The presence of cortical atrophy (focal or diffuse) prior to the development of symptoms of cognitive impairment could predict the earliest cases of neurodegenerative disease in patients with CRSD. We reviewed the usefulness of cranial CT and MRI as early markers of cortical atrophy in patients with RSBD at our center.
Patients and methodsRetrospective observational descriptive analysis of patients diagnosed with RSBD from October 2012 to October 2022. All with cranial CT or MRI, evaluated by a neuroradiologist.
Results54 patients were included, 21 women (38.88%), 33 men (61.12%), mean age at diagnosis of TCSR: 69.04 ± 12.625. Of the 54 patients, 44 (81.48%) had imaging tests consistent with their age, and 10 had atrophy greater than expected for their age. Of the 54 patients, 21 (38.88%) with a diagnosis of neurodegenerative disease, 33 (61.12%) persist as idiopathic, almost all with more than 5 years of evolution (range of 1 to 10 years of evolution without diagnosis). Of the 10 (18.52%) patients with greater atrophy, all were diagnosed with neurodegenerative disease (8 in 1 year, 2 in 8 years).
ConclusionsAlmost half of our series have developed a neurodegenerative disease in the first 10 years of evolution. The majority of them presented global cortical atrophy measured by the GCA scale in the first year of diagnosis, without other neurological symptoms. Patients who did not show cortical atrophy at diagnosis have not yet developed the neurodegenerative disease in 10 years of evolution. In our experience, the absence of cortical atrophy on cranial MRI or CT (measured by scales such as GCA) at the diagnosis of CRST seems to predict slower progression cases. These data should be corroborated with larger series.
La presencia de atrofia cortical (focal o difusa) previa al desarrollo de síntomas de deterioro cognitivo podría predecir los casos más tempranos de enfermedad neurodegenerativa en pacientes con TCSR. Revisamos la utilidad de la TC y RM craneal como marcadores tempranos de atrofia cortical en pacientes con RSBD en nuestro centro.
Pacientes y métodosAnálisis descriptivo retrospectivo observacional de pacientes diagnosticados de RSBD desde octubre de 2012 hasta octubre de 2022. Todos con TC o RM craneal, evaluados por un neurorradiólogo.
ResultadosSe incluyeron 54 pacientes, 21 mujeres (38,88%), 33 hombres (61,12%), edad media al diagnóstico de TCSR: 69,04 ± 12,625. De los 54 pacientes, 44 (81,48%) con pruebas de imagen acordes a la edad, y 10 con atrofia mayor a la esperada para la edad. De los 54 pacientes, 21 (38,88%) con diagnóstico de enfermedad neurodegenerativa, 33 (61,12%) persisten como idiopáticos, casi todos con más de 5 años de evolución (rango de 1 a 10 años de evolución sin diagnóstico). De los 10 (18,52%) pacientes con mayor atrofia, todos fueron diagnosticados de enfermedad neurodegenerativa (8 en 1 año, 2 en 8 años).
ConclusionesCasi la mitad de nuestra serie ha desarrollado una enfermedad neurodegenerativa en los primeros 10 años de evolución. La mayoría de ellos presentaban atrofia cortical global medida por escala GCA en el primer año de diagnóstico, sin otra sintomatología neurológica. Los pacientes que no mostraban atrofia cortical al diagnóstico no han desarrollado todavía la enfermedad neurodegenerativa en 10 años de evolución. En nuestra experiencia, la ausencia de atrofia cortical en RM o TC craneal (medida por escalas como la GCA) al diagnóstico de TCSR parece predecir los casos de evolución más lenta. Estos datos deberían ser corroborados con series más amplias.
REM sleep behaviour disorder (RSBD) associated with neurodegenerative diseases, both as a prodrome and during their development, has been widely described. Since 1996, multiple series have been published in which RSBD has been associated with the subsequent development of idiopathic Parkinson's disease (IPD), dementias, multiple sclerosis or atypical parkinsonism, among others.1–10 Ongoing research is aimed at identifying early markers associated with RSBD that could help to predict the development of specific pathologies. The ultimate goal is early treatment so as to try to delay or even prevent the neurodegenerative disease from developing.
The importance of having an entity that predicts, up to 14 years in advance, the development of a neurodegenerative disease such as dementia or Parkinson's disease is a great opportunity for research aimed at trying to delay or control the onset of these diseases.
The progressive improvement of neuroimaging techniques for the detection of neurological diseases has been a major breakthrough, making it possible to detect pathologies such as multiple sclerosis, tumours, strokes or neurodegenerative diseases at an earlier stage.11–24 The presence of cortical atrophy (focal or diffuse) prior to the development of symptoms of cognitive impairment may be predictive of earlier cases in patients with RSBD.
