Laura Bonanni

Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Default network is not hypoactive in dementia with fluctuating cognition: an Alzheimer disease/dementia with Lewy bodies comparison.

Default mode network resting state activity in posterior cingulate cortex is abnormally reduced in Alzheimer disease (AD) patients. Fluctuating cognition and electroencephalogram abnormalities are established core and supportive elements respectively for the diagnosis of dementia with Lewy bodies (DLB). Our aim was to assess whether patients with DLB with both of these features have different default mode network patterns during resting state functional magnetic resonance imaging compared with AD. Eighteen patients with DLB, 18 AD patients without fluctuating cognition, and 15 control subjects were selected after appropriate matching and followed for 2-5 years to confirm diagnosis. Independent component analysis with functional connectivity (FC) and Granger causality approaches were applied to isolate and characterize resting state networks. FC was reduced in AD and DLB patients compared with control subjects. Posterior cingulate cortex activity was lower in AD than in control subjects and DLB patients (p < 0.05). Right hemisphere FC was reduced in DLB patients in comparison with control subjects but not in patients with AD, and was correlated with severity of fluctuations (ρ = -0.69; p < 0.01). Causal flow analysis showed differences between patients with DLB and AD and control subjects.

Revisiting P300 cognitive studies for dementia diagnosis: Early dementia with Lewy bodies (DLB) and Alzheimer disease (AD)

AIMS OF THE STUDY Earlier P300 studies were conducted when the prevalence of dementia with Lewy Bodies (DLB) was unknown. Our study aims to examine whether P300 abnormalities are present in DLB and to evidence possible differences between DLB and Alzheimers disease (AD). A second aim of this study is to look for correlations between P300 recordings and EEG, as abnormal EEG variability has been described in DLB. PATIENTS AND METHODS Auditory P300 responses were recorded by a classic oddball paradigm in 50 controls, in 36 DLB patients, and in 40 AD patients with MMSE>20. RESULTS Reliable auditory P300 responses were obtained in 26 DLB (72%), 33 AD (82.5%), and 46 controls (92%). P300 was more delayed and had lower amplitude in DLB compared to AD groups. P300 topography was also different as the anterior-to-posterior scalp amplitude gradient was reversed in DLB. P300 latency correlated with neuropsychological test scores and with EEG variables. Gradient inversion and delayed P300 responses in frontal derivations evidenced differences between DLB and AD patients with a sensitivity of 70% and a specificity of 97%. CONCLUSIONS P300 recordings are abnormal in DLB and can be useful to distinguish DLB from AD.

Recurrent and fatal akinetic crisis in genetic‐mitochondrial parkinsonisms

Akinetic crisis (AC) is the most severe and possibly lethal complication of parkinsonism. It occurs with an incidence of 3‰ Parkinsons disease patients per year, but it is not known whether genetically determined parkinsonism is more or less susceptible to this complication.

Long-Term Cognitive Decline in Dementia with Lewy Bodies in a Large Multicenter, International Cohort

BACKGROUND/OBJECTIVE The aim of this study was to describe the rate and clinical predictors of cognitive decline in dementia with Lewy bodies (DLB), and compare the findings with Alzheimers disease (AD) and Parkinsons disease dementia (PDD) patients. METHODS Longitudinal scores for the Mini-Mental State Examination (MMSE) in 1,290 patients (835 DLB, 198 PDD, and 257 AD) were available from 18 centers with up to three years longitudinal data. Linear mixed effects analyses with appropriate covariates were used to model MMSE decline over time. Several subgroup analyses were performed, defined by anti-dementia medication use, baseline MMSE score, and DLB core features. RESULTS The mean annual decline in MMSE score was 2.1 points in DLB, compared to 1.6 in AD (p = 0.07 compared to DLB) and 1.8 in PDD (p = 0.19). Rates of decline were significantly higher in DLB compared to AD and PDD when baseline MMSE score was included as a covariate, and when only those DLB patients with an abnormal dopamine transporter SPECT scan were included. Decline was not predicted by sex, baseline MMSE score, or presence of specific DLB core features. CONCLUSIONS The average annual decline in MMSE score in DLB is approximately two points. Although in the overall analyses there were no differences in the rate of decline between the three neurodegenerative disorders, there were indications of a more rapid decline in DLB than in AD and PDD. Further studies are needed to understand the predictors and mechanisms of cognitive decline in DLB.

