| Disease diagnosis: epidemiology, prevalence, demographics, survival rate |
Mouton et al. (216)
French National Alzheimer Database
A repeated, cross-sectional study |
DLB
AD
PD
PDD |
DLB:
N = 10,309 (80.11 ± 7.84)
M = 4,674\u00B0F = 5,635
AD:
N = 135,664 (81.42 ± 7.98)
M = 40,566\u00B0F = 95,098
PDD:
N = 3,198 (79.45 ± 8.09)
M = 1746\u00B0F = 1,452
PD:
N = 8,744 (73.86 ± 10.79)
M = 4,979\u00B0F = 3,765 |
Demographics and Clinical Assessments:
Variables such as gender, age, living conditions, education level, type of center, and location of patients were collected Cognition: MMSE Sex ratio and demographic data were compared using multinomial logistic regression and a Bayesian statistical model
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Sex ratios (female percent/male percent) were different across the four groups; DLB: 1.21 (54.7%/45.3%); AD: 2.34 (70.1%/29.9%); PD: 0.76 (43.1%/56.9%) and PDD: 0.83 (45.4%/54.6%) There were significant differences between each group (including DLB), but not between PDD and PD, which had a similar sex ratio
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Large sample size Diagnoses were made by clinical judgment and not according to anatomopathological results Data entry by different physicians
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Gan et al. (217)
Beijing, Tianjin, China
Retrospective, clinical study |
DLB
PDD |
DLB & PDD:
N = 455
M = 239 (age onset = 69.2 ± 8.1)
F = 216 (age onset = 68 ± 8.8) |
Clinical Assessments:
Cognitive fluctuations: The Mayo Fluctuations Composite Scale Visual hallucinations: NPI Delusions and depression from Parkinsonism: UPDRS III RBD: RBDSQ/ Video-PSG MRI/PET/DAT
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There were slightly more males than females with DLB (50.9%) and PDD (57.9%) Patients with DLB had a poorer performance compared to those with PDD on the MMSE (p = 0.001), the MoCA (p < 0.001), the CDR (p = 0.002) and the MTA (p = 0.002).
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Retrospective study design which could introduce recall bias Diagnoses of the patients were not subsequently validated by autopsy, which is the gold standard for a diagnosis Not all patients were diagnosed using the updated protocols – inconsistencies Gender differences were only focused on the prevalence not in other domains within PDD and DLB
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Savica et al. (218)
Minnesota, USA
Epidemiologic study |
DLB
PDD |
DLB:
N = 64
PDD:
N = 46 |
Diagnostic criteria included two steps: the definition of parkinsonism as a syndrome and the definition of the different types of parkinsonism within the syndrome Reliability and validity of diagnosis checks
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The incidence rate of DLB was 3.5 per 100,000 per person-years overall, and it increased steeply with age Patients with DLB were younger at onset of symptoms than patients with PDD and had more hallucinations and cognitive fluctuations Males had a higher incidence of DLB than females across the age spectrum. The pathology was consistent with the clinical diagnosis in 24 of 31 patients who underwent autopsy (77.4%)
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It is possible that some patients with mild symptoms might go unrecognized and hence undiagnosed Some of the clinical features (e.g., cognitive fluctuations) were not systematically recorded in medical records Cognitive status was not systematically studied in all patients with parkinsonism
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Price et al. (219)
Cambridge, United Kingdom
Retrospective study |
DLB
AD |
DLB:
N = 251 (age at diagnosis = 79.3 ± 7.6)
M = 122\u00B0F = 129
AD:
N = 222 (age at diagnosis = 80.2 ± 8.8)
M = 83\u00B0F = 139 |
Case identification: Searches of diagnosed DLB on electronic records across an 8-year period Demographics, clinical and temporal data extracted Other information: Medications, mortality
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Median survival was 3.72 years for DLB and 6.95 years for AD Controlling for age at diagnosis, comorbidity and antipsychotic prescribing, the model predicted median survival for DLB was 3.3 years for males and 4.0 years for females
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The retrospective nature of the study meant that accurate estimation of the timing of symptom onset was not possible, limiting the ability to report the duration of illness accurately The findings of this study do not reflect the total populations with these diagnoses–diagnosis in a secondary care setting may reflect greater symptom
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Boot et al. (220)
Rochester, USA
Retrospective study |
DLB
AD |
DLB:
N = 147 (age at diagnosis = 72.5 ± 7.3)
M = 113\u00B0F = 34
AD:
N = 236 (age at diagnosis = 74.9 ± 10.1)
M = 90\u00B0F = 146
Controls:
N = 294
M = 226\u00B0F = 68 |
Demographics and clinical history 19 Candidate risk factors (i.e., family history, depression, diabetes)
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Compared to controls, DLB patients were significantly more likely to have a history of anxiety, depression, a family history of PD, and carry APOE4 alleles but less likely to have had cancer Compared with AD patients, DLB patients were significantly younger and more likely to be male, have a history of depression, be more educated, and have a positive family history of PD.
