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overtly abnormal, and finally plateau. This is indeed the approach taken by the ongoing Domi nantly Inherited Alzheimer’s Network (DIAN) project, which is studying patients with a pathogenic mutation that causes familial AD. In the case of sporadic AD, how ever, which has poor predictability, such a study design would require hundreds if not thousands of individuals to be followed up for decades and to undergo expensive and sometimes invasive biomarkers tests, in order to capture a handful of cases. The simple alter native is a purely cross­sectional study, in which longitudinal changes are inferred by studying indivi duals at different stages of the disease—an option that fails to take interindividual differences into account, and is similar to the approach of a detective reconstructing the chain of events that led to a crime through witness testimony.

Jack and co­workers1 used a mixture of both approaches, whereby three cohorts of people at different stages of the disease (cognitively healthy, showing mild cognitive impairment, and demented) were studied serially for a short time (6–18 months), involving measurement of variable com­binations of markers of brain amyloidosis and neuronal injury. The median follow­up time was approximately 1 year. By modelling biomarker levels both between and within individuals across the spectrum of disease severity, the authors observed a nonlinear trajectory for hippocampal atrophy and amyloid deposition, and this trajectory was observed more consistently in carriers of the APOE ε4 allele than in non­carriers. The nonlinear association is weak but sta­tistically significant, and argues in favour of the dynamic marker hypothesis.

The study has theoretical as well as practi­cal relevance. Reconstruction of bio mar ker trajectories is central to understanding the sequence of events at the molecular, cellu­lar, tissue and organ level that finally lead to cognitive symptoms. In particular, closure of the knowledge gap regarding the pathologi­cal steps that link amyloid deposition and neuronal injury with neuro degeneration could dramatically boost drug develop ment. Of note, two of the mar kers used by Jack and colleagues were not employed to their full informative poten tial. The re searchers reduced the topographical information offered by amyloid PET imaging and volu­metric MRI to a single measure of amyloid load over the whole brain and a measure of atrophy of a single brain structure (the hippo campus). With appropriate spatial regis tration algorithms, which are currently

under development,6 or simply with addi­tional serial scans, reconstruction of the trajectory of neuro biological changes in multi dimensional space might be possible in the near future. This advance would enable amyloid deposition to be related to changes in atrophy and cortical hypo metabolism in 3D brain space over time, thereby shedding light on the spatiotemporal relationship of the three phenomena.

At the practical level, the findings of Jack and colleagues could be used to identify the most accurate diagnostic and disease­track ing marker at any given disease stage (Figure 1).8 This approach could also be used to select the ideal patient groups for treatment with disease­modifying drugs —that is, those who are at an early time point along the disease course—and to detect the efficacy of putative disease­modifying agents in clinical trials.

Future studies will need longer follow­up times to decrease error estimates in the variance of slope of biomarker trajectories, and to enhance the longitudinal signal of a condition that evolves over 30 years or more, analogous to enabling a detective to personally observe all the movements of the suspects of a crime long before the crime is committed. A number of data sets are being collected worldwide7 that will allow scientists to appropriately address this issue. Hopefully, thanks to these studies, my patients and their relatives will feel less disappointed at the end of a consultation.

The National Centre for Alzheimer’s and Mental Diseases, IRCCS Fatebenefratelli, Via Pilastroni 4, 25125 Brescia, Italy. gfrisoni@fatebenefratelli.it

Competing interestsThe author declares no competing interests.

1. Jack, C. R. Jr et al. Shapes of the trajectories of 5 major biomarkers of Alzheimer disease. Arch. Neurol. http://dx.doi.org/10.1001/archneurol.2011.3405.

2. Dubois, B. et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 6, 734–746 (2007).

3. Jack, C. R. Jr et al. Introduction to the recommendations from the National Institute on Aging-–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 257–262 (2011).

4. Mangialasche, F., Solomon, A., Winblad, B., Mecocci, P. & Kivipelto, M. Alzheimer’s disease: clinical trials and drug development. Lancet Neurol. 9, 702–716 (2010).

5. Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010).

