Original language | English |
---|---|
Pages (from-to) | 1430-1432 |
Number of pages | 3 |
Journal | Movement Disorders |
Volume | 34 |
Issue number | 10 |
DOIs | |
State | Published - Oct 1 2019 |
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In: Movement Disorders, Vol. 34, No. 10, 01.10.2019, p. 1430-1432.
Research output: Contribution to journal › Editorial
TY - JOUR
T1 - Striatal DAT SPECT
T2 - Caveat Emptor!
AU - Perlmutter, Joel S.
AU - Stoessl, A. Jon
N1 - Funding Information: J.S.P.: NIH funding from other PI's include: NS092865, NS077384, NS097437, U54TR001456, AG050263, NS097799, NS075527, and DOD 12219880; and Foundation funding includes: Huntington Disease Society of America HDSA Center of Excellence at Washington University. Funding Information: Joel S. Perlmutter MD [email protected] A. Jon Stoessl MD [email protected] Departments of Neurology, Radiology, Neuroscience and Programs in Physical Therapy and Occupational Therapy Washington University School of Medicine St. Louis Missouri USA Division of Neurology & Djavad Mowafaghian Centre for Brain Health University of British Columbia Vancouver BC Canada American Parkinson Disease Association APDA Advanced Research Center at Washington Univer Greater St. Louis Chapter of the APDA Barnes Jewish Hospital Foundation Elliot Stein Family Parkinson Disease Research Fund Canada Research Chairs McDonnell Center for Higher Brain Function PET Research Michael J Fox Foundation NIH NINDS NS058714 NS075321 NS103957 NS107281 Riney Foundation for Parkinson disease research Weston Brain Institute Funding agencies: J.S.P.: NIH (NS058714, NS075321, NS103957, and NS107281); American Parkinson Disease Association (APDA) Center for Advanced PD Research at Washington University; Greater St. Louis Chapter of the APDA; McDonnell Center for Higher Brain Function; Barnes‐Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund), Oertli Fund, Fixel Foundation, and Paula C. and Rodger O. Riney Neurodegenerative Diseases Research Fund. A.J.S.: Canada Research Chairs, Michael J. Fox Foundation, Weston Brain Institute, and Pacific Parkinson's Research Institute. Lauren & Lee Fixel Family Foundation for research support. Relevant conflicts of interest/financial disclosures: A.J.S. chairs a DSMB for Voyager Therapeutics, Inc. and serves as an advisor to Cellular Dynamic, Inc. He is Deputy Editor of Movement Disorders. Full financial disclosures and author roles may be found in the online version of this article. and that the situation is considerably more complex. Surprisingly, the severity of dopaminergic loss may only correlate with the severity of parkinsonism early in the course of the disorder and may begin with as little as 25% to 35% loss of either striatal dopamine or nigral dopaminergic neuronal cell bodies. In contrast, loss of nigral dopaminergic neurons may fully correlate with the severity of parkinsonism. These findings could support the notion that degeneration of the nigrostriatal pathways begins in the striatal terminal fields or striatal fibers with subsequent loss of nigral neurons. What role can single‐photon emission computed tomography (SPECT) imaging of the plasmalemmal dopamine transporter (DAT) play in clarifying these relationships? Nigrostriatal dopaminergic pathways degenerate in people with Parkinson's disease (PD). For decades, many of us have believed and taught that the striatal dopamine deficiency associated with degeneration in this pathway translated directly to the severity of the motor manifestations of PD, and that motor dysfunction was only manifest after 70% to 80% loss of striatal dopamine. The advent and widespread utilization of molecular imaging methods to quantify presynaptic nigrostriatal terminals potentially provided a means to test these hypotheses and, more important, to objectively quantify the severity of PD. As we stand on the threshold of the exciting possibility that disease‐modifying therapies are within our reach, an objective biomarker gains ever greater importance. However, emerging data increasingly indicate that these notions provided an incomplete picture of the role of the nigrostriatal pathway in parkinsonism However, nerve terminal DAT may not reflect what is happening in the cell bodies of origin for a variety of reasons: (1) nerve terminal loss may precede loss of nigral cell bodies; (2) nerve terminal fibers may sprout; and (3) DAT may be subject to regulation as a result of compensation or pharmacological treatment. The authors therefore went on to examine the relationship between striatal DAT binding as measured by SPECT and striatal tyrosine hydroxylase (TH) nerve fiber density, hypothesizing that this may yield a more robust correlation. The article by Honkanen and colleagues in this issue demonstrates that antemortem striatal DAT SPECT measures in 14 parkinsonian patients did not correlate with postmortem measures of striatal dopaminergic fibers. In both studies, the authors appropriately considered the interval between the antemortem SPECT scans and death. Their TH‐stained fiber counts did not use an unbiased stereological counting approach, but they did try to identify brain sections that corresponded with the SPECT images and used histological counts done by two neuropathologists with high inter‐rater reliability. Other limitations of the current study include relatively long intervals (1–8 days) between death and autopsy and lack of details on the fiber counting methods. However, the authors did consider time