Serotonin Transporter Imaging in Multiple System Atrophy and Parkinson's Disease.

BACKGROUND: Both Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit degeneration of brainstem serotoninergic nuclei, affecting multiple subcortical and cortical serotoninergic projections. In MSA, medullary serotoninergic neuron pathology is well documented, but serotonin system changes throughout the rest of the brain are less well characterized. OBJECTIVES: To use serotonin transporter [11 C]3-amino-4-(2-dimethylaminomethyl-phenylsulfaryl)-benzonitrile positron emission tomography (PET) to compare serotoninergic innervation in patients with MSA and PD. METHODS: We performed serotonin transporter PET imaging in 18 patients with MSA, 23 patients with PD, and 16 healthy controls to explore differences in brainstem, subcortical, and cortical regions of interest. RESULTS: Patients with MSA showed lower serotonin transporter distribution volume ratios compared with patients with PD in the medulla, raphe pontis, ventral striatum, limbic cortex, and thalamic regions, but no differences in the dorsal striatal, ventral anterior cingulate, or total cortical regions. Controls showed greater cortical serotonin transporter binding compared with PD or MSA groups but lower serotonin transporter binding in the striatum and other relevant basal ganglia regions. There were no regional differences in binding between patients with MSA-parkinsonian subtype (n = 8) and patients with MSA-cerebellar subtype (n = 10). Serotonin transporter distribution volume ratios in multiple different regions of interest showed an inverse correlation with the severity of Movement Disorders Society Unified Parkinson's Disease Rating Scale motor score in patients with MSA but not patients with PD. CONCLUSIONS: Brainstem and some forebrain subcortical region serotoninergic deficits are more severe in MSA compared with PD and show an MSA-specific correlation with the severity of motor impairments. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Association between autonomic dysfunction and fatigue in Parkinson disease.

OBJECTIVE: Fatigue is a disabling non-motor symptom in Parkinson disease (PD). We investigated the relationship between autonomic dysfunction and fatigue in PD while accounting for possible confounding factors. METHODS: 29 subjects with PD (8F/21M; mean age 61.6±5.9; mean disease duration 4.8±3.0years), underwent clinical assessment and completed several non-motor symptom questionnaires, including a modified version of the Mayo Clinic Composite Autonomic Symptom Score (COMPASS) scale and the Fatigue Severity Scale (FSS). RESULTS: The mean modified COMPASS was 21.6±14.2 (range 1.7-44.2) and the mean FSS score was 3.3±1.6 (range 1.0-6.7). There was a significant bivariate relationship between the modified COMPASS and FSS scores (R=0.69, P<0.0001). Stepwise regression analysis was used to assess the specificity of the association between the modified COMPASS and FSS scores while accounting for possible confounder effects from other variables that were significantly associated with autonomic dysfunction. Results showed that the modified COMPASS (R2=0.52, F=28.4, P<0.0001) was highly associated with fatigue, followed by ESS (R2=0.13, F=8.4, P=0.008) but no other co-variates. Post-hoc analysis exploring the association between the different modified COMPASS autonomic sub-domain scores and FSS scores found significant regressor effects for the orthostatic intolerance (R2=0.45, F=21.2, P<0.0001) and secretomotor sub-domains (R2=0.09, F=4.8, P=0.04) but not for other autonomic sub-domains. CONCLUSIONS: Autonomic dysfunction, in particular orthostatic intolerance, is highly associated with fatigue in PD.

2-Year Natural Decline of Cardiac Sympathetic Innervation in Idiopathic Parkinson Disease Studied with 11C-Hydroxyephedrine PET.

