Form Of Atypical Parkinsonism Research Articles

Cough Correlates of Functional Swallow Outcomes in Atypical Parkinsonism.

Swallow and cough impairments lead to aspiration and reduced clearance of aspirate material. Both behaviors are impaired in Parkinson's disease, but it is unknown whether a similar relationship of dysfunction exists in forms of atypical Parkinsonism (APD). Elucidating this association in APD may lead to early, comprehensive airway protection treatment. We tested the hypotheses that swallow deficits in APD are associated with impaired cough and that airway protective dysfunction is associated with longer disease duration. Swallowing difficulty was described by 11 participants with APD. Penetration-Aspiration Scale (PAS) and DIGEST scores for thin liquid trials were extracted from medical records of videofluoroscopic swallow study reports. Voluntary and capsaicin induced-reflex cough measures of flow, volume, and timing were analyzed. While most participants did not have post-swallow residue, ~80% received abnormal PAS scores and reported swallowing difficulty. Those with abnormal PAS scores had lower voluntary cough expired volume (P = 0.037; mean rank difference = 5.0); lower reflex inspiratory flow rate (P = 0.034; mean rank difference = 5.5); and longer reflex expiratory flow rise time (P = 0.034; mean rank difference = 5.5). Higher PAS scores and reduced reflex cough volume acceleration were significantly correlated (r = -0.63; P = 0.04) and longer disease duration predicted larger voluntary cough expired volume (R2 = 0.72) and longer flow rise times (R2 = 0.47). As swallow safety worsens, so might the ability to clear the airways with effective cough in in APD; particularly with longer disease duration. Assessing cough in conjunction with swallowing is important for informing airway protection treatment plans in APD.

Study protocol for the Heads-Up trial: a phase II randomized controlled trial investigating head-up tilt sleeping to alleviate orthostatic intolerance in Parkinson’s Disease and parkinsonism

BackgroundIn persons with Parkinson’s Disease (PD) or certain forms of atypical parkinsonism, orthostatic hypotension is common and disabling, yet often underrecognized and undertreated. About half of affected individuals also exhibit supine hypertension. This common co-occurrence of both orthostatic hypotension and supine hypertension complicates pharmacological treatments as the treatment of the one can aggravate the other. Whole-body head-up tilt sleeping (HUTS) is the only known intervention that may improve both. Evidence on its effectiveness and tolerability is, however, lacking, and little is known about the implementability.MethodsIn this double-blind multicenter randomized controlled trial (phase II) we will test the efficacy and tolerability of HUTS at different angles in 50 people with PD or parkinsonism who have both symptomatic orthostatic hypotension and supine hypertension. All participants start with one week of horizontal sleeping and subsequently sleep at three different angles, each maintained for two weeks. The exact intervention will vary between the randomly allocated groups. Specifically, the intervention group will consecutively sleep at 6°, 12° and 18°, while the delayed treatment group starts with a placebo angle (1°), followed by 6° and 12°. We will evaluate tolerability using questionnaires and compliance to the study protocol. The primary endpoint is the change in average overnight blood pressure measured by a 24-hour ambulatory blood pressure recording. Secondary outcomes include orthostatic blood pressure, orthostatic tolerance, supine blood pressure, nocturia and various other motor and non-motor tests and questionnaires.DiscussionWe hypothesize that HUTS can simultaneously alleviate orthostatic hypotension and supine hypertension, and that higher angles of HUTS are more effective but less tolerable. The Heads-Up trial will help to clarify the effectiveness, tolerability, and feasibility of this intervention at home and can guide at-home implementation.Trial registrationClinicalTrials.gov NCT05551377; Date of registration: September 22, 2022.

