Bradykinesia in Neurodegenerative Disorders: A Blinded Video Analysis of Pathology-Proven Cases.

BACKGROUND: Bradykinesia is a cardinal feature in parkinsonisms. No study has assessed the differential features of bradykinesia in patients with pathology-proven synucleinopathies and tauopathies. OBJECTIVE: We examined whether bradykinesia features (speed, amplitude, rhythm, and sequence effect) may differ between pathology-proven synucleinopathies and tauopathies. METHODS: Forty-two cases who underwent autopsy were included and divided into synucleinopathies (Parkinson's disease and dementia with Lewy bodies) and tauopathies (progressive supranuclear palsy). Two raters blinded to the diagnosis retrospectively scored the Movement Disorders Society-Unified Parkinson's Disease Rating Scale Part III and Modified Bradykinesia Rating Scale on standardized videotaped neurological examinations. Bradykinesia scores were compared using the Mann-Whitney test and logistic regression models to adjust for disease duration. RESULTS: Demographic and clinical parameters were similar between synucleinopathies and tauopathies. There were no differences between speed, amplitude, rhythm, and sequence effect in synucleinopathies and tauopathies in unadjusted comparisons and adjusted models (all P > 0.05). CONCLUSIONS: Clinical bradykinesia features do not distinguish the underlying neuropathology in neurodegenerative parkinsonisms. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Locus Coeruleus Integrity from 7 T MRI Relates to Apathy and Cognition in Parkinsonian Disorders.

BACKGROUND: Neurodegeneration in the locus coeruleus (LC) contributes to neuropsychiatric symptoms in both Parkinson's disease (PD) and progressive supranuclear palsy (PSP). Spatial precision of LC imaging is improved with ultrahigh field 7 T magnetic resonance imaging. OBJECTIVES: This study aimed to characterize the spatial patterns of LC pathological change in PD and PSP and the transdiagnostic relationship between LC signals and neuropsychiatric symptoms. METHODS: Twenty-five people with idiopathic PD, 14 people with probable PSP-Richardson's syndrome, and 24 age-matched healthy controls were recruited. Participants underwent clinical assessments and high-resolution (0.08 mm3 ) 7 T-magnetization-transfer imaging to measure LC integrity in vivo. Spatial patterns of LC change were obtained using subregional mean contrast ratios and significant LC clusters; we further correlated the LC contrast with measures of apathy and cognition, using both mixed-effect models and voxelwise analyses. RESULTS: PSP and PD groups showed significant LC degeneration in the caudal subregion relative to controls. Mixed-effect models revealed a significant interaction between disease-group and apathy-related correlations with LC degeneration (ß = 0.46, SE [standard error] = 0.17, F(1, 35) = 7.46, P = 0.01), driven by a strong correlation in PSP (ß = -0.58, SE = 0.21, t(35) = -2.76, P = 0.009). Across both disease groups, voxelwise analyses indicated that lower LC integrity was associated with worse cognition and higher apathy scores. CONCLUSIONS: The relationship between LC and nonmotor symptoms highlights a role for noradrenergic dysfunction across both PD and PSP, confirming the potential for noradrenergic therapeutic strategies to address transdiagnostic cognitive and behavioral features in neurodegenerative disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Ocular Motor Abnormalities in Anti-IgLON5 Disease.

