Pharmacologic therapy of dementia with Lewy bodies

As a clinicopathologically defined entity, dementia with Lewy bodies (DLB) has overlapping features of Alzheimer's disease (AD) and Parkinson's disease (PD). Analogous characteristics of DLB offer a provisional rationale for pharmacologic therapy based on remediating cholinergic and dopaminergic deficits, respectively. However, the distinct clinical manifestations and pathophysiologic substrates of DLB pose unique therapeutic opportunities and challenges. More severe cholinergic deficits in DLB relative to AD support clinical evidence that cholinergic therapy may be particularly beneficial in DLB patients. In contrast, DLB patients are generally more sensitive to the adverse effects of antipsychotic agents, warranting caution in treating visual hallucinations and other psychotic symptoms. Similarly, parkinsonian motor signs in DLB, often manifest as rigidity and bradykinesia, may be less amenable to dopaminergic therapies than in PD. Increasing recognition of DLB as a common form of dementia in the elderly underscores the need for large-scale, placebo-controlled therapeutic trials.     

Differential changes in visual and auditory event-related oscillations in dementia with Lewy bodies

ObjectiveAside from the cognitive impairment, patients with dementia with Lewy bodies (DLB) have a high frequency of visual hallucinations and a number of other vision-related symptoms, whereas auditory hallucinations are less frequent. To better understand the differential dysfunction of the visual network in DLB, we compared auditory and visual event-related potentials and oscillations in patients with DLB.MethodsEvent-related potentials elicited by visual and auditory oddball tasks were recorded in 23 patients with DLB and 22 healthy controls and analyzed in time and time-frequency domain.ResultsDLB patients had decreased theta band activity related to both early sensory and later cognitive processing in the visual, but not in the auditory task. Patients had lower delta and higher alpha and beta bands power related to later cognitive processing in both auditory and visual tasks.ConclusionsIn DLB visual event-related oscillations are characterized by a decrease in theta and lack of inhibition in alpha bands.SignificanceDecreased theta and a lack of inhibition in alpha band power might be an oscillatory underpinning of some classical DLB symptoms such as fluctuations in attention and high-level visual disturbances and a potential marker of dysfunction of the visual system in DLB.     

Characterization of diplopia in non-demented patients with Parkinson's disease

IntroductionAlthough diplopia is considered a frequent symptom of Parkinson's disease (PD), little is known about its clinical manifestation, associated mechanisms and treatment. Here we characterized binocular diplopia in non-demented PD patients in an interdisciplinary setting.MethodsPD patients were prospectively screened for diplopia, visual hallucinations, problems with spatial perception, contrast sensitivity, presence of blurred vision, and history of ophthalmological comorbidities via interview. Two groups of PD patients, one with and one without diplopia, underwent clinical and ophthalmological assessment to characterize diplopia in these patients. Clinical features were investigated using the Unified Parkinson's Disease Rating Scale and the Non-Motor Symptoms Scale.ResultsThe frequency of binocular diplopia was 29.6% (n = 37) in our cohort of 125 Parkinson's disease patients. Related mechanisms were heterogeneous including convergence insufficiency, strabismus, and motor fluctuations, as well as symptoms related to visual hallucinations. Diplopia was associated with other visual disturbances like visual hallucinations, blurred vision and problems with spatial perception. Beyond that, diplopia was found to be a predictive factor (3.2, odds ratio) for the occurrence of visual hallucinations in PD.ConclusionBinocular diplopia represents a frequent and relevant symptom in PD patients. Different subtypes should be considered due to different associated mechanisms including ophthalmic pathology and motor fluctuation, as well as intermediate to higher level visual processes. Diplopia seems to be part of a continuous spectrum of positive visual symptoms in Parkinson's disease.     