6. Lorenzi, M., Ayache, N., Frisoni, G. B. & Pennec, X. Mapping the effects of Aβ levels on the longitudinal changes in healthy aging: hierarchical modeling based on stationary velocity fields. In Proc. 14th International Conference on Medical Image Computing and Computer-Assisted Intervention (eds Fichtinger, G. et al.) 663–670 (Springer-Verlag, Berlin/Heidelberg, 2011).

7. Frisoni, G. B. & Weiner, M. W. Alzheimer’s Disease Neuroimaging Initiative special issue. Neurobiol. Aging 31, 1259–1262 (2010).

8. Frisoni, G. B., Fox, N. C., Jack, C. R. Jr, Scheltens, P. & Thompson, P. M. The clinical use of structural MRI in Alzheimer disease. Nat. Rev. Neurol. 6, 67–77 (2010).

STROKE

Is spot sign the answer for intracerebral haemorrhage?Javier M. Romero

Intracerebral haemorrhage continues to carry a poor prognosis despite several recent therapeutic clinical trials. A study has demonstrated that CT angiography of the brain on admission can predict haematoma expansion and clinical outcome. This CT ‘spot sign’ could, therefore, help physicians to select patients who are likely to benefit from treatment.Romero, J. M. Nat. Rev. Neurol. 8, 300–301 (2012); published online 22 May 2012; doi:10.1038/nrneurol.2012.93

Intracerebral haemorrhage (ICH) has a mor­tality rate of approximately 40%, repre senting a considerable unmet medical need. Several trials have been performed that aimed to improve clinical outcome by reducing hae­matoma mass effect, peripheral oedema and haematoma expansion.

Targeting of haematoma expansion gained traction with a phase III trial of recom­binant activated factor VII (rFVIIa).1 How­ever, the study failed to show clinical benefit and raised questions regarding the safety of rFVIIa, in light of arterial thrombo embo­lic complications. A crucial end point of

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this study was the reduction of haematoma expansion, but the utility of this out come measurement was limited as the haema­tomas of most of the enrolled patients did not expand. Such patients were exposed to possible adverse effects of the drug and did not have the poten tial to benefit from the intervention. At the time, prediction of which patients would undergo haematoma expansion was not pos sible. Furthermore, some trials would bene fit from a radio logical sign that detects intra cerebral haemorrhage without active bleeding.

Preliminary results of the phase II MISTIE trial2 suggest that thrombolytic agents can safely be applied to the haematoma prior to surgery, but the procedure should be delayed until cessation of active bleeding is con firmed on CT. The recently published results of the PREDICT (predicting haema­toma growth and outcome in intracerebral haemorrhage using contrast bolus CT) study suggest that CT angiography could be used to predict which patients will undergo haematoma expansion following ICH, and might, therefore, represent a useful tool in selecting patients who stand to benefit from haemostatic treatments.3

PREDICT was a well­designed, prospec­tive multicentre study that recruited 228 adult patients with haematomas smaller than 100 ml who presented less than 6 h after symptom onset.3 The primary out come was haema toma expansion, which was defined as abso lute growth greater than 6 ml or a relative growth of more than 33% from initial CT to follow­up CT approximately 24 h later.3 Clinical out­come was defined using NIH Stroke Scale and modified Rankin Scale scores at 90 days. The researchers sought to detect, in particu lar, the ‘spot sign’—foci of contrast extravasa tion on CT angiography that probably represent active bleeding in the haematoma.

The results of PREDICT3 confirm, in a rela tively large group of patients for an imag­ing trial, the findings of pre vious s ingle­centre, observational studies: presence of the spot sign is a predictor of haematoma expansion and poor clinical outcome.4–8 27% of patients in PREDICT showed a spot sign, in agreement with results of prior trials,4–6 which supports the excellent reproducibility of the spot sign in patients presenting in the initial hours post ictus. In patients with hae­matoma expansion, the positive predictive value of the spot sign for this event was 73%, the negative predictive value was 84%, the sensitivity was 63%, and the specificity was high, at 90%. Compared with patients who were spot­sign­negative, those with a spot

sign had a twofold greater mortality rate at 30 days, lower modified Rankin Scale scores, and earlier clinical deterioration.