between death and autopsy as one of several covariates in the correlational analyses, which did not alter the results. More important, they found a correlation between striatal TH stained fiber counts and nigral TH neuronal counts, enhancing confidence in the adequacy of their methods. In a previous report, Saari and colleagues demonstrated that striatal DAT SPECT did not correlate with counts of nigral dopaminergic cell bodies. but again surprisingly these measures did not correlate with the severity of parkinsonism once parkinsonism exceeded mild‐to‐moderate degrees. The problem is that striatal nigrostriatal terminal fields have a flooring effect as parkinsonism reaches only mild‐to‐moderate severity. Similar findings come from a longitudinal PET study in people with PD in which a flooring effect is observed around 4 to 5 years from diagnosis. Additionally, a postmortem study on people with varying degrees of parkinsonism reported little additional change in nigrostriatal terminal fields starting around 5 years after diagnosis. Furthermore, in support of the Honkanen study, striatal DAT does not correlate with contemporaneous in vitro measures of either TH or DAT immunostained striatal fibers or with nigral TH‐stained cell bodies in animal models. Thus, striatal DAT SPECT should not be considered a faithful measure of the severity of parkinsonism, at least beyond the early stages of the disease. At these stages, striatal DAT does correlate with striatal dopamine, but administration of dopaminergic medications may confound this relationship with striatal dopamine, although not necessarily with terminal fields of nigrostriatal neurons at this early stage. How does this report affect our understanding of striatal DAT SPECT? Based on the findings from these authors, striatal DAT SPECT does not reflect either nigral cell bodies or striatal fibers of dopaminergic nigrostriatal neurons, as measured at the time of death in parkinsonian patients. Previous work in animal models confirms that molecular imaging of striatal DAT does strongly correlate with striatal dopamine measures, at least in animals not given additional pharmacotherapy, Furthermore, longitudinal, long‐term studies of PD using molecular imaging biomarkers of presynaptic nigrostriatal neurons have greater risk of running into this discrepancy. In one of the most recent longitudinal studies, despite striatal DAT binding weakly correlating with motor UPDRS scores at multiple time points, the There may be an alternative strategy. Imaging measures from the SN in the midbrain may correlate with the full range of the severity of parkinsonism; at least this has been demonstrated in animal models of nigrostriatal injury. Therefore, molecular imaging of nigral DAT may be a good measure of PD severity, but this remains to be proven in humans. Of course, no measure based purely on dopaminergic function will give full insight into the overall severity of PD. These findings raise serious questions about the interpretation of striatal DAT SPECT and other presynaptic molecular imaging markers of nigrostriatal neurons and may explain the discord between such molecular imaging and clinical measures of progression in multiple clinical studies. rate of change of the two variables did not correlate, as in numerous other studies. quantification of nigral iron content, nigral free water determination and, of course, if and when available, estimation of α‐synuclein burden. The article by Honkanen supports the view that all molecular imaging studies in PD should be interpreted with caution. Moving forward, multimodal imaging is likely to be needed for the assessment of disease progression and the impact of potential disease‐modifying therapies. In summary, molecular imaging of brain DAT requires nuanced interpretation. Striatal uptake reflects a terminal field measure, striatal dopamine, at least in the absence of exogenous levodopa. Molecular imaging of striatal DAT does not quantify striatal fibers or nigral cell bodies. Thus, striatal DAT may not be a good measure of PD severity throughout the natural history of the disease and may therefore not be an optimal biomarker to assess the impact of neuroprotective and/or disease‐modifying therapies. This strategy, at least when used in isolation, should be abandoned. In addition to other markers of presynaptic dopaminergic integrity, other complementary imaging markers worthy of consideration include measures of other neurotransmitters, quantification of the PD‐related glucose metabolic patterns, Funding Information: agencies: J.S.P.: NIH (NS058714, NS075321, NS103957, and NS107281); American Parkinson Disease Association (APDA) Center for Advanced PD Research at Washington University; Greater St. Louis Chapter of the APDA; McDonnell Center for Higher Brain Function; Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and Parkinson Disease Research Fund), Oertli Fund, Fixel Foundation, and Paula C. and Rodger O. Riney Neurodegenerative Diseases Research Fund. A.J.S.: Canada Research Chairs, Michael J. Fox Foundation, Weston Brain Institute, and Pacific Parkinson's Research Institute. Lauren & Lee Fixel Family Foundation for research support.
PY - 2019/10/1
Y1 - 2019/10/1
UR - http://www.scopus.com/inward/record.url?scp=85073620770&partnerID=8YFLogxK
U2 - 10.1002/mds.27811
DO - 10.1002/mds.27811
M3 - Editorial
C2 - 31769089
AN - SCOPUS:85073620770
SN - 0885-3185
VL - 34
SP - 1430
EP - 1432
JO - Movement Disorders
JF - Movement Disorders
IS - 10
ER -