A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson's disease with and without dementia

OBJECTIVES: To compare the frequency and clinical correlates of neuropsychiatric symptoms in patients with Parkinson's disease (PD) with and without dementia and in those with dementia with Lewy bodies (DLB). METHODS: Neuropsychiatric symptoms during the month prior to assessment were assessed in clinically diagnosed PD patients with dementia (PDD; n = 48) and without dementia (PDND; n = 83) and in 98 DLB patients (33% autopsy confirmed) using standardized instruments. RESULTS: Delusions and hallucinations were significantly more common in DLB (57% and 76%) than PDD (29% and 54%) and PDND (7% and 14%) patients (p < 0.001). In all groups, auditory and visual hallucinations and paranoid and phantom boarder delusions were the most common psychotic symptoms. Frequency of major depression and less than major depression did not differ significantly between the three groups. Clinical correlates of hallucinations in PD were dementia (odds ratio (OR) = 3.9; 95% confidence interval (CI) 1.5-10.4) and Hoehn-Yahr stage 3 or more (OR 3.4; 95% CI 1.0-12.0), whereas no significant clinical correlates of hallucinations were found in DLB patients. CONCLUSIONS: Delusions and hallucinations occur with increasing frequency in PDND, PDD and DLB patients, but the presentation of these symptoms is similar. These findings support the hypothesis that psychiatric symptoms are associated with cortical Lewy bodies or cholinergic deficits in the two disorders.     

The relation between visual hallucinations and visual evoked potential in Parkinson disease

OBJECTIVE: The pathophysiology of hallucinations in Parkinson disease is poorly understood. This study investigated the relation between visual hallucination and visual evoked potentials (VEPs) in Parkinson disease. METHODS: Nineteen patients with Parkinson disease were studied. The authors divided patients into 2 groups: patients with visual hallucinations (VH group) and those without visual hallucinations (no-VH group). VEPs using a checkerboard stimulus were recorded under a drug-free state. RESULTS: On multivariate regression analysis, only the average P100 latency was selected and remained significant after the backward elimination method. CONCLUSION: The authors demonstrated a close association between visual hallucinations and elongated VEP latency in Parkinson disease. VEPs may become one of the predictors for visual hallucination.     

Visual complaints and visual hallucinations in Parkinson's disease

BackgroundVisual symptoms are common in Parkinson's disease (PD) and are frequently under-diagnosed. The detection of visual symptoms is important for differential diagnosis and patient management.AimTo establish the prevalence of recurrent visual complaints (RVC) and recurrent visual hallucinations (RVH) and to investigate their interaction in PD patients and controls.MethodsThis cross-sectional study included 88 PD patients and 90 controls. RVC and RVH were assessed with a visual symptom questionnaire and the North-East-Visual-Hallucinations-Interview (NEVHI).ResultsDouble vision (PD vs. Controls: 18.2% vs. 1.3%; p < 0.001), misjudging objects when walking (PD vs. Controls: 12.5% vs. 1.3%; p < 0.01), words moving whilst reading (PD vs. Controls: 17.0% vs. 1.3%; p < 0.001) and freezing in narrow spaces (PD vs. Controls: 30.7% vs. 0%; p < 0.001) were almost exclusively found in PD patients. The same was true for recurrent complex visual hallucinations and illusions (PD vs. Controls: both 17.0% vs. 0%; p < 0.001). Multiple RVC (43.2% vs. 15.8%) and multiple RVH (29.5% vs. 5.6%) were also more common in PD patients (both p < 0.001). RVC did not predict recurrent complex visual hallucinations; but double vision (p = 0.018, R² = 0.302) and misjudging objects (p = 0.002, R² = 0.302) predicted passage hallucinations. Misjudging objects also predicted the feeling of presence (p = 0.010, R² = 0.321).ConclusionsMultiple and recurrent visual symptoms are common in PD. RVC emerged as risk factors predictive of the minor forms of hallucinations, but not recurrent complex visual hallucinations.     

Visual evoked potentials in parkinsonism and dopamine blockade reveal a stimulus-dependent dopamine function in humans.

VEPs were recorded with three different spatial frequencies of stimulation in patients affected by idiopathic Parkinsonism and by Parkinsonian syndromes. The detection of VEP abnormalities in Parkinson's disease was dependent on the spatial frequency of the visual stimulus (a vertical square wave grating). The VEP latency was normal in Parkinsonian syndrome patients (except in one patient affected by familial Parkinsonism). Dopamine precursor therapy differently reduced the VEP latency, depending on the spatial frequency of the visual stimulus. These findings suggest that the dopaminergic mechanism involved in the generation of VEP delays is sensitive to stimulus spatial frequency. The study of VEPs before and after the administration of haloperidol confirmed this hypothesis. VEP latency did not correlate with the major clinical symptoms of Parkinson's disease and could not predict the results of chronic dopaminergic therapy.     

