Abstract
The cognitive evolution of early dementia with Lewy bodies (DLB) is less well known than that of Alzheimer’s disease (AD). During dementia, DLB progresses like AD. The aim of this study was to analyze the long-term cognitive decline of early DLB. Participants were recruited for either mild cognitive impairment or mild dementia with a suspicion of DLB or AD, or as healthy older subjects (AlphaLewyMA study, NCT01876459, 2013). Using beta regression, we compared the slope of the Mini-Mental State Examination (MMSE) score of 110 DLB patients (DLB group), 57 AD patients (AD group), 19 DLB and AD patients (DLB + AD group), 30 patients with other cognitive diseases (DC group), and 31 healthy older controls (HC group). The mean follow-up was 4.8 years. All patients’ groups had a significant decrease in MMSE score. The slope of MMSE decline of the DLB group (−0.49 point a year) was higher than the HC group (+ 0.03; P < .0001), lower than that of the AD (−2.78; P < .0001) and DLB + AD (−2.92; P < .0001) groups and not different from the DC group (−0.29; P = .8000). The variability of annual variations in MMSE score was greater in the DLB group (2.13 points) than in the AD group (1.73 points). There was no difference between patients’ group in terms of death or admission to a nursing home. Patients with early DLB decline cognitively more slowly while fluctuating, whereas AD and DLB + AD patients decline markedly. These results suggest that there is a more dysfunctional than neurodegenerative phase at the beginning of DLB.
Keywords: Dementia with Lewy bodies, Alzheimer’s disease, Lewy body disease, Mild cognitive impairment, MMSE, Outcome
Introduction
Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are the two main neurodegenerative diseases responsible for dementia and respectively account for 70–80% and 15–20% of neuropathologically defined cases [1]. Diagnostic classification of prodromal DLB (i.e. mild cognitive impairment, MCI) and DLB with dementia is based on revised consensus criteria, the core features being: (1) recurrent visual hallucinations, (2) cognitive fluctuations, (3) REM sleep behavior disorders, and (4) spontaneous motor features of parkinsonism [1, 2]. The presence of one of these core signs is sufficient for a diagnosis of possible DLB, and 2 to 4 for probable DLB. Some studies have compared clinical courses between DLB and AD patients with dementia. According to a systematic review of six studies (N = 841 patients), the annual decline of the Mini-Mental Status Examination (MMSE) score, which measures global cognitive functioning was of 3.3 (SD 1.7, range 1.8 to 4.9 points) for DLB, of 3.4 (SD 1.4, range 1.8 to 5.8 points) for AD, and of 5.0 points for DLB + AD (one study among the six) [3]. A previous prospective study we published (N = 1151 patients) with a mean follow-up of 5.88 years showed a similar rate of decline for DLB (1.37 points) and AD (1.06), but a higher rate of global cognitive decline for DLB + AD patients (1.68) [4]. Another study with 1290 patients and a follow-up of 3 years showed also no different rate of cognitive decline between DLB (2.1 points) and AD (1.6 points) [5].
In the context of MCI, a prospective study in Amsterdam of 197 patients with a mean follow-up of 3.0 years found that prodromal AD patients declined faster than prodromal DLB patients in terms of MMSE score [6], and another from Newcastle-upon-Tyne with 76 patients with a mean follow-up of 1.9 years did not find any difference [7]. In the context of MCI and SCI, the prospective study Memento in France demonstrated a much more pronounced cognitive and functional decline in AD and DLB+AD patients than in DLB patients [8]. In the context of MCI, the presence of characteristics of DLB increases the risk of dementia [9].
The primary aim of this study was thus to compare the early stages of DLB, AD, and DLB + AD patients in terms of cognitive rate of decline, using the MMSE score as the outcome measure in the AlphaLewyMA cohort of patients.
Participants and methods
Study design and participants
AlphaLewyMA is a longitudinal study aimed at searching for DLB biomarkers, taking place in the tertiary memory clinic “Centre Mémoire de Ressources et de Recherche” (CM2R) of Strasbourg and Colmar, France [10]. All patients enrolled in the AlphaLewyMA study had been referred to experienced neurologists and geriatricians of the CM2R for cognitive or behavioral complaints by their specialist, local memory clinic, or general practitioner. Healthy older controls (HCs) were recruited among friends and relatives of the patients or via the listing of controls of the local clinical investigation center. Patients and HCs underwent the following: a standardized screening protocol including medical history, various questionnaires including one on photophobia, physical and neurological examinations, neuropsychological tests including the Mini-Mental State Examination (MMSE), a brain MRI, and blood and CSF collection. Features of parkinsonism were evaluated using the Unified Parkinson’s Disease Rating Scale (UPDRS III): akinesia, rigidity, and tremor at rest (rated from 0 for no symptoms to 4 for severe symptoms). Fluctuations were assessed with the Mayo Clinic fluctuations scale [11]. The Parkinson’s disease-associated psychotic symptoms questionnaire was used to evaluate the presence of hallucinations [12]. RBD was evaluated using a sleep questionnaire on REM sleep behavior disorder (RBD) from the publication by Gjerstad et al. [13], simplified into two questions for the patient and the caregiver: one concerning movements during sleep, the second concerning vivid dreams and nightmares.
The expected follow-up time for participants in the AlphaLewyMA study is 8 years. We present here the results of the cohort after at least 5 years of follow-up for each of the participants, except for those who died, entered an institution, or stopped the follow-up. The participants in our study regularly underwent a neuropsychological assessment, including the MMSE: at inclusion in the AlphaLewyMA study and then every year for the patients and every two years for the healthy subjects.
The diagnosis considered was that made at the patient’s last follow-up visit. Patients with prodromal DLB or DLB dementia were selected according to McKeith’s criteria [1, 2]. Patients with prodromal AD or AD dementia were selected according to Dubois’ criteria [14]. Patients were considered to have DLB and AD if they met both the Dubois’ criteria and the McKeith’s criteria concurrently. For example, a patient with memory storage disorders, a CSF in favor of AD, and two of the four clinical criteria for DLB was considered to have both DLB and AD. A total of 247 participants were included in this study: 110 DLB patients (DLB group), 57 AD patients (AD group), 19 DLB and AD patients (DLB + AD group), 30 diseased control patients (DC group), and 31 HCs (HC group). The DC group consisted of patients originally included in the study with cognitive disorders as found in AD and DLB, who, after a follow-up in the study, were found to have neither AD nor DLB. The DC group had various diagnoses, defined according to international criteria. The detailed diagnoses of the 30 patients of the DC group are as follows: Autoimmune diseases (N = 6; inflammatory rheumatism = 3, Sjögren’s syndrome = 1, multiple sclerosis with parkinsonism = 1, limbic encephalitis = 1), tauopathy (N = 5; 3 progressive supranuclear palsy, 1 corticobasal degeneration, 1 primary age-related tauopathy -PART-), psychiatric disorders (N = 5, 4 depression, 1 bipolar disorder), stable MCI (N = 4), head injury with cognitive sequelae (N = 2), temporal lobe epilepsy (N = 2) fronto-insular glioblastoma (N = 1), temporo-insular cavernoma (N = 1), limbic predominant age-related TDP-43 encephalopathy (LATE, N = 1), Lyme neuroborreliosis (N = 1), stroke (N = 1), and alcoholism (N = 1).