The role of magnetic resonance imaging in the diff erential diagnosis of Parkinson’s disease

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases in the world. While until recently MRI was used exclusively for the diagnosis of symptomatic forms of parkinsonism, recent advances in neuroimaging allow the detection of signs of nigral degeneration (MR biomarkers of PD). The article discusses the possibilities of modern MRI modes sensitive to iron (SWI, T2*) and neuromelanin (neuromelanin-sensitive MRI); emphasis is placed on identifying false-negative and false-positive results of the study. The imaging of nigrosome-1 in the dorsal substantia nigra (SN) in MRI-SWI has been discussed since 2013. In the absence of nigral degeneration, this area is defi ned as a hyperintense ovoid area within the dorsolateral border of the hypointense SN (“swallow’s tail” sign). If the optimistic results of the fi rst studies testifi ed to the high sensitivity and specifi city of this technique in PD (the absence of the “swallow’s tail” sign), then in subsequent studies, similar changes were detected in patients with other neurodegenerations with parkinsonism. In addition, the diagnostic value of this technique occurs when using tomographs with a magnetic fi eld strength of at least 3 Tc. Similar conclusions can be drawn about the use of neuromelanin-sensitive MRI, since it is necessary to use high-fi eld magnetic tomographs of 3 Tc or more to detect nigral degeneration, and results similar to PD can also be found in atypical forms of parkinsonism. However, the search for signs of nigral degeneration may be useful in the diff erential diagnosis of PD and non-neurodegenerative disorders. In addition to MRI in the diagnosis of PD, the article discusses neuroimaging in various types of multisystem atrophy, progressive supranuclear palsy, and dementia with Lewy bodies. The article is illustrated with own MRI scans of the brains of patients with PD and other forms of parkinsonism.

Clinical case of a patient with progressive supranuclear palsy – from symptom to diagnosis

Progressive supranuclear palsy (PSP) is a neurodegenerative disease classified among the atypical forms of parkinsonism. PSP is characterized by great variability in the involvement of different areas of the central nervous system (CNS). The clinical picture is associated with impaired gait and balance, generalized bradykinesia, visual impairment, dysarthria, dysphagia, pelvic incontinence, dementia and others. We present a clinical case of a 50-year-old woman who, at the end of 2021, was admitted to the Rheumatology department, UMBAL "St. Ivan Rilski" - Sofia, due to weakness in the hands, dropping objects, pain in small joints of the hands, disorder in coordination, difficulty walking and frequent stumbling, slurred speech, tremors involving both hands (more pronounced on the right), memory impairment, pelvic incontinence and hair loss. The clinical case is very indicative of the long journey that a patient with progressive supranuclear palsy takes before being correctly diagnosed.

C9ORF72 repeat expansion is not associated with atypical parkinsonism in the Serbian population

These include, among others, two forms of atypical Parkinsonism, multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). This study aimed to assess the potential role of C9orf72 repeat expansions among Serbian patients diagnosed with MSA and PSP. Genomic DNA of 44 MSA patients, 73 PSP patients, and 96 controls was extracted from peripheral blood, and normal C9orf72 alleles were analyzed by standard quantitative fluorescence polymerase chain reaction (QF-PCR) and fragment analysis. Subsequently, for all samples presenting a single allele, repeat-primed PCR was performed with two different sets of primers to avoid a false-negative result. Thirty repeats were used as a pathogenic cut-off and 20-29 repeats for the intermediate alleles. No pathological C9orf72 expansions were detected in the MSA and PSP patients nor the control subjects. In the MSA group, the most common was the allele with 2 repeats, and the largest repeat number was 14. Among PSP patients, the most common allele also had 2 repeats, while the largest detected repeat size within the normal range was 17. Also, we identified one PSP patient that had an intermediate size allele (25 repeats). We did not find correlation between the number of repeats and disease onset, age at the time of examination, or disease duration in MSA or PSP patients. Regarding family history, in PSP the sum of both allele repeats numbers was higher in patients with positive family history than in sporadic cases. The results presented in this study are the first systematic assessment of C9orf72 allele sizes among patients diagnosed with MSA and PSP in the Serbian population. Although the potential role of intermediate C9orf72 repeats in neurodegenerative disorders is still to be elucidated, our results support the current knowledge that C9orf72 repeat expansions are not associated with MSA and PSP.