Neural correlates of minor hallucinations in non-demented patients with Parkinson's disease

BackgroundHallucinations are a frequent and severe complication in Parkinson's disease (PD). Minor hallucinations are generally not disturbing, but likely progress to well-structured hallucinations with loss of insight and a great impact on quality of life. Knowledge on the neural bases of minor hallucinations may help to describe those systems associated with the early development of psychotic phenomena in PD.In this study, we aimed to identify the pattern of structural brain alterations associated with minor hallucinations in PD by using voxel-based morphometry (VBM).MethodsWe prospectively collected a sample of 46 non-demented PD patients, with (N = 17) and without (n = 29) minor hallucinations (passage and/or presence hallucinations), and 15 healthy controls. Groups were matched for age, education and global cognitive function. Presence and type of minor psychotic phenomena was assessed by the new MDS-UPDRS. Three dimensional T1-weighted MRI images were acquired with a 1.5 T magnet, and analyzed using optimized VBM.ResultsCompared to controls, PD with minor hallucinations (PD-mH) showed reduced gray matter volume bilaterally in different areas of the dorsal visual stream, and in functionally related midbrain and cerebellar structures. Additionally, bilateral gray matter volume increases were observed in the PD-mH group in limbic and paralimbic regions.ConclusionsOur data support a major role of the dorsal visual stream in the genesis of minor hallucinations in PD, reinforcing the importance of posterior cortical regions for the development of cognitive and psychiatric complications in PD.     

Multimodal characterization of the visual network in Huntington’s disease gene carriers

ObjectiveA sensorimotor network structural phenotype predicted motor task performance in a previous study in Huntington’s disease (HD) gene carriers. We investigated in the visual network whether structure – function – behaviour relationship patterns, and the effects of the HD mutation, extended beyond the sensorimotor network.MethodsWe used multimodal visual network MRI structural measures (cortical thickness and white matter connectivity), plus visual evoked potentials and task performance (Map Search; Symbol Digit Modalities Test) in healthy controls and HD gene carriers.ResultsUsing principal component (PC) analysis, we identified a structure – function relationship common to both groups. PC scores differed between groups indicating white matter disorganization (higher RD, lower FA) and slower, and more disperse, VEP signal transmission (higher VEP P100 latency and lower VEP P100 amplitude) in HD than controls while task performance was similar.ConclusionsHD may be associated with reduced white matter organization and efficient visual network function but normal task performance.SignificanceThese findings indicate that structure – function relationships in the visual network, and the effects of the HD mutation, share some commonalities with those in the sensorimotor network. However, implications for task performance differ between the two networks suggesting the influence of network specific factors.     

Characteristics,correlates, and assessment of psychosis in Parkinson disease without dementia

IntroductionConsidering that psychosis in Parkinson disease (PD) is associated with worse outcomes, including dementia, we aimed to study the characteristics, correlates, and assessment of PD psychosis in those without dementia.Methods101 PD subjects without dementia (Montreal Cognitive Assessment ≥21/30) were recruited to participate in a study of neuropsychiatric symptoms in PD. This study included a baseline standard neurological exam and common PD symptom assessments. Using the Scale for the Assessment of Positive Symptoms (SAPS) and separate assessment of visual illusions and sense of presence, NINDS-NIMH criteria for PD psychosis were applied.ResultsOf the 33 (32.7%) PD subjects who met diagnostic criteria for psychosis in PD, visual illusions were most common (72.7%), followed by visual hallucinations (39.4%). Adjusted for presence of REM sleep behavior disorder (RBD) (p = 0.097), use of dopamine agonists (OR = 3.7, p = 0.012) and greater autonomic symptom burden (OR = 1.1 (per 1-unit change in score on SCOPA-AUT), p = 0.012) were associated with greater risk of psychosis. Use of dopamine agonists (OR = 5.0, p = 0.007), higher MDS-UPDRS Part II score (OR = 1.1, p = 0.010), and presence of RBD (OR = 4.8, p = 0.012) were independent predictors of visual hallucinations and visual illusions. MDS-UPDRS item 1.2 score ≥1 had highly correlated with the SAPS score (r = 0.65, p < 0.0001), but was 42% sensitive and 96% specific for identifying psychosis.ConclusionThis study confirms the association between dopamine agonists and psychosis in PD patients without dementia. The association of RBD, autonomic symptoms, and MDS-UPDRS Part II scores with psychosis underscore its link to brainstem dysfunction and greater PD motor symptom severity.     