Objective: Anti-IgLON5 disease forms an interface between neuroinflammation and neurodegeneration and includes clinical phenotypes that are often similar to those of neurodegenerative diseases. An early diagnosis of patients with anti-IgLON5 disease and differentiation from neurodegenerative diseases is necessary and may have therapeutic implications. Methods: In our small sample size study we investigated oculomotor function as a differentiating factor between anti-IgLON5 disease and neurodegenerative disorders. We examined ocular motor and vestibular function in four patients suffering from anti-IgLON5 disease using video-oculography (VOG) and a computer-controlled rotational chair system (sampling rate 60 Hz) and compared the data with those from ten age-matched patients suffering from progressive supranuclear palsy (PSP) and healthy controls (CON). Results: Patients suffering from anti-IgLON5 disease differed from PSP most strikingly in terms of saccade velocity and accuracy, the presence of square wave jerks (SWJ) (anti-IgLON5 0/4 vs. PSP 9/10) and the clinical finding of supranuclear gaze palsy (anti-IgLON5 1/4). The presence of nystagmus, analysis of smooth pursuit eye movements, VOR and VOR suppression was reliable to differentiate between the two disease entities. Clear differences in all parameters, although not always significant, were found between all patients and CON. Discussion: We conclude that the use of VOG as a tool for clinical neurophysiological assessment can be helpful in differentiating between patients with PSP and patients with anti-IgLON5 disease. VOG could have particular value in patients with suspected PSP and lack of typical Parkinson's characteristics. future trials are indispensable to assess the potential of oculomotor function as a biomarker in anti-IgLON5 disease.

Sleep disturbances in the speech-language variant of progressive supranuclear palsy.

INTRODUCTION: Progressive supranuclear palsy (PSP) variants other than PSP-Richardson Syndrome (PSP-RS) have been recognized, including PSP with speech and language problems (PSP-SL). Given the reported sleep disruptions in PSP-RS, we investigated sleep abnormalities in PSP-SL. METHODS: Four sleep-related screening questions were given to the caregivers of 90 patients with PSP-SL (59 suggestive of PSP-SL and 31 possible PSP-SL) and 71 probable PSP-RS (prob. PSP-RS) patients. RESULTS: At least one sleep-related disturbance was observed in 35.6% of suggestive of PSP-SL, 38.7% of possible PSP-SL, and 67.6% of prob. PSP-RS, the most common being "unable to fall or stay asleep". Prob. PSP-RS showed higher frequency of "screaming or talking in sleep", "acting out dreams", and "unable to fall or stay asleep" compared to both PSP-SL groups, but did not differ from possible PSP-SL in "excessive daytime sleepiness". CONCLUSION: Sleep abnormalities are common in PSP-SL, but less frequent than prob.PSP-RS.

Altered network stability in progressive supranuclear palsy.

The clinical syndromes of Progressive Supranuclear Palsy (PSP) may be mediated by abnormal temporal dynamics of brain networks, due to the impact of atrophy, synapse loss and neurotransmitter deficits. We tested the hypothesis that alterations in signal complexity in neural networks influence short-latency state transitions. Ninety-four participants with PSP and 64 healthy controls were recruited from two independent cohorts. All participants underwent clinical and neuropsychological testing and resting-state functional MRI. Network dynamics were assessed using hidden Markov models and neural signal complexity measured in terms of multiscale entropy. In both cohorts, PSP increased the proportion of time in networks associated with higher cognitive functions. This effect correlated with clinical severity as measured by the PSP-rating-scale, and with reduced neural signal complexity. Regional atrophy influenced abnormal brain-state occupancy, but abnormal network topology and dynamics were not restricted to areas of atrophy. Our findings show that the pathology of PSP causes clinically relevant changes in neural temporal dynamics, leading to a greater proportion of time in inefficient brain-states.

Digital Speech Analysis in Progressive Supranuclear Palsy and Corticobasal Syndromes.

