Prodromal Dementia With Lewy Bodies Research Articles

Different effect of hypo- and hypermetabolism on cognition in dementia with Lewy bodies: are they coupled or independent?

Patients with dementia with Lewy bodies (DLB) show widespread brain metabolic changes. This study investigated whether brain hypo- and hypermetabolism in DLB have differential effects on cognition. We enrolled 55 patients with DLB (15 prodromal DLB [MCI-LB] and 40 probable DLB) and 13 healthy controls who underwent 18F-fluorodeoxyglucose positron emission tomography and detailed neuropsychological tests. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism were calculated as follows: index(-) for hypometabolism [DLB-hypo] and index(+) for hypermetabolism [DLB-hyper]. The effects of DLB-hypo or DLB-hyper on cognitive function were assessed using a multivariate linear regression model. Additionally, a linear mixed model was used to investigate the association between each index and the longitudinal cognitive decline. There was no correlation between DLB-hypo and DLB-hyper in the disease group. The multivariate linear regression model showed that DLB-hypo was associated with language, visuospatial, visual memory, and frontal/executive functions; whereas DLB-hyper was responsible for attention and verbal memory. There was significant interaction between DLB-hypo and DLB-hyper for verbal and visual memory, which was substantially affected by DLB-hyper in relatively preserved DLB-hypo status. A linear mixed model showed that DLB-hypo was associated with longitudinal cognitive outcomes, regardless of cognitive status, and DLB-hyper contributed to cognitive decline only in the MCI-LB group. The present study suggests that DLB-hypo and DLB-hyper may be independent of each other and differentially affect the baseline and longitudinal cognitive function in patients with DLB.

Discrimination between dementia with Lewy bodies and Alzheimer’s disease based on biofluid monoamines, biomarker values and cognitive parameters

AbstractBackgroundDespite disease‐specific symptoms, differentiation between Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) remains challenging, especially in early, prodromal stages. This is fueled by overlapping pathology in both diseases (Slaets et al., 2013). Monoamine neurotransmitters are significantly altered between DLB and AD and are capable of distinguishing DLB from AD, when added to the panel of cerebrospinal fluid (CSF) dementia biomarkers (Aβ1‐40, Aβ1‐42, T‐tau, P‐tau) and as standalone biomarkers (Janssens et al., 2018). Additionally, cognitive and behavioral differences linked to monoaminergic changes between DLB, AD patients and non‐demented control individuals, have been previously described (Engelborghs et al., 2006, Vermeiren et al., 2015).This study aimed to further explore these dissimilarities for improving discrimination between prodromal and advanced DLB and AD stages.MethodMonoamine neurotransmitter levels were measured in CSF and plasma of 160 prodromal AD (proAD), prodromal DLB (proDLB), AD and DLB patients and 40 non‐demented individuals, using ultra‐high‐performance liquid chromatography. CSF biomarker levels were determined through ELISA. A battery of cognitive and behavioral tests was performed. Monoaminergic, biomarker, cognitive and demographic data were integrated in stepwise regression models to discriminate between (prodromal) DLB and AD.ResultSignificant serotonergic differences in CSF between DLB and AD, as well as noradrenergic, dopaminergic and serotonergic differences in plasma between DLB and AD and with non‐demented individuals were noted. CSF dementia biomarkers levels differed significantly between proAD, proDLB, DLB and AD stages and with non‐demented individuals. There were no CSF, plasma monoamines or CSF biomarker changes between proDLB versus DLB, and proAD versus AD stages. Cognitive functioning differed significantly between prodromal and advanced DLB and AD stages and with non‐demented individuals. Stepwise regression identified that models including plasma and CSF serotonergic components, as well as cognitive tests were the most accurate at discriminating between proDLB versus DLB, proAD versus AD, proDLB versus proAD and DLB versus AD, with area under the curve (AUC), sensitivity and specificity values > 0.9.ConclusionThese findings support differentially affected monoaminergic, pathological biomarker levels and cognitive abilities between (prodromal) AD and DLB, and with non‐demented individuals. In addition, this study provides robust models for discrimination between (prodromal) DLB and AD.

Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐ß plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐ß deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

Alzheimer’s disease biomarkers of amyloid and tau influence white matter neurite alterations in dementia with Lewy bodies: a NODDI study

AbstractBackgroundCo‐morbid Alzheimer’s disease (AD) pathology in the form of amyloid‐β plaques and tau neurofibrillary tangles are frequently observed in people with probable dementia with Lewy bodies (DLB). Neurite Orientation Dispersion and Density Imaging (NODDI) is an emerging technique to characterize white matter (WM) tissue microstructure, although NODDI alterations and associations with AD biomarkers remain undefined in DLB. The objectives of this study are to compare NODDI and DTI parameters between DLB and controls and (ii) evaluate the pattern of DTI and NODDI changes associated with amyloid and tau deposition.MethodConsecutive patients within the DLB spectrum (n = 45), including probable DLB (n = 32) and probable Mild Cognitive Impairment with Lewy bodies (MCI‐LB) (n = 13) from the Mayo Clinic ADRC underwent multi‐shell diffusion MRI, [18F]‐Flortaucipir and [11C]‐PiB PET. A comparison group of 45 age‐ and gender‐matched clinically unimpaired controls (CU) was included. Voxelwise non‐parametric permutation models were used to determine pair‐wise group differences and assess the associations of AD biomarkers with fractional anisotropy (FA), mean diffusivity (MD), tissue‐weighted neurite density index (tNDI; NDI x (1 – Free water fraction)) and orientation dispersion index (ODI), controlling for age. Complementary analyses were performed using regions‐of‐interest (ROI) obtained from the JHU atlas.ResultCompared to CU, the DLB spectrum group exhibited widespread decreases in FA and tNDI and increases in MD and ODI, with the most pronounced effects in the cingulum bundles, uncinate, inferior and superior longitudinal fasciculi (Fig. 1). Greater [18F]‐Flortaucipir uptake was also associated with lower FA and tNDI, and higher MD and ODI in the DLB spectrum compared to CU, independently of age and [11C]‐PiB uptake (Fig. 2). In contrast, no associations were found between [11C]‐PiB uptake and any of the DTI or NODDI parameters. Complementary ROI analyses corroborated these findings.ConclusionWidespread loss of WM integrity was observed on DTI and NODDI in probable DLB and prodromal DLB. These findings were associated with greater cortical tau, but not with amyloid‐β deposition. Although alpha‐synuclein pathology underlies the loss of WM integrity in DLB, amyloid‐independent tau pathology may also be an important influence on white matter integrity within the DLB spectrum.

The ANeED Study: Ambroxol in New and Early Dementia with Lewy bodies

AbstractBackgroundNo disease modifying treatment is available for dementia with Lewy bodies (DLB). DLB patients have a rapid disease progression to the end stage of severe dementia, nursing home admission and death as compared to persons living with AD (1). Reported findings suggests reduced glucocerebrosidase (GCase) activity may be involved in pathomechanisms of synucleinopathies. Ambroxol is a well‐known drugs able to enhance GCase activity and thus increases synuclein clearance in CNS (2,3).MethodThe ANeED study is a national, multicentre, phase IIa RCT, placebo controlled clinical intervention trial including patients with prodromal and mild DLB with MMSE >14 (NCT04588285). The drug intervention is 1260 mg/d and treatment duration is 18 month. We additionally stratify participants based on genotypes for APOE and the CSF biomarker amyloid‐beta. Allocation ratio 1:1 for ambroxol and placebo.ResultThe study started in May 2021. As of February 2023, six out of seven sites have started recruitment. Of 47 included patients 38 started treatment with compliance >90%. Five patients completed the blind phase after 18 months and continue in the extended open label phase with ABX for 12 months. Adverse events reported are falls, nausea and sleep disturbances, but the relationship with ambroxol is uncertain. The goal for inclusions is 180 participants. Demographical and clinical data we present in table.ConclusionThe ANeED study continue to recruit patients as planned. We did not register any serious adverse events related to the study medication. The compliance is high and the tolerability and safety of study medication is good.

Occipital atrophy signature in prodromal Lewy bodies disease.

