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Sutphen CL, McCue L, Herries EM, Xiong C, Ladenson JH, Holtzman DM, Fagan AM, ADNI. Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer's disease. Alzheimers Dement. 2018 Jul;14(7):869-879. Epub 2018 Mar 23 PubMed.
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VU University Medical Center
The interesting aspect of this study is that the longitudinal decrease in biomarkers observed in the familial DIAN cohort is now replicated in the ADNI cohort of LOAD patients.
Such longitudinal data are highly needed for clinical trials, and the observed variation in clinical, MRI, and biomarker outcome measures (e.g., high in YKL-40) and decreases indeed are very relevant when evaluating treatment effects. However, a trial will normally include placebo, so any effect should be different in the treatment group compared to controls. But now we are more aware that biomarker levels do not only increase but can also decrease as part of the natural course.
There is a gap to fill next, because in ADNI participants are relatively old and in DIAN they are quite young. There are clear age relationships of many biomarkers, which increase due to normal aging. So, it would be interesting if similar findings can be obtained in early onset, sporadic AD patients.
It is interesting that levels of tau, but not the other markers, increase over time. This may suggest that some different biology is involved. Alternatively, the stronger dynamics of tau might be due to having assays of higher quality (lower variation) or to the protein being under stronger influence of altered CSF flow than the other biomarkers.
Assuming that the different biomarker changes are due to biology, this data suggests that axonal damage does not precede tissue destruction but that markers of axonal damage are released due to tissue injury. Moreover, there is a need for earlier biomarkers that change as early as does Aβ42.
The five-year change for the majority of markers is clear, but given the slope of the spaghetti plots, inter-individual variation will be high. So, the ideal biomarker that shows a change in every single patient is not yet discovered.
Moreover, the cause of change could indeed be a loss of tissue mass or ventricular enlargement, i.e., a general physiological parameter, rather than pathology-specific alteration. The true dynamic change downstream of neuroprotection has yet to be proven in positive trials.
View all comments by Charlotte TeunissenLund University
Longitudinal biomarker studies are very important to better understand the molecular changes in AD. However, considering the protracted disease course of AD (spanning two to three decades), we probably need intra-individual measurements over at least eight to 15 years to be able to make firm conclusions. There have been a few such studies (e.g. Stomrud et al., 2015), but they have been quite small.
I fully agree with the authors that the current study warrants the need of further long-term studies on CSF biomarkers that might reflect ongoing neurodegeneration (total tau, Ng, SNAP25) before such biomarkers are used as outcome measures in trials evaluating the efficacy of new treatments. We need to better understand which factors are associated with increases or decreases in the levels of these biomarkers over time, including the effects of changes in neuronal activity, neuronal degeneration, as well as changes in the dynamics of the flow of ISF and CSF during different stages of the disease. That said, the combinations of the CSF Aβ42/40 ratio together with t-tau or phospho-tau have been very thoroughly validated for their ability to accurately identify cases with preclinical or prodromal AD, and these biomarkers can be used when selecting individuals for treatment trials.
References:
Stomrud E, Minthon L, Zetterberg H, Blennow K, Hansson O. Longitudinal cerebrospinal fluid biomarker measurements in preclinical sporadic Alzheimer's disease: A prospective 9-year study. Alzheimers Dement (Amst). 2015 Dec;1(4):403-11. Epub 2015 Oct 9 PubMed.
View all comments by Oskar HanssonEisai Inc.
To investigate longitudinal dynamics of pathophysiological biomarkers across all AD stages is of paramount importance for the understanding of disease initiation, progression, and biomarker-guided, targeted drug development. Ideally, we should obtain comparative paired CSF and plasma/blood dynamics over time in a large-scale observational study of healthy elderly individuals until a proportion of them reaches clinical endpoints, such as mild cognitive impairment or AD dementia. This is currently been done by the Alzheimer Precision Medicine Initiative (APMI) through the APMI cohort program (APMI-CP) using the large-scale observational mono-center INSIGHT-preAD cohort in Paris (Hampel et al., 2016; Hampel et al., 2017; Hampel et al., 2018). In addition to longitudinal (more than seven years) fluid biomarker analysis, the APMI-CP includes complementary, comprehensive modalities, such as structural, functional, and metabolic imaging and neurodynamics (including EEG and ERP). Previously, we applied up to seven serial CSF measurements in patients with AD demonstrating that p-tau231 concentrations decreased linearly with time (Hampel et al., 2001).