BACKGROUND: Progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) as well as non-fluent/agrammatic primary progressive aphasia (naPPA) are often associated with misfolded 4-repeat tau pathology, but the diversity of the associated speech features is poorly understood. OBJECTIVE: Investigate the full range of acoustic and lexical properties of speech to test the hypothesis that PSPS-CBS show a subset of speech impairments found in naPPA. METHODS: Acoustic and lexical measures, extracted from natural, digitized semi-structured speech samples using novel, automated methods, were compared in PSPS-CBS (n = 87), naPPA (n = 25), and healthy controls (HC, n = 41). We related these measures to grammatical performance and speech fluency, core features of naPPA, to neuropsychological measures of naming, executive, memory and visuoconstructional functioning, and to cerebrospinal fluid (CSF) phosphorylated tau (pTau) levels in patients with available biofluid analytes. RESULTS: Both naPPA and PSPS-CBS speech produced shorter speech segments, longer pauses, higher pause rates, reduced fundamental frequency (f0) pitch ranges, and slower speech rate compared to HC. naPPA speech was distinct from PSPS-CBS with shorter speech segments, more frequent pauses, slower speech rate, reduced verb production, and higher partial word production. In both groups, acoustic duration measures generally correlated with speech fluency, measured as words per minute, and grammatical performance. Speech measures did not correlate with standard neuropsychological measures. CSF pTau levels correlated with f0 range in PSPS-CBS and naPPA. CONCLUSION: Lexical and acoustic speech features of PSPS-CBS overlaps those of naPPA and are related to CSF pTau levels.

Skeletal muscle loss and body composition in progressive supranuclear palsy: A retrospective cross-sectional study.

INTRODUCTION: Skeletal muscle mass loss has been associated with decreased physical performance; however, the body composition characteristics in progressive supranuclear palsy (PSP) are not well understood. We investigated body composition parameters, focusing on skeletal muscle mass, in patients with PSP and compared them with those of healthy older adults. METHODS: This retrospective cross-sectional study included 39 patients with PSP and 30 healthy older adults (control group). Using a multi-frequency bioelectrical impedance analysis, we measured the skeletal mass index (SMI), basal metabolism, extracellular water/total body water ratio (ECW/TBW), and body fat percentage and examined the relationship between SMI and age, body mass index (BMI) and other body composition parameters. RESULTS: The PSP group had a higher rate of low muscle mass (56.4%) than the control group (10.0%), although the ages and BMIs were similar. The leg SMI was lower for the PSP group, while the ECW/TBW was higher for the PSP group. The basal metabolism was lower for the PSP group than for the controls but only in the women. The basal metabolism and BMI showed a significant correlation with SMI in the PSP group. There was a significant correlation between SMI and age, ECW/TBW, and body fat percentage in the PSP group but only in the women. CONCLUSION: This study is the first to show that a high proportion of patients with PSP have low muscle mass. We showed differences in terms of sex in muscle mass loss in women with PSP, which was associated with inactivity and aging.

Gait analysis may distinguish progressive supranuclear palsy and Parkinson disease since the earliest stages.

Progressive supranuclear palsy (PSP) is a rare and rapidly progressing atypical parkinsonism. Albeit existing clinical criteria for PSP have good specificity and sensitivity, there is a need for biomarkers able to capture early objective disease-specific abnormalities. This study aimed to identify gait patterns specifically associated with early PSP. The study population comprised 104 consecutively enrolled participants (83 PD and 21 PSP patients). Gait was investigated using a gait analysis system during normal gait and a cognitive dual task. Univariate statistical analysis and binary logistic regression were used to compare all PD patients and all PSP patients, as well as newly diagnosed PD and early PSP patients. Gait pattern was poorer in PSP patients than in PD patients, even from early stages. PSP patients exhibited reduced velocity and increased measures of dynamic instability when compared to PD patients. Application of predictive models to gait data revealed that PD gait pattern was typified by increased cadence and longer cycle length, whereas a longer stance phase characterized PSP patients in both mid and early disease stages. The present study demonstrates that quantitative gait evaluation clearly distinguishes PSP patients from PD patients since the earliest stages of disease. First, this might candidate gait analysis as a reliable biomarker in both clinical and research setting. Furthermore, our results may offer speculative clues for conceiving early disease-specific rehabilitation strategies.

GABAergic cortical network physiology in frontotemporal lobar degeneration.