Dementia with Lewy bodies (DLB) is typically characterized by parietal, temporal, and occipital atrophy, but less is known about the newly defined prodromal phases. The objective of this study was to evaluate structural brain alterations in prodromal DLB (p-DLB) as compared to healthy controls (HC) and full-blown dementia (DLB-DEM). The study included 42 DLB patients (n=20 p-DLB; n=22 DLB-DEM) and 27 HC with a standardized neurological assessment and 3-tesla magnetic resonance imaging. Voxel-wise analyses on gray-matter and cortical thickness were implemented to evaluate differences between p-DLB, DLB-DEM, and HC. p-DLB and DLB-DEM exhibited reduced occipital and posterior parieto-temporal volume and thickness, extending from prodromal to dementia stages. Occipital atrophy was more sensitive than insular atrophy in differentiating p-DLB and HC. Occipital atrophy correlated to frontotemporal structural damage increasing from p-DLB to DLB-DEM. Occipital and posterior-temporal structural alterations are an early signature of the DLB continuum and correlate with a long-distance pattern of atrophy.

Clinical characteristics of pathological confirmed prodromal dementia with Lewy bodies

IntroductionMisdiagnosis rate of Dementia with Lewy Bodies (DLB) remains high despite being second most common cause of neurodegenerative dementia. To date, understanding of clinical profile of pathologically confirmed prodromal DLB remains limited. The main objective of this study was to describe and compare it with pathologically confirmed Alzheimer's disease (AD). MethodsWe accessed the National Alzheimer's Coordinating Center database from 2005 to December 2022 data freeze and included 111 and 501 prodromal DLB and AD patients respectively. First visit data was analyzed. ResultsClinician-determined memory impairment is common in prodromal DLB (>70%) but associated with higher risk for AD diagnosis (OR 0.355, p = 0.0003). DLB had a higher proportion of non-amnestic mild cognitive impairment (MCI) diagnoses but statistically insignificance in differentiating the two. Inattention (OR 2.273, p = 0.0015), and neuropsychiatric features, such as visual hallucinations (OR 11.98, p < 0.0001), depressed mood (OR1.709, p = 0.0292), apathy (1.824, p = 0.0345), and night/REM sleep behaviors, are associated with DLB diagnosis. Hallucinations are infrequent (7–11%). Motor symptoms, particularly gait disorders (OR 4.570, p < 0.001), falls (OR3.939, p = 0.0003), tremors (OR2.237, p = 0.0154), slowness (OR3.573, p < 0.0001), and parkinsonism signs (OR2.443, p < 0.0001), are common. 32% showed no parkinsonism during initial presentation. Neuropsychological examination revealed less impaired memory and language but impaired executive function in DLB. ConclusionIn clinical practice, it is important to note that memory symptoms although being higher risk associated with AD diagnosis, are prominent in prodromal DLB. Psychosis is infrequent, and non-amnestic MCI is not necessarily associated with higher risk of DLB diagnosis. A careful clinical approach is key to improve the diagnosis of prodromal DLB.

Neural Correlates of Photophobia in Prodromal and Mild Dementia with Lewy Bodies.

Photophobia is a sensory disturbance provoked by light. Little is known about the association between photophobia and dementia with Lewy bodies (DLB). In this study, we aimed to identify the frequency and the neural basis of photophobia in prodromal and mild DLB. One hundred thirteen DLB patients, 53 Alzheimer's disease (AD) patients, 20 AD and DLB patients, 31 patients with other neurocognitive diseases - including prodromal and mild demented patients -, and 31 healthy elderly controls were included in this case-control study. Photophobia was systematically looked for and compared between groups. Among a selection of 77 DLB patients, we used voxel-based morphometry (VBM) to compare those with and those without photophobia (gray matter volume; SPM12, XjView and Matlab R2021b software). The frequency of photophobia was higher in the DLB group (47.3%) than in the other groups (P=.002). The photophobia questionnaire score was higher in the DLB group than in the AD group (P=.001). Comparison between DLB patients with and those without photophobia showed decreased gray matter in the photophobia subgroup, in the right precentral cortex, in the eyelid motor region of Penfield's homunculus (P=.007, FWE corrected). Photophobia is a quite frequent symptom of prodromal and mild DLB. The neural basis of photophobia in DLB involves the right precentral cortex, which could have a role in the decrease of cerebral excitability, but also the motricity of the eyelids.

