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Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series.
This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences.
We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions.
The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs.
Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.
Mild cognitive impairment (MCI) may gradually worsen to dementia, but often remains stable for extended periods of time. Little is known about the predictors of decline to help explain this variation. We aimed to explore whether this heterogeneous course of MCI may be predicted by the presence of Lewy body (LB) symptoms in a prospectively-recruited longitudinal cohort of MCI with Lewy bodies (MCI-LB) and Alzheimer's disease (MCI-AD).
A prospective cohort (n = 76) aged ⩾60 years underwent detailed assessment after recent MCI diagnosis, and were followed up annually with repeated neuropsychological testing and clinical review of cognitive status and LB symptoms. Latent class mixture modelling identified data-driven sub-groups with distinct trajectories of global cognitive function.
Three distinct trajectories were identified in the full cohort: slow/stable progression (46%), intermediate progressive decline (41%) and a small group with a much faster decline (13%). The presence of LB symptomology, and visual hallucinations in particular, predicted decline v. a stable cognitive trajectory. With time zeroed on study end (death, dementia or withdrawal) where available (n = 39), the same subgroups were identified. Adjustment for baseline functioning obscured the presence of any latent classes, suggesting that baseline function is an important parameter in prospective decline.
These results highlight some potential signals for impending decline in MCI; poorer baseline function and the presence of probable LB symptoms – particularly visual hallucinations. Identifying people with a rapid decline is important but our findings are preliminary given the modest cohort size.
The accurate clinical characterisation of mild cognitive impairment (MCI) is becoming increasingly important. The aim of this study was to compare the neuropsychiatric symptoms and cognitive profile of MCI with Lewy bodies (MCI-LB) with Alzheimer's disease MCI (MCI-AD).
Participants were ⩾60 years old with MCI. Each had a thorough clinical and neuropsychological assessment and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single photon emission computed tomography FP-CIT SPECT). MCI-LB was diagnosed if two or more diagnostic features of dementia with Lewy bodies were present (visual hallucinations, cognitive fluctuations, motor parkinsonism, rapid eye movement sleep behaviour disorder or positive FP-CIT SPECT). A Lewy body Neuropsychiatric Supportive Symptom Count (LBNSSC) was calculated based on the presence or absence of the supportive neuropsychiatric symptoms defined by the 2017 DLB diagnostic criteria: non-visual hallucinations, delusions, anxiety, depression and apathy.
MCI-LB (n = 41) had a higher LBNSSC than MCI-AD (n = 24; 1.8 ± 1.1 v. 0.7 ± 0.9, p = 0.001). 67% of MCI-LB had two or more of those symptoms, compared with 16% of MCI-AD (Likelihood ratio = 4.2, p < 0.001). MCI-LB subjects scored lower on tests of attention, visuospatial function and verbal fluency. However, cognitive test scores alone did not accurately differentiate MCI-LB from MCI-AD.
MCI-LB is associated with neuropsychiatric symptoms and a cognitive profile similar to established DLB. This supports the concept of identifying MCI-LB based on the presence of core diagnostic features of DLB and abnormal FP-CIT SPECT imaging. The presence of supportive neuropsychiatric clinical features identified in the 2017 DLB diagnostic criteria was helpful in differentiating between MCI-LB and MCI-AD.
Fluctuating cognition (FC), particularly in attention, is a core and defining symptom in dementia with Lewy bodies (DLB) but is seen much less frequently in Alzheimer's dementia (AD). However, its neurobiological origin is poorly understood. The aim of our study was therefore to characterize perfusion patterns in DLB patients that are associated with the severity and frequency of FC as measured both clinically and using objective neuropsychological assessments.
Spatial covariance analyses were applied to data derived from single photon emission computed tomography (SPECT) HMPAO brain imaging in 19 DLB and 23 AD patients. Patients underwent clinical assessment of their FC and cognitive function as well as objective testing of their attention.
Covariant perfusion principal components (PCs) were not associated with either FC or cognitive or attentional measures in AD. However, in DLB patients, the second PC (defined as DLB-cognitive motor pattern, DLB-PCI2) which was characterized by bilateral relative increases in cerebellum, basal ganglia, and supplementary motor areas and widespread bilateral decreases in parietal regions, positively correlated with poorer cognitive function, increased FC and worse attentional function measured both clinically and neurophysiologically (p < 0.05) as well as with the severity of bradykinesia (p = 0.04).