Several relevant pathophysiological processes, i.e., synaptic dysfunction and loss of plasticity, neuroinflammation, and mitochondrial dysfunction, have been reported to underlie polygenic AD and should be investigated longitudinally using appropriate candidate fluid biomarkers. AD transgenic animal studies have previously shown a complex interplay among synaptic pathways, glial activity, and regulatory mechanisms of both Aβ and tau metabolism (Bachhuber et al., 2015). It is well established that these pathophysiological processes occur along the continuum of AD, beginning from asymptomatic phases, and directly contribute to neurodegeneration and successive cognitive decline.
Fagan and colleagues have demonstrated in this study that synaptic dysfunction, neuroinflammation, and neuronal injury are tightly linked to AD pathophysiological “hallmarks”—i.e., Aβ and tau, both misfolding and widespread toxic accumulation. This is an important step toward exploring pathophysiological dynamics informative for clinical drug development programs.
It is reported that the global and regional amount of brain amyloid plaques correlates well with neither the extent of neurodegeneration nor the degree of cognitive decline (Karran and Hardy, 2014). However, Aβ biomarkers do not seem to cover the entire temporal spectrum of polygenic AD pathophysiology.
To date, a holistic and comprehensive understanding of the pathophysiological dynamics across the spectrum of individuals affected by polygenic AD is far from being reached, however, this study carried out by Fagan and colleagues provides relevant, novel incremental insights into the longitudinal CSF dynamics of the disease.
From a pharmacological point of view, research should integrate and focus to better understand whether and how aberrant synaptic and inflammatory pathways synergistically interact with misfolding and accumulation of Aβ and tau. To move forward, a shift to, and integration of, evolving and available blood-based candidate biomarker panels seems rational (O’Bryant et al., 2017).
The findings by Fagan and colleagues support the perspective of a biomarker-guided, multi-targeted therapeutic approach to AD under the Precision Medicine paradigm rather than “magic-bullet, one-size-fits-all” drug targeting of one pathophysiological process at unspecified time points along yet undefined AD stages.
References:
Hampel H, O'Bryant SE, Castrillo JI, Ritchie C, Rojkova K, Broich K, Benda N, Nisticò R, Frank RA, Dubois B, Escott-Price V, Lista S. PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease. J Prev Alzheimers Dis. 2016 Dec;3(4):243-259. Epub 2016 Sep 6 PubMed.
Hampel H, O'Bryant SE, Durrleman S, Younesi E, Rojkova K, Escott-Price V, Corvol JC, Broich K, Dubois B, Lista S, Alzheimer Precision Medicine Initiative. A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling. Climacteric. 2017 Apr;20(2):107-118. Epub 2017 Feb 9 PubMed.
Hampel H, Toschi N, Babiloni C, Baldacci F, Black KL, Bokde AL, Bun RS, Cacciola F, Cavedo E, Chiesa PA, Colliot O, Coman CM, Dubois B, Duggento A, Durrleman S, Ferretti MT, George N, Genthon R, Habert MO, Herholz K, Koronyo Y, Koronyo-Hamaoui M, Lamari F, Langevin T, Lehéricy S, Lorenceau J, Neri C, Nisticò R, Nyasse-Messene F, Ritchie C, Rossi S, Santarnecchi E, Sporns O, Verdooner SR, Vergallo A, Villain N, Younesi E, Garaci F, Lista S, Alzheimer Precision Medicine Initiative (APMI). Revolution of Alzheimer Precision Neurology. Passageway of Systems Biology and Neurophysiology. J Alzheimers Dis. 2018;64(s1):S47-S105. PubMed.
Hampel H, Buerger K, Kohnken R, Teipel SJ, Zinkowski R, Moeller HJ, Rapoport SI, Davies P. Tracking of Alzheimer's disease progression with cerebrospinal fluid tau protein phosphorylated at threonine 231. Ann Neurol. 2001 Apr;49(4):545-6. PubMed.
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O'Bryant SE, Mielke MM, Rissman RA, Lista S, Vanderstichele H, Zetterberg H, Lewczuk P, Posner H, Hall J, Johnson L, Fong YL, Luthman J, Jeromin A, Batrla-Utermann R, Villarreal A, Britton G, Snyder PJ, Henriksen K, Grammas P, Gupta V, Martins R, Hampel H, Biofluid Based Biomarker Professional Interest Area. Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic. Alzheimers Dement. 2017 Jan;13(1):45-58. Epub 2016 Nov 18 PubMed.
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