Memory Outcome in Prodromal and Mild Dementia with Lewy Bodies and Alzheimer's Disease: A Longitudinal Study.

Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are likely to induce memory impairments from the prodromal stage but, to our knowledge, no longitudinal study of these patients' memory profile has been conducted to date. The aim of our study was to describe the characteristics and the evolution of the long-term memory profile of patients with prodromal and mild DLB and AD. We collected verbal (RL/RI-16) and visual (DMS48) memory scores from 91 DLB patients, 28 AD patients, 15 patients with both conditions (DLB/AD), and 18 healthy control subjects at their inclusion visit and at 12, 24, and 48 months. On the RL/RI-16, DLB patients performed better than AD patients in terms of total recall (p < 0.001), delayed total recall (p < 0.001), recognition (p = 0.031), and loss of information over time (p = 0.023). On the DMS48, differences between these two groups were not significant (p > 0.05). Longitudinally, the memory performance of DLB patients was stable over 48 months, unlike that of AD patients. Four indicators were relevant to distinguish between DLB and AD patients in terms of memory performance: DLB patients benefitted greatly from semantic cueing, their recognition and consolidation abilities were well-preserved, and both their verbal and visual memory performance remained remarkably stable over four years. However, no performance differences between DLB and AD patients were found regarding visual memory, either qualitatively (memory profile) or quantitatively (severity of impairment), indicating the lesser relevance of this test in distinguishing between these two diseases.

Aphasic mild cognitive impairment in prodromal dementia with Lewy bodies.

This study aimed to determine the characteristics of aphasic mild cognitive impairment (aphasic MCI), which is characterized by a progressive and relatively prominent language impairment compared with other cognitive impairments, in the prodromal phase of dementia with Lewy bodies (DLB). Of the 26 consecutive patients with aphasic MCI who had been prospectively recruited at our hospital, 8 patients were diagnosed with prodromal DLB and underwent language, neurological, neuropsychological, and neuroimaging (N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography; IMP-SPECT) testing. Three of these patients also underwent cholinesterase inhibitor therapy with donepezil. In our aphasic MCI cohort, the clinical diagnosis of probable prodromal DLB accounted for more than 30% of cases; therefore, the presence of language impairment in prodromal DLB was not very uncommon. Five patients were diagnosed with progressive anomic aphasia and three with logopenic progressive aphasia. Anomic aphasia was characterized by apparent anomia but relatively preserved repetition and comprehension ability and logopenic progressive aphasia by anomia, phonemic paraphasia, and impaired repetition. IMP-SPECT revealed hypoperfusion of the temporal and parietal lobes in the left hemisphere in all but one patient. All patients who underwent cholinesterase inhibitor therapy with donepezil showed improvement in general cognitive function, including language function. The clinical and imaging features of aphasic MCI in prodromal DLB are similar to those observed in Alzheimer's disease. Progressive fluent aphasia, such as progressive anomic aphasia and logopenic progressive aphasia, is one of the clinical presentations in prodromal state of DLB. Our findings provide further insight into the clinical spectrum of prodromal DLB and may contribute to the development of medication for progressive aphasia caused by cholinergic insufficiency.

New Insights into Potential Biomarkers in Patients with Mild Cognitive Impairment Occurring in the Prodromal Stage of Dementia with Lewy Bodies