For CSF analysis, each sample was transported to the laboratory within 4 h after collection; the sample was homogenized on receipt at the laboratory and was then centrifuged at 1700 g for 10 min at room temperature. All samples were free of blood contamination (the samples were checked visually; if a stain in the sample was detected, the sample was not measured). Samples were then transferred in 0.5-mL polypropylene tubes (Dutscher ref.: 033283) and stored at − 80 °C until analysis. CSF Aβ42, Aβ40, t-Tau, and phospho-tau181 were measured by sandwich enzyme-linked immunosorbent assay (ELISA) using commercially available kits (INNOTEST®; Fujirebio Europe, Ghent, Belgium). All assays were performed according to the manufacturer’s instructions, and the methodology did not change during the period in which the analyses were performed.
Ethics declaration
All participants provided written informed consent for the study, in accordance with the Declaration of Helsinki, and the study was approved by the Ethics Committee of East France (IV), with the following number EudraCT 2012–100992-41 (https://clinicaltrials.gov/study/NCT01876459).
Statistical analysis
The Statistical Package for Social Sciences software (SPSS ver. 31.0.0.0, http://www-01.ibm.com/software/analytics/spss/) was used for differences in demographic and clinical data at baseline. Where appropriate, differences in demographic and clinical data were assessed using parametric (ANOVA, t-tests) and nonparametric tests (Kruskal-Wallis H, Mann–Whitney U). Post hoc analyses employed Tukey and Mann–Whitney U for ANOVA and Kruskal-Wallis tests, respectively. For categorical measures, χ2 tests were applied. Spearman nonparametric correlations were performed to examine the association between photophobia, the photophobia questionnaire score, and core symptoms of DLB (parkinsonism, hallucinations, RBD, and fluctuations). For each test statistic, a probability value of < 0.05 was regarded as significant.
Because the MMSE score has discrete values bounded by 0 and 30, we relied on beta regression for modelling a transformation of the score on (0, 1): MMSE was divided by 30 and, to exclude 0 and 1 values, transformed using the Smithson and Verkuilen method [15]. The transformed scores were assumed to be beta distributed. The precision of these distributions was not modelled, but in the logit of its mean, we added several terms: a specific intercept for each group (DLB, AD, DLB + AD, DC, and HC) and a specific temporal linear (on the logit scale) trend for each disease. All post hoc comparisons between intercepts and slopes were simultaneously inferred using contrasts and accurate corrections for first type error. On a logit scale, the values of the parameters are meaningless. When necessary, the back-transformation on the natural scale was achieved using the “expit” function (inverse function of logit) for the mean estimates and the delta method for the variance. We retrieved here only the P-value of different statistical comparisons (intercepts and trends between diseases) but, when relevant, back-transformed mean, standard error, and 5% confidence interval of parameters.
To deal with potential differences between subjects within each group at their time of inclusion in the study, we carried out two different analyses: first a “ground reality” beta regression as described above and the same beta regression but using propensity scores based on demographic and clinical variables as weights (age, sex, educational level). Calculation for this score was done using boosted logistic regression [16].
In terms of the variability of each subject’s MMSE score from one year to the next, we hypothesized that the decrease in MMSE score in AD is not very variable: every year the subjects will decrease by X points, but the variability of these differences will be low; in DLB, however, there are fluctuations in MMSE score, which means that for each subject, the difference with the previous year may be -X or + X, and the variability of these differences will be thus be higher.
Statistical analyses were performed using the R statistical software [17] (version 3.2.3) with ad hoc packages (betareg, multcomp, and twang). Results are shown to four significant digits.
Results
Participants’ characteristics
The demographic data of the first visit for patients and controls are summarised in Table 1. The DC and HC groups were younger than the AD and DLB + AD groups, and the HC group was younger than the DLB group (P < 0.001). The DC and HC groups had higher MMSE scores than the AD and DLB + AD groups, and the DLB group had a lower MMSE score than the HC group (P < 0.001). Core clinical features of DLB (parkinsonism, hallucinations, fluctuations, and RBD) were more frequent in the DLB group than in the AD group (P < 0.001). The DLB + AD group had more akinesia and rigidity than the HC and AD groups (P < 0.001).
Table 1.
Clinical, demographic and follow-up features of the five groups: prodromal and mild dementia with Lewy bodies patients (DLB group), prodromal and mild dementia Alzheimer’s disease patients (AD group), prodromal and mild dementia with Lewy bodies and Alzheimer’s disease patients (DLB + AD group), prodromal and mild dementia diseased controls (DC), and healthy controls (HC)
| DLB N = 110 | AD N = 57 | DLB + AD N = 19 | DC N = 30 | HC N = 31 | Statistic test, P | Post hocd | ||
|---|---|---|---|---|---|---|---|---|
| Age, yearsa | 71.4 (9.3) | 74.5 (8.4) | 74.8 (8.5) | 67.3 (9.4) | 66.0 (9.0) | F = 6.653, P < 0.001* | HC < DLB, AD and DLB + AD | |
| DC < AD and DLB + AD | ||||||||
| Educationa, b | 11.9 (4.3) | 12.0 (3.9) | 11.7 (2.9) | 12.0 (3.3) | 12.7 (2.1) | H = 1.994, P = 0.737 | ||
| Gender (F/M) | 58/52 | 30/27 | 9/10 | 17/13 | 18/13 | χ2 = 0.711, P = 0.950 | ||
| Handedness (R/L/A) | 94/9/1 | 49/6/1 | 18/0 | 25/3/1 | 29/2 | χ2 = 4.645, P = 0.795 | ||
| MMSE score (/30)a | 25.3 (3.9) | 24.1 (3.3) | 23.2 (3.9) | 27.0 (2.8) | 28.8 (1.2) | H = 61.781, P < 0.001* | HC > DLB + AD, AD, and DLB | |
| DC > DLB + AD, AD | ||||||||
| Parkinsonism | Rigidity 0/1/2/3/4 | 36/59/6/1/0 | 34/4/1/0/0 | 6/6/1/0/0 | 16/6/1/1/0 | 30/1/0/0/0 | H = 51.150, P < 0.001* | DLB > HC and AD |
| DLB + AD > HC and ADc | ||||||||
| Akinesia 0/1/2/3/4 | 39/52/11/0/0 | 35/3/0/0/0 | 7/7/1/0/0 | 18/3/3/0/0 | 30/1/0/0/0 | H = 54.148, P < 0.001* | DLB > HC, AD and DC | |
| DLB + AD > HC and AD | ||||||||
| Tremor 0/1/2/3/4 | 75/21/0/0/0 | 35/2/0/0/0 | 11/4/0/0/0 | 21/2/0/0/0 | 27/2/0/0/0 | H = 9.876, P < 0.043* | DLB > AD | |