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Relatively small sample size Some reports of missing data
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Abdelnour et al. (234)
European DLB (E-DLB) Consortium
A multicentre, international study |
DLB |
N = 107 (68 ± 8.7)
M = 77\u00B0F = 30 |
Clinical, neuroimaging and CSF assessments:
Assessments for parkinsonism, visual hallucinations, RBD and other clinical core features Atrophy: MRI Amyloid-b and tau neurofibrillary tangles were assessed through CSF levels of AB42 and phosphorylated tau (p-tau) using enzyme-linked immunosorbent assays (ELISAs)
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Hierarchical clustering identified 4 clusters: (1) Cluster 1 was characterized by amyloid-b and cerebrovascular pathologies, medial temporal atrophy, and cognitive fluctuations; (2) Cluster 2 had posterior atrophy and showed lowest frequency of visual hallucinations and cognitive fluctuations and the worst cognitive performance; (3) Cluster 3 had the highest frequency of tau pathology, showed posterior atrophy, and had a lower frequency of parkinsonism; (4) Cluster 4 displayed normal AD biomarkers, the least region brain atrophy and cerebrovascular pathology, and the highest MMSE scores Cluster 4 showed a slight predominance of females, while the whole cohort was mostly constituted by males
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Relatively small sample size
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Jones and O’Brian (221)
Newcastle, Cambridge, United Kingdom
Systematic review |
DLB |
Total of 31 studies included in this review |
Literature review of all relevant population and clinical studies conducted using PubMed
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Only eight prevalence studies included the sex of those with DLB Five of these studies reported disproportionately more females with the disease when controlling for the sex of DLB population (271–275) The three remaining studies reported disproportionately more males (276–278).
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Need more representative samples There is a need to increase the likelihood of accurate diagnosis on a case-to-case basis.
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| Genetics |
Gámez-Valero et al. (228)
Barcelona, Spain
Post-mortem, clinical cohort study |
DLB |
Post-mortem:
DLB = 50
PD = 43
Controls = 34
Clinical cohort:
DLB = 47 (75.8)
Controls = 131 (72.3) |
Post-mortem brain samples with clinical and neuropathological diagnoses were obtained from tissue bank GBA Mutation Screening: 11 DNA fragmentations and sequencing
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16 GBA mutation carriers were identified, 5 of which were brains with pure DLB The most common mutation, E326K, was strongly associated with pure DLB and PD with dementia 3. GBA mutations were overrepresented in males and associated with earlier DLB onset
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There is lack of consideration of other factors such as clinical characteristics and lifestyle factors
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Liu et al. (229)
Jilin, China
Meta-analysis |
DLB |
Total of 14 studies included in this review |
PubMed, Cochrane and EMBASE databases were used to retrieve related studies The odds ratios and 95% confidence interval were calculated to determine the association between GBA and DLB and between GBA and the clinical characteristics of DLB
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This meta-analysis confirmed that the GBA variant rate was significantly higher in DLB group than in the control group, as were the variant rates of L444P, N370S, and E326K, whereas the variant rate of T369M showed no significant difference between the groups. The GBA variant group had a younger age of onset and lower MoCA score than the GBA non-variant group in DLB patients There were no significant sex differences in GBA variants between sexes
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Lack of consideration of other factors that might affect occurrence and severity of DLB such as education level, smoking history and living habits
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| Clinical Features: Non-motor Symptoms |
Utsumi et al. (13)
Hokkaido, Japan
Retrospective, clinical study |
Probable DLB |
N = 234 (age at diagnosis = 79 ± 7.5)
M = 101 (age at diagnosis = 78.6 ± 6.7)
F = 133 (age at diagnosis = 79.2 ± 8) |
Initial symptoms assessment by an interview with patients and caregivers in nine initial symptoms:
