Transcranial magnetic stimulation (TMS) may differentiate Alzheimer’s disease (AD) from frontotemporal dementia (FTD) with a high degree of diagnostic accuracy, new research suggests.
The findings show the different cortical circuitry in AD vs FTD. With use of two different TMS protocols, results showed differences mainly in short-latency afferent inhibition (SAI) and short-interval intracortical inhibition in relation to intracortical facilitation (SICI-ICF).
TMS to measure activity in cortical circuits is noninvasive, readily available, and inexpensive and has accuracy similar that of cerebrospinal fluid (CSF) analysis or amyloid positron emission tomography (PET), study author Giacomo Koch, MD, PhD, Non-invasive Brain Stimulation Unit, Santa Lucia Foundation, and Department of Neuroscience, Tor Vergata Polyclinic, Rome, Italy, told Medscape Medical News.
A biomarker that identifies a specific neurotransmitter signature can be useful for tracking drug activity, said Dr Koch.
“The better we know the physiology of the brain, the better we will be able to test new drugs that will hopefully be coming onto the market.”
The new study was published online July 26 in Neurology.
Impaired Circuitry
Researchers have developed TMS paradigms of intracortical circuits to indirectly assess the function on cholinergic, GABAergic, and glutamatergic cortical circuits.
“We know that cortical circuits are modulated by specific neurotransmitters,” said Dr Koch. “So, for example, in the case of intracortical inhibition, this is related to GABA [γ-aminobutyric acid] activity and in the case of short-latency afferent inhibition, we know from pharmacological studies that the activity of the circuits is mediated by cholinergic transmission.”
The analysis included 79 patients diagnosed with AD (mean age, 71.2 years) and 61 patients diagnosed with FTD (mean age, 65.6 years).
Of the patients with FTD, 23 had primary progressive aphasia and 38 had behavioral-variant FTD. The study also included 32 age-matched healthy controls.
Once thought to be rare, FTD is now believed to make up 10% to 15% of dementia cases. Because of its wide range of symptoms, it is often initially misdiagnosed as AD, a psychiatric problem, or Parkinson’s disease.
All patients in the study underwent paired-pulse TMS, administered by operators blinded to whether the patient had AD or FTD, but not to whether they were controls.
The researchers compared FTD vs AD, AD vs healthy controls, and FTD vs healthy controls. TMS measures were derived from receiver-operating curve analysis.
The study confirms earlier work, in smaller samples, that patients with AD have an impaired SAI circuit. SAI is believed to rely on central cholinergic circuits and has been found to be impaired not only in AD but also in Lewy body dementia. Both these conditions are characterized by a degeneration of the central cholinergic system.
This finding “strongly reinforces the notion that SAI may be a useful marker of central cholinergic dysfunction in patients with AD but not in patients with FTD,” the authors write.
The study did not show impairment of SICI in AD, which is thought to depend on the postsynaptic inhibition exerted by local interneurons through the GABAA receptor and ICF, which is considered to be mediated in part by glutamatergic N-methyl-D-aspartate receptors.
High Accuracy
SAI was similar between patients with FTD and healthy controls, a finding that was not unexpected since cholinergic dysfunction is not part of FTD pathology.
Conversely, patients with FTD showed impairment in SICI-ICF and partial impairment in long-interval intracortical inhibition (LICI), which is probably mediated by GABAB receptors, the authors note.
Researchers were able to accurately distinguish FTD from AD with 90% accuracy, AD from healthy controls with 87% accuracy, and FTD from healthy controls with 86% accuracy.
Such levels are “quite reassuring,” said Dr Koch.
The sensitivity was 91.8% and specificity was 88.6% in differentiating AD from FTD. The sensitivity and specificity of differentiating AD from healthy controls and FTD from healthy controls were also relatively high.
Diagnostic accuracy were also similar in patients with early-stage disease for both AD and FTD.
Researchers performed analyses in patients with a high biomarker probability of an underlying AD or FTD pathophysiologic process. The overall diagnostic accuracy here was also much the same.
The high diagnostic accuracy levels are similar to those obtained by using CSF analysis or amyloid PET, said Dr Koch.
The SICI-ICF/SAI measure has several advantages as a diagnostic marker. As well as being noninvasive, easy to apply, inexpensive, and not time-consuming, it is also free from strict exclusion criteria. In this study, the exclusion rate was 2.8%.
“You can directly measure neurotransmission in patients, and you can get this measurement quite easily,” said Dr Koch. “This method is well established. It doesn’t require particular expertise, and you can get results in a few minutes.”
He noted that TMS “is much easier” to perform than, for example, MRI.
Well-Tolerated
TMS is sometimes used to diagnose motor impairment and to treat various conditions, including depression. Such treatments involve delivering repetitive magnetic pulses at various frequencies.
The type of stimulation used in the current study is not painful and was “well tolerated,” with few patients complaining about the sensation, said Dr Koch.
An important advantage of the technology, he noted, is that the tests can be repeated. “That’s not something you can do with PET tracers for amyloid or with lumbar punctures” to assess cerebrospinal fluid.
He noted that PET amyloid or PET tau investigations “are not quantifiable” and so provide only a “yes or no answer” to whether a toxin is present.
“That’s not very useful for clinical trials or for monitoring patients,” said Dr Koch.
Routinely sending patients suspected of having dementia for a TMS session “is not far from reality,” said Dr Koch. “We feel that in the next few years, this could be available in most dementia centers.”
Dr Koch believes TMS testing will become an important part of an evaluation for patients with dementia.
“The next step will be to include this neurophysiological evaluation in the overall panel of diagnostic tools that we have, and this could be useful to test the next-generation drugs.”
Use of TMS to differentiate AD from FTD requires two magnetic stimulators, which may affect its availability. Another possible drawback to TMS as a diagnostic tool in dementia is the presence of an implanted pacemaker. However, said Dr Koch, this should not be a problem if safety guidelines are followed.
New Diagnostic Tool?
Commenting on the findings for Medscape Medical News, Steven T. DeKosky, MD, deputy director, McKnight Brain Institute, associate director, Florida Alzheimer’s Disease Center, and professor of neurology and neuroscience, University of Florida College of Medicine in Gainesville, and fellow of the American Academy of Neurology, said the finding that AD and FTD can be differentiated from each other and from controls is not only of interest for potential diagnostic possibilities but may also allow researchers to track changes in brain circuitry over time.
This, he added, could shed light on which areas of the brain are functionally impaired and possibly provide another objective of outcome to measure during a therapeutic intervention.
“This research group is both skilled and experienced at the methodology of the work they have presented. They have done an excellent job of gathering a sufficient number of cases of Alzheimer’s disease and frontotemporal dementia to assure that they can draw some firm conclusions from the data,” said Dr DeKosky.
He noted that because FTD is far less common than AD, it’s much more difficult to assemble such cases to study.
Dr DeKosky also found it “interesting” that both FTD groups — those with primary progressive aphasia and those with the behavioral variant of FTD — had the same electrophysiologic pattern.
It’s not clear if this test would be routinely used in clinical practice, said Dr DeKosky. “But it certainly might be utilized both in research and in cases that are difficult to diagnose accurately, even after other biomarker and clinical studies have been done.”
The study was supported by a grant of the Italian Ministry of Health and the Alzheimer’s Drug Discovery Foundation. Dr Koch reported grants from the Italian Ministry of Health and the Alzheimer’s Drug Discovery Foundation. Dr DeKosky has disclosed no relevant financial relationships.
Neurology. Published online July 26, 2017. Abstract
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