Brilliant Signs: Advancements in Brain & Neuroendocrine Imaging
The past year has been a groundbreaking one for neurology. Not only have at least three new biomarkers been identified for Alzheimer’s disease, but various molecular imaging agents used to visualize neurodegenerative disorders are now either available or being conveyed toward regulatory approval for clinical use. Parkinson’s research, too, has progressed at an astonishing rate with the spoils being a new method of detection and a therapeutic technique that could potentially leave patients tremor-free for life. Several psychiatric disorders are being seen first-hand by targeting the dopaminergic system of the brain. Neuroendocrine tumor (NET) imaging also is pushing forward with a preliminary nod from the FDA in the form of an orphan drug application for NET management.
Beyond beta-amyloid
Some of the most striking news in neurology this past year was in the area of Alzheimer’s research. Beta-amyloid studies have dominated this space for years, but last year tau imaging took a significant leap forward. One group of tau agents, called phenyl/pyridinyl-butadienyl-benzothiazoles/benzothiazoliums (PBBs), demonstrated remarkable tau binding in a living brain (Neuron. 2013 Sep 18;79(6):1094-108).
Another tau agent, F-18 T807, seeks out aggregates of hyperphosphorylated tau (PHF-tau), including neurofibrillary tangles, and is being evaluated in first-in-human trials for dementia imaging (J Alzheimers Dis. 2014;38(1):171-84).
Tau imaging agents, alone or in combination with amyloid or other imaging techniques, have the potential to tell clinicians more about Alzheimer’s disease progression. It is now an established fact that amyloid deposition plateaus in the brain instead of worsening as clinical symptoms continue to develop. Efforts to formulate disease modifying anti-amyloid agents have so far been lackluster. Also complicating matters is beta amyloid burden’s presence in other forms of dementia besides Alzheimer’s disease, including dementia with Lewy bodies. Efforts to develop anti-amyloid therapies also have run aground. Alexander E. Drzezga, MD, assistant professor from Harvard University Medical School in Boston, while speaking out about the newest research in Alzheimer’s disease during a scientific session at the most recent Radiological Society of North America (RSNA) annual meeting early Decemeber, notes a recent study of the impact of anti-amyloid treatments on amyloid deposition and clinical symptoms.
“Unfortunately no therapy effect with regard to symptoms was at all measurable in this study, and it is much debated today whether it makes sense at all to remove amyloid from the brain,” says Drzezga. “In general, the view of anti-amyloid drugs is disappointing so far.”
Tau research has made such strides that tau-targeted therapeutic agents are now the order of the day. In early January, TauRx Therapeutics announced that phase III research into a potential anti-tau drug called LMTX was expanding across the U.S. Later that month, a preliminary, unpublished study by biopharmaceutical company Intellect Neurosciences hinted toward the development of an immuno-therapeutic agent called TauC3, which, if approved, would enlist specialized timing of CAB expression 1 (TOC-1) monoclonal antibodies to snipe truncated oligomeric tau.
TauC3 targets the heightened immune reactivity of tau oligomers—isolated fragments of the protein exposed by beta-amyloid burden in the brain and influenced by grim reaper caspase enzymes involved in cell death, or apoptosis. These broken pieces of tau are thought to be involved in the development of neurofibrillary tangles, another trademark of Alzheimer’s disease (J Alzheimers Dis. 2013;37(3):593-602).
In addition to amyloid and tau proteins, a third protein has entered the spotlight of Alzheimer’s pathology: clusterin. Beta-amyloid plaques appear to develop in the presence of elevated levels of the chaperone glycoprotein, which seems to mediate entorhinal cortex atrophy, according to a study published just before the new year. It was reportedly the first to prove that clusterin is not a benign factor, but rather a harbinger of neurodegenerative disease. Another study published in the same issue of JAMA Neurology presented the dangers of high serum cholesterol levels and their impact on the development of amyloid plaques. Researchers were encouraged that lifestyle modification and drug treatment could have a significant effect on people’s risk of developing Alzheimer’s (JAMA Neurol. 2013 Dec 30).