The objective of this study was to detect regional patterns of cardiac sympathetic denervation in idiopathic Parkinson disease (IPD) using 11C-hydroxyephedrine (11C-HED) PET and determine the denervation rate over 2 y. METHODS: We obtained 62 cardiac 11C-HED PET scans in 39 patients (30 men and 9 women; mean age ± SD, 61.9 ± 5.9 y), including 23 patients with follow-up scans at 2 y. We derived 11C-HED retention indices (RIs; mL of blood/min/mL of tissue) reflecting nerve density and integrity for 480 left ventricular (LV) sectors. We compared IPD patients with 33 healthy controls using z score analysis; RI values ≤ 2.5 SDs were considered abnormal. We expressed global and regional LV denervation as the percentage extent of z score severity and severity-extent product (SEP) on 9-segment bullseye maps and decline in cardiac sympathetic innervation as the 2-y difference in SEP (diff-SEP). RESULTS: Baseline 11C-HED PET in the 39 IPD patients revealed an RI mean of 0.052 ± 0.022 mL of blood/min/mL of tissue. In comparison with data from normal controls, 12 patients had normal 11C-HED PET, 5 showed mild denervation (percentage extent < 30%), and 22 had moderate to severe denervation (percentage extent > 30%, z score ≤ 2.5 SD). In the 23 paired PET scans, worsening cardiac denervation (global diff-SEP > 9) occurred in 14 of 23 (60.9%) patients over 2 y, including percentage LV abnormality (59% increasing to 66%), z-severity (-2.4 down to -2.5), and SEP (-195 to -227) (P = 0.0062). We found a mean annual decline of 4.6% ± 5.6 (maximum, 13%) in 11C-HED retention from a baseline global RI mean of 0.0481 ± 0.0218 to 0.0432 ± 0.0220 (P = 0.0009). At baseline, 5 patients with normal uptake had no interval change; 3 with mild denervation developed interval decline in lateral and inferior segments (diff-SEP -82 to -99) compared with anterior and septal segments (-65 to -79), whereas the reverse pattern occurred in 15 patients with severe baseline denervation. CONCLUSION: Progressive decline in cardiac sympathetic neural integrity in IPD patients occurs at a modest rate over 2 y on 11C-HED scans with marked heterogeneity and a regional pattern of involvement and decline.

Natural history of multiple system atrophy in the USA: a prospective cohort study.

BACKGROUND: Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis. METHODS: We recruited participants with probable multiple system atrophy-of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)-at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables. FINDINGS: We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8-10·7) and median survival from enrolment was 1·8 years (0·9-2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5-9·5 vs 10·3 years, 9·3-11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest. INTERPRETATION: Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. FUNDING: US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.

Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial.

BACKGROUND: Multiple system atrophy is a complex neurodegenerative disorder for which no effective treatment exists. We aimed to assess the effect of rasagiline on symptoms and progression of the parkinsonian variant of multiple system atrophy. METHODS: We did this randomised, double-blind, placebo-controlled trial between Dec 15, 2009, and Oct 20, 2011, at 40 academic sites specialised in the care of patients with multiple systemic atrophy across 12 countries. Eligible participants aged 30 years or older with possible or probable parkinsonian variant multiple system atrophy were randomly assigned (1:1), via computer-generated block randomisation (block size of four), to receive either rasagiline 1 mg per day or placebo. Randomisation was stratified by study centre. The investigators, study funder, and personnel involved in patient assessment, monitoring, analysis and data management were masked to group assignment. The primary endpoint was change from baseline to study end in total Unified Multiple System Atrophy Rating Scale (UMSARS) score (parts I and II). Analysis was by modified intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00977665. FINDINGS: We randomly assigned 174 participants to the rasagiline group (n=84) or the placebo group (n=90); 21 (25%) patients in the rasagiline group and 15 (17%) in the placebo group withdrew from the study early. At week 48, patients in the rasagiline group had progressed by an adjusted mean of 7·2 (SE 1·2) total UMSARS units versus 7·8 (1·1) units in those in the placebo group. This treatment difference of -0·60 (95% CI -3·68 to 2·47; p=0·70) was not significant. 68 (81%) patients in the rasagiline group and 67 (74%) patients in the placebo group reported adverse events, and we recorded serious adverse events in 29 (35%) versus 23 (26%) patients. The most common adverse events in the rasagiline group were dizziness (n=10 [12%]), peripheral oedema (n=9 [11%]), urinary tract infections (n=9 [11%]), and orthostatic hypotension (n=8 [10%]). INTERPRETATION: In this population of patients with the parkinsonian variant of multiple system atrophy, treatment with rasagiline 1 mg per day did not show a significant benefit as assessed by UMSARS. The study confirms the sensitivity of clinical outcomes for multiple system atrophy to detect clinically significant decline, even in individuals with early disease. FUNDING: Teva Pharmaceutical Industries and H Lundbeck A/S.

Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy. METHODS: In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. FINDINGS: Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0.62 points [SD 0.85] per month in the rifampicin group vs 0.47 points [0.48] per month in the placebo group; futility p=0.032; efficacy p=0.76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0.5 points (SD 0.7) per month for rifampicin and 0.5 points (0.5) per month for placebo (difference 0.0, 95% CI -0.24 to 0.24; p=0.82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. INTERPRETATION: Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy. FUNDING: National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.

The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer's disease.

BACKGROUND: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum's (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. RESULTS: We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aß plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk. CONCLUSIONS: The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response.

Assessing mild cognitive impairment with amyloid and dopamine terminal molecular imaging.

UNLABELLED: We evaluated PET-based classification of neurodegenerative pathology in mild cognitive impairment (MCI). METHODS: Our study was a cross-sectional and prospective evaluation of a cohort of 27 MCI subjects drawn from a university-based cognitive disorders clinic. We compared expert clinical consensus classification of MCI at entry and possible dementia at follow-up with molecular imaging-based classification using (11)C-dihydotetrabenazine PET measurement of striatal dopamine terminal integrity and (11)C-Pittsburgh compound B ((11)C-PiB) PET measurement of cerebral amyloid burden. RESULTS: Eleven subjects were initially classified clinically as amnestic MCI, 7 as multidomain MCI, and 9 as nonamnestic MCI. At a mean follow-up of 3 y, 18 subjects converted to dementia. PET imaging evidence of significant cerebral amyloid deposition or nigrostriatal denervation was a strong predictor of conversion to dementia. There was only moderate concordance between expert clinical classifications and PET-based classifications of dementia subtypes. CONCLUSION: Combined PET molecular imaging of cerebral amyloid burden and striatal dopamine terminal integrity may be useful for identifying subjects at high risk for progression to dementia and in defining neurochemically differentiated subsets of MCI subjects.

Pattern of cardiac sympathetic denervation in idiopathic Parkinson disease studied with 11C hydroxyephedrine PET.

PURPOSE: To determine whether cardiac sympathetic denervation in idiopathic Parkinson disease (IPD) affects the left ventricle in a distinct regional pattern versus a more global pattern with use of carbon 11 (11C) meta-hydroxyephedrine (HED) positron emission tomography (PET). MATERIALS AND METHODS: This prospective study was approved by the institutional review board and was compliant with HIPAA. Informed consent was obtained from all subjects. Cardiac PET was performed with 11C HED in 27 patients with IPD (20 men and seven women aged 50-74 years; mean age, 62 years±6 [standard deviation]). 11C HED retention indexes (RIs), which reflect nerve density and integrity, were determined. RIs for 33 healthy control subjects (15 men and 18 women aged 20-78 years; mean age, 47 years±17) were used as a control database. Patients with IPD were compared with control subjects by using z score analysis. Global and segmental measurements of sympathetic denervation were expressed as percentage extent, z score severity, and severity-extent product (SEP). Group comparisons were performed with the Student t test. RESULTS: The mean 11C HED RI was 0.086 mL of blood per minute per milliliter tissue±0.015 for control subjects and 0.043 mL of blood per minute per milliliter tissue±0.016 for patients with IPD (P<0001). When compared with normative data from the control database, profound cardiac denervation (global extent>50%) was seen in most patients (19 of 27 patients, 70%). Four patients had normal 11C HED studies and four had mild denervation (global extent<25%). The mean global denervation extent was 62%±38, the mean severity z score was -2.7±1.2, and the mean SEP was -202±131 (range, -358 to 0). Segmental analysis revealed relative sparing of anterior and proximal septal segments (mean extent, 48%-51%; mean severity z score, -2.47 to -2.0; mean SEP, -167 to -139), with lateral and proximal inferior segments more severely affected (mean extent, 68%-73%; mean severity z score, -2.8 to -2.62; mean SEP, -271 to -230). Patients with normal findings or preserved denervation did not significantly differ in mean age (t=1.09) or disease duration (t=0.44) compared to patients with severe sympathetic denervation. CONCLUSION: Cardiac sympathetic denervation in IPD is extensive, with a segmental pattern that involves the proximal lateral left ventricular wall most severely, with relative sparing of the anterior and proximal septal walls.

