A review of nuclear neurology 

Many people are living longer, but not all are healthy. How can molecular medicine help to diagnose the cognitive impairments that come with age? 

Takeshi Shimizu
Published on June 1, 2021

Population aging has transformed many aspects of society throughout our world. Senior citizens are increasingly acknowledged as important contributors to the community, and developments in social infrastructure facilitate their continued engagement. In addition, their improved levels of activity, productivity, and socioeconomic status affect society and healthcare demands in unexpected ways. 

<p>“When I read the newspaper in the morning, I may find an article on a traffic accident involving a driver with a cognitive impairment. Most of them are patients with conditions such as dementia, which is a risk to the whole of society,” says Jun Hatazawa, MD, PhD, chief executive director of the Japan Radioisotope Association. During his 40-year career in nuclear medicine, Hatazawa has witnessed the evolution of the field as it continually adapts to technological advancements and changing healthcare needs.&nbsp;&nbsp;</p>
<p>The demand for nuclear medicine in neurology examinations is partly driven by the high level of accessibility throughout Japan. Beyond this practicality of access, the use of nuclear neurology is continuing to increase because of its ability to provide objective evidence. “In clinical routine, patients suspected of cognitive impairment are evaluated by a neurologist and a psychiatrist using interview questions, which is a nonspecific and subjective method. <a href="SPECT and PET" class="cp-fab-text-highlight">SPECT and PET</a> can provide objective evidence of such diseases,” Hatazawa says.&nbsp;</p>

SPECT (single-photon emission computed tomography) and PET (positron emission tomography) visualize the accumulation of radioactive markers in the body. The markers demonstrate metabolic processes in organs where there is accumulation. Abnormal marker accumulation may indicate the presence of disease or abnormal function.

Molecular Imaging

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<p>Jun Hatazawa, MD, PhD, currently serves as chief executive director of the Japan Radioisotope Association. Before his current role, he was a professor of nuclear medicine and tracer kinetics at Osaka University Graduate School of Medicine.&nbsp;</p>
Jun Hatazawa, MD, PhD, currently serves as chief executive director of the Japan Radioisotope Association
<p>Hatazawa’s specialisms include functional imaging of the human brain, early diagnosis of malignant tumors, and radionuclide cancer therapy. As an advisory member of the International Atomic Energy Agency, he has been an advocate for the safe use of radioisotopes in medicine. He is committed to education and, as chair of the Asia Oceania Federation of Nuclear Medicine and Biology, he regularly teaches educational seminars throughout Asia and the Middle East.</p><p>Hatazawa explains how the introduction of a glucose-analog tracer in PET imaging led to the decrease of SPECT examinations throughout Japan. However, the steady utilization of SPECT technology in neurology examinations proves to be an exception to this ongoing trend. Reflecting on the current use of nuclear medicine in the assessment of neurological cases, he says: “The demand for nuclear neurology is still increasing, even during this difficult time of the COVID-19 pandemic.” </p><p>The objective evidence that nuclear medicine provides is crucial when monitoring disease progression and assessing the efficacy of a treatment plan. This evidence will now also play an important role in the anticipated introduction of new therapeutics.</p><p>Hiroshi Matsuda, MD, PhD, director of the Cyclotron and Drug Discovery Research Center at the Southern Tohoku Research Institute for Neuroscience, emphasizes that the objective, quantitative nature of nuclear medicine allows physicians to harness the power of new therapeutics by offering “the critical time window for intervention by a disease-modifying drug.” To illustrate his point, Matsuda describes his research using <a href="dopamine" class="cp-fab-text-highlight">dopamine</a> transporter (DaT) imaging, which aids in the diagnosis of movement disorders such as Parkinson’s disease. Patients with Parkinson’s disease develop various motor symptoms such as resting tremor, rigidity, and slowness in voluntary-motion initiation that can lead to an increased risk of falls and fractures. A selective loss of dopamine-producing neurons, specific to the substantia nigra structure that is found in the midbrain and plays an important role in reward and movement, is implicated in the disease origin.[1] DaT imaging with SPECT/CT enables visualization of the striatal dopamine transporter deficiency associated with Parkinson’s disease.[2] The corpus striatum is a component of neuronal control circuits that realize the interaction of motivation, emotion, cognition, and movement at the neuronal level. <br></p>

Dopamine is an important neurotransmitter in the brain. It mediates motivation- and drive-increasing effects. If the levels of the neurotransmitter are too low or too high, Parkinson's-like or mania-like symptoms may occur. 

<p>In a multicenter study, Matsuda and his team constructed a normal database of quantitative DaT imaging. In the process, they confirmed that dopamine transporter density largely depends on age.[3] Matsuda says: “Dopamine transporter density decreases by six percent in 10 years. That’s a near 25 percent decrease when you compare someone in their 30s and 70s. Modern SPECT/CT allows <a href="attenuation correction" class="cp-fab-text-highlight">attenuation correction</a> and is important for accurate measurement of receptor density. With objective assessment, we can predict the occurrence of movement disorder, which is useful for the prevention of Parkinson’s disease.”&nbsp;<br></p>

Attenuation correction is a mechanism that removes artifacts from clinical images. 