Prodromal dementia with Lewy bodies (DLB) can emerge with the onset of mild cognitive impairment (MCI). Standard biomarkers can help identify such patients to improve therapy and treatment strategies. Our review aims to describe the latest evidence on promising biomarkers in prodromal DLB with MCI onset (MCI-LB). We selected articles on different biomarkers in MCI-LB from PubMed and conducted a narrative review. We identified potentially promising clinical biomarkers, e.g., (1) assessing autonomic symptoms specifically, (2) describing the cognitive profile in several subdomains including executive and visual functions, and (3) measuring the speed of speech. In addition, we describe the measurement of seeding amplification assays of alpha-synuclein in cerebrospinal fluid as a relevant biomarker for MCI-LB. Electroencephalographic markers, as in calculating the theta/beta ratio or intermittent delta activity, or analyzing peak frequency in electroencephalography-methods also potentially useful once they have been validated in large patient cohorts. The 18F fluorodesoxyglucose positron emission tomography (FDG-PET) technique is also discussed to investigate metabolic signatures, as well as a specific magnetic resonance imaging (MRI) technique such as for the volumetric region of interest analysis. These biomarker results suggest that MCI-LB is a promising field for the use of biomarkers other than established ones to diagnose early prodromal DLB. Further large-scale studies are needed to better evaluate and subsequently use these promising biomarkers in prodromal DLB.

Characterising the prodromal phase in dementia with Lewy bodies

IntroductionThree presentations of prodromal dementia with Lewy bodies (DLB) have recently been proposed. This study investigates the frequency of symptoms in the prodromal phase of DLB. MethodPatients diagnosed with DLB between the 1st of February 2017 and 1st of February 2021 were retrospectively identified and matched to a group of patients diagnosed with Alzheimer's disease (AD). Patient case files were reviewed identifying the first symptoms and symptoms in the prodromal phase (cognitive impairment, psychiatric symptoms, delirium/acute confusional episodes, RBD, motor symptoms indicative of Parkinson's disease, anosmia, and autonomic dysfunction). ResultsA total of 166 DLB patient and 168 AD patients were included. Of the proposed presentations in patients diagnosed with DLB, 30% presented with cognitive impairment at onset in isolation, 6% with psychiatric symptoms, and 2% with delirium/acute confusional episodes. Prodromal DLB was more likely to present with no cognitive symptoms at initial presentation (38% vs 10%) and was more likely to involve other symptoms (69% vs 26%). Of other possible presentations, Rapid eye-movement sleep Behaviour Disorder (RBD) was found at onset in 22% with a mean prodromal length of 8.4 years (all symptoms: mean 4.3 years, SD 5.8). ConclusionWe found some supportive evidence of the proposed cognitive and psychiatric presentations of prodromal DLB. Our findings build on previous findings that an RBD presentation exist, and further research is needed to characterise this presentation.

Characterising the prodromal phase of dementia with Lewy bodies

AbstractBackgroundThree subtypes of prodromal dementia with Lewy bodies (DLB) have recently been proposed. This study investigates the frequency of symptoms in the prodromal phase of DLB.MethodPatients diagnosed with DLB between the 1st of February 2017 and 1st of February 2021 were retrospectively identified and matched to a group of patients with Alzheimer’s disease (AD). Patient case files were reviewed identifying the first symptoms and symptoms in the prodromal phase (cognitive impairment, psychiatric symptoms, delirium/acute confusional episodes, RBD, motorsymptoms indicative of Parkinson’s disease, anosmia, and autonomic dysfunction).ResultsA retrospective cohort of 166 DLB patient and 168 AD patients were included. Of the proposed subtypes in patients diagnosed with DLB, 30% presented with cognitive impairment at onset in isolation, 6% with psychiatric symptoms, and 2% with delirium/acute confusional episodes (Figure). Eighty‐three percent of DLB patients had two or more non‐cognitive symptoms in the prodromal phase. Further, 82 % had at least one psychiatric symptom, and 33 % had an episode with delirium/acute confusional episode in the prodromal phase. Of other possible subtypes, Rapid eye movement sleep Behaviour Disorder was found at onset in 22% with a mean prodromal length of 8.4 years (as opposed to 4.3 years in DLB generally)ConclusionWe found no supportive evidence of the proposed clinical subtypes of prodromal DLB. Our findings indicate that RBD subtypes may exist, but further research is needed.

Exploring the Sensitivity of Prodromal Dementia with Lewy Bodies Research Criteria.