Heterogeneity of cholinergic denervation in Parkinson's disease without dementia.

Parkinson's disease (PD) is a multisystem neurodegenerative disorder. Heterogeneous clinical features may reflect heterogeneous changes in different brain regions. In contrast to the pronounced nigrostriatal denervation characteristic of PD, cholinergic changes are less marked. We investigated cholinergic innervation activity in PD subjects relative to normal subjects. Nondemented PD subjects (n=101, age 65.3±7.2 years) and normal subjects (n=29, age 66.8±10.9 years) underwent clinical assessment and [(11)C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11)C]dihydrotetrabenazine monoaminergic positron emission tomography (PET) imaging. Cholinergic projection changes were heterogeneous for 65 out of 101 PD subjects who had neocortical and thalamic acetylcholinesterase activity within the normal range. The remainder had combined neocortical and thalamic (13/101), isolated neocortical (18/101), or isolated thalamic (5/101) acetylcholinesterase activity below the normal range. The low neocortical acetylcholinesterase activity subgroup had significantly lower global cognitive performance compared with the normal range subgroup (F=7.64, P=0.0069) with an independent effect for nigrostriatal denervation (F=7.60, P=0.0074). The low thalamic acetylcholinesterase activity subgroup did not differ from the normal thalamic acetylcholinesterase activity subgroup in cognitive performance or motor impairments except for a history of falls (P=0.0023). Cholinergic denervation is heterogeneous with reduced neocortical and/or thalamic acetylcholinesterase activity in 36% of nondemented PD subjects with corresponding clinical phenotypic variation. Results also show independent cognitive effects for both cholinergic and dopaminergic system changes in nondemented PD subjects.

Autopsy confirmed multiple system atrophy cases: Mayo experience and role of autonomic function tests.

BACKGROUND: Multiple system atrophy (MSA) is a sporadic progressive neurodegenerative disorder characterised by autonomic failure, manifested as orthostatic hypotension or urogenital dysfunction, with combinations of parkinsonism that is poorly responsive to levodopa, cerebellar ataxia and corticospinal dysfunction. Published autopsy confirmed cases have provided reasonable neurological characterisation but have lacked adequate autonomic function testing. OBJECTIVES: To retrospectively evaluate if the autonomic characterisation of MSA is accurate in autopsy confirmed MSA and if consensus criteria are validated by autopsy confirmation. METHODS: 29 autopsy confirmed cases of MSA evaluated at the Mayo Clinic who had undergone formalised autonomic testing, including adrenergic, sudomotor and cardiovagal functions and Thermoregulatory Sweat Test (TST), from which the Composite Autonomic Severity Score (CASS) was derived, were included in the study. PATIENT CHARACTERISTICS: 17 men, 12 women; age of onset 57±8.1 years; disease duration to death 6.5±3.3 years; first symptom autonomic in 18, parkinsonism in seven and cerebellar in two. Clinical phenotype at first visit was MSA-P (predominant parkinsonism) in 18, MSA-C (predominant cerebellar involvement) in eight, pure autonomic failure in two and Parkinson's disease in one. Clinical diagnosis at last visit was MSA for 28 cases. Autonomic failure was severe: CASS was 7.2±2.3 (maximum 10). TST% was 65.6±33.9% and exceeded 30% in 82% of patients. The most common pattern was global anhidrosis. Norepinephrine was normal supine (203.6±112.7) but orthostatic increment of 33.5±23.2% was reduced. Four clinical features (rapid progression, early postural instability, poor levodopa responsiveness and symmetric involvement) were common. CONCLUSION: The pattern of severe and progressive generalised autonomic failure with severe adrenergic and sudomotor failure combined with the clinical phenotype is highly predictive of MSA.

Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography.

We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of aß-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score≥18) underwent a conventional clinical evaluation followed by 11C-dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical aß-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer's disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer's disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer's disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ∼35% of subjects (Cohen's κ=0.39). Discordant classifications were least frequent in clinical consensus Alzheimer's disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia.

The diagnosis of postencephalitic parkinsonism at the neurological unit of Boston City Hospital, 1930-1981.

The objective of the study is to ascertain the rationale for the diagnosis of postencephalitic parkinsonism (PEP) at Boston City Hospital's Neurological Unit (1930-1981). 5,270 discharge summaries were evaluated for the diagnoses of PEP. Sixteen cases of PEP were identified; the diagnosis of PEP was justified in approximately half of these cases based on the published criteria for distinguishing PEP from Parkinson's disease (PD). In conclusions, the absence of a clear justification for the diagnosis of PEP in many of the 16 cases suggests that the accepted relationship between encephalitis lethargica and PEP may be less definitive than currently believed.

A historical analysis of the relationship between encephalitis lethargica and postencephalitic parkinsonism: a complex rather than a direct relationship.

Postencephalitic parkinsonism has been considered unique among disorders with parkinsonian features because it is believed to have a unitary etiology associated with the virus that presumably caused encephalitis lethargica. Careful analysis of the historical record, however, suggests that this relationship is more complex than commonly perceived. In most cases, the diagnosis of acute encephalitis lethargica was made post hoc, and virtually any catarrh-like illness was considered to have represented encephalitis lethargica, often after an oral history-taking that was undoubtedly subject to patient recall and physician bias. Also, postencephalitic parkinsonism and oculogyric crises were not recognized as sequelae to encephalitis lethargica until well after other sequelae such as movement disorders and mental disturbances had been identified (see previous paper). We suggest here that the relationship between encephalitis lethargica and postencephalitic parkinsonism is not simplistic, i.e., encephalitis lethargica was not solely responsible for the etiology of postencephalitic parkinsonism, thus aligning the latter with most other parkinsonian disorders that are now believed to have multiple causes.

Does the historical literature on encephalitis lethargica support a simple (direct) relationship with postencephalitic Parkinsonism?

This article and the subsequent one suggest that the currently accepted view of a simplistic (direct) relationship between encephalitis lethargica (EL) and postencephalitic Parkinsonism (PEP) is based on a incomplete evaluation of the epidemic period literature. In this article we provide a detailed analysis of the literature from the period that demonstrates that Parkinsonism was not initially part of acute EL symptomatology, that PEP was not typically the prevailing type of chronic EL and that oculogyric crises were never part of acute EL symptomatology and not initially associated with PEP. The second paper uses these finding, and also examines the clinical justifications for concluding that all patients with PEP had prior acute episodes of EL, to reevaluate the presumed direct etiologic relationship between EL and PEP.

Comparing fludeoxyglucose F18-PET assessment of regional cerebral glucose metabolism and [11C]dihydrotetrabenazine-PET in evaluation of early dementia and mild cognitive impairment.

