vos 2013	231/214	CSF t‐tau/ABeta ratio 147/214 (69%)	ABeta1–42/(240 1 [1.18 3 t‐tau]) ˂ 1.0 (Yes)	91/214 (42%) FP = 60; FN = 4	96%	51%	mean 2.5 ± 1.0 years
^{AD: Alzheimer's disease; FN: false negative; FP: false positive; MCI: mild cognitive impairment} ^{*Studies involved the same participants. Only Hansson 2006 is included in the meta‐analysis}

Table 2. Conversion from MCI to Alzheimer's disease dementia

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Table 3. Conversion from MCI to All dementia

Included studies, index test and test accuracy at study level for conversion from MCI to All dementias
Study	Participants n/N (included in analysis)	Index test (Number and % of positive tests)	Threshold (test abnormal) (pre‐specified Yes / No)	Number of converters (%) FP and FN	Test accuracy at study level		Duration of follow‐up
Study	Participants n/N (included in analysis)	Index test (Number and % of positive tests)	Threshold (test abnormal) (pre‐specified Yes / No)	Number of converters (%) FP and FN	Sensitivity	Specificity	Duration of follow‐up
Eckerstrom 2010	42/42	CSF t‐tau 15/42 (36%)	≥ 500 ng/L (No)	21/42 (50%) FP = 1 FN = 7	67%	95%	Total sample: 19.6 ± 9.0 months; MCI‐MCI: 19.5 ± 9.3 months; MCI‐progressive: 17.6 ± 8.8 months (4/8 MCI‐AD: 23.7 ± 2.0 months)
Galluzzi 2010	90/64	CSF t‐tau 24/64 (37.5%)	> 450 pg/mL for subjects with an age range between 51 and 70 determined; > 500 pg/mL for subjects with an age range between 71 and 93 (Yes)	34/64 (53%) FP = 5 FN = 15	56%	83%	Total sample: 8.4 ± 5.1 months (range 2 to 24 months); follow‐up interval for converters was 9.6 ± 5.4, and for non‐converters 7.0 ± 4.3 months
Hansson 2006	137/134	CSF t‐tau 38/134 (28%)	> 350 pg/mL (No)	78/134 (58%) FP = 5 FN = 45	42%	91%	Total sample: median 5.2 years (range 4.0 to 6.8); MCI‐AD: median: 4.3 years (range 1.1 to 6.7); MCI‐other dementias: median 4.2 (1.5 to 6.3)
Herukka 2007	79/79	CSF t‐tau 43/79 (54%)	> 400 pg/mL (Yes)	33/79 (42%) FP = 17 FN = 7	79%	63%	Mean 3.52 ± 1.95 years in MCI converters; mean 4.56 ± 3.09 years in MCI‐stable
^{AD: Alzheimer's disease; FN: false positive; FP: false negative; MCI: mild cognitive impairment}

Table 3. Conversion from MCI to All dementia

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Table Tests. Data tables by test

Test	No. of studies	No. of participants
1 CSF t‐tau conversion to AD dementia Show forest plot	7	709

2 CSF p‐tau conversion to AD dementia Show forest plot	6	492

3 CSF p‐tau/ABeta ratio to AD dementia Show forest plot	5	433

4 CSF t‐tau conversion to All dementias Show forest plot	4	319

Table Tests. Data tables by test

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