Abnormal psychophysical visual perception in Parkinson's disease patients

Several visual dysfunctions in Parkinson's disease (PD) are described. Most of them are subtle or only demonstrated by stimulus-specific electrophysiologic or psychophysical testing. However, these minor deficits are thought to be of clinical relevance as they are related to direct or indirect complaints. Special emphasis is laid on visual hallucinations. These are most likely of multifactorial origin. The relation between hallucinations in PD and in dementia with Lewy bodies has to be elaborated further. Visual loss, as a possible and reversible cause of visual hallucinations should be actively sought and corrected as far as possible. An underlying role of dopaminergic retinal cells in visual dysfunction of PD patients is widely recognised. However, whether the basic abnormality resides also in the visual cortex remains to be elucidated. Other neurotransmitters may also be involved. It has not been answered whether visual dysfunction might distinguish PD from other forms of parkinsonism.     

Visual hallucinations and regional cerebral metabolism in dementia with Lewy bodies (DLB).

To investigate the neurobiological bases of visual hallucinations in dementia with Lewy bodies (DLB), regional cerebral glucose metabolism was compared among three patient groups; DLB with visual hallucinations, DLB without visual hallucinations and Alzheimer's disease (AD) without visual hallucinations. The regional metabolism was significantly lower in both DLB groups than in the AD group in the primary visual area and the posterior temporal, parietal and lateral occipital association areas. The hypometabolism in the right posterior temporal and parietal areas was significantly milder in DLB with visual hallucinations than in DLB without hallucinations. The hypometabolism in the primary visual cortex and the relatively preserved metabolism in the right temporoparietal association cortices may be associated with the occurrence of visual hallucinations in DLB patients.     

Visual evoked potential abnormalities in Charcot-Marie-Tooth disease and comparison with Friedreich's ataxia

Pattern-reversal visual evoked potentials (VEPs), recorded in 15 visually asymptomatic patients fulfilling the clinical and electrophysiological criteria of Charcot-Marie-Tooth disease (CMTD), were abnormal in 5 and possibly abnormal in another 3. Five patients showed a prolongation of P100 latency, one a reduction of amplitude and one a possibly abnormal "scotomatous" waveform. In 9 cases abnormalities were detected on neuro-ophthalmological examination. These were poorly correlated with VEP abnormalities, except for patients with 2 or more clinical eye signs. Relative central scotomata were found in the patient with an abnormal waveform. VEP abnormalities, where present, were usually fairly comparable in the 2 eyes. In comparison with a group of Friedrich's ataxia cases there was a lower overall incidence of VEP abnormalities in CMTD, but little to suggest a qualitative difference in the nature of the visual pathway pathology. All 4 patients with unequivocally abnormal VEPs had experienced atypical symptoms suggestive of CNS involvement. In none of these was it possible to sustain an alternative diagnosis. It is concluded that a minor degree of visual pathway involvement may be present in many CMTD cases, in spite of the fact that optic atrophy is only rarely reported, and that the VEP latency may reflect the degree to which other parts of the CNS are involved.     