| Hallucinations (/10)a | 1.5 (1.9) | 0.3 (0.8) | 0.4 (0.7) | 1.3 (2.0) | 0.1 (0.3) | H = 42.335, P < 0.001* | DLB > HC and AD; DC > AD | |
| Fluctuationsc | 0/1/2/3/4 | 19/34/30/15/6 | 36/7/5/0/0 | 6/8/1/2/0 | 14/7/1/2/1 | 22/6/1/0/1 | H = 61.408, P < 0.001* | DLB > AD, HC and DC |
| RBD | 0/1/2 | 37/22/28 | 36/6/2 | 9/3/4 | 12/6/2 | 19/9/1 | H = 22.780, P < 0.001* | DLB > AD |
| CSFa | Abeta-42 (ng/L) | 822.7 (291.9) | 582.5 (201.6) | 598.8 (241.0) | 1115.5 (275.8) | - | F = 22.139, P < 0.001* | DLB > AD, DLB + AD; DC > AD, DLB + AD, DLB |
| P-Tau (ng/L) | 44.1 (15.2) | 87.3 (30.1) | 92.4 (28.7) | 44.4 (12.4) | - | F = 52.146, P < 0.001* | DLB < AD and DLB + AD; DC < AD and DLB + AD | |
| Tau (ng/L) | 292.1 (185.8) | 651.9 (291.5) | 622.8.6 (173.1) | 287.1 (102.0) | - | F = 34.203, P < 0.001* | DLB < AD and DLB + AD; DC < AD and DLB + AD | |
| Follow-up, monthsa | 64.3 (26.2) | 51.5 (27.0) | 50.8 (23.4) | 49.7 (30.0) | 53.9 (31.5) | H = 13.498, P = 0.009 | DLB > AD | |
| Events during follow-up: | ||||||||
| Infectionsa | 0.36 (0.78) | 0.06 (0.23) | 0.16 (0.38) | 0.31 (0.85) | 0.06 (0.25) | H = 11.329, P = 0.023 | DLB > AD | |
| Surgery or invasive procedurea | 0.58 (1.03) | 0.09 (0.35) | 0.32 (0.58) | 0.21 (0.49) | 0.39 (0.62) | H = 15.805, P = 0.003 | DLB > AD | |
| Fallsa | 0.27 (0.74) | 0.00 (0.00) | 0.47 (1.12) | 0.41 (1.21) | 0.13 (0.34) | H = 11.220, P = 0.024 | DLB > AD | |
| Hospitalizationa | 0.95 (1.69) | 0.28 (0.63) | 0.68 (1.29) | 0.66 (1.26) | 0.30 (0.54) | H = 13.882, P = 0.008 | DLB > AD | |
| Total medical eventsa | 3.27 (4.34) | 0.67 (1.39) | 1.74 (2.58) | 1.83 (3.00) | 1.45 (1.57) | H = 27.517, P < 0.001 | DLB > AD | |
| Nursing home | 3 | 2 | 2 | 0 | 0 | χ2 = 5.584, P = 0.232 | ||
| Death | 12 | 7 | 2 | 1 | 0 | χ2 = 5.961, P = 0.202 | ||
aMean (standard deviation). bEducation: years from primary school. cScores on the Mayo Fluctuation Scale (/4). dTukey post-hoc test for ANOVA (F), Kruskal-Wallis post-hoc test on SPSS (H)
AD Alzheimer’s disease, DC diseased controls, DLB dementia with Lewy bodies, HBP high blood pressure, HC healthy controls, MMSE Mini-Mental State Examination, N number, RBD rapid eye movement sleep behavior disorder, UPDRS Unified Parkinson’s Disease Rating Scale
Risk factors and previous diseases are detailed in Table 2. The DLB group had more history of high blood pressure, sleep apnea syndrome, diabetes, previous infections, and previous depression than the HC group. The AD group had more history of diabetes, high cholesterol, and more previous depression than the HC group. The DLB + AD group had more history of high blood pressure, diabetes, high cholesterol, previous infection, and depression than the HC group. Drug treatments at the time of inclusion in this AlphaLewyMA study are detailed in Table 3. The DLB group had more anti-hypertensive or anti-hypotensive drugs, anti-epileptic, anti-depressant, anti-psychotic, levodopa, benzodiazepine, hypnotics, melatonin, and anti-diabetic than the HC group. The AD group had more anti-epileptic, anti-depressant, anti-psychotic, benzodiazepine, and hypnotics than the HC group. The DLB + AD group had more anti-hypertensive or anti-hypotensive drugs, anti-epileptic, anti-depressant, anti-psychotic, levodopa, benzodiazepine, hypnotics and melatonin than the HC group.
Table 2.
Risk factors and previous or concomitant diseases of the five groups: prodromal and mild dementia with Lewy bodies patients (DLB group), prodromal and mild dementia Alzheimer’s disease patients (AD group), prodromal and mild dementia with Lewy bodies and Alzheimer’s disease patients (DLB + AD group), prodromal and mild dementia diseased controls (DC), and healthy controls (HC)
| Risk factor or disease | DLB N = 110 | AD N = 57 | DLB + AD N = 19 | DC N = 30 | HC N = 31 | Probability of yes more frequent, P value | |
|---|---|---|---|---|---|---|---|
| High blood pressure | N (%) | 51 (50.5) | 21 (47.7) | 8 (61.5) | 7 (26.9) | 10 (33.3) | DLB > DC (P = 0.0128); DLB > HC (P = 0.0419); AD > DC (P = 0.0376); DLB + AD > DC (P = 0.017); DLB + AD > HC (P = 0.0362) |
| Estimated % yes | 50.4 [40.8;60.1]95% | 47.7 [33.5;62.0]95% | 62.6 [40.8;60.1]95% | 26.4 [11.0;45.4]95% | 33.0 [18.1;50.7]95% | ||
| Smoking | N (%) | 19 (20.2) | 9 (23.08) | 2 (15.4) | 1 (4.2) | 3 (16.7) | DLB > DC (P = 0.0105); AD > DC (P = 0.001) |
| Estimated % yes | 20.1 [12.8;28.9]95% | 22.7 [11.6;37.2]95% | 13.6 [2.2;38.3]95% | 3.0 [0.1;14.6]95% | 15.5 [3.9;36.5]95% | ||
| Sleep apnea syndrome | N (%) | 34 (35.4) | 5 (11.9) | 2 (16.7) | 5 (18.5) | 2 (6.9) | DLB > AD (P = 0.0001); DLB > DC (P = 0.0358); DLB > HC (P = 0.0003) |
| Estimated % yes | 35.4 [26.2;45.3]95% | 11.2 [4.0;22.9]95% | 14.4 [2.3;41.3]95% | 17.8 [6.6;34.7]95% | 6.0 [0.8;18.1]95% | ||
| Diabetes | N (%) | 26 (26.8) | 6 (13.9) | 4 (28.6) | 5 (18.5) | 1 (3.4) | DLB > HC (P = 0.0007); AD > HC (P = 0.0379); DLB + AD > HC (P = 0.0074); DC > HC (P = 0.0196) |
| Estimated % yes | 26.7 [18.5;36.1]95% | 13.4 [5.3;25.6]95% | 27.7 [9.1;54.0]95% | 17.7 [6.5;34.9]95% | 2.4 [0.08;12.2]95% | ||
| Excess alcohol | N (%) | 11 (12.3) | 4 (10.5) | 3 (25.0) | 4 (16.0) | 1 (5.6) | No difference |
| Estimated % yes | 12.2 [6.4;19.9]95% | 9.8 [3.0;21.8]95% | 23.6 [6.1;51.5]95% | 15.2 [4.9;32.4]95% | 4.1 [0.1;19.4]95% | ||
| High cholesterol | N (%) | 30 (30.3) | 15 (34.1) | 8 (57.1) | 5 (20.0) | 5 (17.2) | AD > HC (P = 0.0466); DLB + AD > DC (P = 0.0089); DLB + AD > HC (P = 0.0034) |
| Estimated % yes | 30.2 [21.6; 39.8]95% | 33.9 [21.2;48.5]95% | 57.3 [31.3;80.6]95% | 19.2 [7.1;37.5]95% | 16.4 [6.1;32.3]95% | ||
| Autoimmune diseases | N (%) | 2 (2.2)) | 0 (0) | 0 (0) | 1 (3.9) | 1 (3.5) | Lack of model convergence |
| Previous Infections | N (%) | 20 (20.2) | 6 (13.6) | 5 (35.7) | 8 (29.6) | 2 (6.9) | DLB > HC (P = 0.0245); DLB + AD > HC (P = 0.0083); DC > HC (P = 0.0081) |
| Estimated % yes | 20.0 [13.1; 28.7]95% | 13.1 [5.4; 25.2]95% | 35.3 [14.1;61.4]95% | 29.0 [14.3;48.0]95% | 5.9 [0.9;18.2]95% | ||
| Depression | N (%) | 59 (54.6) | 16 (32.7) | 6 (35.3) | 13 (50.0) | 3 (10.3) | DLB > AD (P = 0.0037); DLB > HC (P = 0.00001); AD > HC (P = 0.0064); DLB + AD > HC (P = 0.0171); DC > HC (P.0002) |
| Estimated % yes | 54.6 [45.3;63.7]95% | 32.6 [20.8;46.1]95% | 35.0 [15.3;58.3]95% | 49.5 [31.2;68.3]95% | 9.4 [2.3;23.1]95% | ||
| Bipolar disorder | N (%) | 6 (7.1) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | Lack of model convergence |
| Stroke | N (%) | 10 (9.9) | 2 (4.6) | 0 (0) | 1 (3.9) | 0 (0) | Lack of model convergence |
Table 3.