The clinical syndromes caused by frontotemporal lobar degeneration are heterogeneous, including the behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy. Although pathologically distinct, they share many behavioural, cognitive and physiological features, which may in part arise from common deficits of major neurotransmitters such as γ-aminobutyric acid (GABA). Here, we quantify the GABAergic impairment and its restoration with dynamic causal modelling of a double-blind placebo-controlled crossover pharmaco-magnetoencephalography study. We analysed 17 patients with bvFTD, 15 patients with progressive supranuclear palsy, and 20 healthy age- and gender-matched controls. In addition to neuropsychological assessment and structural MRI, participants undertook two magnetoencephalography sessions using a roving auditory oddball paradigm: once on placebo and once on 10 mg of the oral GABA reuptake inhibitor tiagabine. A subgroup underwent ultrahigh-field magnetic resonance spectroscopy measurement of GABA concentration, which was reduced among patients. We identified deficits in frontotemporal processing using conductance-based biophysical models of local and global neuronal networks. The clinical relevance of this physiological deficit is indicated by the correlation between top-down connectivity from frontal to temporal cortex and clinical measures of cognitive and behavioural change. A critical validation of the biophysical modelling approach was evidence from parametric empirical Bayes analysis that GABA levels in patients, measured by spectroscopy, were related to posterior estimates of patients' GABAergic synaptic connectivity. Further evidence for the role of GABA in frontotemporal lobar degeneration came from confirmation that the effects of tiagabine on local circuits depended not only on participant group, but also on individual baseline GABA levels. Specifically, the phasic inhibition of deep cortico-cortical pyramidal neurons following tiagabine, but not placebo, was a function of GABA concentration. The study provides proof-of-concept for the potential of dynamic causal modelling to elucidate mechanisms of human neurodegenerative disease, and explains the variation in response to candidate therapies among patients. The laminar- and neurotransmitter-specific features of the modelling framework, can be used to study other treatment approaches and disorders. In the context of frontotemporal lobar degeneration, we suggest that neurophysiological restoration in selected patients, by targeting neurotransmitter deficits, could be used to bridge between clinical and preclinical models of disease, and inform the personalized selection of drugs and stratification of patients for future clinical trials.

Phonemic Verbal Fluency and Midbrain Atrophy in Progressive Supranuclear Palsy.

BACKGROUND: The neuropsychological profile of progressive supranuclear palsy (PSP) patients is mainly characterized by executive dysfunction, but the relationship between the latter and midbrain atrophy is still unclear. OBJECTIVE: The aims of the study were to investigate which test evaluating executive functioning is more frequently impaired in PSP patients and to evaluate the relationship between midbrain-based MRI morphometric measures and executive dysfunction. METHODS: PSP patients who had undergone a neuropsychological battery assessing executive functioning with the Frontal Assessment Battery (FAB), the phonemic verbal fluency F-A-S, the Raven's Progressive Colored Matrix, and the Stroop word colors test (time and errors) were enrolled in the study. A group of Parkinson's disease (PD) patients matched by age, sex, education, and global cognitive status was selected. All the enrolled patients also underwent a volumetric T1-3D brain MRI. RESULTS: Thirty-five PSP patients and 35 PD patients were enrolled. Patients with PSP as compared to patients with PD showed a significant greater impairment in verbal fluency (16.0±7.9 and 23.4±8.7 words/180 s; p < 0.001) and a significant lower score at the FAB total score (11.5±3.8 and 13.7±3.4; p = 0.013). Midbrain area was significantly smaller in PSP patients than in PD patients (83.9±20.1 and 134.5±19.9 mm2; p < 0.001). In PSP patients, a significant positive correlation between verbal fluency and the midbrain area (r = 0.421; p = 0.028) was observed. CONCLUSION: Our findings suggest that the phonemic verbal fluency is among the most frequently impaired executive functions in PSP patients and is strongly correlated to midbrain atrophy.

Salience driven attention is pivotal to understanding others' intentions.

