DNAJC13 p.Asn855Ser mutation screening in Parkinson's disease and pathologically confirmed Lewy body disease patients.

BACKGROUND: Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi-incident Mennonite family. METHODS: In the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD). RESULTS: Our sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed. CONCLUSION: Our results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder.

OBJECTIVE: To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: 172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features. CONCLUSIONS: In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

Pathology and temporal onset of visual hallucinations, misperceptions and family misidentification distinguishes dementia with Lewy bodies from Alzheimer's disease.

OBJECTIVE: To determine whether the temporal onset of visual phenomena distinguishes Lewy body disease (LBD) from Alzheimer's disease (AD), and to characterize the extent Lewy bodies and neurofibrillary tangles are associated with these clinical features. METHODS: Consecutive cases of autopsy-confirmed LBD (n = 41), AD (n = 70), and AD with amygdala-predominant Lewy bodies (AD-ALB) (n = 14) with a documented clinical history of dementia were included. We mailed questionnaires to next-of-kin asking about symptoms during life. Lewy pathology and neurofibrillary tangle pathology were assessed. RESULTS: The occurrence of visual hallucinations, misperceptions and family misidentification did not distinguish LBD from AD or AD-ALB, but the onset was earlier in LBD compared to AD and AD-ALB. When visual hallucinations developed within the first 5 years of dementia, the odds were 4-5 times greater for autopsy-confirmed LBD (or intermediate/high likelihood dementia with Lewy bodies) and not AD or AD-ALB. In LBD, limbic but not cortical Lewy body pathology was related to an earlier onset of visual hallucinations, while limbic and cortical Lewy body pathology were associated with visual misperceptions and misidentification. Cortical neurofibrillary tangle burden was associated with an earlier onset of misidentification and misperceptions in LBD and AD, but only with earlier visual hallucinations in AD/AD-ALB. CONCLUSION: When visual hallucinations occur within the first 5 years of the dementia, a diagnosis of LBD was more likely than AD. Visual hallucinations in LBD were associated with limbic Lewy body pathology. Visual misperceptions and misidentification delusions were related to cortical Lewy body and neurofibrillary tangle burden in LBD and AD/AD-ALB.

Neuropathological analysis of brainstem cholinergic and catecholaminergic nuclei in relation to rapid eye movement (REM) sleep behaviour disorder.

AIMS: Rapid eye movement sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during rapid eye movement sleep and is associated with dream enactment behaviour. RBD is often associated with α-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurones in a neighbouring nucleus, the locus coeruleus (LC). METHODS: This retrospective study utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 Alzheimer's disease (AD) and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurones of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and α-synuclein pathology was measured in the same regions with immunohistochemistry. RESULTS: Both the LC and PPN/LDT were vulnerable to α-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of α-synuclein pathology in LBD with and without RBD. CONCLUSIONS: Whether decreases in brainstem cholinergic neurones in LBD contribute to RBD is uncertain, but our findings indicate these neurones are highly vulnerable to α-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective α-synuclein-mediated neuronal loss in these nuclei remains to be determined.

Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies.

OBJECTIVE: To determine whether adding REM sleep behavior disorder (RBD) to the dementia with Lewy bodies (DLB) diagnostic criteria improves classification accuracy of autopsy-confirmed DLB. METHODS: We followed 234 consecutive patients with dementia until autopsy with a mean of 4 annual visits. Clinical diagnoses included DLB, Alzheimer disease (AD), corticobasal syndrome, and frontotemporal dementia. Pathologic diagnoses used the 2005 DLB consensus criteria and included no/low likelihood DLB (non-DLB; n = 136) and intermediate/high likelihood DLB (DLB; n = 98). Regression modeling and sensitivity/specificity analyses were used to evaluate the diagnostic role of RBD. RESULTS: Each of the 3 core features increased the odds of autopsy-confirmed DLB up to 2-fold, and RBD increased the odds by 6-fold. When clinically probable DLB reflected dementia and 2 or more of the 3 core features, sensitivity was 85%, and specificity was 73%. When RBD was added and clinically probable DLB reflected 2 or more of 4 features, sensitivity improved to 88%. When dementia and RBD were also designated as probable DLB, sensitivity increased to 90% while specificity remained at 73%. The VH, parkinsonism, RBD model lowered sensitivity to 83%, but improved specificity to 85%. CONCLUSIONS: Inclusion of RBD as a core clinical feature improves the diagnostic accuracy of autopsy-confirmed DLB.

