Increased white matter hyperintensities (WMH) are strongly associated with Alzheimer’s disease (AD), but new research reveals they are also a “core feature” of frontotemporal dementia (FTD) in findings that may help physicians make this difficult diagnosis that affects adults in their prime.
“The assessment of WMH can aid differential diagnosis of bvFTD [behavioral-variant FTD] against other neurodegenerative conditions in the absence of vascular risk factors, especially when considering their spatial distribution,” senior author Ramón Landin-Romero, PhD, Appenzeller Neuroscience Fellow, Frontotemporal Dementia Research Group, University of Sydney, Sydney, Australia, told Medscape Medical News.
“Clinicians can ask for specific sequences in routine MRI scans to visually detect WMH,” said Landin-Romero, who is also a senior lecturer in the School of Psychology and Brain and Mind Center.
The study was published online February 17 in Neurology.
“FTD is a collection of unrecognized young-onset (before age 65) dementia syndromes that affect people in their prime,” said Landin-Romero.
He added that heterogeneity in progression trajectories and symptoms, which can include changes in behavior and personality, language impairments, and psychosis, make it a difficult disease to diagnose.
“As such, our research was motivated by the need of sensitive and specific biomarkers of FTD, which are urgently needed to aid diagnosis, prognosis, and treatment development,” he said.
Previous research has been limited; there have only been a “handful” of cohort and case studies and studies involving individuals with mutations in one FTD-causative gene.
FTD is genetically and pathologically complex, and there has been no clear correlation between genetic mutations/underlying pathology and clinical presentation, Landin-Romero said.
WMH are common in older individuals and are linked to increased risk for cognitive impairment and dementia. Traditionally, they have been associated with vascular risk factors, such as smoking and diabetes. “But the presentation of WMH in FTD and its associations with the severity of symptoms and brain atrophy across FTD symptoms remains to be established,” said Landin-Romero.
Higher Disease Severity
To explore the possible association, the researchers studied 129 patients with either bvFTD (n = 64; mean age, 64 years) or AD (n = 65; mean age, 64.66 years).
Neuropsychological assessments, medical and neurologic examinations, clinical interview, and structural brain MRI were conducted for all patients, who were compared to 66 age-, sex-, and education-matched healthy control persons (HCs) (mean age, 64.69 years).
Some participants in the FTD, AD, and HC groups (n = 54, 44, and 26, respectively) also underwent genetic screening. Postmortem pathology findings were available for a small number of FTD and AD participants (n = 13 and 5, respectively).
The medical history included lifestyle and cardiovascular risk factors, as well as other health and neurologic conditions and medication history. Hypertension, hypercholesterolemia, diabetes, and smoking were used to assess vascular risk.
The FTD and AD groups did not differ with regard to disease duration (3.55 years [SD, 1.75] and 3.24 years [SD, 1.59], respectively). However, disease severity was significnatly higher among those with FTD than among those with AD, as measured by the FTD Rating Scale Rasch score (-0.52 [SD, 1.28] vs 0.78 [SD, 1.55]; P < .001).
Compared to HCs, patients in the FTD and AD groups scored significantly lower on the Addenbrooke’s Cognitive Examination–Revised (ACE-R) or ACE-III scale. Patients with AD showed “disproportionally larger deficits” in memory and visuospatial processing compared to those with FTD, whereas those with FTD performed significantly worse than those with AD in the fluency subdomain.
A larger number of patients in the FTD group screened positive for genetic abnormalities than in the AD group; no participants in the HC group had genetic mutations.
Mean WMH volume was significantly higher in participants with FTD than in participants with AD and in HCs (mean, 0.76 mL, 0.40 mL, and 0.12 mL, respectively).
These larger volumes contributed to greater disease severity and cortical atrophy. Moreover, disease severity was “found to be a strong predictor of WMH volume in FTD,” the authors state.
Among patients with with FTD, WMH volumes did not differ significantly with regard to genetic mutation status or presence of strong family history.
After controlling for age, vascular risk did not significantly predict WMH volume in the FTD group (P = .16); however, that did not hold true in the AD group.
Increased WMH were associated with anterior brain regions in FTD and with posterior brain regions in AD. In both disorders, higher WMH volume in the corpus callosum was associated with poorer cognitive performance in the domain of attention.
“The spatial distribution of WMH mirrored patterns of brain atrophy in FTD and AD, was partially independent of cortical degeneration, and was correlated with cognitive deficits,” said Landin-Romero.
The findings were not what he expected.
“We were expecting that the amounts of WMH would be similar in FTD and AD, but we actually found higher levels in participants with FTD,” he said. Additionally, he anticipated that patients with either FTD or AD who had more severe disease would have more WMH, but that finding only held true for people with FTD.
“In sum, our findings show that WMH are a core feature of FTD and AD that can contribute to cognitive problems, and not simply as a marker of vascular disease,” said Landin-Romero.
Major Research Contribution
Commenting on the study for Medscape Medical News, Jordi Matias-Guiu, PhD, MD, of the Department of Neurology, Hospital Clinico, San Carlos, Spain, considers the study to be a “great contribution to the field.”
Matias-Guiu, who was not involved with the study, said that WMH “do not necessarily mean vascular pathology, and atrophy may partially explain these abnormalities and should be taken into account in the interpretation of brain MRI.
“WMH are present in both AD and FTD and are relevant to cognitive deficits found in these disorders,” he added.
The study was funded by grants from the National Health and Medical Research Council of Australia, the Dementia Research Team, and the ARC Center of Excellence in Cognition and Its Disorders. Landin-Romero is supported by the Appenzeller Neuroscience Fellowship in Alzheimers Disease and the ARC Center of Excellence in Cognition and its Disorders Memory Program. The other authors’ disclosures are listed on the original article. Matias-Guiu reports no relevant financial relationships.
Neurology. Published online February 17, 2021. Abstract