Multiple system atrophy and C9orf72 hexanucleotide repeat expansions in a cohort of Italian patients

Exanucleotide expansions in C9orf72 gene have been described as potential risk factor in some patients with Multiple system atrophy (MSA) and other forms of atypical parkinsonism. The goal of our study was to extend the knowledge on the involvement of C9orf72 in MSA studying a cohort of 100 patients from Italy. We identified 2 heterozygous patients in the pathological range (> 30 repeats) and 4 heterozygous patients for expansions in the premutation range (20 -30 repeats). Our findings strengthen the previously hypothesized role for this gene as a risk factor for MSA and raise the possibility of a more complex and still unknown involvement of this gene in the heterogeneity of MSA.

The Architecture of Contemporary Care Networks for Rare Movement Disorders: Leveraging the ParkinsonNet Experience.

In this paper, we present a universal model for implementing network care for persons living with chronic diseases, specifically those with rare movement disorders. Building on our longstanding experience with ParkinsonNet, an integrated care network for persons living with Parkinson's disease or a form of atypical parkinsonism, we provide a series of generic, supportive building blocks to (re)design comparable care networks. We discuss the specific challenges related to rare movement disorders and how these challenges can inform a tailored implementation strategy, using the basic building blocks to offer practical guidance. Lastly, we identify three main priorities to facilitate network development for these rare diseases. These include the clustering of different types of rare movement disorders at the network level, the implementation of supportive technology, and the development of interdisciplinary guidelines.

Genotype-Phenotype Relations for the Atypical Parkinsonism Genes: MDSGene Systematic Review.

This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated (“bagged”) decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95% CI, 86.3%–86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10−12) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57–70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism.

Autophagy lysosomal pathway dysfunction in Parkinson's disease; evidence from human genetics

In recent years, multiple lines of evidence from human genetic and molecular studies have highlighted the importance of the autophagy lysosomal pathway (ALP) in Parkinson's disease (PD). Genes such as GBA and LRRK2, which harbor some of the most common mutations associated with PD, have essential roles in the ALP. α-synuclein, encoded by the SNCA gene, is degraded mainly by the ALP, and mutations/multiplications in SNCA may lead to impairment of chaperone mediated autophagy or other ALP functions. Numerous other PD-related genes, such as PRKN, PINK1, TMEM175, SMPD1, CTSD, CTSB and many more, have also been reported to have important roles in the ALP. Understanding the relationship between ALP impairment and PD pathogenesis may be crucial for uncovering the mechanisms underlying PD, and for the development of long-awaited neuroprotective therapies. In this review, we will discuss the data linking the ALP to PD (other, atypical forms of Parkinsonism, will not be discussed in this review). We will focus on evidence from studies on specific genes and proteins, their roles in the ALP, and the potential mechanisms underlying the involvement of these genes in PD.

Corticobasal degeneration: advances in clinicopathology and biomarkers.

Corticobasal degeneration (CBD) is a rapidly progressive neurodegenerative tauopathy diagnosed postmortem by pathological examination. The clinical presentation of corticobasal syndrome (CBS) is an apraxic, dystonic, and rigid limb with asymmetrical cortical signs and myoclonus. However, less than half of the patients with CBS receive a CBD diagnosis. As tau-lowering therapies have entered clinical trials, improved antemortem diagnosis of CBD is needed. Here, clinicopathological, neuroimaging, and biofluid data in CBS and/or CBD patients are briefly summarized and some knowledge gaps identified. Developments of MRI-based and nuclear medicine imaging modalities have increased pathophysiological insights of CBS and may improve diagnostic accuracy. In particular, several tau-PET ligands have been evaluated in CBS patients. Cerebrospinal fluid and plasma levels of neurofilament light chain can distinguish CBS from Parkinson's disease but not from other atypical forms of Parkinsonism. Structural and functional imaging approaches provide some aid in the diagnosis of CBD but have low-content validity. None of the currently available tau-PET ligands is suitable for detecting straight filament 4repeat tau disease in clinical routine. Biofluid markers reflecting the distinct tau and/or astrocyte disease of CBD are needed. Examining biosamples along with clinical parameters from longitudinally followed patients with autopsy-confirmed CBD diagnosis shall hopefully delineate improved biomarkers.

