Brain perfusion SPECT, in the diagnostic workup of the dementias

Dementia is an increasing important topic in Medicine. As the world ages, the rates of dementia will increase. Between 1997 and 2025, individuals over the age of 65 will increase from 381 million to 823 million1,2. Approximately 1% of those ages 60-65 will have a dementing illness. This rate doubles every 5 years of age over 60. Thus, 2% of those age 65-70, 8% of those 75-80, and more than 16% of those over the age of 80 will have a dementing illness3. This equates of over 13 million people in the United States and 81 million worldwide will have dementia by 20502,4. An additional 156 million worldwide will have the precursor to dementia, referred to as mild cognitive impairment (MCI)2.

Brain perfusion SPECT is highly useful for the diagnosis of the dementias, including Alzheimer’s disease, Frontotemporal Dementia and Lewy Body Disease. SPECT is particularly useful because the clinical diagnosis of dementia is often inaccurate, especially in early dementia when patients have only mild cognitive impairment. The clinical tools which are used include the “Draw A Clock” test, have a sensitivity (ability to detect the disease when it is present) of 66%, but a specificity (ability to detect that the disease is not present and something else is causing the symptom) of 65%2,5,6. For example, in the Figure below, we see a very impaired attempt to draw a clock. One might assume this patient had dementia, but it turned out she was taking an excessive dose of the benzodiazepine, alprazolam. When she was weaned of the benzodiazepine, her cognitive function recovered7.

Figure 1:  A patient’s attempt to draw a clock with the numbers included and the hands set at 10 minutes past eleven o’clock.

Early in the course of dementia, the initial symptoms can be confused with depression, bipolar disorder, metabolic disorder or multiple infarct dementia – a potentially treatable cause of dementia8. The anatomic imaging modalities – CT and MRI – often show no abnormality or only “age-related changes”, particularly in early dementia.  Structural abnormalities in the hippocampus, which can be seen on MRI, are currently difficult to assess in routine clinical practice, because it requires specialized volumetric analysis software.

New amyloid PET tracers show promise in early detection of Alzheimer’s disease, but to date are not reimbursed for routine use9. A positive amyloid scan can be considered proof of Alzheimer’s disease or its precursor (MCI) with a sensitivity of 89% and a specificity of 87%10; however, the specificity falls sharply with age as non-specific binding of amyloid increases to as much as 40% in patients over the age of 80 years2,11.

Since brain perfusion SPECT is widely available and reimbursed, many argue that it should be a first line diagnostic tool for dementia2,12. Ideally, brain perfusion SPECT should be performed with optimal dedicated nuclear medicine SPECT systems with high spatial resolution, three dimensional reconstruction software, parametric mapping and fan beam or multi-pinhole collimators13. New SPECT detectors using multiple pinholes show resolutions comparable to PET detectors and can simultaneously image both perfusion and Dopamine receptor agents such as I-123 beta-CIT, to more accurately diagnose dementia with Lewy-bodies14.

While much maligned, SPECT is not the “unclear medicine” that many old-school neurologists and psychiatrists claim it to be. Studies of the accuracy of SPECT for diagnosing Alzheimer’s disease report sensitivities of 65%–89% and specificities (for other dementias) of 72%–89%2. In meta-analysis wherein studies were separated by single-headed cameras (early technology) and multi-headed cameras, the sensitivity ranged from 84-89% and the specificity was 83-89%2. Notably, the addition of quantitative analysis resulted in higher sensitivity and specificity2. In the largest single study to date, both HMPAO SPECT and 18F-FDG PET were able to completely separate 26 AD cases from controls15(2). SPECT has been advocated over 18F-FDG PET on the basis of its wider availability, lower cost and perceived better patient tolerability. Guidelines of the European Association of Nuclear Medicine and the American College of Radiology endorse the clinical use of Brain Perfusion SPECT in the workup and diagnosis of dementia16,17.

Patterns of abnormal perfusion in dementia can appear very characteristic for different types of dementia, although no perfusion patterns are 100% sensitive or specific.  In very advanced dementias, the differences blur and eventually markedly decreased global cortical perfusion may be present, making all dementias essentially indistinguishable. Below, we will illustrate the typical appearance of different types of dementias.