Yet another area of research in neurodegenerative disease and Alzheimer’s is the role that cerebral blood flow and particularly a lack of blood flow plays in disease pathology and the earliest stages of Alzheimer’s. Researchers have concluded that arterial disease is a major player in Alzheimer’s pathology. In fact, a recent near-infrared spectroscopy study took the science a step further and evaluated Alzheimer’s patients who were given memantine and donepezil as a method of inhibiting dwindling prefrontal blood flow and found encouraging results that pointed to improvements in cognitive function and clinical symptoms (Int J Geriatr Psychiatry. 2014 Jan 17).
By late 2013, an additional amyloid agent had received approval for clinical use. Now both F-18 florbetapir (Amyvid) and F-18 flutemetamol (Vizamyl) are approved by the FDA for dementia imaging. Amyvid also has received the European Commission (CE) approval and an application for CE mark review was accepted for Vizamyl early last year. Piramal Imaging, makers of F-18 florbetaben, otherwise known as NeuroCeq, announced Dec. 20 that the agent had received a recommendation by the Committee for Medicinal Products for Human Use (CHMP), a rung on the ladder toward CE approval. A new drug application was accepted by the FDA in March.
From the policy side, Alzheimer’s research was bolstered financially in both the U.S., which saw $122 million in additional funding from the fiscal year 2014 budget, as well as the United Kingdom. U.K. Prime Minister David Cameron promised, after a major G8 Alzheimer’s summit that met in London this past December, that funding for research would double by the year 2025 and that the National Health Service would move toward reimbursement of a diagnostic scan to rule out Alzheimer’s disease.
A mirror of mental illness
Psychiatric imaging is gaining a foothold as some researchers are developing agents that delve into the dopaminergic system of the brain. A growing number of studies have presented F-18 fallypride as one of prime movers among these. Fallypride is a high affinity ligand for dopamine receptors and it highlights disordered dopamine transport systems and the like at the heart of not only schizophrenia, but a host of mood and other disorders including chronic depression, bipolar disorder and attention deficit hyperactivity disorder (ADHD). Others such as those who suffer from post-traumatic stress also could benefit.
“We could use fallypride to image the whole gamut of dopamine diseases,” says Monte S. Buchsbaum, MD, professor of psychiatry and radiology at the University of California, San Diego, where he leads the NeuroPET Center. This new understanding presents a path toward psychiatric diagnostic imaging.
In the case of schizophrenia, the proof has been in new research focusing on the frontal lobe and the thalamus, rather than the traditionally targeted basal ganglia. The implications are that a new kind of diagnostic protocol based on the biology of the brain could be applied. The ability to determine with acuity the nature of an individual’s dopamine disease could mean faster, more effective dopamine-based therapies to treat a range of disorders, even when clinical severity is relatively low or under the surface.
Patients with psychotic disorders and their first-degree relatives tend to display a pronounced reactivity to stress. This has been correlated with ventromedial prefrontal and mesolimbic neural activity and disordered striatal dopamine processing. A new study, the first human imaging research of its kind, revealed hyporeactive, or less dopamine processing, in response to stress in individuals who were directly related to family members with a psychotic disorder. A familial link to dopamine disorder was found in these direct relatives, who were subsequently considered at increased risk of suffering clinical symptoms (Schizophr Bull. 2014 Jan;40(1):66-77).
Some voices have raised concerns about whether there is an ethical dilemma in making psychiatric imaging commonplace. Could a scan that quickly determines whether people are mentally ill be used to discriminate against them when complying with background checks or at the workplace? Is there even the slightest chance that this technique could be used to screen out or incarcerate the mentally ill? No, not really, says Buchsbaum.
This is a technique which is best used in the severely mentally ill to identify the type of mental illness they have, not as a screening measure.” In fact, it may never even be used in the context of first-line diagnosis.
An area where increased imaging may be especially beneficial is in the case of ADHD children and young adults. Opponents of stimulant treatment argue that diagnoses are a dime a dozen and may be overestimating instances of disease. “We need biomarkers to help us in this decision. Not just short observations of children, but if we had biomarkers of their neurotransmitters, we might better understand who really needs treatment and it might help with the controversy,” comments Buchsbaum. Still, pediatric imaging of ADHD is hampered by considerations of radiation exposure. If a non-ionizing technique were to be developed, it could change the face of attention deficit disorder by throwing out all doubt and providing substantive proof of diseased dopamine centers of the brain.
Imaging the dopaminergic system has gained a lot of ground not only for schizophrenia and other psychiatric and attention deficit disorders, but also in movement disorders—namely Parkinson’s disease.