There are currently several validated radiological visual measurement scores to assess global cortical atrophy (GCA), focal medial temporal lobe atrophy (MTA), parietal atrophy (Koedam score), or white matter vascular lesions (Fazekas score).12–19
We reviewed the usefulness of cranial computed tomography (CT) and cranial magnetic resonance imaging (MRI) as early markers of cortical atrophy in patients with RSBD at our centre.
Patients and methodsObservational retrospective descriptive analysis of patients with a diagnosis of RSBD seen in the Neurology Department of the Sleep Disorders Unit of our centre from October 2012 to October 2022. All consecutive patients over 18 years of age, all confirmed by overnight polysomnography (PSG), were included, following the diagnostic criteria of the International classification of sleep disorders ICSD, 3-TR, revised June 2023. Those with diagnostic doubts, incomplete data or inconclusive sleep testing were excluded.
The variables analysed were: age at diagnosis, sex, age, diagnostic delay, specific neurological clinical symptoms (anosmia, tremor, rigidity, mnesic changes, bradykinesia), year of symptom onset, year of PSG, confirmation of diagnosis in PSG, neuroimaging tests (cranial MRI, cranial CT), frontotemporal atrophy scores and Koedam parietal score, global cortical atrophy (GCA) score, medial temporal atrophy (MTA) score, white matter lesion assessment score (Fazekas), age-adjusted atrophy assessment, treatments used, other sleep disorders, final diagnosis, time course since onset of RSBD and neurodegenerative diagnosis.
Patients were assessed by the Neurology Department and the imaging studies were analysed by the neuroradiologists at our centre.
The software used for data processing is IBM SPSS statistical software, version 25. The number of diagnosed cases, adjusted to the population figures assigned to our centre in 2020, was used to calculate prevalence. Categorical variables are presented as frequencies and percentages, and continuous variables as means and standard deviations (SDs). Chi-square was used for the association of qualitative variables and Student's t-test for quantitative variables. A specific database was created for statistical analysis. The data were processed in an anonymised and aggregated form, in accordance with the provisions of Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016.
This work has been approved by our centre's research committee.
ResultsThere were 54 patients included: 21 females (38.88%) and 33 males (61.12%); mean age at diagnosis of RSBD: 69.04 ± 12.625, age range 36–87 years.
Of the 54 patients, 21 (38.88%) were diagnosed with neurodegenerative disease, 33 (61.12%) persisted as idiopathic, almost all with more than 5 years of progression (range 1–10 years of progression without diagnosis). Of the patients with neurodegenerative disease, 6 (11.11%) patients had IPD, 1 (1.85%) had chorea, 5 (9.26%) had Lewy body dementia, 8 (14.81%) patients had dementia (all Alzheimer's type, except one with vascular dementia), 1 (1.85%) had corticobasal degeneration (Table 1).
Distribution of neurodegenerative disease type among patients.
| Type of neurodegenerative disease | n | Mean | Standard deviation | 95% Confidence Interval | Minimum | Maximum | |
|---|---|---|---|---|---|---|---|
| Lower limit | Upper limit | ||||||
| Dementia | 9 | 69.78 | 8.729 | 63.07 | 76.49 | 56 | 85 |
| Parkinson | 6 | 72.50 | 2.345 | 70.04 | 74.96 | 68 | 75 |
| Lewy bodies | 5 | 73.80 | 8.167 | 63.66 | 83.94 | 63 | 83 |
| Chorea | 1 | 78.00 | – | – | – | 78 | 78 |
| Corticobasal degeneration | 1 | 73.00 | – | – | – | 73 | 73 |
| Total | 22 | 71.95 | 6.911 | 68.89 | 75.02 | 56 | 85 |
Diagnostic delay time from symptom onset to PSG confirmation: 2.26 ± 2.755 years, median: 1. Time from onset of symptoms to development of neurodegenerative disease: 3.54 ± 3.107 years.
Of the 54 patients, 23 (42.59%) had subjective cognitive impairment symptoms, with no impact on assessment tests (Lobo Mini-Mental State Examination [MMSE] or Montreal Cognitive Assessment [MOCA] in clinic), without criteria of mild cognitive impairment or dementia.
Of the 54 patients, all had undergone cranial CT (20 patients) or cranial MRI (34 patients) at the time of diagnosis, without symptoms of cognitive impairment or symptoms suggestive of Parkinson's disease.
Of the 54 patients, 33 (61.11%) had global atrophy (GCA), 3 patients had grade 2 and 30 had grade 1 (Fig. 1). The rest were classified with 0 score (no atrophy). The mean age of these 33 patients was 73 years ± 8,90. Of the total, 17 (31.48%) patients had medial temporal atrophy (MTA): 1 with a score of 3, 6 with a score of 2 and 14 with a score of 1; of the total, 16 patients had parietal atrophy on the Koedam score (1 with grade 2, and 15 with grade 1). We found frontotemporal atrophy in 6 patients and vascular lesions according to the Fazekas score in 19 patients (Grade 1: 13 patients, Grade 2: 5 patients, and Grade 3: 1).