Scans of patients with advanced Alzheimer’s dementia usually show a typical hypo-perfusion in the temporal and parietal regions. An early hallmark of Alzheimer’s disease is the decrease in function and perfusion in the posterior cingulate gyrus18.

Figure 3:  Illustration of the pattern of decreased perfusion typical of

Alzheimer’s disease. The SPECT scan data is presented as an isocontour image – areas of decreased perfusion appear as “holes” (Picker). Note the decreased perfusion in the parietal lobes and the absence of perfusion in the posterior cingulate gyrus (arrow). A healthy SPECT scan is offered for comparison.

In Frontotemporal Dementia, hypoperfusion is usually seen in the frontal cortex and anterior temporal lobes. Hypoperfusion can also be seen in the caudate nuclei and the anterior cingulate gyrus. In FTD, perfusion is generally spared in the posterior cingulate gyrus/precuneus2,19,20. Based on correlation to autopsy data, posterior cingulate perfusion has a positive predictive value of 93% and a negative predictive value of 81%20.

Figure 4: Illustration of the pattern of decreased perfusion typical of Frontotemporal Dementia. The SPECT scan data is presented as an isocontour image – areas of decreased perfusion appear as “holes” (Picker). Note the decreased perfusion in the frontal lobes, the anterior poles of the temporal lobes, and to a lesser extent in the anterior cingulate gyrus. Note the sparing of the posterior cingulate gyrus.

Figure 5: A. Sagittal tomogram at the level of the caudate nucleus from a patient with Alzheimer’s disease illustrating decreased perfusion of the posterior cingulate gyrus (white arrow), but sparing of the perfusion of the frontal cortex (red arrow). B. Sagittal tomogram at the level of the caudate nucleus from a patient with Frontotemporal dementia illustrating decreased perfusion in the frontal lobe (red arrow), but relative sparing of the posterior cingulate gyrus (white arrow). Decreased temporal lobe perfusion is evident in both disorders. C. Patient with Alzheimer’s disease wherein patient’s data compared to a normative database. A map of statistically significant differences can be generated using the Oasis software by Segami, Inc. Here, the color scale indicates gray for areas that do not differ significantly from the normative database. In contrast, areas of green, light blue, and dark blue represent areas of more than 2, 3, and 4 SD below the mean perfusion of the normative database, respectively. Statistically significant increases in perfusion are illustrated in the red color scale. Decreased perfusion in the temporal cortex and parietal cortex (thin arrow) can be appreciated. D. A similar statistical comparison map from a patient with Frontotemporal Dementia illustrating decreased perfusion of the temporal cortex and the frontal cortex, but sparing of the parietal cortex (thin arrow).

In dementia with Lewy-Bodies, decreased perfusion is seen in the occipital cortex, and studies with SPECT dopamine tracers (DaTScan I-123 beta-CIT or Tc-99m Trodat) show decreased uptake of dopamine in the basal ganglia21. Multi-infarct dementias show multiple perfusion defects throughout the cortex and white structures.  In the earliest stages of Alzheimer’s disease, impaired memory deficit has been shown to correlate with hypometabolism of temporal mesial structures (especially the hippocampus), posterior cingulate gyrus and basal frontal cortex19.

Figure 6: A dopamine transporter site (DaTScan) scan illustrating decreased dopamine reuptake site density in the basal ganglia of a patient with Lewy Body dementia (left) compared to the preserved and normal-appearing dopamine reuptake site density in the basal ganglia of a patient with Alzheimer’s disease.

Figure 7:  Brain FDG-PET scan shown in horizontal tomograms illustrating decreased function in the occipital lobes. Brain perfusion SPECT scan shows matching hypoperfusion in the occipital lobes. This illustrates a global point about brain perfusion SPECT and brain FDG-PET scans – they demonstrate matching functional deficits in the brain.

1. Cummings JL. The Neuropsychiatry of Alzheimer’s Disease and Related Dementias. London: Martin Dunitz, Ltd; 2003.

2. Henderson TA. The diagnosis and evaluation of dementia and mild cognitive impairment with emphasis on SPECT perfusion neuroimaging. CNS Spectrums 2012. 17:176–206.