Dementia with Lewy bodies (DLB) is an insidious neurodegenerative disease characterised by a precipitous decline in cognition, sleep disturbances, motor impairment and psychiatric features. Recently, criteria for prodromal DLB (pDLB) including clinical features and biomarkers have been put forward to aid the classification and research of this ambiguous cohort of patients. Researchers can use these criteria to classify patients with mild cognitive impairment (MCI) with Lewy bodies (MCI-LB) as either possible (either one core clinical feature or one biomarker are present) or probable pDLB (at least two core clinical features, or one core clinical feature and at least one biomarker present). However, as isolated REM sleep behaviour disorder (iRBD) confirmed with polysomnography (PSG) can be included as both a clinical and a biomarker feature, potentially reducing the specificity of these diagnostic criteria. To address this issue, the current study classified a cohort of 47 PSG-confirmed iRBD patients as probable prodromal DLB only in the presence of an additional core feature or if there was an additional non-PSG biomarker. Thirteen iRBD patients demonstrated MCI (iRBD-MCI). In the iRBD-MCI group, one presented with parkinsonism and was thus classified as probable pDLB, whilst the remaining 12 were classified as only possible pDLB. All patients performed three tasks designed to measure attentional deficits, visual hallucinations and visuospatial impairment. Patients also attended clinical follow-ups to monitor for transition to DLB or another synucleinopathy. Findings indicated that the only patient categorised by virtue of having two core clinical features as probable pDLB transitioned over 28 months to a diagnosis of DLB. The performance of this probable pDLB patient was also ranked second-highest for their hallucinatory behaviours and had comparatively lower visuospatial accuracy. These findings highlight the need for more stringent diagnostic research criteria for pDLB, given that only one of the 13 patients who would have satisfied the current guidelines for probable pDLB transitioned to DLB after two years and was indeed the patient with two orthogonal core clinical features.

Characteristics of very late-onset schizophrenia-like psychosis as prodromal dementia with Lewy bodies: a cross-sectional study

BackgroundThis study aimed to identify cases of potential prodromal DLB in very late-onset schizophrenia-like psychosis (VLOSLP), using indicative biomarkers of dementia with Lewy bodies (DLB), and to evaluate the characteristics of psychosis as prodromal DLB.MethodsData of patients with VLOSLP without dementia and Parkinsonism, who underwent testing for at least one indicative biomarker of DLB, were retrospectively collected from the database of the psychiatry clinic at the Osaka University Hospital. Patients were divided into two groups based on the positive (VLOSLP+LB) and negative (VLOSLP–LB) results of the indicative biomarkers of DLB. Age, gender, cognitive battery scores, prevalence of each type of delusions and hallucinations, cerebral volume, and cerebral perfusion were compared between the two groups.ResultsEleven VLOSLP+LB and 23 VLOSLP–LB participants were enrolled. There were no significant differences in age, proportion of females, and MMSE scores between the two groups. The standardized score of the digit symbol substitution test was significantly lower in the VLOSLP+LB than in VLOSLP–LB group (6.9 [3.1] vs. 10.0 [2.7], p = 0.005). The prevalence of visual hallucinations was significantly higher in the VLOSLP+LB group than in the VLOSLP-LB group (81.8% vs. 26.1%, p = 0.003). Auditory hallucinations were prevalent in both groups (43.5% in VLOSLP–LB, and 45.5% in VLOSLP+LB). Among patients with auditory hallucinations, auditory hallucinations without coexistent visual hallucinations tended to be more prevalent in VLOSLP–LB (7 out of 10) than in VLOSLP+LB patients (1 out of 5). Although cerebral volume was not different in any region, cerebral perfusion in the posterior region, including the occipital lobe, was significantly lower in the VLOSLP+LB group.ConclusionsPsychomotor slowing, visual hallucinations, and reduced perfusion in the occipital lobe may be suggestive of prodromal DLB in VLOSLP patients, even though the clinical manifestations were similar in many respects between VLOSLP+LB and VLOSLP–LB. Although auditory hallucinations were prevalent in both groups, most patients in VLOSLP+LB complained of auditory hallucinations along with visual hallucinations. Future studies with a larger number of patients without selection bias are desirable.

Neural basis of impaired narrative discourse comprehension in prodromal and mild dementia with lewy bodies.