Dementia with Lewy bodies and Alzheimer disease: neurodegenerative patterns characterized by DTI.

OBJECTIVE: To identify the patterns of diffusivity changes in patients with dementia with Lewy bodies (DLB) and Alzheimer disease (AD) and to determine whether diffusion tensor MRI (DTI) is complementary to structural MRI in depicting the tissue abnormalities characteristic of DLB and AD. METHODS: We studied clinically diagnosed age-, gender-, and education-matched subjects with DLB (n = 30), subjects with AD (n = 30), and cognitively normal (CN) subjects (n = 60) in a case-control study. DTI was performed at 3T with a fluid-attenuated inversion recovery-based DTI sequence that enabled cortical diffusion measurements. Mean diffusivity (MD) and gray matter (GM) density were measured from segmented cortical regions. Tract-based diffusivity was measured using color-coded fractional anisotropy (FA) maps. RESULTS: Patients with DLB were characterized by elevated MD in the amygdala and decreased FA in the inferior longitudinal fasciculus (ILF). ILF diffusivity was associated with the presence of visual hallucinations (p = 0.007), and amygdala diffusivity was associated with Unified Parkinson's Disease Rating Scale (r = 0.50; p = 0.005) in DLB. In contrast, patients with AD were characterized by elevated MD in the medial temporal, temporal, and parietal lobe association cortices and decreased FA in the fornix, cingulum, and ILF. Amygdala diffusivity was complementary to GM density in discriminating DLB from CN; hippocampal and parahippocampal diffusivity was complementary to GM density in discriminating AD from CN. CONCLUSION: Increased amygdalar diffusivity in the absence of tissue loss in dementia with Lewy bodies (DLB) may be related to microvacuolation, a common pathology associated with Lewy body disease in the amygdala. Diffusivity measurements were complementary to structural MRI, demonstrating that measures of diffusivity on diffusion tensor MRI are valuable tools for characterizing the tissue abnormalities characteristic of Alzheimer disease and DLB.

A plateau in pre-Alzheimer memory decline: evidence for compensatory mechanisms?

OBJECTIVE: To compare logistic and bilogistic models to describe the pattern of cognitive decline in the preclinical phase of Alzheimer disease (AD). METHODS: We conducted mixed effects modeling of Mayo Cognitive Factors Scores to determine the longitudinal pattern of cognitive decline in the period 10 years prior to and 5 years following a clinical diagnosis of AD. Our analysis included 199 people that eventually received a diagnosis of clinically probable AD. Participants had at least two neuropsychological evaluations including one before the evaluation at which they received the AD diagnosis. RESULTS: A bilogistic model, including terms for a plateau in the course of cognitive decline, better fit longitudinal memory scores than a simple logistic model. On average the plateau began about 4 years prior to the clinical diagnosis of AD and ended with a decline that probably contributed to the clinical diagnosis of AD. A similar plateau was not evident in four other cognitive domains. CONCLUSIONS: The current findings may support proposed compensatory hypotheses involving redundant memory systems, up-regulation of neurotransmitters, or recruitment of other neural networks.

Mayo's Older Americans Normative Studies: Visual Form Discrimination and copy trial of the Rey-Osterrieth Complex Figure.

Age-adjusted normative data are presented for persons age 70-89 years for the Visual Form Discrimination Test and Rey-Osterrieth Complex Figure (copy trial only). Adjustment for the effect of education on test performance is also provided. These data were collected as part of Mayo's Older Americans Normative Studies (MOANS). The normative information provided here should prove useful for characterizing performance on these measures as well as comparing the person's performance against his or her functioning on any other test with MOANS norms. Limitations and unique features of the MOANS normative data are also discussed.

Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease.

REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of normal skeletal muscle atonia during REM sleep with prominent motor activity accompanying dreaming. The terminology relating to RBD, and mechanisms underlying REM sleep without atonia and RBD based on data in cat and rat are presented. Neuroimaging data from the few published human cases with RBD associated with structural lesions in the brainstem are presented, in which the dorsal midbrain and pons are implicated. Pharmacological manipulations which alter RBD frequency and severity are reviewed, and the data from human neuropathological studies are presented. An anatomic framework and new schema for the pathophysiology of RBD are proposed based on recent data in rat regarding the putative flip-flop switch for REM sleep control. The structure in man analogous to the subcoeruleus region in cat and sublaterodorsal nucleus in rat is proposed as the nucleus (and its associated efferent and afferent pathways) crucial to RBD pathophysiology. The association of RBD with neurological disease ('secondary RBD') is presented, with emphasis on RBD associated with neurodegenerative disease, particularly the synucleinopathies. The hypothesized pathophysiology of RBD is presented in relation to the Braak staging system for Parkinson's disease, in which the topography and temporal sequence of synuclein pathology in the brain could explain the evolution of parkinsonism and/or dementia well after the onset of RBD. These data suggest that many patients with 'idiopathic' RBD are actually exhibiting an early clinical manifestation of an evolving neurodegenerative disorder. Such patients may be appropriate for future drug therapies that affect synuclein pathophysiology, in which the development of parkinsonism and/or dementia could be delayed or prevented. We suggest that additional clinicopathological studies be performed in patients with dementia or parkinsonism, with and without RBD, as well as in patients with idiopathic RBD, to further elucidate the pathophysiology and also characterize the clinical and pathophysiological relevance of RBD in neurodegenerative disease. Furthermore, longitudinal studies in patients with idiopathic RBD are warranted to characterize the natural history of such patients and prepare for future therapeutic trials.

Insights into REM sleep behavior disorder pathophysiology in brainstem-predominant Lewy body disease.

BACKGROUND AND PURPOSE: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia reflecting changes in the brain, but which specific neuronal networks are involved in human RBD pathogenesis has not yet been determined. To date, only one case of idiopathic RBD has undergone autopsy, in which "incidental Lewy body disease" was found. Due to the severe neuronal loss and gliosis in the substantia nigra (SN) and locus ceruleus (LC) in this case, degeneration of brainstem monoaminergic neurons was postulated as the underlying substrate for RBD. Additional cases of idiopathic RBD with neuropathologic examination may help clarify which key brainstem structures are involved. PATIENT AND METHODS: Case report with neuropathologic analysis. RESULTS: A man with polysomnographically proven RBD (onset age 57 years), but no other neurologic signs or symptoms, underwent neuropathologic examination upon his death at age 72. Histopathologic analysis showed Lewy body disease, but no significant neuronal loss or gliosis was present in the SN or LC. CONCLUSIONS: This case represents another example of Lewy body disease associated with RBD. The minimal degenerative changes in the SN and LC call into question the role of these nuclei in RBD, at least in our case. We suggest additional cases of idiopathic RBD undergo neuropathologic analyses to better delineate the neurologic substrate of this intriguing parasomnia.

Family history of dementia is a risk factor for Lewy body disease.

Genetic factors are important in Alzheimer disease (AD) and Parkinson disease but have not been well characterized in Lewy body dementia (LBD). The authors obtained family history in patients from an autopsy series of AD and LBD and in living healthy controls. A family history of dementia was more common in both LBD and AD compared with controls, suggesting that genetic factors are as important in LBD as they are in AD.

1H MR spectroscopy in common dementias.

OBJECTIVE: To determine the 1H MR spectroscopic (MRS) findings and intergroup differences among common dementias: Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal lobar degeneration (FTLD). METHODS: The authors consecutively recruited 206 normal elderly subjects and 121 patients with AD, 41 with FTLD, 20 with DLB, and 8 with VaD. The 1H MRS metabolite ratio changes in common dementias were evaluated with respect to normal and also differences among the common dementias. RESULTS: N-acetylaspartate (NAA)/creatine (Cr) was lower than normal in patients with AD, FTLD, and VaD. Myo-inositol (mI)/Cr was higher than normal in patients with AD and FTLD. Choline (Cho)/Cr was higher than normal in patients with AD, FTLD, and DLB. There were no metabolite differences between patients with AD and FTLD or between patients with DLB and VaD. NAA/Cr was lower in patients with AD and FTLD than DLB. MI/Cr was higher in patients with AD and FTLD than VaD. MI/Cr was also higher in patients with FTLD than DLB. CONCLUSIONS: NAA/Cr levels are decreased in dementias that are characterized by neuron loss, such as AD, FTLD, and VaD. MI/Cr levels are elevated in dementias that are pathologically characterized by gliosis, such as AD and FTLD. Cho/Cr levels are elevated in dementias that are characterized by a profound cholinergic deficit, such as AD and DLB.