OBJECTIVE: To compare assessment of regional cerebral metabolic changes with [(11)C]dihydrotetrabenazine (DTBZ)-positron emission tomography (PET) measurement of regional cerebral blood flow (K(1)) and fludeoxyglucose F18 (FDG)-PET measurement of regional cerebral glucose uptake (CMR(glc)) in a clinically representative sample of subjects with mild dementia and mild cognitive impairment (MCI). DESIGN: [(11)C]Dihydrotetrabenazine-PET K(1) and FDG-PET CMR(glc) measurements were performed. SETTING: University-based cognitive disorders clinic. PARTICIPANTS: Fifty subjects with either mild dementia (Mini-Mental State Examination score > or = 18) or MCI. Their results were compared with those of 80 normal control subjects. MAIN OUTCOME MEASURES: The DTBZ-PET regional K(1) and FDG-PET CMR(glc) measurements were compared with standard correlation analysis. The overall patterns of DTBZ-PET K(1) and FDG-PET CMR(glc) deficits were assessed with stereotaxic surface projections (SSPs) of parametric images. RESULTS: The DTBZ-PET regional K(1) and FDG-PET CMR(glc) measurements were highly correlated, both within and between subjects. The SSP maps of deficits in DTBZ-PET regional K(1) and FDG-PET CMR(glc) measurements were markedly similar. The DTBZ-PET K(1) SSP maps exhibited a mild decrease in sensitivity relative to FDG-PET CMR(glc) maps. CONCLUSIONS: Both DTBZ-PET K(1) and FDG-PET CMR(glc) measurements provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. Blood flow measures can assess regional cerebral metabolism deficits accurately in mild dementia and MCI. Blood flow assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve utility of PET imaging in mild dementia and MCI.

Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

Prospective differentiation of multiple system atrophy from Parkinson disease, with and without autonomic failure.

OBJECTIVE: To report preliminary results of a prospective ongoing study of multiple system atrophy (MSA) and Parkinson disease (PD), with a large subset of patients with PD with autonomic failure (25%), to evaluate autonomic indices that distinguish MSA from PD. METHODS: We used consensus criteria, detailed autonomic studies (Composite Autonomic Symptom Scale, Composite Autonomic Scoring Scale, thermoregulatory sweat test, and plasma catecholamines), and functional scales (Unified MSA Rating Scale [UMSARS] I-IV and Hoehn-Yahr grading) on a prospective, repeated, and ongoing basis. RESULTS: We report the results of a study on 52 patients with MSA (mean [SD], age, 61.1 [7.8] years; body mass index (calculated as weight in kilograms divided by height in meters squared), 27.2 [4.6]; Hoehn-Yahr grade, 3.2 [0.9]; UMSARS I score, 21.5 [7.4]; and UMSARS II score, 22.7 [9.0]) and 29 patients with PD, including PD with autonomic failure (mean [SD], age, 66.0 [8.1] years; body mass index, 26.6 [5.5]; Hoehn-Yahr grade, 2.2 [0.8]; UMSARS I score, 10.4 [6.1]; and UMSARS II score, 13.0 [5.9]). Autonomic indices were highly significantly more abnormal in MSA than PD (P < .001) for the Composite Autonomic Scoring Scale (5.9 [1.9] vs 3.3 [2.3], respectively), Composite Autonomic Symptom Scale (54.4 [21.8] vs 24.7 [20.5], respectively), and thermoregulatory sweat test (percentage anhidrosis, 57.4% [35.2%] vs 9.9% [17.7%], respectively). These differences were sustained and greater at 1-year follow-up, indicating a greater rate of progression of dysautonomia in MSA than PD. CONCLUSIONS: The severity, distribution, and pattern of autonomic deficits at study entry will distinguish MSA from PD, and MSA from PD with autonomic failure. These differences continue and are increased at follow-up. Our ongoing conclusion is that autonomic function tests can separate MSA from PD. Autonomic indices support the notion that the primary lesion in PD is ganglionic and postganglionic, while MSA is preganglionic.