Drug treatments of the five groups at the time of inclusion in the AlphaLewyMA study: prodromal and mild dementia with Lewy bodies patients (DLB group), prodromal and mild dementia Alzheimer’s disease patients (AD group), prodromal and mild dementia with Lewy bodies and Alzheimer’s disease patients (DLB + AD group), prodromal and mild dementia diseased controls (DC), and healthy controls (HC)
| Treatment | DLB N = 110 | AD N = 57 | DLB + AD N = 19 | DC N = 30 | HC N = 31 | Probability of yes more frequent, P value | |
|---|---|---|---|---|---|---|---|
| Anti-hypertensive/hypotensive | N (%) | 64 (56.6) | 25 (46.3) | 12 (63.2) | 13 (44.8) | 11 (36.7) | DLB > HC (P = 0.0252); DLB + AD > HC (P = 0.0337) |
| Estimated % yes | 56.8 [47.4;65.7]95% | 46.2 [33.2;59.4]95% | 63.4 [41.3;82.4]95% | 44.3 [27.6;62.8]95% | 36.5 [20.7;54.2]95% | ||
| Anti-epileptic | N (%) | 26 (23.0) | 3 (5.6) | 5 (26.3) | 9 (31.0) | 1 (3.3) | DLB > AD (P = 0.0004); DLB > HC (P = 0.0015); DLB + AD > HC (P = 0.0052); DC > HC (P = 0.0009) |
| Estimated % yes | 22.9 [15.8;31.2]95% | 5.0 [1.2;12.7]95% | 25.5 [9.9;47.3]95% | 30.6 [15.7;48.7]95% | 2.4 [0.1;12.1]95% | ||
| Anti-depressant | N (%) | 58 (51.3) | 21 (38.9) | 11 (57.9) | 15 (51.7) | 0 (0) | DLB, AD, DLB + AD and DC > HC (P = 0.0001) |
| Estimated % yes | 51.3 [42.1;60.5]95% | 38.8 [26.5;52.3]95% | 58.2 [36.3;78.6]95% | 51.6 [34.2;69.9]95% | 6.4 × 10–83 [9.5 × 10–191;1.6 × 10–6]95% | ||
| Anti-psychotic | N (%) | 21 (18.6) | 7 (13.0) | 4 (21.1) | 3 (10.3) | 1 (3.3) | DLB > HC (P = 0.0045); AD > HC (P = 0.00364); DLB + AD > HC (P = 0.0149) |
| Estimated % yes | 18.4 [12.1;26.3]95% | 12.6 [5.7;23.0]95% | 20.0 [6.3;41.4]95% | 9.4 [2.3;23.5]95% | 2.3 [0.07;11.9]95% | ||
| Anti-cholinesterase | N (%) | 51 (45.1) | 27 (50.0) | 9 (47.4) | 4 (13.8) | 0 (0) | Lack of model convergence |
| Memantine | N (%) | 5 (4.4) | 13 (24.1) | 6 (31.6) | 0 (0) | 0 (0) | Lack of model convergence |
| Levodopa or Dopa agonist | N (%) | 46 (40.7) | 1 (1.9) | 6 (31.6) | 6 (20.7) | 1 (3.3) | DLB > DC (P = 0.0173); DLB > HC (P > 0.00001); DLB + AD > HC (P = 0.0016); DC > HC (P = 0.0112) |
| Estimated % yes | 40.6 [31.9; 49.8]95% | 1.3 [0.04;6.7]95% | 31.2 [13.4;53.6]95% | 19.9 [8.2;36.8]95% | 2.4 [0.1;1.8]95% | ||
| Benzodiazepine | N (%) | 34 (30.1) | 14 (25.9) | 6 (31.6) | 6 (20.7) | 2 (6.7) | DLB > HC (P = 0.0015); AD > HC (P = 0.0072); DLB + AD > HC (P = 0.0095); DC > HC (P = 0.0446) |
| Estimated % yes | 30.1 [21.9; 38.9]95% | 25.7 [15.4; 38.4]95% | 30.9 [13.1;52.8]95% | 20.0 [8.2;37.0]95% | 5.6 [0.9;37.0]95% | ||
| Hypnotics | N (%) | 17 (15.0) | 1 (1.9) | 1(5.3) | 2 (6.9) | 0 (0) | DLB > HC (P > 0.00001); DLB > AD (P > 0.0009); AD > HC (P = 0.0016); DLB + AD > HC (P = 0.0005); DC > HC (P = 0.0002) |
| Estimated % yes | 14.9 [9.1;22.2]95% | 1.2 [0.04;6.8]95% | 3.7 [0.1;17.6]95% | 6.0 [0.9;17.8]95% | 1.2 × 10–108 [3.0 × 10–213;2.4 × 10–6]95% | ||
| Melatonin | N (%) | 15 (13.3) | 0 (0) | 4 (21.0) | 1 (3.4) | 0 (0) | DLB > HC (P > 0.00001); DLB + AD > HC (P > 0.00001); DLB > DC (P = 0.031); DLB + AD > DC (P = 0.02); DC > HC (P = 0.0005) |
| Estimated % yes | 13.1 [7.6;20.1]95% | 2.0 × 10–79 [2.5 × 10–172;1.4 × 10–9]95% | 20.1 [6.3;41.3]95% | 2.5 [0.1;12.5]95% | 2.5 × 10–91 [3.8 × 10–183;1.5 × 10–12]95% | ||
| Lipid lowering | N (%) | 5 (4.4) | 3 (5.6) | 0 (0) | 2 (6.9) | 3 (10.0) | Lack of model convergence |
| Anti-diabetic | N (%) | 21 (18.6) | 3 (5.6) | 2 (10.5) | 3 (10.3) | 5 (3.3) | DLB > AD (P = 0.006); DLB > HC (P = 0.0053) |
| Estimated % yes | 18.4 [12.1;26.3]95% | 5.0 [1.2;12.8]95% | 9.2 [1.4;27.3]95% | 9.2 [2.3;23.6]95% | 2.4 [0.1;12.0]95% | ||
| Anticoagulant or anti-antiplatelet | N (%) | 13 (11.5) | 7 (13.0) | 0 (0) | 1 (3.4) | 2 (6.7) | DLB > DLB + AD (P > 0.00001); AD > DLB + AD (P > 0.00001) |
| Estimated % yes | 11.3 [6.3;18.0]95% | 12.5 [5.5;23.0]95% | 8.9 × 10–55 [9.7 × 10–154;5.1 × 10–3]95% | 2.4 [0.1;12.0]95% | 5.7 [0.8;18.2]95% | ||
| Analgesic | N (%) | 5 (4.4) | 0 (0) | 1 (5.3) | 1 (3.5) | 0 (0) | Lack of model convergence |
| Vitamins, dietary supplements | N (%) | 11 (9.7) | 5 (9.3) | 1 (5.3) | 2 (6.9) | 6 (20.0) | No difference |
AD Alzheimer’s diseaseDC, diseased controls; DLB dementia with Lewy bodies; HC, healthy controls
The proportion of patients with a CSF analysis was 72.2% (71.8% for the DLB group, 71.9% for the AD group, 84.2% for the DLB + AD group, and 66.7% for the DC group). CSF Abeta42 was higher in the DLB group (822.7 ± 291.9 ng/L) than in the AD group (582.5 ± 201.6 ng/L) and the DLB + AD group (598.8 ± 241.0 ng/L), and CSF ABeta42 was higher in the DC group (1115.5 ± 275.8 ng/L) than in the other groups (P < 0.001). P-Tau and Tau in the CSF were higher in the AD and DLB + AD groups than in the DLB and DC groups (P < 0.001).