Peering into Parkinson’s
An area that is likened to a teardrop on both the left and right sides of the brain is is now a telltale MR marker for Parkinson’s disease. Substructures of the substantia nigra pars compacta, called nigrosome 1, appear to be a clear-cut marker for when Parkinson’s has arrived. When these two regions start to evaporate and disappear from the scan, there is trouble. Whereas the presence of what looks like dark oval droplets on the MR scan is a sign of health, explains Penny A. Gowland, PhD, professor of physics at the Sir Peter Mansfield magnetic Resonance MRI University of Nottingham in the United Kingdom.
This Parkinson’s research was conducted on a 7 Tesla research scanner. Questions have popped up regarding whether this technique will translate to the wider world of conventional, 3 Tesla MRI scanners for the detection of Parkinson’s, but preliminary work has been encouraging. What is not well understood is when these two beady eyes in the brain actually disappear.
“That is the million dollar question,” says Gowland. “What we don’t know yet is how early this sign becomes visible.”
Diagnostic imaging has not been the only new topic relevant to managing patients with Parkinson’s disease. Stem cell therapy research is currently being conducted to evaluate whether a definitive cure is a possibility if faulty pathways were swapped out. An exciting non-embryonic stem cell therapy is raring to replace damaged dopamine cells with mother cells harvested from patients’ own skin, which could eliminate all clinical symptoms and provide a definitive cure (Expert Opin Biol Ther. 2014 Jan 17). Approval from the FDA for the stem cell therapy is rumored some time in the next year.
New era of neuroendocrine imaging
Neuroendocrine tumor imaging is another area of brain science that got a nod from the FDA, being granted orphan drug designation for gallium-68 (DOTA0-Phel-Tyr3) octreotide (Ga-68 DOTATOC). Irina Velikyan, PhD, associate professor at the PET-Centre and Centre for Medical Imaging at Uppsala University Hospital, Uppsala, Sweden, is an expert on NET imaging and discusses how DOTATOC is ready to overtake more conventional imaging methods.
Currently there is a range of radiotracers available for NET imaging. Included here are F-18 FDG, which looks at transmembrane glucose transporter expression; C-11 hydroxytryptophan (HTP) and F-18 labeled fluorodihydroxyphenylalanine (F-18 FDOPA) for metabolic imaging of amino acids and MIBG conjugated with either Indium-123 or -131 for metabolic imaging of nucleosides, a sugar compound usually found in RNA or DNA, such as adenosine. F-18 sodium fluoride (NaF) also is used for osteoblast imaging. From the perspective of this camp, a recent study pushed F-18 FDOPA PET/CT into the limelight for NET detection because more neuroendocrine cancer was found with FDOPA PET than with somatostatin scintigraphy (J Nuc Med. 2013 Dec 16).
In an entirely different camp, gallium-68 DOTATOC is a peptide imaging agent that sneaks up on somatostatin receptors, but more aggressively than conventional somatostatin scintigraphy. DOTATOC finds hyperactive areas where tumors may be developing. In addition to pinpointing amino-acid uptake, DOTATOC and similar Ga-68 agents have been found to point out glucose transport and angiogenesis. The FDA approved orphan drug status for DOTATOC on the condition that it must be proven superior to the incumbent treatment—I-111 pentetreotide.
“Ga-68 PET-CT using somatostatin ligand analogues is becoming a new golden standard in imaging of NETs with specificity and sensitivity well above 90 percent and advantages over conventional radiologic and scintigraphic imaging, replacing [I-111]-pentetreotide (Octreoscan),” comments Velikyan, who lists the advantages of these agents, including ease of manufacturing, specificity of binding to somatostatin receptors, and selection for radiotherapy with Y-90 or Lu-177 labeled somatostatin analogues.
Last but not least, Berlin-based OctreoPharm Sciences announced in late January that Ga-68 OPS202, a novel peptide agent, has been given European Medicines Agency orphan drug designation for the detection of gastro-entero-pancreatic neuroendocrine tumors. The antagonist-based agent is differentiated from the Ga-68 family of agonist agents detailed here.
Brain teasers
While many of these developments are very much still in the works, all of these studies regarding new efforts in Alzheimer’s disease, Parkinson’s, schizophrenia and other psychiatric disorders, as well as NET imaging, speak for themselves and are blazing trails for future research in years to come.