Cognitive impairment Visual hallucinations Parkinsonism RBD (e.g., frequent shouting) Depression Auditory hallucinations Delusions Disturbance of consciousness Syncope DLB-related symptoms at diagnosis, all the above (except cognitive impairment) and four symptoms:
Fluctuations in attention and arousal levels Orthostatic hypotension Constipation Hyposmia
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Initial symptoms findings:
A larger proportion of females than males initially present with psychiatric symptoms. For all assessed psychotic symptoms, females had higher rates than males, and there was a significantly higher rate of auditory hallucinations in females than in males RBD was significantly more frequent in male than female patients DLB-related symptoms at diagnosis:
There were significantly higher rates in males than females in the incidence of RBD There was also a significant difference between males and females in RBD, parkinsonism, hyposmia and syncope (higher rates in males) at diagnosis Females experienced significantly more auditory hallucinations than males
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No PSG was used to confirm RBD
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Chiu et al. (231)
Taiwan, China
Cross-sectional, longitudinal clinical study |
DLB |
N = 152
M = 87\u00B0F = 65 |
Demographics and Clinical Assessments:
Patients were interviewed by a trained neuropsychologist for the assessment of the NPI domain of hallucinations that included ratings on eight individual forms of hallucinations CDR Cognitive function: MMSE, CASI UPDRS Cumulative frequency, 1-month frequency and phenomenology of VHs were summarized and compared between females and males with DLB.
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Females had a higher frequency of visual hallucinations of nonfamily people, passed families and nonchildren families. After adjusting for age and dementia severity, factors associated with VHs among all patients with DLB were female gender, longer duration of psychiatric disorder, higher total NPI score, a higher caregiver burden score and higher rates of antipsychotics
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Comparison of the factors associated with VHs DLB in this study is cross-sectional. Hence, we cannot speculate on the causal relationship of factors with dementia Diagnostic criteria: lack of dopamine transporter uptake imaging until 2010, the revised consensus criteria were not available in the hospital for the first two years; therefore, a lower diagnostic rate for probable DLB may be observed
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Tsunoda et al. (230)
Kumamoto, Japan
Cross-sectional, retrospective study |
DLB |
N = 124 (78.3 ± 5.6)
M = 54\u00B0F = 70 |
Screening/Assessment:
Routine laboratory testing: Vitamin B1, Vitamin B12, thyroid function Cognitive function: MMSE NPI MRI/Computed tomography and single-photon emission computed tomography for cerebral perfusion Neuropsychiatric Symptoms:
Hearing impairment Semi-quantitative interview with primary caregivers using NPI: Auditory hallucinations, visual hallucinations
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35.5% of patients had AHs, and 60.5% had VHs 90.9% with AHs also had VHs 90% of patients hear the AHs in the form of a soundtrack of the scene The presence of AHs was significantly more likely to be associated with female patients and those with hearing impairments
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Internal psychiatric symptoms such as AHs cannot be directly studied because of patients’ incomplete recollection Selection bias because of clinical diagnostic criteria for DLB – makes the prevalence of DLB patients with pure AHs lower than it is Multiple comparison problem: Type I error
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Bayram et al. (233)
Data obtained from the NACC Neuropathology Data Set, Genetic Data, and Uniform Data Set (UDS)
Case-controlled retrospective study |
Pathological confirmed DLB |
N = 211
M = 156 (age at last visit = 75.9 ± 8.4)
F = 55 (age at last visit = 80 ± 8.7) |
Before death:
CDR-SOB NPI-Q UPDRS-III Clinician report of DLB core features (i.e., cognitive fluctuations, VHs) at any visit during data collection Autopsy:
LB pathology staging
Thal phase (amyloid-B plaque score) Braak tau stage (neurofibrillary tangle stage) CERAD (neuritic plaque score) Level of substantia nigra
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Females were more likely to die older, have fewer years of education, and had a higher tau burden Females were also less likely with dementia and clinical DLB Females reported lesser VHs than males