All the patients and controls had a brain MRI (Table 4). Right hippocampal atrophy was higher in the DLB + AD group than in the HC and DC groups (P < 0.001). Left hippocampal atrophy was higher in the DLB + AD, AD, and DLB groups than in the HC group (P < 0.001). There was no difference in terms of white matter hyperintensities between groups, but more basal ganglia hyperintensities during the first brain MRI in AD and DLB + AD groups, than in the HC group (P = 0.019).
Table 4.
Brain MRI evolution for atrophy and ischemic microvascular lesions on 8 years of the five groups: prodromal and mild dementia with Lewy bodies patients (DLB group), prodromal and mild dementia Alzheimer’s disease patients (AD group), prodromal and mild dementia with Lewy bodies and Alzheimer’s disease patients (DLB + AD group), prodromal and mild dementia diseased controls (DC), and healthy controls (HC)
| N | DLB N = 110 | AD N = 57 | DLB + AD N = 19 | DC N = 30 | HC N = 31 | Statistic test, P | Post hocf | ||
|---|---|---|---|---|---|---|---|---|---|
| Hippocampus (/4), 1 st visita, b | 184 | Right | 1.3 (1.2) | 1.4 (0.9) | 2.0 (1.0) | 0.9 (0.7) | 0.7 (0.7) | H = 17.496, P = 0.002 | DLB + AD > HC, DC |
| Left | 1.3 (1.2) | 1.5 (1.1) | 1.9 (1.1) | 1.0 (0.9) | 0.5 (0.7) | H = 20.368, P < 0.001* | DLB + AD, AD, DLB > HC | ||
| Hippocampus, 2 yearsa, b | 55 | Right | 1.9 (1.2) | 2.5 (0.8) | 3.3 (0.6) | 1.2 (1.3) | None | H = 9.643, P =,047* | None |
| Left | 2.0 (1.1) | 2.6 (0.8) | 3.0 (1.0) | 1.1 (1.3) | None | H = 9.604, P =,048* | None | ||
| Hippocampus, 4 yearsa, b | 49 | Right | 1.4 (1.0) | 2.6 (0.8) | 1.5 (0.7) | 1.2 (1.1) | 0.7 (0.8) | H = 12.122, P.016* | AD > HC |
| Left | 1.6 (1.3) | 2.6 (1.1) | 2.0 (0.0) | 0.8 (0.4) | 0.2 (0.4) | H = 15.957, P = 0.003* | AD, DLB > HC | ||
| Hippocampus, 6 yearsa, b | 49 | Right | 0.8 (1.1) | 3.0 (1.2) | 2.0 (2.8) | 1.2 (1.8) | 0.7 (0.9) | H = 8.523, P = 0.074 | |
| Left | 1.0 (1.2) | 3.3 (1.0) | 2.0 (2.8) | 0.8 (1.8) | 0.7 (0.8) | H = 9.214, P = 0.056 | |||
| Hippocampus, 8 yearsa, b | 50 | Right | 1.2 (1.0) | 1.5 (0.7) | 2.0 | 0.3 (0.5) | 0.6 (0.7) | H = 7.640, P = 0.106 | |
| Left | 1.2 (1.2) | 2 (0.0) | 2.0 | 0.0 (0.0) | 0.5 (0.7) | H = 12.261, P = 0.016* | None | ||
| Parietal (/3), 1 st visita, c | 179 | Right | 1.1 (0.9) | 1.3 (0.9) | 1.6 (0.7) | 1.1 (1.1) | 0.9 (0.9) | H = 6.509, P = 0.164 | |
| Left | 1.2 (0.9) | 1.3 (0.9) | 1.6 (0.7) | 1.1 (1.1) | 1.0 (0.9) | H = 4.860, P = 0.302 | |||
| Parietal, 2 yearsa, c | 55 | Right | 1.6 (0.8) | 1.8 (1.0) | 1.3 (0.6) | 1.2 (0.8) | None | H = 2.780, P = 0.595 | |
| Left | 1.6 (0.8) | 1.8 (0.9) | 1.7 (0.6) | 1.3 (0.9) | None | H = 2.365, P = 0.669 | |||
| Parietal, 4 yearsa, c | 50 | Right | 1.3 (0.9) | 2.0 (1.0) | 2.5 (0.7) | 0.8 (0.8) | 0.7 (1.0) | H = 10.223, P = 0.037* | None |
| Left | 1.4 (1.0) | 2.3 (1.1) | 2.0 (0.0) | 0.8 (0.8) | 0.9 (0.9) | H = 9.293, P = 0.054 | |||
| Parietal, 6 yearsa, c | 49 | Right | 1.1 (0.9) | 1.7 (1.5) | 1.5 (0.7) | 0.8 (0.8) | 1.2 (1.0) | H = 2.018, P = 0.732 | |
| Left | 1.1 (0.9) | 1.7 (1.5) | 1.5 (0.7) | 1.0 (0.7) | 1.2 (1.0) | H = 1.278, P = 0.865 | |||
| Parietal, 8 yearsa, c | 48 | Right | 1.3 (0.8) | 2.0 (0.0) | 3.0 | 0.5 (0.5) | 0.4 (0.6) | H = 18.401, P = 0.001* | DLB > HC |
| Left | 1.3 (0.8) | 2.5 (0.7) | 3.0 | 0.7 (0.5) | 0.5 (0.7) | H = 17.688, P = 0.001* | AD, DLB > HC | ||
| Frontal (/4), 1 st visita, d | 118 | Right | 1.4 (0.9) | 1.5 (0.9) | 1.6 (0.7) | 1.0 (0.6) | 0.9 (0.7) | H = 8.818 P = 0.066 | |
| Left | 1.4 (0.9) | 1.6 (1.0) | 1.5 (0.7) | 1.2 (0.6) | 0.9 (0.7) | H = 6.671, P = 0.154 | |||
| Frontal, 2 yearsa, d | 52 | Right | 1.8 (0.8) | 2.3 (0.8) | 2.0 (1.0) | 1.3 (1.2) | None | H = 4.762 P = 0.313 | |
| Left | 1.9 (0.8) | 2.3 (0.8) | 2.3 (0.6) | 1.3 (1.2) | None | H = 5.081, P = 0.279 | |||
| Frontal, 4 yearsa, d | 49 | Right | 1.7 (0.9) | 2.4 (0.8) | 2.0 (1.4) | 1.8 (0.8) | 0.7 (1.0) | H = 10.736 P = 0.030* | AD > HC |
| Left | 1.9 (0.8) | 2.4 (0.8) | 2.0 (1.4) | 2.0 (0.7) | 0.7 (1.0) | H = 11.178, P = 0.025* | AD > HC | ||
| Frontal, 6 yearsa, d | 49 | Right | 1.1 (1.0) | 2.0 (0.0) | 2.0 (0.0) | 0.6 (0.9) | 0.9 (0.8) | H = 7.267 P = 0.122 | |
| Left | 1.2 (1.0) | 2.0 (0.0) | 2.0 (0.0) | 0.4 (0.9) | 0.9 (0.8) | H = 8.745, P = 0.068 | |||
| Frontal, 8 yearsa, d | 50 | Right | 0.8 (0.8) | 2.5 (0.7) | 3.0 | 1.3 (1.5) | 0.4 (0.5) | H = 12.182 P = 0.016* | None |
| Left | 1.0 (0.8) | 3.0 (1.4) | 3.0 | 1.5 (1.5) | 0.4 (0.6) | H = 12.828, P = 0.012* | None | ||
| WMH (/3), 1 st visita, e | 172 | 0.8 (0.9) | 0.9 (1.0) | 1.4 (0.9) | 0.7 (0.6) | 0.8 (0.6) | H = 6.203 P = 0.184 | ||
| WMH, 2 yearsa, e | 52 | 1.6 (1.1) | 1.7 (1.1) | 1.3 (0.6) | 1.0 (0.7) | None | H = 3.054 P = 0.549 | ||
| WMH, 4 yearsa, e | 49 | 1.3 (1.0) | 0.7 (0.8) | 0.5 (0.7) | 1.0 (1.2) | 1.0 (0.6) | H = 3.062 P = 0.547 | ||