Autonomic dysfunction in dementia with Lewy bodies.

OBJECTIVE: To assess autonomic function in patients with dementia with Lewy bodies (DLB). METHODS: The authors compared data from 20 DLB patients evaluated from 1995 to 2000 to 20 age-matched multiple system atrophy (MSA) and Parkinson disease (PD) patients evaluated from 1999 to 2002. Analysis of variance, Fisher exact test, and Student t-test were applied to compare disease characteristics, autonomic symptoms, and function tests on the Composite Autonomic Scoring Scale (CASS) and Thermoregulatory Sweat Test (TST). RESULTS: In DLB, mean age at onset of autonomic symptoms was 70.3 +/- 8.9 years. Orthostatic symptoms were common and orthostatic hypotension occurred in 10/20 DLB, 17/20 MSA, and 1/20 PD patients (p = 0.023, 0.003). CASS-sudomotor for DLB, MSA, and PD were 1.6 +/- 1.2, 2.5 +/- 0.7, and 0.9 +/- 0.8 (p < 0.00001). CASS-cardiovagal were 1.4 +/- 0.9, 2.1 +/- 0.8, and 0.7 +/- 0.6 (p < 0.00001). CASS-adrenergic function were 2.4 +/- 1.2, 3.5 +/- 0.9, and 0.5 +/- 0.6 (p < 0.00001). Total CASS were 5.2 +/- 2.0, 8.1 +/- 1.3, and 2.2 +/- 1.2 (p < 0.00001). The most common pattern of TST in DLB was distal anhidrosis. Mean duration of follow-up was 3.0 +/- 1.8 years. Six patients needed medication to maintain blood pressure and five had good response. CONCLUSIONS: Autonomic dysfunction is frequent in dementia with Lewy bodies and the severity is intermediate between that of multiple system atrophy and Parkinson disease.

DLB fluctuations: specific features that reliably differentiate DLB from AD and normal aging.

OBJECTIVE: To determine whether certain aspects of fluctuations reliably distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and normal aging. METHODS: Participants included 200 community-dwelling cognitively normal elderly persons, 70 DLB patients, and 70 AD patients with collateral informants. A 19-item questionnaire was administered to the informants that queried about symptoms of fluctuations and delirium. RESULTS: Fluctuations occur infrequently in nondemented elderly persons aged 58 to 98 years. In contrast, four characteristics of fluctuations were found to significantly differentiate AD from DLB. These composite features include daytime drowsiness and lethargy, daytime sleep of 2 or more hours, staring into space for long periods, and episodes of disorganized speech. The presence of three or four features of this composite occurred in 63% of DLB patients compared with 12% of AD patients and 0.5% of normal elderly persons. Informant endorsement of three or four of these items yielded a positive predictive value of 83% for the clinical diagnosis of DLB against an alternate diagnosis of AD. Endorsement of fewer than three items had a negative predictive value of 70% for the absence of a clinical diagnosis of DLB in favor of AD. The authors present evidence of test-retest reliability, convergent validity, and empirical verification with a separate cross-validation sample. Fluctuations were not associated with any particular combination of hallucinations, parkinsonism, or REM sleep behavior disorder. CONCLUSIONS: Based on informant report, disturbed arousal and disorganized speech are specific aspects of fluctuations in dementia with Lewy bodies that reliably distinguish dementia with Lewy bodies from Alzheimer's disease and normal aging.

Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism.

OBJECTIVE: To determine if synucleinopathy pathology is related to REM sleep behavior disorder (RBD) plus dementia or parkinsonism. METHODS: The clinical and neuropathologic findings were analyzed on all autopsied cases evaluated at Mayo Clinic Rochester from January 1990 to April 2002 who were diagnosed with RBD and a neurodegenerative disorder. Ubiquitin and/or alpha-synuclein immunocytochemistry was used in all cases. The clinical and neuropathologic diagnoses were based on published criteria. RESULTS: Fifteen cases were identified (14 men). All had clear histories of dream enactment behavior, and 10 had RBD confirmed by polysomnography. RBD preceded dementia or parkinsonism in 10 (66.7%) patients by a median of 10 (range 2 to 29) years. The clinical diagnoses included dementia with Lewy bodies (DLB) (n = 6); multiple-system atrophy (MSA) (n = 2); combined DLB, AD, and vascular dementia (n = 1); dementia (n = 1); dementia with parkinsonism (n = 1); PD (n = 1); PD with dementia (n = 1); dementia/parkinsonism/motor neuron disease (n = 1); and AD/Binswanger's disease (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD) in 12 (neocortical in 11 and limbic in 1) and MSA in 3. Three also had argyrophilic grain pathology. In the LBD cases, concomitant AD pathology was present in six (one also with Binswanger's pathology, and one also with multiple subcortical infarcts). CONCLUSION: In the setting of degenerative dementia or parkinsonism, RBD often reflects an underlying synucleinopathy.