Cerebrospinal fluid Alzheimer's disease biomarkers across the spectrum of lewy body diseases: Results from a large multicenter cohort

BACKGROUND Concomitant Alzheimers disease (AD) pathology is observed in Lewy body diseases (LBD), but the clinical impact is unknown. Only a few biomarker studies in LBD exist and have included small cohorts from single centers. OBJECTIVE We aimed to evaluate the prevalence of abnormal cerebrospinal fluid (CSF) AD biomarkers across the spectrum of LBD in a large multicenter cohort and to assess whether an AD biomarker profile was associated with demographic and clinical differences in dementia with Lewy bodies (DLB). METHODS We included 375 DLB patients, 164 Parkinsons disease (PD) patients without dementia, and 55 PD patients with dementia (PDD) from 10 centers. CSF amyloid-beta42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) values were dichotomized as abnormal or normal according to locally available cut-off values. A CSF AD profile was defined as abnormal Aβ42 combined with abnormal t-tau and/or p-tau. RESULTS A substantial proportion of DLB patients had abnormal values for CSF Aβ42, t-tau, and p-tau, while abnormal values were uncommon in PD without dementia. Patients with PDD had values in between. A CSF AD profile was observed in 25% of DLB patients, compared with only 9% of PDD and 3% of PD without dementia. Within DLB, patients with a CSF AD profile were older, more often female, performed worse on the Mini-Mental State Examination, and had shorter disease duration compared with patients with normal CSF. CONCLUSION A CSF AD profile is more common in DLB compared with PDD and PD, and is associated with more severe cognitive impairment in DLB.

Multimodal EEG-MRI in the differential diagnosis of Alzheimer's disease and dementia with Lewy bodies.

Differential diagnosis of Alzheimers disease (AD) and dementia with Lewy bodies (DLB) remains challenging; currently the best discriminator is striatal dopaminergic imaging. However this modality fails to identify 15–20% of DLB cases and thus other biomarkers may be useful. It is recognised electroencephalography (EEG) slowing and relative medial temporal lobe preservation are supportive features of DLB, although individually they lack diagnostic accuracy. Therefore, we investigated whether combined EEG and MRI indices could assist in the differential diagnosis of AD and DLB. Seventy two participants (21 Controls, 30 AD, 21 DLB) underwent resting EEG and 3 T MR imaging. Six EEG classifiers previously generated using support vector machine algorithms were applied to the present dataset. MRI index was derived from medial temporal atrophy (MTA) ratings. Logistic regression analysis identified EEG predictors of AD and DLB. A combined EEG-MRI model was then generated to examine whether there was an improvement in classification compared to individual modalities. For EEG, two classifiers predicted AD and DLB (model: χ2 = 22.1, df = 2, p < 0.001, Nagelkerke R2 = 0.47, classification = 77% (AD 87%, DLB 62%)). For MRI, MTA also predicted AD and DLB (model: χ2 = 6.5, df = 1, p = 0.01, Nagelkerke R2 = 0.16, classification = 67% (77% AD, 52% DLB). However, a combined EEG-MRI model showed greater prediction in AD and DLB (model: χ2 = 31.1, df = 3, p < 0.001, Nagelkerke R2 = 0.62, classification = 90% (93% AD, 86% DLB)). While suggestive and requiring validation, diagnostic performance could be improved by combining EEG and MRI, and may represent an alternative to dopaminergic imaging.