Interpreting others' beliefs, desires and intentions is known as "theory of mind" (ToM), and is often evaluated using simplified measurement tools, which may not correctly reflect the brain circuits that are required for real-life ToM functioning. We aimed to identify the brain structures necessary to correctly infer intentions from realistic scenarios by administering The Awareness of Social Inference Test, Enriched subtest to 47 patients with behavioural variant frontotemporal dementia, 24 patients with progressive supranuclear palsy syndrome, 31 patients with Alzheimer's syndrome, and 77 older healthy controls. Neuroimaging data was analyzed using voxel based morphometry, and participants' understanding of intentions was correlated with voxel-wise and region-of interest data. We found that structural integrity of the cinguloinsular cortex in the salience network (SN) was more pivotal for accurate ToM than previously described, emphasizing the importance of the SN for selectively recognizing and attending to social cues during ToM inferences.

Association of PSP phenotypes with survival: A brain-bank study.

INTRODUCTION: The MDS-PSP criteria expand the phenotypic spectrum of PSP by adding to Richardson's syndrome (PSP-RS) other presentations such as PSP-parkinsonism (PSP-P), PSP-pure-gait-freezing (PSP-PGF), PSP-speech-language (PSP-SL), PSP-frontal (PSP-F), PSP-postural-instability (PSP-PI) and PSP-corticobasal-syndrome (PSP-CBS). Evidence about the prognostic differences between PSP phenotypes is scarce and focused on PSP-RS vs. non-PSP-RS. Using a brain-bank cohort we assessed PSP survival not only in PSP-RS vs. non-PSP-RS, but also in PSP-RS + cortical vs. subcortical phenotypes. Besides, we assessed sensitivity and specificity of the MDS-PSP criteria in of PSP and other degenerative parkinsonisms. METHODS: We retrospectively applied the MDS-PSP diagnostic criteria to 32 definite PSP cases and 30 cases with other degenerative parkinsonian syndromes (Parkinson's disease [PD; n = 11], multiple system atrophy [MSA; n = 11], corticobasal degeneration [CBD; n = 8]). We conducted survival statistics in neuropathologically confirmed PSP cases considering PSP-RS vs. non-PSP-RS and PSP-RS + PSP-cortical (PSP-F + PSP-SL + PSP-CBS) vs. PSP-subcortical (PSP-P + PSP-PGF) phenotypes. We also adjusted survival analyses for PSP tau scores. RESULTS: Diagnostic sensitivity was 100% and specificity ranged from 47% to 87% when excluding cases that met the "suggestive of PSP" definition early in their disease course but with other clinical features better matching with a non-PSP pathological diagnosis. Survival was significantly shorter in PSP-RS vs. non-PSP-RS cases, but it was more markedly shorter in PSP-RS + PSP-cortical vs. PSP-subcortical, independently of PSP tau scores, which were not associated with survival. CONCLUSIONS: PSP-subcortical phenotypes appear to have longer survival than PSP-RS and cortical phenotypes. This might be of prognostic relevance when informing patients upon clinical diagnosis.

Central nystagmus in progressive supranuclear palsy: A neglected clinical feature?

BACKGROUND: Progressive supranuclear palsy (PSP) features parkinsonism characterized by early postural instability, falls and prominent eye movement abnormalities that consist of saccadic slowing, followed by gaze limitation. Nystagmus is not considered typical for PSP, being more commonly associated with multiple system atrophy. OBJECTIVES: To describe the prevalence and phenomenology of nystagmus in patients with PSP. METHODS: 42 patients with probable PSP underwent detailed clinical eye movement examination. Patients with nystagmus performed video-nystagmography. T-test, Chi-Square test and Wilcoxon signed-rank test were used to test differences in demographic data, disease duration and PSP subtype between patients with and without nystagmus, and for analysis of video-nystagmographic data. RESULTS: Among 42 patients with PSP, we identified 15 patients (35,7%) with gaze-evoked nystagmus, predominantly horizontal. Clinically, 10/15 patients had symmetrical or asymmetrical gaze - evoked nystagmus (Type 1), while 5/15 patients had dissociated gaze-evoked nystagmus related to internuclear ophthalmoplegia (Type 2). Nystagmus and eye movement abnormalities were further characterized by video-nystagmography. There was no significant difference in age, disease duration or PSP subtypes between patients with and without nystagmus. CONCLUSION: Central nystagmus is present in more than a third of patients with progressive supranuclear palsy. It may present as symmetrical or asymmetrical gaze-evoked nystagmus or as dissociated gaze-evoked nystagmus related to internuclear ophthalmoplegia and probably arises from neurodegeneration of the neural integrator. Nystagmus in PSP has been a hitherto under-described feature and its presence should not deter clinicians from a diagnosis of PSP.

