Abstract
This special issue of the journal will be focusing on presenting updated information on the most prevalent of the non-AD dementias: the Lewy body dementias (LBD) including both Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB), vascular dementia (VaD), and frontotemporal dementias (FTDs). Together they represent half of all dementia cases either alone or often in combination with each other or in combination with AD. Despite their high prevalence, these disorders often get little attention and patients are still often misdiagnosed. Unfortunately, only PDD so far has a licensed symptomatic treatment approved in rivastigmine. Unlike the situation for AD, clinical drug trials with potential disease-modifying effects have not yet started for the non-AD dementias.
Researchers now aim to identify earlier stages of disease for the non-AD dementias testing out possible new diagnostic criteria for predementia stages or mild cognitive impairment (MCI). In PD, such criteria have been in use for some time now, 1 but MCI stages or predementia stages of disease for the other non-AD dementias such as DLB, FTD, or VaD are not yet well established. Defining early predementia stages of these diseases is important to identify persons suitable for inclusion in clinical trials for potential disease-modifying treatments building on lessons learned from drug trials in AD. An important step in this process is to identify predictive biomarkers for subsequent disease progression. In LBD, reduced uptake of dopamine transporter visualized with CIT-SPECT might identify those who will develop dementia later on, and REM sleep behavior disorder is probably a very early marker for LBD. However, blood or cerebrospinal-based markers have not yet been established in LBD, despite many years of research on α-synuclein species. Biopsies from the rectal mucosa or salivary glands and genotyping may be possible future biomarkers in LBD. In FTD, genetic markers are already important biomarkers of disease, but in VaD, few risk genes have been established.
In this special issue of the journal, we first present a paper from the Newcastle group with Professor Ian McKeith, the founder of the DLB diagnostic criteria, as first author discussing the predementia stages of DLB and their possible future diagnostic criteria including clinical symptoms, cognition, and potential biomarkers, similar to the predementia stages of AD. In DLB, early diagnosis will be more challenging as compared to in AD due to the many different possible presentations of this disease. Dementia with Lewy bodies is the newest of the non-AD dementias, and DLB was defined by consensus criteria 20 years ago and has now finally been recognized alongside the other dementias in the fifth edition of the Diagnostic and Statistical Manual of the American Psychiatric Association as major neurocognitive disorder due to Lewy bodies or mild neurocognitive disorder with Lewy bodies, the latter incorporating the MCI stages of the disease. Hopefully, the World Health Organization and International Classification of Diseases, Eleventh Revision will recognize the DLB diagnosis accordingly.
Rosie Watson and Sean Colloby have contributed with a review paper on both structural and functional imaging in DLB reminding us that less atrophy will be found as compared to in AD, particularly in the medial temporal lobe including hippocampus, but in functional imaging such as FP-CIT SPECT, most patients with DLB will have reduced uptake of the dopamine transporter in the striatum, although some 20% of patients with DLB have predominantly cortical pathology and will be missed applying this type of functional imaging. Recent studies find that about half of people diagnosed with DLB have amyloid accumulation in their brains showing on amyloid PET scanning.
The third paper by Garcia-Ptacek and Kramberger will update readers on PDD, an important and frequent complication in PD. In their review paper, they are focusing particularly on subtypes of cognitive impairment and recent findings regarding the risk genes for developing cognitive impairment and dementia in PD like the GBA mutations. The heritability in PD was recently estimated at about 28% as compared to 30% in DLB and 60% in AD. 2
In the fourth paper, readers will find updated information on FTD where Rosness and colleagues are focusing on possible early signs in behavior and language and new genetic types of FTD. Familial FTD is highly heritable with possibilities for genetical testing challenging the clinical geneticist in collaboration with old age psychiatry and geriatric medicine and neurology. Recent FTD consortia have defined new important genetic risk factors like the expansion on chromosome 9, and in this special issue, we present an update on FTD for clinicians working with these patients and their families. Gene therapy is now being tested in models for FTD and ALS giving hope for future patients and their families.
The last paper in this special issue of the journal is focusing on the many different subtypes of vascular cognitive impairment and dementia. The VaD field has a long and strong research tradition with several diagnostic criteria and suggested criteria for MCI or predementia stages of the disease. Stroke prevention studies lowering systolic blood pressure have shown reduced number of strokes, and as a consequence, fewer persons will develop VaD, but still no licensed treatment for VaD has been approved. Epidemiological studies in recent years comparing dementia prevalence today with the prevalence in previous generations have found reduced frequency of dementia now as compared to 10 or 20 years ago. Possible explanations for the lower prevalence of dementia now are better prevention of cardiovascular diseases also contributing to better brain health as well with optimized treatment of hypertension, diabetes, and hypercholesterolemia, less smoking, better education, more physical activity, and more focus on body weight.
One way forward is applying the new technology in high-throughput sequencing on the non-AD dementias, but a prerequisite is international collaboration in consortia to increase sample size both for genome wide association studies and for deep sequencing. The European DLB consortium (E-DLB) 3 facilitates cohort studies, clinical intervention studies in collaboration with the pharmaceutical industry, and enables large sample size for genetical studies on DLB, and now includes more than 20 European centers. We hope the E-DLB network will contribute to future benefits for patients and their caregivers, and we aim for clinical drug trials to be carried out within these frames for the benefit of the patients with DLB. By combining specialist centers of DLB and PD, E-DLB enables the exploration of the relationship between these 2 disorders.
In summary, declining prevalence of dementia overall now gives hope that multimodal interventions on cardiovascular risk factors, such as hypertension, smoking, hypercholesterolemia, diabetes, overweight, will also affect the prevalence of the non-AD dementias, although some disorders such as FTD have strong genetic underpinnings.