Functional and neurochemical interactions within the amygdala–medial prefrontal cortex circuit and their relevance to emotional processing

The amygdala–medial prefrontal cortex (mPFC) circuit plays a key role in emotional processing. GABA-ergic inhibition within the mPFC has been suggested to play a role in the shaping of amygdala activity. However, the functional and neurochemical interactions within the amygdala–mPFC circuits and their relevance to emotional processing remain unclear. To investigate this circuit, we obtained resting-state functional magnetic resonance imaging (rs-fMRI) and proton MR spectroscopy in 21 healthy subjects to assess the potential relationship between GABA levels within mPFC and the amygdala–mPFC functional connectivity. Trait anxiety was assessed using the State-Trait Anxiety Inventory (STAI-Y2). Partial correlations were used to measure the relationships among the functional connectivity outcomes, mPFC GABA levels and STAI-Y2 scores. Age, educational level and amount of the gray and white matters within 1H-MRS volume of interest were included as nuisance variables. The rs-fMRI signals of the amygdala and the vmPFC were significantly anti-correlated. This negative functional coupling between the two regions was inversely correlated with the GABA+/tCr level within the mPFC and the STAI-Y2 scores. We suggest a close relationship between mPFC GABA levels and functional interactions within the amygdala–vmPFC circuit, providing new insights in the physiology of emotion.

Akinetic crisis in dementia with Lewy bodies

Background and purpose Dementia with Lewy bodies (DLB) is characterised by neuroleptic hypersensitivity. It is unclear, however, whether the neuroleptic hypersensitivity implies an increased incidence of neuroleptic malignant syndrome (NMS) or of akinetic crisis (AC), which are expressions of the same possibly lethal clinical event, and whether AC in DLB can appear independently of neuroleptic treatment. In our prospective study, we assessed the incidence of AC in a cohort of DLB as compared with that in patients with Parkinson disease (PD). Methods In total, 614 patients with PD and 236 DLB were recruited and followed during 2005–2013. AC was diagnosed as sudden akinetic state unresponsive to dopaminergic rescue drugs, dysphagia and serological alterations without recovery for 48 h or more requiring hospital admission. Exposure to neuroleptics was specifically evaluated, because of the high implicit risk in DLB. Results 24 patients with PD (3.9%) and 16 patients with DLB (6.8%) developed AC. 77 (32.6%) DLB and 32 (5.2%) PD were exposed to typical neuroleptics, but only 8 DLB and 3 PD presented with AC. Disease duration before AC was lower in DLB than in PD group (p<0.01). Outcome was fatal in 8 patients with (50%) DLB and 3 (12.5%) PD (p=0.05). When age and use of neuroleptics were adjusted for into a Cox proportional hazards model predicting time to AC, the HR of patients with DLB was 13.0 (95% CI 4.23 to 39.9; p<0.001). Conclusions AC in DLB can appear independently of neuroleptic treatment, occurs earlier and is more frequently fatal than in PD.

Electrophysiological indices of interference resolution covary with individual fluid intelligence: investigating reactive control processes in a 3-back working memory task☆

It has been proposed that the well-established relationship between working memory (WM) and fluid intelligence (gf) is mediated by executive mechanisms underlying interference control. The latter relies upon the integrity of a frontoparietal brain network, whose activity is modulated by general cognition. In regards to the chronology of this activation, only few EEG studies investigated the topic, although none of them examined the regional interaction or the effects of individual differences in gf. The current investigation sought at extending previous research by characterizing the EEG markers (temporal activation and regional coupling) of interference control and the effects of the individual variation in gf. To this end, we recorded the EEG activity of 33 participants while performing verbal and spatial versions of a 3-back WM task. In a separate session, participants were administered with a test of fluid intelligence. Interference-inducing trials were associated with an increased negativity in the frontal scalp region occurring in two separate time windows and probably reflecting two different stages of the underlying cognitive process. In addition, we found that scalp distribution of such activity differed among individuals, being the strongest activation of the left and right frontolateral sites related to high gf level. Finally, high- and low-gf participants showed different patterns in the modulation of regional connectivity (electrodes coherence in the range of 4.5-7.5Hz) according to changes in attention load among types of trials. Our findings suggest that high-gf participants may rely upon effective engagement and modulation of attention resources to face interference.