Of the 21 patients diagnosed with neurodegenerative disease, 18 had atrophy on the GCA score (and of these, 8 had atrophy greater than expected for their age). Only 3 patients had no cortical atrophy on imaging tests and 7 patients showed abnormalities on all scores.
Of the 54 patients, 44 (81.48%) had age-appropriate imaging and 10 had more atrophy than expected for their age. Of the 10 (18.52%) patients with greater atrophy, all were diagnosed with neurodegenerative disease: 8 in 1 year and 2 in 8 years. Of the 10 patients: 1 had corticobasal degeneration, 1 IPD, 1 chorea, 3 Lewy body dementia and 4 Alzheimer's type dementia.
DiscussionWhen we started requesting routine imaging tests (CT, cranial MRI) in patients with RSBD, we aimed to rule out other structural pathologies that could be causing the symptoms. We were struck by the number of patients in whom cortical-subcortical atrophy was reported, and in several of them more than expected for their age. This was also the case in young patients (under 60 years of age) without the presence of other more common abnormalities, such as white matter lesions (non-specific or vascular), and without evidence of any other structural lesions.
When we reviewed recent publications, we found few articles on the usefulness of MRI or FDG-PET as early detectors of disease in these cases, and most of them were published in the last 5−6 years, so we considered reviewing our caseload.12–16
The mean age and prevalence by sex in our series are within the range published elsewhere. The diagnostic delay of RSBD from the onset of first symptoms to confirmation by PSG is low in our series, probably due to the availability of a Sleep Unit in our department.
In terms of diagnostic tests, in our centre all patients with RSBD undergo a cranial MRI or CT scan at the onset of diagnosis to rule out cases secondary to structural pathology. These are simple routine tests, which can be performed in almost any hospital. In our series, almost half of the patients had cortico-subcortical atrophy at the time of diagnosis, without any prodromal symptoms or symptoms suggestive of dementia, Parkinson's disease or other neurodegenerative disorders. Of these, most have already developed a confirmed neurodegenerative disease, while none of the patients who had the test reported as normal have so far developed pathology (more than 5 years of progression). This may suggest that patients who do not have early cortical atrophy at the time of testing may have a slower rate of progression.
With regard to the analysis of the imaging studies, as clinical neurologists we were struck by the cortical atrophy in the majority of patients. However, when these images were reviewed by expert neuroradiologists at our hospital, they found that in more than half of the cases they were age-appropriate.
Almost all of our patients had no other significant comorbidity except for the classic vascular risk factors (dyslipidaemia, arterial hypertension), all of which were well controlled, and no evidence of significant cranial lesions due to this cause as measured by the Fazekas score.
Within the limitations of our series, the sample size is probably the most important determinant of the results, although it is similar to most series published individually.6–8 Fewer patients met all the inclusion criteria than expected, as many patients with symptoms suggestive of RSBD already had clear symptoms of IPD or dementia at diagnosis, and met disease criteria, so we did not include them.
Another selection bias in our series is the occurrence of a higher number of patients with dementia than with IPD when RSBD is generally considered to be associated with alpha-synucleinopathy. In addition to the 33 patients who have not yet developed degenerative disease, patients with RSBD who have other prodromal symptoms or signs on examination suggestive of PID are referred to the Movement Disorders Unit rather than the Sleep Clinic, so these patients are not included in our series. RSBD is the prodromal symptom most commonly associated with the development of IPD (more than 90%, above others, such as constipation or anosmia), so it is often directly associated with this entity, and referrals are made to specific clinics.
We believe that basic neuroimaging tests performed early in patients with idiopathic RSBD, when patients have not yet developed the symptoms of each neurodegenerative disease (or have only suspected symptoms), can help to provide early diagnostic guidance and predict cases with a slower progression. This can facilitate patient participation in clinical trials and targeted research.
ConclusionsAlmost half of the patients in our series developed a neurodegenerative disease in the first 10 years of progression, with dementia in more than half of these cases. Most had global cortical atrophy measured by GCA score in the first year of diagnosis, with no neurological symptoms other than the sleep disorder. Almost a quarter of patients had more atrophy than expected for their age at diagnosis of RSBD, and almost all developed dementia early in the first year. Patients without cortical atrophy at diagnosis have not developed neurodegenerative disease in 10 years of progression. In our experience, the absence of cortical atrophy on cranial MRI or CT (measured by scores such as the GCA) at diagnosis of RSBD seems to predict slower progressing cases. These data should be corroborated with larger series.
FundingThe first author has received funding from the FIIB HUIS HUHEN Foundation only for the cost of publishing the paper in open access.
Ethical considerationsThe research committee of our centre approved the work. The data have been processed in an anonymised form, so no specific consent has been signed by the patients.
Conflict of interestThe first author has received funding from the FIIB HUIS HUHEN Foundation only for the cost of publishing the paper in open access.