Narrative discourse (ND) comprehension is a complex task that implies not only linguistic abilities but also other cognitive abilities, including efficient executive functioning. An executive dysfunction has been described in dementia with Lewy bodies (DLB) from the early stage. Here, we question the link between executive dysfunction in DLB and narrative comprehension. The aim of our study was to evaluate ND comprehension and to investigate the neuroanatomical basis for its impairment in the early stage of DLB. DLB patients (N = 26) and controls (N = 19) underwent the ND comprehension test of the Montreal Protocol for Evaluation of Communication (MEC). An additional, qualitative analysis was conducted on their verbal productions. Cognitive tests assessing verbal episodic memory, executive functions, naming and oral syntactic comprehension were also performed. Brain gray matter correlates of the ND comprehension test were examined using voxel-based morphometry (VBM). An ND comprehension impairment was found for prodromal and mild DLB patients as compared to controls. These difficulties were correlated with the Frontal Assessment Battery (FAB) score. ND comprehension impairment in DLB was further characterized by a deficit in the organization and the logic of the discourse. Moreover, VBM analysis revealed a correlation between striatal gray matter volumes and DLB patients’ ability to extract and organize relevant information (p < 0.05, FDR correction, cluster level). The ND comprehension impairment in DLB patients could be related to their executive dysfunction through a deficit of information selection and organization that correlates with the volumetric reduction of striatal gray matter.

Prodromal characteristics of dementia with Lewy bodies: baseline results of the MEMENTO memory clinics nationwide cohort

BackgroundIsolated subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) are the prodromal phases of dementia with Lewy bodies (DLB). MEMENTO is a nationwide study of patients with SCI and MCI with clinic, neuropsychology, biology, and brain imaging data. We aimed to compare SCI and MCI patients with symptoms of prodromal DLB to others in this study at baseline.MethodsParticipants of the French MEMENTO cohort study were recruited for either SCI or MCI. Among them, 892 were included in the Lewy sub-study, designed to search specifically for symptoms of DLB. Probable prodromal DLB diagnosis (pro-DLB group) was done using a two-criteria cutoff score among the four core clinical features of DLB. This Pro-DLB group was compared to two other groups at baseline: one without any core symptoms (NS group) and the one with one core symptom (1S group). A comprehensive cognitive battery, questionnaires on behavior, neurovegetative and neurosensory symptoms, brain 3D volumetric MRI, CSF, FDG PET, and amyloid PET were done.ResultsThe pro-DLB group comprised 148 patients (16.6%). This group showed more multidomain (59.8%) MCI with slower processing speed and a higher proportion of patients with depression, anxiety, apathy, constipation, rhinorrhea, sicca syndrome, and photophobia, compared to the NS group. The pro-DLB group had isolated lower P-Tau in the CSF (not significant after adjustments for confounders) and on brain MRI widening of sulci including fronto-insular, occipital, and olfactory sulci (FDR corrected), when compared to the NS group. Evolution to dementia was not different between the three groups over a median follow-up of 2.6 years.ConclusionsPatients with symptoms of prodromal DLB are cognitively slower, with more behavioral disorders, autonomic symptoms, and photophobia. The occipital, fronto-insular, and olfactory bulb involvement on brain MRI was consistent with symptoms and known neuropathology. The next step will be to study the clinical, biological, and imaging evolution of these patients.Trial registrationClinicaltrials.gov, NCT01926249

Biomarkers of Dementia with Lewy Bodies: Differential Diagnostic with Alzheimer's Disease.

Dementia with Lewy Bodies (DLB) is a common form of cognitive neurodegenerative disease. Only one third of patients are correctly diagnosed due to the clinical similarity mainly with Alzheimer’s disease (AD). In this review, we evaluate the interest of different biomarkers: cerebrospinal fluid (CSF), brain MRI, FP-CIT SPECT, MIBG SPECT, PET by focusing more specifically on differential diagnosis between DLB and AD. FP-CIT SPECT is of high interest to discriminate DLB and AD, but not at the prodromal stage (i.e., MCI). MIBG SPECT with decreased cardiac sympathetic activity, perfusion SPECT with occipital hypoperfusion, FDG PET with occipital hypometabolism and cingulate island signs are of interest at the dementia stage but with a lower validity. Brain MRI has shown differences in group study with lower grey matter concentration of the Insula in prodromal DLB, but its interest in clinical routines is not demonstrated. Concerning CSF biomarkers, many studies have already examined the relevance of AD biomarkers but also alpha-synuclein assays in DLB, so we will focus as comprehensively as possible on other biomarkers (especially those that do not appear to be directly related to synucleinopathy) that may be of interest in the differential diagnosis between AD and DLB. Furthermore, we would like to highlight the growing interest in CSF synuclein RT-QuIC, which seems to be an excellent discrimination tool but its application in clinical routine remains to be demonstrated, given the non-automation of the process.