| WMH, 6 yearsa, e | 51 | 0.9 (0.8) | 0.5 (0.6) | 0.5 (0.7) | 0.8 (0.5) | 0.9 (0.6) | H = 1.868 P = 0.760 | ||
| WMH, 8 yearsa, e | 48 | 0.9 (0.8) | 1.0 (1.4) | 0.0 | 1.4 (1.1) | 0.9 (0.9) | H = 2.622 P = 0.623 | ||
| BGH (/3), 1 st visita, e | 165 | 0.4 (0.7) | 0.5 (0.9) | 0.6 (0.8) | 0.3 (0.5) | 0.0 (0.0) | H = 11.749 P = 0.019* | AD and DLB + AD > HC | |
| BGH, 2 yearsa, e | 51 | 0.9 (1.0) | 0.8 (1.1) | 0.3 (0.6) | 0.4 (0.5) | None | H = 3.463 P = 0.484 | ||
| BGH, 4 yearsa, e | 46 | 0.6 (0.9) | 0.3 (0.5) | 0.5 (0.7) | 0.3 (0.5) | 0.4 (0.8) | H = 0.599 P = 0.963 | ||
| BGH, 6 yearsa, e | 48 | 0.5 (0.8) | 0.3 (0.5) | 0.0 (0.0) | 0.8 (0.5) | 0.6 (0.8) | H = 3.478 P = 0.481 | ||
| BGH, 8 yearsa, e | 48 | 0.7 (0.8) | 0.5 (0.7) | 0.0 | 0.4 (0.5) | 0.7 (0.9) | H = 1.283 P = 0.864 |
aMean (standard deviation). bHippocampal atrophy scale according to Scheltens et al., JNNP, 1992. cParietal atrophy scale according to Koedam et al., European Radiology, 2011. dFrontal atrophy scale according to Kipps et al., DGCD, 2007. eHyperintensities according to Wahlund et al., Stroke, 2001. fKruskal-Wallis post-hoc test on SPSS (H), with Bonferroni correction
AD Alzheimer’s disease, BGH basal ganglia hyperintensities, DC diseased controls, DLB dementia with Lewy bodies, HC healthy controls, WMH white matter hyperintensities
The number of prodromal DLB was of 77, prodromal AD of 29, prodromal DLB + AD of 5. FP-CIT SPECT (DAT-scan) has been done to 45 prodromal and mild DLB patients: we found dopamine transporter loss in 31 patients.
Changes over time
The mean follow-up of the participants was 4.8 years (SD ± 2.1). During the follow-up, 22 died and seven went to a nursing home. Among the 12 DLB deaths (10.9% of the DLB group), five patients had a prodromal form and seven had dementia; mean time to death was 36.8 months (SD ± 15.0). Among the seven AD deaths (12.3% of the AD group), two patients had a prodromal form and five had dementia; mean time to death was 30.4 months (SD ± 12.3). There were two DLB + AD deaths (10.5% of the DLB + AD group); both patients had dementia; mean time to death was 35.5 months. The patient in the DC group who died had prodromal cortico-basal degeneration, and death occurred 55 months after the first visit. Among the seven patients that went to a nursing home, three had DLB (at the first visit, two were demented and one was prodromal; mean time to nursing home, 55.3 months), two had AD (1 was prodromal and 1 had dementia; mean time to nursing home, 30 months) and two had DLB + AD (both had dementia; mean time to nursing home, 27 months).
Figure 1 shows the estimated evolution of the MMSE scores of the five groups over time. The AD (−0.4788, P < 0.0001), DLB + AD (−0.5411, P < 0.0001), DLB (−0.1036, P < 0.0001) and DC (−0.0848, P < 0.0219) groups had a significant decrease in MMSE score over time. The HC group had no significant decrease (+ 0.0272, P = 0.2831).
Fig. 1.
Estimated outcome of global cognition (MMSE score) in the five groups: prodromal and mild dementia with Lewy bodies (DLB group), prodromal and mild Alzheimer’s disease (AD group), prodromal and mild dementia with Lewy bodies and Alzheimer’s disease (DLB+AD group), diseased controls (DC group) and healthy controls (HC group)
Using beta regression, the slope of MMSE decline of the DLB group was lower than that of the AD group (−0.3753, P < 0.0001) and that of the DLB + AD group (−0.4376, P < 0.0001). The slope of MMSE decline of the DC group was lower than that of the AD group (−0.5059, P < 0.0001) and that of the DLB + AD group (−0.5684, P < 0.0001). There was no difference in terms of the slope of MMSE decline between the DLB and DC groups (0.1308, P = 0.8000) or between the AD and DLB + AD groups (0.0618, P = 0.2000).
Assuming a linear temporal evolution of MMSE, the rate of cognitive decline was 2.92 points per year for the DLB + AD group, 2.78 points per year for the AD group, 0.49 points per year for the DLB group, and 0.29 points per year for the DC group; in contrast, the HC group showed an increase of 0.03 points per year.
The variability of annual variations in MMSE was greater in the DLB group (standard deviation of differences in each year from the previous one of 2.13 points) than in the AD (1.73 points), DLB + AD (1.45 points), DC (1.99), and HC (0.97) groups. The brain MRI evolution could not be reliably measured because the number of patients between the first and second visit at 2 years who underwent MRI evaluation decreased dramatically from 184 to 55 (Table 4).
Discussion
We report here a very low cognitive decline in prodromal to mild DLB patients, while prodromal to mild AD and DLB + AD patients differed significantly, with a greater cognitive decline. There was also greater year-to-year variability in MMSE scores in prodromal to mild DLB patients than in the other patients, including AD patients.