Early and pre-symptomatic neuropsychological dysfunction in the PPND family with the N279K tau mutation.

The N279K mutation on the tau gene of chromosome 17 leads to an inherited condition that involves pallido-ponto-nigral degeneration (PPND). Patients with PPND develop dementia, but the pattern and onset of cognitive dysfunction has not yet been delineated. Four affected patients underwent neurocognitive evaluation within the first 2 years of PPND motor onset; one of whom underwent five serial neurocognitive evaluations, and another who was not diagnosed with PPND until the third annual evaluation. Impaired letter fluency was found in the early stages of PPND and was also shown to precede the onset of motor symptoms by 2 years. Trail Making A (visual scanning and motor speed) and Trail Making B (divided attention) were impaired within the first 2 years of the disease in all but one patient, but this individual showed clinically significant decline on these tasks by the third year of the disease. Learning, memory, and timed visuospatial sequencing skills were variably affected. Results reveal disproportionate frontal-executive dysfunction early in PPND disease course, a pattern similar to what has been reported in other FTDP-17 kindreds and in sporadic PSP. In addition, results suggest that letter fluency may be a sensitive predictor of incipient PPND.

Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy.

Our objective was to examine whether rapid eye movement (REM) sleep behavior disorder occurs in disproportionally greater frequency in multiple system atrophy (MSA), Parkinson's disease (PD), and dementia with Lewy bodies (DLB), collectively known as the synucleinopathies, compared to other nonsynucleinopathy neurodegenerative disorders. In study 1, we reviewed the clinical records of 398 consecutive patients evaluated at Mayo Clinic Rochester for parkinsonism and/or cognitive impairment. The frequency of suspected and polysomnogram (PSG)-confirmed REM sleep behavior disorder (RBD) among subjects with the synucleinopathies MSA, PD, or DLB was compared to the frequency among subjects with the nonsynucleinopathies Alzheimer's disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), mild cognitive impairment (MCI), primary progressive aphasia (PPA), and posterior cortical atrophy (PCA). In study 2, we reviewed the clinical records of 360 consecutive patients evaluated at Mayo Clinic Jacksonville for parkinsonism and/or cognitive impairment. The frequency of probable RBD among patients with PD and DLB was compared to the frequency among patients with AD and MCI. In study 3, we reviewed the brain biopsy or postmortem autopsy diagnoses of 23 Mayo Clinic Rochester patients who had been clinically examined for possible RBD and a neurodegenerative disorder. In study 1, patients with MSA, PD, or DLB were more likely to have probable and PSG-confirmed RBD compared to subjects with the nonsynucleinopathies (probable RBD 77/120=64% vs. 7/278=3%, p < 0.01; PSG-confirmed RBD 47/120=39% vs. 1/278=0%, p < 0.01). In study 2, patients with PD and DLB were more likely to have probable RBD compared to those with AD and MCI (56% vs. 2%, p < 0.01). In study 3, of the 23 autopsied patients who had been questioned about possible RBD, 10 were clinically diagnosed with RBD. The neuropathologic diagnoses in these 10 included Lewy body disease in nine, and MSA in one. Of the other 13 cases, 12 did not have a history suggesting RBD, and the one case who did had normal electromyographic atonia during REM sleep on PSG and autopsy findings of PSP. Only one of these 13 had a synucleinopathy. The positive predictive values for RBD indicating a synucleinopathy for studies 1-3 were 91.7%, 94.3%, and 100.0%, respectively. Clinically suspected and PSG-proven RBD occurs with disproportionally greater frequency in MSA, PD, and DLB compared to other neurodegenerative disorders. In the setting of degenerative dementia and/or parkinsonism, we hypothesize that RBD is a manifestation of an evolving synucleinopathy.