FC in DLB appears distinct from those seen in AD, and likely to be driven by internal neurobiological perturbations in brain circuitry as evidenced using spatial covariance analyses of cerebral perfusion. FC and certain aspects of attentional dysfunction in DLB may, in part, depend upon both distributed motor and non-motor networks.
Alzheimer's disease (AD) is considered to be a disorder predominantly affecting memory. It is increasingly recognized that the cognitive profile may be heterogeneous. We hypothesized that it would be possible to define distinct “cognitive phenotypes” in older people with AD.
Participants from three individual studies were included, consisting of 109 patients with a diagnosis of probable AD, and 91 age- and gender-matched control participants. All had demographic and cognitive assessment data available, including the Cambridge Cognitive Examination of the Elderly (CAMCOG). The CAMCOG scores and sub-scores were further analyzed using hierarchical cluster analysis and factor analysis.
Three clusters were identified. The scores loaded onto three factors representing the domains of attention, praxis, calculation, and perception; memory; and language comprehension and executive function. The main difference between the clusters related to degree of memory impairment. The composite score for memory between the clusters remained significantly different despite adjustment for illness duration and age of onset (p < 0.001).
These data suggest clinical heterogeneity within an older group of people with AD. This may have implications for diagnosis, prognosis, response to currently available treatments, and the development of novel therapies.
Visual hallucinations and visuoperceptual deficits are common in dementia
with Lewy bodies, suggesting that cortical visual function may be
To investigate: (1) cortical visual function using functional magnetic
resonance imaging (fMRI); and (2) the nature and severity of perfusion
deficits in visual areas using arterial spin labelling (ASL)-MRI.
In total, 17 participants with dementia with Lewy bodies (DLB group) and
19 similarly aged controls were presented with simple visual stimuli
(checkerboard, moving dots, and objects) during fMRI and subsequently
underwent ASL-MRI (DLB group n = 15, control group
n = 19).
Functional activations were evident in visual areas in both the DLB and
control groups in response to checkerboard and objects stimuli but
reduced visual area V5/MT (middle temporal) activation occurred in the
DLB group in response to motion stimuli. Posterior cortical perfusion
deficits occurred in the DLB group, particularly in higher visual
Higher visual areas, particularly occipito-parietal, appear abnormal in
dementia with Lewy bodies, while there is a preservation of function in
lower visual areas (V1 and V2/3).
The aetiology of visual hallucinations is poorly understood in dementia with Lewy bodies. Pathological alterations in visual cortical excitability may be one contributory mechanism.
To determine visual cortical excitability in people with dementia with Lewy bodies compared with aged-matched controls and also the relationship between visual cortical excitability and visual hallucinations in dementia with Lewy bodies.
Visual cortical excitability was determined by using transcranial magnetic stimulation (TMS) applied to the occiput to elicit phosphenes (transient subjective visual responses) in 21 patients with dementia with Lewy bodies and 19 age-matched controls.
Phosphene parameters were similar between both groups. However, in the patients with dementia with Lewy bodies, TMS measures of visual cortical excitability correlated strongly with the severity of visual hallucinations (P = 0.005). Six patients with dementia with Lewy bodies experienced visual hallucination-like phosphenes (for example, seeing people or figures on stimulation) compared with none of the controls (P = 0.02).
Increased visual cortical excitability in dementia with Lewy bodies does not appear to explain visual hallucinations but it may be a marker for their severity.
Background: Elevated plasma homocysteine concentrations have been associated with both cognitive impairment and dementia. However, it is unclear whether some cognitive domains are more affected than others, or if this relationship is independent of B12 and folate levels, which can also affect cognition. We examined the relationship between plasma homocysteine and cognitive decline in an older hypertensive population.
Methods: 182 older people (mean age 80 years) with hypertension and without dementia, were studied at one center participating in the Study on COgnition and Prognosis in the Elderly (SCOPE). Annual cognitive assessments were performed using a computerized assessment battery and executive function tests, over a 3–5 year period (mean 44 months). Individual rates of decline on five cognitive domains were calculated for each patient. End of study plasma homocysteine, folate and B12 concentrations were measured. The relationship between homocysteine levels and cognitive decline was studied using multivariate regression models, and by comparing high versus low homocysteine quartile groups.