A meta-analysis of six studies (N = 841 patients) including 589 AD, 252 DLB, and 65 dual disease (DLB + AD) with dementia, showed that the annual decline of the MMSE was of 3.3 (SD 1.7, range 1.8 to 4.9 points) for DLB, of 3.4 (SD 1.4, range 1.8 to 5.8 points) for AD, and of 5.0 points for DLB + AD (only one study among the six) [4, 18]. The average follow-up for each of the 6 studies in this meta-analysis was 1 to 4 years. In the present study with a mean follow-up of 4.8 years and with prodromal and mild dementia patients, we found that the annual decline of the MMSE was slower for all groups: −2.78 points for AD, −2.92 points for DLB + AD, but above all for the DLB group with −0.49 point of MMSE a year.
In the context of MCI, a prospective study in Amsterdam of 73 DLB and 124 AD patients with a mean follow-up of 3.0 years found also that prodromal AD patients declined faster than prodromal DLB patients in terms of MMSE score [6]. Interestingly, several studies had shown that at the stage of dementia, the association of DLB with AD or with biomarkers of AD led to a worsening of cognitive decline [4, 19, 20]. Our study confirms this, but this time at an earlier stage. This suggests that the addition of amyloidopathy and/or tauopathy, in addition to prior synucleopathy, accelerates the neurodegenerative process [21].
With our study, we confirm the very low cognitive decline in the early stages of DLB. Thus, there may be two phases in DLB, an early phase at prodromal to mild stages where the cognitive decline is slight for at least 8 years, and then a second phase where the cognitive decline is more severe, mirroring that of AD (Fig. 2) [5]. A two-phase course of DLB disease could therefore consist of a first, more functional phase with very little neuronal destruction, and a second, more neurodegenerative phase. This more neurofunctional phase of DLB was recently confirmed in a cohort of prodromal patients, where we demonstrated less cognitive, functional, brain volume, and metabolism decrease in the prodromal DLB group [22]. For the first phase more neurofunctional, the very mild cerebral atrophy, affecting in particular the anterosuperior part of the insula, is clearly different from AD, where there is already considerable atrophy in the temporal—including the hippocampi—and parietal lobes [23, 24]. During this initial phase, there are also marked changes in functional MRI of DLB patients, especially in the salience and attention networks [25]. During the second phase more neurodegenerative, the brain atrophy is diffuse, as in AD [23, 24], probably partly due to amyloid involvement [26].We hypothesized that year-to-year MMSE variability was greater in DLB than in AD, reflecting cognitive fluctuations. This hypothesis was confirmed. For clinician specialists, this has important implications: (1) they must consider the cognitive evolution over several years, not just from one year to another; (2) they must keep in mind the hypothesis of fluctuations when the MMSE varies.
Fig. 2.
Hypothetical figure showing the evolution of global cognition (Mini Mental Status Examination -MMSE- score) in dementia with Lewy bodies for 20 years, from the data of this paper (in blue) and our previous paper in demented patients (in red) [4]
The outcome of patients with DLB in the late stages is known to have a greater impact on survival than is the case with AD [27], particularly when patients have autonomic dysfunction such as constipation or orthostatic hypotension [28]. We showed that in the early stages there was no difference in terms of death or institutionalization in a nursing home between DLB, AD, and DLB + AD.
Interestingly, the DLB group had many psychotropic treatments at the inclusion in the study (Table 3), and this does not seem to have had any harmful effects on evolution, and may even have had a positive effect, but only if they are used wisely [29]. Similarly, despite extensive medical history and risk factors that are common in the DLB group (Table 2), despite more medical events (infections, surgery of invasive procedure, falls, hospitalization) in the DLB group than in the AD group during the follow-up, DLB patients declined significantly less than patients in the AD or DLB + AD group.
Our study has some limitations. Firstly, we did not have any autopsy verification of the patients. Thus, we cannot exclude the possibility that an incorrect classification of patients may have confounded the results. However, we used McKeith’s criteria, which have excellent specificity for dementia (more than 95%) [30, 31] when compared to the gold standard neuropathological diagnosis. Moreover, the use of an autopsy series may, due to survival bias, overestimate the rate of decline, as slower progressing cases are less likely to have come to autopsy [32]. In addition, 72.2% of patients had a CSF analysis, which allowed us to classify these patients more accurately during their lifetime. There were insufficient follow-up brain MRIs to show any differences. Finally, Fig. 2 is questionable because it combines results from two different cohorts. Nevertheless, it provides a schematic representation of the hypothetical 20-year evolution of DLB.
In conclusion, this study found that, patients in the early stages of DLB declined very little in terms of global cognition whereas patients with early AD and DLB + AD declined more markedly, despite the presence of more frequent medical events during follow-up, despite the presence of more risk factors, and despite more frequent use of psychotropic drugs in the DLB group. The proportion of patients going to a nursing home or dying was not different between the groups. There may be two phases in DLB: a first phase with little cognitive decline in the first 8 years and a second phase with a slope of decline identical to that of AD. The next step will be to analyse the evolution of cognitive functions in a more focused manner (attention, memory, executive functions) and to analyse the evolution of the functional level.
Acknowledgements
We warmly thank all the patients and their relatives for participating in this study. We also thank Nick Barton for language editing.
Abbreviations
- AD
Alzheimer’s disease
- DLB
Dementia with Lewy bodies
- MMSE
Mini-Mental State Examination
Author contributions
Frédéric Blanc: writing original draft, conceptualization, investigation, methodology, formal analysis; Benjamin Cretin: investigation, methodology; Candice Muller: investigation, methodology; Anne Botzung: investigation, project administration; Léa Sanna: investigation, project administration; Olivier Bousiges: investigation, methodology; Alix Ravier: investigation; Benoît Schorr: investigation; Pierre Anthony: investigation; Nathalie Philippi: investigation, methodology; Catherine Demuynck: investigation, methodology; Erik Sauleau: methodology, software, formal analysis.
Funding
This study was funded by Appel à Projet Interne (API) of the University Hospital of Strasbourg, France Alzheimer, Fondation Université de Strasbourg, and Projet Hospitalier de Recherche Clinique (PHRC) inter-régional (IDRCB 2012-A00992-41).
Data availability
The datasets generated and analyzed during the present study are not publicly available, owing to ethics considerations and privacy restriction. Data may be made available from the corresponding author.