Impaired metabolic brain networks associated with neurotransmission systems in the α-synuclein spectrum

IntroductionWhile the involvement of multiple neurotransmitter systems in α-synucleinopathies is reported, a comprehensive study on their metabolic connectivity reconfiguration in the preclinical and clinical disease-spectrum is lacking. We aimed to investigate shared and disease-specific neural vulnerabilities of the nigro-striato-cortical dopaminergic, noradrenergic and cholinergic networks within the α-synuclein-spectrum, by means of metabolic connectivity approach.MethodsWe collected 34 polysomnography-confirmed isolated REM sleep behaviour disorder (iRBD) subjects, 29 idiopathic Parkinson's disease (PD) patients without dementia, 30 patients with probable dementia with Lewy bodies (DLB), and 50 healthy controls for comparisons. Neurotransmission networks' analyses were performed through multivariate partial correlations based on FDG-PET brain metabolic data.ResultsWe found: a) the nigro-striato-cortical dopaminergic network with a limited reconfiguration in individuals with iRBD, but moderate-to-severe alterations in patients with DLB and PD; b) an extended connectivity alteration of the noradrenergic network in all groups; c) changes within the cholinergic networks connectivity in the whole disease-spectrum, with some differences: PD with only moderate connectivity reconfiguration and DLB with the most severe alterations, some of these shared with iRBD.ConclusionsSynucleinopathies can be considered multisystem disorders, with common and disease-specific neurotransmission networks reconfigurations. The present findings indicate dopaminergic connectivity alterations only when associated with parkinsonism, a very early involvement of noradrenergic networks, occurring in both the iRBD and in symptomatic PD/DLB patients and cholinergic alterations with disease-specific vulnerabilities shared by iRBD and DLB. The latter finding may represent an early biomarker of disease progression to dementia.     

Correlation of visual hallucinations with occipital rCBF changes by donepezil in DLB

The authors explored the neural substrate of visual hallucinations in dementia with Lewy bodies (DLB) by investigating changes in regional cerebral blood flow (rCBF) and psychiatric symptoms, before and after cholinesterase inhibitor treatment. Twenty subjects with DLB were treated with donepezil for a 12-week period. Hallucinations attenuated while receiving therapy, whereas occipital rCBF focally increased, suggesting that functional visual association cortex deficits may cause visual hallucinations in patients with DLB.     

Differentiation of dementia with Lewy bodies from Alzheimer's disease using a dopaminergic presynaptic ligand

BACKGROUND: Dementia with Lewy bodies (DLB) is one of the main differential diagnoses of Alzheimer's disease (AD). Key pathological features of patients with DLB are not only the presence of cerebral cortical neuronal loss, with Lewy bodies in surviving neurones, but also loss of nigrostriatal dopaminergic neurones, similar to that of Parkinson's disease (PD). In DLB there is 40-70% loss of striatal dopamine. OBJECTIVE: To determine if detection of this dopaminergic degeneration can help to distinguish DLB from AD during life. METHODS: The integrity of the nigrostriatal metabolism in 27 patients with DLB, 17 with AD, 19 drug naive patients with PD, and 16 controls was assessed using a dopaminergic presynaptic ligand, (123)I-labelled 2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT), and single photon emission tomography (SPET). A SPET scan was carried out with a single slice, brain dedicated tomograph (SME 810) 3.5 hours after intravenous injection of 185 MBq FP-CIT. With occipital cortex used as a radioactivity uptake reference, ratios for the caudate nucleus and the anterior and posterior putamen of both hemispheres were calculated. All scans were also rated by a simple visual method. RESULTS: Both DLB and PD patients had significantly lower uptake of radioactivity than patients with AD (p<0.001) and controls (p<0.001) in the caudate nucleus and the anterior and posterior putamen. CONCLUSION: FP-CIT SPET provides a means of distinguishing DLB from AD during life.     