α-Synuclein real-time quaking-induced conversion in the cerebrospinal fluid of uncertain cases of parkinsonism.

A reliable biomarker is needed for accurate and early differentiation between Parkinson disease and the various forms of atypical parkinsonism. We used a novel real‐time quaking‐induced conversion (RT‐QuIC) assay to detect α‐synuclein (α‐syn) aggregates in cerebrospinal fluid (CSF) of 118 patients with parkinsonism of uncertain clinical etiology and 52 controls. Diagnostic accuracy to distinguish α‐synucleinopathies from non–α‐synucleinopathies and controls was 84% (sensitivity = 75%, specificity = 94%, area under the curve = 0.84, 95% confidence interval = 0.78–0.91, p < 0.0001, positive predictive value = 93%). CSF α‐syn RT‐QuIC could be a useful diagnostic tool to help clinicians differentiate α‐synucleinopathies from other forms of parkinsonism when the clinical picture is uncertain. Ann Neurol 2019;85:777–781

The cognitive profile and executive function of progressive supranuclear palsy and multiple system atrophy patients

Introduction: Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are two relatively common forms of atypical parkinsonism seen in movement disorder clinics. This study provides an insight into the cognitive dysfunction in these two diseases. Aims: This study aims at assessing the cognitive and executive dysfunction and investigating the relationship between age, education, Montreal cognitive assessment (MOCA), and frontal assessment battery (FAB) score in a group of Indian patients with MSA and PSP. Materials and Methods: This is a hospital-based observational study with the recruitment of patients of MSA and PSP based on consensus criteria and The National Institute of Neurological Disorders and Stroke and Society for Progressive Supranuclear Palsy criteria, respectively. A total of 50 patients of MSA and PSP admitted or attending outpatient department in the Department of Neurology, SMS hospital, Jaipur, were analyzed for cognitive and executive functions between December 2016 and December 2018 using MOCA and FAB. The Student's t-test was used. The level of significance was determined as itsP value withP Conclusions: Cognitive dysfunction is a major finding in PSP and MSA patients. Thus, cognitive dysfunction in a patient does not rule out MSA as considered in the previous literature and is an important diagnostic finding in PSP; yet requires future research on a larger scale.

Epidemiology and causes of Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disease and has agrowing socioeconomic impact due to demographic changes in the industrial nations. There are several forms of PD, afraction of which (<5%) are monogenic, i. e. caused by mutations in single genes. At present, six genes have been established for the clinically classical form of parkinsonism including three autosomal dominantly (SNCA, LRRK2, VPS35) and three autosomal recessively inherited ones (Parkin, PINK1, DJ-1). In addition, there are aplethora of genes causing atypical forms of parkinsonism. In contrast, idiopathic PD is of a multifactorial nature. Genome-wide association studies have established atotal of 26genetic loci for this form of the disease; however, for most of these loci the underlying functional genetic variants have not yet been identified and the respective disease mechanisms remain unresolved. Furthermore, there are anumber of environmental and life style factors that are associated with idiopathic PD. Exposure to pesticides and possibly a history of head trauma represent genuine risk factors. Other PD-associated factors, such as smoking and intake of coffee and alcohol may not represent risk factors per se and the cause-effect relationship has not yet been elucidated for most of these factors. Apatient with apositive family history and/or an early age of disease onset should undergo counseling with respect to apossible monogenic form of the disease. Disease prediction based on genetic, environmental and life style factors is not yet possible for idiopathic PD and potential gene-specific therapies are currently in the development or early testing phase.