Declarations
Competing interests
F.B. was the national coordinator for France for the Eisai Delphia (E2027), Axovant Headway-DLB and Roche Graduate therapeutic trials; he had received honoraria from Roche, Eisai and Biogen for oral presentations and from Eisai and Novo Nordisk for a board. The other authors declare that they have no competing interests related to the present work.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. Neurology. 2017;89(1):88–100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.McKeith IG, Ferman TJ, Thomas AJ, Blanc F, Boeve BF, Fujishiro H, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94(17):743–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Breitve MH, Chwiszczuk LJ, Hynninen MJ, Rongve A, Brønnick K, Janvin C, Aarsland D. A systematic review of cognitive decline in dementia with Lewy bodies versus Alzheimer's disease. Alzheimers Res Ther. 2014;6(5–8):53. 10.1186/s13195-014-0053-6. [DOI] [PMC free article] [PubMed]
- 4.Blanc F, Mahmoudi R, Jonveaux T, Galmiche J, Chopard G, Cretin B, et al. Long-term cognitive outcome of Alzheimer’s disease and dementia with Lewy bodies: dual disease is worse. Alzheimers Res Ther. 2017;9(1):47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Kramberger MG, Auestad B, Garcia-Ptacek S, Abdelnour C, Olmo JG, Walker Z, et al. Long-term cognitive decline in dementia with Lewy bodies in a large multicenter, international cohort. J Alzheimers Dis. 2017;57(3):787–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.van de Beek M, van Steenoven I, van der Zande JJ, Barkhof F, Teunissen CE, van der Flier WM, et al. Prodromal dementia with Lewy bodies: clinical characterization and predictors of progression. Mov Disord. 2020;35(5):859–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Hamilton CA, Matthews FE, Donaghy PC, Taylor JP, O’Brien JT, Barnett N, et al. Cognitive decline in mild cognitive impairment with Lewy bodies or Alzheimer disease: a prospective cohort study. Am J Geriatr Psychiatry. 2021;29(3):272–84. [DOI] [PubMed] [Google Scholar]
- 8.Blanc F, Bouteloup V, Paquet C, Chupin M, Pasquier F, Gabelle A, Ceccaldi M, de Sousa PL, Krolak-Salmon P, David R, Fischer C, Dartigues JF, Wallon D, Moreaud O, Sauvée M, Belin C, Roubaud C, Botzung A, Ravier A, DemuynckC, Namer I, Habert MO, Bousiges O, Schorr B, Muller C, Philippi N, Chêne G, Cretin B, Mangin JF, Dufouil C. Cognitive and neuroimaging outcome of very prodromal dementia with Lewy bodies. Geroscience. 2025. 10.1007/s11357-025-01701-x. [DOI] [PMC free article] [PubMed]
- 9.Hamilton CA, Matthews FE, Donaghy PC, Taylor JP, O’Brien JT, Barnett N, et al. Progression to dementia in mild cognitive impairment with Lewy bodies or Alzheimer disease. Neurology. 2021;96(22):e2685–2693. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Bousiges O, Philippi N, Lavaux T, Perret-Liaudet A, Lachmann I, Schaeffer-Agalede C, et al. Differential diagnostic value of total alpha-synuclein assay in the cerebrospinal fluid between Alzheimer’s disease and dementia with Lewy bodies from the prodromal stage. Alzheimers Res Ther. 2020;12(1):120. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Ferman T, Smith G, Boeve B, Ivnik R, Petersen R, Knopman D, et al. DLB fluctuations specific features that reliably differentiate DLB from AD and normal aging. Neurology. 2004;62(2):181–7. [DOI] [PubMed] [Google Scholar]
- 12.Fenelon G, Soulas T, Zenasni F. Cleret de Langavant L: The changing face of Parkinson’s disease-associated psychosis: a cross-sectional study based on the new NINDS-NIMH criteria. Mov Disord. 2010;25(6):763–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Gjerstad MD, Boeve B, Wentzel-Larsen T, Aarsland D, Larsen JP. Occurrence and clinical correlates of REM sleep behaviour disorder in patients with Parkinson’s disease over time. J Neurol Neurosurg Psychiatry. 2008;79(4):387–91. [DOI] [PubMed] [Google Scholar]
- 14.Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8):734–46. [DOI] [PubMed] [Google Scholar]
- 15.Smithson M, Verkuilen J. A better lemon squeezer? Maximum-likelihood regression with beta-distributed dependent variables. Psychol Methods. 2006;11(1):54. [DOI] [PubMed] [Google Scholar]
- 16.McCaffrey DF, Griffin BA, Almirall D, Slaughter ME, Ramchand R, Burgette LF. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med. 2013;32(19):3388–414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.R: A language and environment for statistical computing [ https://www.R-project.org/.]
- 18.Breitve MH, Chwiszczuk LJ, Hynninen MJ, Rongve A, Brønnick K, Janvin C, et al. A systematic review of cognitive decline in dementia with Lewy bodies versus Alzheimer’s disease. Alzheimers Res Ther. 2014;6(5):1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Abdelnour C, van Steenoven I, Londos E, Blanc F, Auestad B, Kramberger MG, et al. Alzheimer’s disease cerebrospinal fluid biomarkers predict cognitive decline in Lewy body dementia. Mov Disord. 2016;31(8):1203–8. [DOI] [PubMed] [Google Scholar]
- 20.Gonzalez MC, Ashton NJ, Gomes BF, Tovar-Rios DA, Blanc F, Karikari TK, et al. Association of plasma p-tau181 and p-tau231 concentrations with cognitive decline in patients with probable dementia with Lewy bodies. JAMA Neurol. 2022;79:32–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Nelson PT, Kryscio RJ, Jicha GA, Abner EL, Schmitt FA, Xu LO, et al. Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies. Neurology. 2009;73(14):1127–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Blanc F, Bouteloup V, Paquet C, Chupin M, Pasquier F, Gabelle A, Ceccaldi M, de Sousa PL, Krolak-Salmon P, David R et al: Cognitive and neuroimaging outcome of very prodromal dementia with Lewy bodies. Geroscience 2025. [DOI] [PMC free article] [PubMed]
- 23.Blanc F, Colloby SJ, Philippi N, de Pétigny X, Jung B, Demuynck C, et al. Cortical thickness in dementia with Lewy bodies and Alzheimer’s disease: a comparison of prodromal and dementia stages. PLoS ONE. 2015;10(6):e0127396. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Roquet D, Noblet V, Anthony P, Philippi N, Demuynck C, Cretin B, et al. Loureiro de Sousa P, Blanc F: Insular atrophy at the prodromal stage of dementia with Lewy bodies: a VBM DARTEL study. Sci Rep. 2017;7(1):9437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Chabran E, Noblet V. Loureiro de Sousa P, Demuynck C, Philippi N, Mutter C, Anthony P, Martin-Hunyadi C, Cretin B, Blanc F: Changes in gray matter volume and functional connectivity in dementia with Lewy bodies compared to Alzheimer’s disease and normal aging: implications for fluctuations. Alzheimers Res Ther. 2020;12(1):9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Gabriel V, Bousiges O, Mondino M, Cretin B, Philippi N, Muller C, et al. Abeta42 biomarker linked to insula, striatum, thalamus and claustrum in dementia with Lewy bodies. Geroscience. 2025;47(3):4009–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Oesterhus R, Soennesyn H, Rongve A, Ballard C, Aarsland D, Vossius C. Long-term mortality in a cohort of home-dwelling elderly with mild Alzheimer’s disease and Lewy body dementia. Dement Geriatr Cogn Disord. 2014;38(3–4):161–9. [DOI] [PubMed] [Google Scholar]
- 28.Stubendorff K, Aarsland D, Minthon L, Londos E. The impact of autonomic dysfunction on survival in patients with dementia with Lewy bodies and Parkinson’s disease with dementia. PLoS ONE. 2012;7(10):e45451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Taylor JP, McKeith IG, Burn DJ, Boeve BF, Weintraub D, Bamford C, et al. New evidence on the management of Lewy body dementia. Lancet Neurol. 2020;19(2):157–69. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Nelson PT, Jicha GA, Kryscio RJ, Abner EL, Schmitt FA, Cooper G, et al. Low sensitivity in clinical diagnoses of dementia with Lewy bodies. J Neurol. 2010;257(3):359–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.McKeith IG, Ballard CG, Perry RH, Ince PG, O’Brien JT, Neill D: Prospective validation of consensus criteria for the diagnosis of dementia with Lewy bodies. Neurology 2000, 54. [DOI] [PubMed]
- 32.Olichney JM, Galasko D, Salmon D, Hofstetter C, Hansen L, Katzman R, et al. Cognitive decline is faster in Lewy body variant than in Alzheimer’s disease. Neurology. 1998;51(2):351–7. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated and analyzed during the present study are not publicly available, owing to ethics considerations and privacy restriction. Data may be made available from the corresponding author.