Correlates of Conversion from Mild Cognitive Impairment to Dementia with Lewy Bodies: Data from the National Alzheimer's Coordinating Center.

Many patients with dementia with Lewy bodies (DLB) miss out on the best standards of care and psychosocial support due to diagnostic delays or inaccuracies following symptom onset. This study seeks to identify baseline characteristics in individuals with mild cognitive impairment (MCI) that correlate with eventual conversion to DLB or Alzheimer's disease (AD). Baseline neuropsychological and neuropsychiatric data were analyzed in National Alzheimer's Coordinating Center participants who completed the Uniform Data Set between 2006 and 2020 and subsequently converted from MCI to DLB or AD (n = 1632). Only 6% of participants with MCI converted to DLB. Among those who converted to DLB, multidomain amnestic MCI (aMCI) was the most common subtype at study entry. As part of logistic regression analyses, odds ratios (ORs) were estimated for conversion to DLB versus AD based on study-entry characteristics, adjusting for age, sex, education, and years to diagnosis. The strongest predictors of conversion to DLB (p≤0.0001) were nonamnestic MCI versus aMCI (OR 8.2, CI [5.0, 14]), multidomain MCI versus single-domain MCI (OR 2.7, CI [1.7. 4.2]), male sex (OR 4.2, CI [2.5, 7.1]), and presence of nighttime behaviors (OR 4.4 CI [2.8, 6.9]). A diagnosis of prodromal DLB should be considered in individuals with MCI who present with prominent executive/visuospatial deficits, neuropsychiatric symptoms, and less memory impairment. Early diagnosis of DLB may guide treatment planning, including the avoidance of antipsychotic medications in patients who develop psychotic symptoms, caregiver support, and initiation of early treatment(s) once medications become available.

Neurophysiological Correlates of Motor and Cognitive Dysfunction in Prodromal and Overt Dementia with Lewy Bodies.

The neurophysiological correlates of cognitive and motor symptoms in prodromal and overt dementia with Lewy bodies (DLB) are still to be elucidated. To evaluate if cognitive and motor features of patients with prodromal and overt DLB are associated with the impairment of specific neurotransmitter circuits, evaluated in vivo with transcranial magnetic stimulation (TMS). Fifty-one patients with DLB (twenty-five prodromal; twenty-six with dementia) underwent neuropsychological and clinical evaluation, with twenty-five patients having at least one follow-up evaluation. All patients were assessed with TMS at baseline, with protocols assessing cholinergic circuits (short latency afferent inhibition, SAI), GABAergic circuits (short interval intracortical inhibition, SICI), and glutamatergic circuits (intracortical facilitation, ICF). Compared to HC, SICI, ICF, and SAI resulted significantly impaired in both prodromal and overt DLB, with the latter showing a reduced SICI and SAI also compared to prodromal DLB. There was a significant correlation between motor deficits, evaluated with the UPDRS-III, and the impairment of GABAergic (SICI) (r = 0.729, p < 0.001) and glutamatergic (ICF) (r -0.608, p < 0.001) circuits; global cognition, evaluated with the Mini-Mental State Examination, correlated with the impairment of cholinergic (SAI) circuits (r=-0.738, p < 0.001). Worsening of cognitive functions at follow-up was associated with reduced cholinergic functions at baseline (R2 = 0.53, p < 0.001). These results suggest that motor and cognitive dysfunctions in prodromal and overt DLB depend on specific and independent neurotransmitter circuits.