<p>Beyond movement disorders, SPECT/CT procedures can also identify relative changes in blood flow. Unlike other organs, brain tissue does not have the capacity to store energy; it requires a constant supply of oxygen and nutrients from the blood. Cerebral perfusion SPECT/CT shows how the brain is irrigated by blood and enables visualization of brain functional impairment, which is indicative of underlying cerebral pathology. For example, symptoms of cognitive impairment can be attributed to different underlying causes. Such behavioral changes precede cerebral structural changes caused by atrophy. In these cases, the functional impairment patterns visualized by perfusion SPECT/CT can be useful in the early-stage differential diagnosis of dementia types.[4]&nbsp;&nbsp;</p>
<p>While SPECT examinations illustrate the vital role of nuclear medicine in neurological imaging, the recent development of new <a href="" target="_blank" class="">PETNET tracers</a> has raised expectations for molecular imaging. Since 2012, three new PET tracers were approved by the United States Food and Drug Administration (FDA) for imaging <a href="amyloid plaque" class="cp-fab-text-highlight">amyloid plaque</a> accumulation. The scans must be visually interpreted by trained readers to conclude a positive or negative finding.[5] However, a multicenter study to assess the efficacy of an amyloid tracer in Japan found that up to 10 percent of cases show a focal, mild increase that can be interpreted as either negative or positive.[6]&nbsp;</p>

Beta amyloid is a fragment of a protein. In a healthy brain, these fragments are broken down and destroyed. In Alzheimer's disease, they accumulate into hard, insoluble plaques. 

<p>Hiroshi Matsuda, MD, PhD, is the current director of the Cyclotron and Drug Discovery Research Center at the Southern Tohoku Research Institute for Neuroscience. He previously served as director general of the Integrative National Centre for Neurology and Psychiatry in Tokyo, Japan.&nbsp;</p>
Hiroshi Matsuda, MD, PhD, is the current director of the Cyclotron and Drug Discovery Research Center at the Southern Tohoku Research Institute for Neuroscience.
<p>As an expert in both nuclear medicine and magnetic resonance imaging, Matsuda was the principal investigator of the MRI Core in the Japanese Alzheimer’s Disease Neuroimaging Initiative (J-ADNI). His research led to the establishment of statistical imaging analysis software programs for the interpretation of cerebral perfusion SPECT examinations, and to the hippocampal MRI voxel-based morphometry used in the diagnosis of Alzheimer’s disease. </p><p>To address the need for quantification in amyloid scans, Matsuda and his colleagues used the Centiloid scale, a 100-point scale that provides a standardized quantitative amyloid-imaging measurement system. A score of zero can be interpreted as an amyloid-negative case. Matsuda says: “We determined the threshold for the Centiloid scale, and it helps visual assessment.”[7]</p><p>In addition to PET/CT, Matsuda explains how the use of <a href="PET/MR" class="cp-fab-text-highlight">PET/MR</a> is an important aspect in amyloid imaging: “To evaluate the amyloid imaging, we need to differentiate cortical from white matter accumulation. Fusion between MR and amyloid PET shows exactly whether the signals that are seen will be useful for interpretation.” His current research also expands the possibility of the PET/MR system.</p><p></p><p><br></p>

Positron emission tomography/magnetic resonance is a hybrid imaging technology that combines PET functional imaging and MRI soft-tissue morphological imaging. 

Biograph mMR

<p>The growth of nuclear neurology in Japan is partly due to its successful promotion by the nuclear medicine community. “In the Japanese Society of Nuclear Medicine membership, about 10 percent come from neurology, surgery, and psychiatry. We reached out to other societies and organized nuclear medicine workshops many times. We established many sophisticated methods because if referring doctors are not aware of it, our achievement will not be accessible for patients,” says Hatazawa. </p><p>For many years, Hatazawa led the <a href="" target="_blank" class="">Asia Oceania Federation of Nuclear Medicine and Biology</a>. During his tenure, he advocated for increased training and education for new and existing nuclear medicine professionals. He explains that, at times in a developing country, the government will establish a nuclear medicine facility and staff it with healthcare professionals who are not sufficiently trained. “We have 84 member states, and nuclear medicine practice is very heterogeneous. In developing countries, the most important thing is human resource development,” he says.&nbsp;</p>

<p>Despite the challenges, Hatazawa is inspired by the evolution of nuclear medicine and the opportunities still to come, especially in neurology: “I am very pleased to see the technical advances I witness through my career and am convinced about the bright future of nuclear neurology.”&nbsp;</p>

By Takeshi Shimizu

Takeshi Shimizu, PhD, is a molecular imaging clinical marketing specialist at Siemens Healthineers. He holds a PhD in biochemistry, microbiology, and molecular biology, and worked as a molecular imaging collaboration scientist for Siemens Healthineers in Japan for 10 years prior to assuming his current role.