Results: Higher homocysteine showed an independent association with greater cognitive decline in three domains: speed of cognition (β = −27.33, p = 0.001), episodic memory (β = −1.25, p = 0.02) and executive function (β = −0.05, p = 0.04). The association with executive function was no longer significant after inclusion of folate in the regression model (β = −0.032, p = 0.22). Change in working memory and attention were not associated with plasma homocysteine, folate or B12. High homocysteine was associated with greater decline with a Cohen's d effect size of approximately 0.7 compared to low homocysteine.
Conclusions: In a population of older hypertensive patients, higher plasma homocysteine was associated with cognitive decline.
123I-FP-CIT SPECT (single photon emission computed tomography) can help in the differential diagnosis of probable dementia with Lewy bodies (Lewy body dementia) and Alzheimer's disease.
Our aim was to determine the accuracy of 123I-FP-CIT SPECT in diagnosing people with possible dementia with Lewy bodies.
We undertook a 12-month follow-up of 325 individuals with probable or possible Lewy body or non-Lewy body dementia who had previously undergone 123I-FP-CIT SPECT. A consensus panel masked to SPECT findings, established diagnosis at 12 months in 264 people.
Of 44 people with possible dementia with Lewy bodies at baseline, at follow-up the diagnosis for 19 people was probable dementia with Lewy bodies (43%), in 7 people non-Lewy body dementia (16%) and for 18 individuals it remained possible dementia with Lewy bodies (41%). Of the 19 who at follow-up were diagnosed with probable dementia with Lewy bodies, 12 had abnormal scans at baseline (sensitivity 63%); all 7 individuals with a possible diagnosis who were diagnosed as having Alzheimer's disease at follow-up had normal scans (specificity 100%).
Our findings confirm the diagnostic accuracy of 123I-FP-CIT SPECT in distinguishing Lewy body from non-Lewy body dementia and also suggest a clinically useful role in diagnostically uncertain cases, as an abnormal scan in a person with possible dementia with Lewy bodies is strongly suggestive of dementia with Lewy bodies.
Background: The aim of this study is to investigate the diagnostic value of perfusion 99mTc-exametazime single photon emission computed tomography (SPECT) in the diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) in comparison with dopaminergic 123I-2β-carbomethoxy-3β-(4-iodophenyl)-n-(3-fluoropropyl) nortropane (FP-CIT) SPECT imaging.
Methods: Subjects underwent 99mTc-exametazime scanning (39 controls, 36 AD, 30 DLB) and 123I-FP-CIT scanning (33 controls, 33 AD, 28 DLB). For each scan, five raters performed visual assessments blind to clinical diagnosis on selected transverse 99mTc-exametazime images in standard stereotactic space. Diagnostic accuracy of 99mTc-exametazime was compared to 123I-FP-CIT results for the clinically relevant subgroups AD and DLB using receiver operating characteristic (ROC) curve analysis.
Results: Inter-rater agreement for categorizing uptake was “moderate” (mean κ = 0.53) for 99mTc-exametazime and “excellent” (mean κ = 0.88) for 123I-FP-CIT. For AD and DLB, consensus rating matched clinical diagnosis in 56% of cases using 99mTc-exametazime and 84% using 123I-FP-CIT. In distinguishing AD from DLB, ROC analysis revealed superior diagnostic accuracy with 123I-FP-CIT (ROC curve area 0.83, sensitivity 78.6%, specificity 87.9%) compared to occipital 99mTc-exametazime (ROC curve area 0.64, sensitivity 64.3%, specificity 63.6%) p = 0.03.
Conclusion: Diagnostic accuracy was superior with 123I-FP-CIT compared to 99mTc-exametazime in the differentiation of DLB from AD.
We surveyed old age psychiatrists in the north-east of England to determine what they considered relevant indicators of driving ability. The survey asked about their satisfaction with the current Driver and Vehicle Licensing Agency (DVLA) procedure of assessing competence to drive in patients with dementia and how they thought this could be improved.