Global-local processing in schizophrenia: hemispheric asymmetry and symptom-specific interference.

The hypothesis of atypical functional hemispheric asymmetry in schizophrenia is tested using the directed global-local paradigm, a lateralizing measure of visual perception. Results indicate low error rates (< 2%) for schizophrenia and normal control groups, but longer response times for the schizophrenia group. In the normal group, detection speed of global and local forms did not differ. In contrast, the schizophrenia group responded significantly faster to local relative to global forms, which supports the asymmetry hypotheses of left hemisphere overactivity-right hemisphere underactivity in schizophrenia. The normal group exhibited a global interference effect (slowed response latency to the local target in the presence of a dissimilar global distractor). When the schizophrenia group was examined according to symptom type and severity, high positive symptom severity was associated with local interference (slowed response latency to the global target in the presence of dissimilar local distractors). Negative symptoms were not associated with interference from the competing local or global forms. Patients with a combination of high positive and low negative symptoms showed significantly greater local interference than patients with high negative and low positive symptoms. Interconnected temporal and frontal systems are postulated to contribute to this pattern of perceptual processing efficiency and distractibility in schizophrenia.

REM sleep behavior disorder and dementia: cognitive differences when compared with AD.

OBJECTIVE: To determine whether the dementia associated with REM sleep behavior disorder (RBD) differs from Alzheimer's disease (AD) and, if so, whether differences in cognitive performance between RBD/dementia and AD resemble reported differences between dementia with Lewy bodies (DLB) and AD. METHODS: This retrospective study compares neurocognitive performance between 31 patients with degenerative dementia and polysomnography-confirmed RBD and 31 patients without brainstem Lewy body pathology who met Consortium to Establish a Registry for Alzheimer's Disease (CERAD) clinical and neuropathologic criteria for AD. The patient groups did not differ in dementia severity (based on Global Deterioration Scale score) or duration. RESULTS: RBD preceded or coincided with the onset of cognitive decline in 94% of the patients. All but one patient with RBD/dementia had one or more of the following clinical features of DLB: visual hallucinations, extrapyramidal signs, or fluctuating cognition/alertness. The data revealed significantly worse performance on attention, perceptual organization, visual memory, and letter fluency for the RBD/dementia group, whereas the AD group showed significantly worse performance on confrontation naming and verbal memory. CONCLUSIONS: Patients with RBD and degenerative dementia demonstrate a significantly different pattern of cognitive performance from patients with AD. Most of the patients in the RBD/dementia sample also meet criteria for possible or probable DLB, and the pattern of cognitive differences from AD is similar to reported comparisons between DLB and AD. The cognitive and clinical data provide evidence to suggest that the dementia associated with RBD may represent DLB.

REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease.

BACKGROUND: REM sleep behavior disorder (RBD) has been reported with various neurodegenerative disorders, most frequently in disorders with Lewy body pathology. RBD often precedes the onset of PD, and a recent prospective study showed that 38% of patients with RBD eventually developed PD. METHODS: We identified 37 patients with degenerative dementia and a history of bursts of vigorous movement of the arms and legs with vocalization during sleep and associated with dream recall. Patients with and without two or more signs of parkinsonism were compared. Clinical, laboratory, and neuropsychometric features were analyzed, and criteria for the clinical diagnosis of dementia with Lewy bodies (DLB) were applied to all patients. RESULTS: Thirty-four of the 37 patients were male with mean age at onset of 61.5 years for RBD and 68.1 years for cognitive decline. RBD commenced before or concurrently with dementia in all patients but two. Parkinsonism (two or more signs) occurred in 54% of the sample (20/37), with a mean age at onset of 69.1 years. Polysomnography (PSG) confirmed RBD in all patients studied. Neuropsychological testing demonstrated impaired perceptual-organizational skills, verbal fluency, and marked constructional dyspraxia in more than one-half the patients. There were no statistically significant differences in the frequency of clinical features or in neuropsychological performance between patients with and without parkinsonism. Thirty-four patients (92%) met criteria for clinically possible or probable DLB. Three patients were autopsied; all had limbic with or without neocortical Lewy bodies. CONCLUSIONS: We report a group of predominantly male patients with a characteristic association of RBD and degenerative dementia. The clinical and neuropsychometric features of the groups of patients with and without parkinsonism are similar. We hypothesize that the underlying pathology in these patients is DLB.