Levodopa response in dementia with lewy bodies: A 1-year follow-up study

PurposeTo evaluate levodopa responsiveness in patients with probable dementia with Lewy bodies (DLB) compared to early Parkinson’s disease (PD) patients.MethodsTwenty four cases with DLB and 21 with PD underwent a baseline assessment with UPDRS (sub-item II and III) and an acute levodopa challenge test. Positive response to acute levodopa test was defined as an improvement of at least 15% in the tapping test, and at least 25% in the walking test and rigidity or tremor score. Subsequently, all patients were treated continuously with levodopa and evaluated after 6 and 12 months by means of UPDRS II/III.ResultsPositive response to the acute levodopa test was observed in 55% of DLB patients (acute DLB responders), and in 90% of PD patients (acute PD responders). Acute DLB responders showed increased latency, and reduction of both duration and amplitude of response to acute levodopa in comparison with acute PD responders. At the 6-month follow-up visit, acute DLB responders showed a greater motor benefit compared with acute DLB non-responders. This improvement was similar to that observed in PD patients. However, at 1-year follow-up acute DLB responders showed a faster worsening of UPDRS III scores compared with acute PD responders, implying a reduction of levodopa efficacy.ConclusionsPositive response to acute levodopa test can occur in DLB patients and may be predictive of long-term benefit of chronic levodopa therapy, although the motor improvement is less impressive than in PD patients.     

Features associated with the development of hallucinations in Parkinson's disease

OBJECTIVE: To identify features related to the development of hallucinations in Parkinson's disease (PD). MATERIALS AND METHODS: Seventy PD patients with hallucinations (group 1) and 60 PD patients without hallucinations (group 2) were evaluated for disease severity, presence of motor complications, rapid eye movement (REM) behavior disorder (RBD), and antiparkinsonian drug profile. The ages at the emergence of hallucinations and duration of disease in group 1 were matched with the ages at the last visit of those in group 2. RESULTS: Disease severity and presence of motor complications were similar in both groups. RBD was more frequently encountered among hallucinators than among non-hallucinators (P = 0.007). The mean duration and daily doses of levodopa and other dopaminergic drugs did not differ in both groups; however, the usage of anticholinergics and amantadine were significantly more frequent in group 2, unexpectedly. CONCLUSIONS: The presence of RBD was significantly more common in hallucinators; however, severity of PD, duration and daily doses of dopaminergic drugs were not associated with the emergence of hallucinations.     

Foveal interocular time thresholds and latency differences in multiple sclerosis

Summary Nineteen patients with suspected multiple sclerosis (MS) and 28 control subjects were foveally stimulated by a small cross formed by rectangular red-light-emitting diodes. By means of crossed polarizers one eye was exposed only to the horizontal bar of the cross, the other to the vertical. Stimulus onset asynchrony ranged from 0 to ±300 ms (the horizontal bar preceding or following the vertical). The task was to indicate whether the horizontal or vertical bar had appeared first. Compared with normal subjects, MS patients exhibited much higher time thresholds (ranging from –150 to +130 ms) and had considerable interocular latency differences (up to 29 ms), indicating unilateral or asymmetrical impairment of the visual pathways. The psychophysical latency differences of the patients were compared to monocular latencies and interocular latency differences of the visually evoked cortical potential (VEP) obtained by foveal stimulation. Under the stimulus conditions chosen in this study, the diagnostic value of the psychophysical measurements was equal to or, for McAlpine's classes I and II of definite and probable MS patients, better than that based on VEP recordings.     

Reality monitoring and visual hallucinations in Parkinson's disease

Between 8 and 40% of Parkinson disease (PD) patients will have visual hallucinations (VHs) during the course of their illness. Although cognitive impairment has been identified as a risk factor for hallucinations, more specific neuropsychological deficits underlying such phenomena have not been established. Research in psychopathology has converged to suggest that hallucinations are associated with confusion between internal representations of events and real events (i.e. impaired-source monitoring). We evaluated three groups: 17 Parkinson's patients with visual hallucinations, 20 Parkinson's patients without hallucinations and 20 age-matched controls, using tests of visual imagery, visual perception and memory, including tests of source monitoring and recollective experience. The study revealed that Parkinson's patients with hallucinations appear to have intact visual imagery processes and spatial perception. However, there were impairments in object perception and recognition memory, and poor recollection of the encoding episode in comparison to both non-hallucinating Parkinson's patients and healthy controls. Errors were especially likely to occur when encoding and retrieval cues were in different modalities. The findings raise the possibility that visual hallucinations in Parkinson's patients could stem from a combination of faulty perceptual processing of environmental stimuli, and less detailed recollection of experience combined with intact image generation.