The sensitivity of the spot sign for haema­toma expansion was low in PREDICT3 com­pared with other studies involving a similar time interval from onset to imaging, which reported sensitivities of 91–93%.4,5 This result could have been influenced by key radiological factors that were not examin ed in the recent trial; in particular, fac tors per­taining to contrast extravasation, such as kinetics of the contrast bolus, which depend on patient­related and injection­related vari­ables. These variables include cardiac output, concentration of the contrast medium, injec­tion rate, and delay from injection to imag­ing. Although these factors are crucial to the spot sign appearance and magnitude, they were not mentioned in PREDICT.

The spot sign is purely a dynamic radio­logical parameter that, as noted in prior studies, has different sensitivity and speci­ficity depending on the imaging delay after contrast administration.4,9 Delayed imag­ing would probably increase the sensitivity of the spot sign for predicting haema toma expan sion, given the increased interval of time during which contrast is circulating and permeating into the haematoma. A higher concentration of contrast agent would increase the visualization of the spot sign. The CT scanner models that were used at the different centres in PREDICT were not documented. The use of new, faster scanners at some centres could have led to imaging of the haematoma too early for the spot sign to develop, thereby decreasing the overall sensi­tivity. Further investigation into the delay to image that occurs with certain scanners could shed light on an ideal imaging protocol for patients with ICH.

Spot­sign­related radiological charac­teristics, which are directly proportional to the amount of contrast that has leaked from the artery or vein, are considered impor tant because they might reflect the rate at which the haematoma is bleeding. The presence of multiple spot signs, or spot signs that are dense and/or large, is probably attributable to a high rate of contrast leak and, therefore, to ongoing bleeding. These radiological charac teristics, when included in prior scales of spot­sign scores, showed excellent cor­relation with relative and absolute haema­toma expansion, clinical outcome and, more recently, the average rate of expansion.10

Determining which patients are likely to show early clinical deterioration or haema­toma expansion following ICH is a difficult

task, particularly when the neurological exami nation is unreliable, or assessment of the patient for surgical intervention only occurs 24–48 h after admission, once the results of follow­up imaging are available. The use of an imaging biomarker that is capable of iden tifying patients with haema tomas that are bleed ing would be beneficial both in clinical prac tice and in trials for ICH therapies. The PREDICT study has advanced our knowl­edge on the reliability of the spot sign as a radio logical marker for active intracerebral bleeding.3 Future trials should aim to evalu­ate the spot sign’s application as a useful tool for selecting patients who will benefit from treatments to limit haematoma expansion.

Department of Radiology, Massachusetts General Hospital, Harvard School of Medicine, 55 Fruit Street, Office Gray 279, Boston, 02114 MA, USA. jmromero@partners.org

Competing interestsThe author declares no competing interests.

1. Mayer, S. A. et al. Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N. Engl. J. Med. 358, 2127–2137 (2008).

2. Morgan, T. et al. Preliminary findings of the minimally-invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE) clinical trial. Acta Neurochir. Suppl. 105, 147–151 (2008).

3. Demchuk. A. M. et al. Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study. Lancet Neurol. 11, 307–314 (2012).

4. Delgado Almandoz, J. E. et al. Systematic characterization of the computed tomography angiography spot sign in primary intracerebral hemorrhage identifies patients at highest risk for hematoma expansion: the spot sign score. Stroke 40, 2994–3000 (2009).

5. Wada, R. et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage. Stroke 38, 1257–1262 (2007).

6. Li, N. et al. Contrast extravasation on computed tomography angiography predicts clinical outcome in primary intracerebral hemorrhage: a prospective study of 139 cases. Stroke 42, 3441–3446 (2011).

7. Goldstein, J. N. et al. Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage. Neurology 68, 889–894 (2007).

8. Delgado Almandoz, J. E. et al. The spot sign score in primary intracerebral hemorrhage identifies patients at highest risk of in-hospital mortality and poor outcome among survivors. Stroke 41, 54–60 (2010).

9. Ederies, A. et al. Postcontrast CT extravasation is associated with hematoma expansion in CTA spot negative patients. Stroke 40, 1672–1676 (2009).

10. Romero, J. M. et al. Spot sign score predicts rapid bleeding in spontaneous intracerebral hemorrhage. Emerg. Radiol. http://dx.doi.org/ 10.1007/s10140-012-1020-9.

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