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This study used a relatively small sample size of participants with limbic or neocortical stage LB pathology without cognitive impairment No consideration of medications being taken for motor, behavioral, and cognitive symptoms Pathological assessments recorded did not focus on regional severity – need finer grain comparisons
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| Symptomology: non-motor symptoms; sleep |
Choudhury et al. (232)
Minnesota, USA
Longitudinal clinical study at the Mayo Clinic Alzheimer’s Disease Research Center (ADRC) |
DLB |
N = 488 (age at first visit = 73)
M = 370 (age at first visit = 72)
F = 118 (age at first visit = 75) |
Clinical assessments:
The clinician obtained information regarding each core feature’s presence or absence Recurrent episodes of dream enactment behavior during sleep with movements that appeared to match dream content Parkinsonism neurological examination:
Parkinsonism severity: UPDRS 4-item Mayo Fluctuation Scale for cognition GLDS Cognition: MMSE and DRS Neuropathological examination |
RBD is more apparent at a younger age in males than in females Males were more likely to develop RBD before the onset of cognitive symptoms, while females were more likely to develop RBD and cognitive symptoms within the same time frame Females met clinical criteria for probable DLB at an older age and after a longer latency from cognitive onset Only half of the females in this study reported a history of RBD, compared to 84% of the males At initial visit, females were older and more cognitively impaired than males Females were also more likely to have visual hallucinations than males. In males, the clinical cohort and autopsy subset showed that visual hallucinations were more likely to emerge after the other core features in men, while females did not demonstrate this time lag
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This study was carried out in a tertiary care setting with referral patterns that may limit generalizability to other settings This study did not include biomarkers, clinical symptoms
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| Mechanisms: inflammatory responses, brain structures etc. |
Van de Beek et al. (236)
Amsterdam, Netherlands; Amsterdam Dementia Cohort
Retrospective, clinical study |
DLB |
N = 223
M = 184 (67.7 ± 7.3)
F = 39 (70.1 ± 6) |
Clinical and cognitive features:
Hallucinations: NPI Neurological examination: i.e., tremor/bradykinesia and/or rigidity Semi-structured patient history interview RBD Depression: GDS MMSE Memory: Verbal learning test (RAVLT) Attention and speed: TMT-A, TMT-B Apolipoprotein E genotyping
QIAamp DNA blood isolation kit
CSF Analysis |
Females had lower CSF alpha-synuclein and CSF AB42 levels compared with male Females were significantly older, had a shorter duration of complaints, more frequent hallucinations and scored lower on MMSE and fluency task No significant differences were found for fluctuations, RBD, parkinsonism, other cognitive tests, or tau concentrations
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Well-defined, large sample of DLB patients with a clinical diagnosis of DLB supported by DAT Retrospective design – not all features reported for all patients CSF total alpha-synuclein is not yet validated as a clinically useful marker in DLB – there may be differences in sensitivity between different alpha-synuclein species A small number of patients had normal DAT imaging, which is not supportive of DLB diagnosis, but clinical diagnosis made in tertiary centers
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Ferreira et al. (227)
Multicentre cohort (Combination of E-DLB and the Mayo Clinic DLB Cohort)
Prospective study |
DLB |
N = 417
M = 287 (70.2 ± 8.6)
F = 129 (72.5 ± 8.2) |
Demographics and clinical assessments:
Medical history review, informant interview, neurological examination, and neuropsychological assessment (i.e., MMSE)
B-amyloid and tau biomarkers:
B-Amyloids (A+) and tau NFT (T+) were measured with CSF biomarkers and PET imaging Patients were stratified into 4 groups: A-T-, A + T-, A-T+, and A + T+
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The percentage of A-T-decreased with age, and A+ and T+ increased with age in both males and females A+ increased more in APOE e4 carriers with age than in noncarriers A+ was the main predictor of lower cognitive performance when considered together with T+ T+ was associated with a lower frequency of parkinsonism and probable RBD A + T+ was more common in females than males compared with the A − T− and A − T+ groups.