3. Jorm AF. Cross-national comparisons of the occurrence of Alzheimer’s and vascular dementias. Eur Arch Psychiatry Clin Neurosci. 1991. 240(4–5): 218–222.

4. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005. 366(9503): 2112–2117.

5. Kantarci K, Jack CR, Jr. Neuroimaging in Alzheimer disease: an evidence-based review. Neuroimaging Clin N Am. 2003. 13(2):197–209.

6. Seigerschmidt E, Mösch E, Siemen M, Förstl H, Bickel H. The clock drawing test and questionable dementia: reliability and validity. Int J Geriatr Psychiatry 2002. 17:1048–1054.

7. Theodore A. Henderson. The Anti-Youth Pill? Alprazolam Toxicity Can Add Years to Brain Age and Appearance. Psychiatric Times, December 21, 2016.

8. Woodford H.J., George J. Cognitive assessment in the elderly: a review of clinical methods DOI: 469-484 First published online: 12 June 2007.

9. Kubota T, Ushijima Y, Yamada K, Okuyama C, Kizu O, Nishimura T. Diagnosis of Alzheimer’s disease using brain perfusion SPECT and MR imaging: which modality achieves better diagnostic accuracy? Eur J Nucl Med Mol Imaging 2005. 32:414-421.

10. Yeo JM, Waddell B, Khan Z, Pal S. A systematic review and meta-analysis of (18)F-labeled amyloid imaging in Alzheimer’s disease. Alzheimers Dement (Amst) 2015. 1: 5–13.

11. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, et al. Imaging beta amyloid burden in aging and dementia. Neurology 2007. 68:1718–1725.

12. Henderson TA, Uszler JM, Rossiter-Thornton JF, Yin-Hui S, Pavel DG, et al. The American Psychiatric Association Fails to Recognize the Value of Neuroimaging in Psychiatry. Interv Med Clin Imaging 2019. 1(2): 1–8.

13. Juni J, Waxman A, Devous, M et al Society of Nuclear Medicine Procedure Guideline for Brain Perfusion Single Photon Emission Computed Tomography (SPECT) Using Tc-99m Radiopharmaceuticals version 2.0, approved February 7, 1999.

14. O’Brien JT, Colloby S, Fenwick J, et al. Dopamine transporter loss visualized with FP-CIT SPECT in the differential diagnosis of dementia with Lewy bodies. Arch Neurol. 2004. 61:919–925.

15. Herholz K, Schopphoff H, Schmidt M, et al. Direct comparison of spatially normalized PET and SPECT scans in Alzheimer’s disease. J Nucl Med. 2002. 43:21–26.

16. Kapucu, OL Nobili F, Varrone A, Booij J, Vander Borght T,  Någren K, Darcourt J, Tatsch K,  Van Laere.K EANM procedure guideline for brain perfusion SPECT using 99mTc-labelled radiopharmaceuticals, version 2 Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-009-1266-y

17. ACR Res. 25 – 2012, Amended 2ACR–SPR Practice Parameter for the Performance of Single Photon Emission CT (SPECT) Brain Perfusion and Brain Death Examinations014 (Res. 39).

18. Bonte FJ, Weiner MF, Bigio EH, White CL, III. Brain blood flow in the dementias: SPECT with histopathologic correlation in 54 patients. Radiology. 1997. 202(3): 793–797). 

19. Bonte FJ, Harris TS, Roney CA, Hynan LS. Differential diagnosis between Alzheimer’s and frontotemporal disease by the posterior cingulate sign. J Nucl Med. 2004. 45(5): 771–774.

20. Bonte FJ, Harris TS, Hynan LS, Bigio EH, White CL, III. Tc-99m HMPAO SPECT in the differential diagnosis of the dementias with histopathologic confirmation. Clin Nucl Med. 2006. 31(7): 376–378.

21. O’Brien JT, Colloby S, Fenwick J, et al. Dopamine transporter loss visualized with FP-CIT SPECT in the differential diagnosis of dementia with Lewy bodies. Arch Neurol. 2004. 61:919–925.

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