Imaging in Parkinson’s disease

The clinical presentation of Parkinson's disease (PD) is heterogeneous and overlaps with other conditions, including the parkinsonian variant of multiple system atrophy (MSA-P), progressive supranuclear palsy (PSP) and essential tremor. Imaging of the brain in patients with parkinsonism has the ability to increase the accuracy of differential diagnosis. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) allow brain imaging of structural, functional and molecular changes in vivo in patients with PD. Structural MRI is useful to differentiate PD from secondary and atypical forms of parkinsonism. 123I-ioflupane (DaTSCAN(TM)) SPECT is a valid tool in the differential diagnosis between PD and non-degenerative tremors, while cardiac 123I-metaiodobenzylguanidine SPECT and 18F-fluorodeoxyglucose PET are valid in the differential diagnosis between PD and atypical parkinsonism (MSA-P, PSP). However, despite significant evidence for the utility of neuroimaging in assessing parkinsonian patients, none of the neuroimaging techniques are specifically recommended for routine use in clinical practice. Hopefully, future larger trials will help to demonstrate additional evidence for the clinical utility of neuroimaging and will include an analysis of the financial benefits for the NHS in the longer term management of the patients.

A systematic review of lessons learned from PET molecular imaging research in atypical parkinsonism.

PurposeTo systematically review the previous studies and current status of positron emission tomography (PET) molecular imaging research in atypical parkinsonism.MethodsMEDLINE, ISI Web of Science, Cochrane Library, and Scopus electronic databases were searched for articles published until 29th March 2016 and included brain PET studies in progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS). Only articles published in English and in peer-reviewed journals were included in this review. Case-reports, reviews, and non-human studies were excluded.ResultsSeventy-seven PET studies investigating the dopaminergic system, glucose metabolism, microglial activation, hyperphosphorilated tau, opioid receptors, the cholinergic system, and GABAA receptors in PSP, MSA, and CBS patients were included in this review. Disease-specific patterns of reduced glucose metabolism have shown higher accuracy than dopaminergic imaging techniques to distinguish between parkinsonian syndromes. Microglial activation has been found in all forms of atypical parkinsonism and reflects the known distribution of neuropathologic changes in these disorders. Opioid receptors are decreased in the striatum of PSP and MSA patients. Subcortical cholinergic dysfunction was more severe in MSA and PSP than Parkinson’s disease patients although no significant changes in cortical cholinergic receptors were seen in PSP with cognitive impairment. GABAA receptors were decreased in metabolically affected cortical and subcortical regions in PSP patients.ConclusionsPET molecular imaging has provided valuable insight for understanding the mechanisms underlying atypical parkinsonism. Changes at a molecular level occur early in the course of these neurodegenerative diseases and PET imaging provides the means to aid differential diagnosis, monitor disease progression, identify of novel targets for pharmacotherapy, and monitor response to new treatments.

Pulmonary embolism: ‘the great masquerader’ of pneumonia in a patient with progressive supranuclear palsy

Patients with Parkinson’s disease are at risk of developing aspiration pneumonia. Pulmonary embolism is a rare but life-threatening complication in such patients, but could the same be true in progressive supranuclear palsy, an atypical form of Parkinsonism? This case report aims at highlighting the development of unprovoked pulmonary embolism in a patient with progressive supranuclear palsy and also describes how pulmonary embolism can mimic pneumonia in such patients.

Chapter 49 - Movement disorders

Movement disorders can be hypokinetic (e.g., parkinsonism), hyperkinetic, or dystonic in nature and commonly arise from altered function in nuclei of the basal ganglia or their connections. As obvious structural changes are often limited, standard imaging plays less of a role than in other neurologic disorders. However, structural imaging is indicated where clinical presentation is atypical, particularly if the disorder is abrupt in onset or remains strictly unilateral. More recent advances in magnetic resonance imaging (MRI) may allow for differentiation between Parkinson's disease and atypical forms of parkinsonism. Functional imaging can assess regional cerebral blood flow (functional MRI (fMRI), positron emission tomography (PET), or single-photon emission computed tomography (SPECT)), cerebral glucose metabolism (PET), neurochemical and neuroreceptor status (PET and SPECT), and pathologic processes such as inflammation or abnormal protein deposition (PET) (Table 49.1). Cerebral blood flow can be assessed at rest, during the performance of motor or cognitive tasks, or in response to a variety of stimuli. In appropriate situations, the correct imaging modality and/or combination of modalities can be used to detect early disease or even preclinical disease, and to monitor disease progression and the effects of disease-modifying interventions. Various approaches are reviewed here.