Fifty-seven out of 76 psychiatrists (75%) responded; 26 (45%) respondents thought the forms issued by the DVLA were unsatisfactory but 32 (57%) were satisfied with the eventual decisions made about individual patients. Factors thought to be relevant indicators of driving ability were occupational therapy (n=46, 81%), neuropsychological assessments (n=43, 75%) and carer's report of driving (n=48, 84%). Factors thought not to be relevant were patient's report of driving ability (n=13, 23%) and the Mini Mental State Examination (n=21, 38%).
The current system for determining driving ability in people with cognitive impairment and dementia was felt to be unsatisfactory. A multidisciplinary approach and use of on-road driving assessments may improve decision-making.
Patients with dementia with lewy bodies (DLB) have progressive deficits in cognition, parkinsonism, and neuropsychiatric symptoms. Cholinesterase inhibitors have been used to ameliorate cognitive decline and neuropsychiatric symptoms in short-term trials. In this study, patients with DLB were treated with rivastigmine up to 96 weeks. Improvement from baseline was seen in cognitive function as measured by the Mini-Mental State Examination (MMSE), and neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI) over the first 24 weeks of treatment. By 96 weeks, neither the MMSE scores nor the NPI scores were significantly worse than at baseline.
Dementia with Lewy bodies (DLB) is the currently preferred term for a variety of clinical diagnoses that have risen to prominence during the last decade (McKeith et al., 1996). These include diffuse Lewy body disease, dementia associated with cortical Lewy bodies, the Lewy body variant of Alzheimer's disease (AD) (Hansen et al., 1990), senile dementia of the Lewy body type, and Lewy body dementia. Initially thought to be uncommon, DLB is now recognized as the second most common pathologic cause of dementia, accounting for up to 20% of all elderly cases reaching autopsy.
In 1995, a new European system for the authorization of medicinal products went into effect. After 10 years of cooperation between National Registration Authorities at the European Union (EU) level and 4 years of negotiation, in June 1993 the Council of the EU adopted three directives and a regulation that together form the legal basis of the current system. The European Medicines Evaluation Agency (EMEA) was established on July 22, 1993, and London was chosen as its coordinating center, housing the Committee for Proprietary Medicinal Products (CPMP), which is the body that advises the European Licensing Authority (European Commission). The EMEA has the opportunity to harness the expertise and resources of member states and their ability to oversee local implementation.
Dementia with Lewy bodies (DLB) is a common dementia subtype that has only been recognised in the past decade and that remains widely underdiagnosed.
To review the pathological and clinical features of DLB, to consider methods of investigation and diagnosis, and to recommend safe and effective management strategies.
A selective review was made of the key literature.
Using operationalised criteria, DLB can be clinically diagnosed with an accuracy similar to that achieved for Alzheimer's disease or Parkinson's disease. Underdetection is largely due to poor definition of the criterion of cognitive fluctuation. Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis. Extreme caution in the use of neuroleptic medication is advised. Cholinesterase inhibitors may be particularly effective in DLB.
Clinicians should be aware of DLB as part of a spectrum of Lewy body disorders. Neuroleptic sensitivity reactions and good response to cholinergic therapies are important aspects of management.
Single photon emission computerised tomography (SPECT) was used to measure regional brain uptake of technetium-99m hexamethyl-propyleneamine oxine (Tc99m-HMPAO) in elderly patients with Alzheimer's disease (AD), multi-infarct dementia (MID) and normals (n = 20 in each group). Different patterns of uptake were found between groups when cortical uptake was normalised to cerebellar uptake. Reductions occurred in all regions in AD, being most marked in temporal and posterior parietal areas. Significant correlations were found in AD between memory impairment and decreased temporal uptake bilaterally, and between duration of illness and reduced uptake in most brain regions. MID patients showed higher uptake in the anterior parietal region than did the other groups. A variable comparing anterior to posterior uptake significantly discriminated the two patient groups.
The dexamethasone suppression test (DST) was administered to 95 patients referred to a psychogeriatric assessment service. Non-suppression of plasma cortisol was found in 28 out of 48 patients (58%) with senile dementia and all patients with arteriosclerotic dementia or acute confusional states. Non-suppression could not be explained by associated depressive symptoms. The DST was confirmed as a valid diagnostic test for endogenous depression in the elderly, but its value in distinguishing true dementing illnesses from depressive pseudodementia was not supported. The clinical implications of these findings for interpreting DST results in the elderly are discussed.
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