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Multicentre study added the value of increased statistical power and ability to generalize the findings
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Bayram et al. (226)
NACC Uniform Data Set (UDS)
Retrospective study |
DLB |
N = 691
M = 468 (Age at last visit = 76.4 ± 8.9)
F = 223 (Age at last visit = 79.9 ± 10) |
Clinical and neuropathological assessments:
Males and females were divided into two groups based on the staging of LB and AD pathologies CDR-Dementia Staging Instrument-Sum of Boxes Thal phase (amyloid-B plaque score), Braak tau stage (neurofibrillary tangle stage) and Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) score (neuritic plaque score)
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Females with more severe AD copathology and tau had worse cognitive decline and higher likelihood of AD clinical phenotype than males Males with more severe AD copathology had lower likelihood of LB clinical phenotype than females Interaction of sex and pathology was more prominent in those aged between 70 and 80 years
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Analyzes included only clinician reports of LB core clinical features, because of significant amounts of missing data for other features that may help with clinical identification of LB disease Clinical diagnosis and cognitive status of NACC were determined by a single clinician, a group of clinicians or an ad hoc consensus group which may include a combination of detailed examination
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Sarro et al. (237)
NACC; Rochester, USA
Retrospective study |
DLB
AD Dementia |
DLB:
N = 81 (Age at MRI = 72 ± 8)
M = 67\u00B0F = 14
AD Dementia:
N = 240 (Age at MRI = 75 ± 10)
M = 135\u00B0F = 105 |
Clinical and neuropathological assessments:
MMSE, DRS, CDR-Sum of Boxes, UPDRS-III, Mayo Fluctuations Questionnaire Neuropathology assessment: Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) MRI |
DLB patients had a higher white matter hyperintensities (WMHs) volume compared to controls, and WMH volume was higher in the occipital and posterior periventricular regions in DLB compared to AD Female sex and older age were associated with higher WMH volumes in both DLB and AD dementia groups
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Relatively smaller sample size There is lack of consideration of other clinical characteristics and lifestyle factors
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Wennström et al. (238)
Malmö, Sweden
Retrospective study |
DLB
AD |
DLB:
N = 18 (74 ± 7)
AD:
N = 26 (73 ± 6)
Non-demented controls:
N = 24 (72 ± 8) |
Clinical assessments and CSF profile:
Demographics and neuropsychological assessments (i.e., MMSE) a1-antichymotrypsin (ACT) concentrations in CSF and the basic CSF AD-biomarker profile (AB1-42, T-Tau, P-Tau181) CSF Orexin samples were determined using radioimmunoassay CSF alphasynuclein was determined using enzyme-linked immunosorbent assay (ELISA)
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There was a decrease in CSF orexin concentrations in DLB as compared to AD patients and controls. The observed differences in orexin levels were found to be specific to females with DLB patients Females with DLB also exclusively displayed lower levels of alphasynuclein compared to AD patients and controls Orexin was associated to alphasynuclein and total Tau in female non-demented controls whereas associations between orexin and AB1-42 concentrations were absent in all groups regardless of gender
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Very small sample size
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| Interventions: pharmacological |
Agbomi et al. (235)
South Carolina,
USA: PRISMA Health Registry
Retrospective study |
DLB
PDD |
DLB:
N = 608
M = 332 (75.93 ± 9.18)
F = 276 (81.74 ± 9.24)
PDD:
N = 7,594 |
From PRISMA Health registry:
Cognition: MMSE, MoCA, Saint Louise University Mental Status Examination History of alcohol, tobacco, and length of stay in the hospital Medication use: ChEIs, SGAs, or SSRIs
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ChEIs, including donepezil, galantamine, and rivastigmine, were associated with DLB SGAs such as risperidone were associated with females with DLB Olanzapine, escitalopram, and tobacco use were associated with males with DLB
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Data entry by different physicians – no external validation that standard criteria were met No differentiation was made for patients with early and late DLB PRISMA patients are not fully representative of the total DLB/PDD population No outcomes of tests mentioned, i.e., MMSE Retrospective study
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