Spin-Lattice Distribution MRI Maps Nigral Pathology in Progressive Supranuclear Palsy (PSP) during Life: A Pilot Study

An MRI biomarker for Parkinsonism has long been sought, but almost all attempts at conventional field strengths have proved unsatisfactory, since patients and controls are not separated. The exception is Spin-Lattice Distribution MRI (SLD-MRI), a technique which detects changes in the substantia nigra (SN) due to changes in the spin-lattice relaxation time, T1. This easily separates patients with Parkinson's disease (PD) from control subjects at 1.5 Tesla, suggesting that it may be sensitive to presymptomatic disease. SLD-MRI demonstrates a topography of signal change within the SN which is the same as the known topography of pathological change, where the lateral portions of the nucleus are more affected than the medial. In a further step towards its validation, we apply SLD-MRI to a disease control, Progressive Supranuclear Palsy (PSP), the most common of the atypical forms of Parkinsonism. In PSP the topography of pathological change in the SN is reversed. We therefore hypothesized that PSP would show a topography of SLD-MRI signal change in the SN that is the reverse of PD (i.e. the medial portion is more affected than the lateral). All 7 patients showed such a topography of MR signal, and all patients were separated from control subjects. Although this is a step toward validation of SLD-MRI with respect to sensitivity and disease specificity, nevertheless we stress that this is a pilot project only. Validation will only be possible when comparing larger cohorts of PSP, PD and control subjects.

Medio-lateral balance impairment differentiates between Parkinson's disease and atypical parkinsonism.

In early disease stages, it can be difficult to differentiate clinically between Parkinson's disease and the various forms of atypical parkinsonism, like multiple system atrophy or progressive supranuclear palsy. Balance impairment in the medio-lateral plane (i.e. sideways) is often seen in patients with a form of atypical parkinsonism, but not in patients with Parkinson's disease. This is reflected by the distance between the feet during gait, which is typically normal (or even narrow) in Parkinson's disease, but widened in atypical parkinsonism. Estimating this stance width depends on subjective judgement, and is difficult to quantify in clinical practice. Here, we emphasize that this medio-lateral balance impairment can also be revealed using two simple tests: (1) inability to perform tandem gait (taking one or more side steps being abnormal); and (2) self-report by patients who have lost the ability to ride a bicycle. Both tests have a good diagnostic yield in differentiating between Parkinson's disease and atypical parkinsonism, even early in the course of the disease.

The value of putaminal diffusion imaging versus 18‐fluorodeoxyglucose positron emission tomography for the differential diagnosis of the Parkinson variant of multiple system atrophy

Differentiating the Parkinson variant of multiple system atrophy (MSA-P) from idiopathic Parkinson's disease (PD) and other forms of atypical parkinsonism can be difficult because symptoms overlap considerably. 18-Fluorodeoxyglucose positron emission tomography (FDG-PET) is a powerful imaging technique that can assist in the diagnosis of MSA-P via detection of putaminal and cerebellar hypometabolism. Recent studies suggest that diffusion-weighted imaging (DWI) might be of similar diagnostic value, as it can detect microstructural damage in the putamen by means of an increased mean diffusivity (MD). The aim of this study was a direct comparison of DWI and FDG-PET by using both methods on the same subject cohort. To this end, combined DWI and FDG-PET were employed in patients with MSA-P (n = 11), PD (n = 13), progressive supranuclear palsy (n = 8), and in 6 control subjects. MD values and FDG uptake ratios were derived from volumetric parcellations of the putamen and subjected to further analysis of covariance (ANCOVA) and receiver operating characteristics analyses. MSA-P was found to be associated with an increased posterior putaminal MD (P < 0.001 in all subgroup comparisons) that correlated strongly with local reductions in FDG uptake (r = -0.85, P = 0.002). DWI discriminated patients with MSA-P from other subgroups nearly as accurately as FDG-PET (area under the curve = 0.89 vs 0.95, P = 0.27 [pooled data]). Our data suggest a close association between the amount of putaminal microstructural damage and a reduced energy metabolism in patients with MSA-P. The clinical use of DWI for the differential diagnosis of MSA-P is encouraged.