The Role of Vocal Fold Bowing on Cough and Swallowing Dysfunction in Progressive Supranuclear Palsy.

OBJECTIVES: Progressive supranuclear palsy (PSP) is a neurodegenerative disease which results in cough and swallowing dysfunction and aspiration pneumonia. Relationships among vocal fold atrophy, cough, and swallowing have been identified in related diseases, but remain unknown in PSP. This study examined: 1) the prevalence of vocal fold bowing in PSP, and 2) the influence of vocal fold bowing on cough and swallowing in PSP. STUDY DESIGN: Prospective Cohort Study. METHODS: Twenty-three participants with PSP completed instrumental assessments of cough and swallowing. Vocal fold bowing (BI) and swallowing safety (PAS) was assessed using flexible laryngoscopy. Measures of cough effectiveness were obtained using spirometry. Statistical analyses were used to determine the frequency of mild-moderate (BI > 0) and severe (BI > 12.2) bowing, and to assess the influence of BI on PAS and cough effectiveness in PSP. RESULTS: Fifty-two percent (n = 12) of participants exhibited severe bowing while 48% (n = 11) exhibited mild-to-moderate bowing. Voluntary cough peak expiratory flow rate (P = .01), as well as reflex (P = .02) and voluntary (P = .005) cough volume acceleration were lower for participants with severe BI when compared to mild-to-moderate BI. However, BI did not influence PAS (P > .05). CONCLUSIONS: Findings from this study suggest that vocal fold bowing is highly prevalent in PSP and associated with reduced reflex and voluntary cough effectiveness. These findings provide insight into the pathophysiology of compromised airway protection in this patient population. Future studies should examine vocal fold atrophy as a treatment target for behavioral and medical intervention in PSP. LEVEL OF EVIDENCE: 3 (Prospective Observational Study) Laryngoscope, 131:1217-1222, 2021.

Pain in neurodegenerative diseases with atypical parkinsonism: a systematic review on prevalence, clinical presentation, and findings from experimental studies.

Parkinson's disease-related pain has increasingly been investigated in research studies. Still, only a few studies have addressed the prevalence and clinical characteristics of pain in neurodegenerative disorders with atypical parkinsonism. The existing evidence, although scarce, suggests that, similarly as in Parkinson's disease, individuals with neurodegenerative diseases with atypical parkinsonism might be predisposed to the development of persistent pain. Today, as the global population is aging and we face an epidemic of neurodegenerative disorders, under-treated pain is taking a great toll on an ever-rising number of people. Here, we provide an up-to-date review of the current knowledge on the prevalence of pain, its clinical features, and findings from experimental studies that might signpost altered pain processing in the most prevalent neurodegenerative disorders with atypical parkinsonism: multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, and dementia with Lewy bodies. Finally, we point out the current gaps and unmet needs that future research studies should focus on. Large-scale, high-quality clinical trials, coupled with pre-clinical research, are urgently needed to reveal the exact pathophysiological mechanisms underpinning heightened pain and pave the path for mechanistically-driven analgesic interventions to be developed, ultimately leading to an improvement in the quality of life of individuals with neurodegenerative disorders.

Abnormal structural connectivity in progressive supranuclear palsy-Richardson syndrome.

OBJECTIVES: Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is characterized by symmetrical parkinsonism with postural instability and frontal dysfunction. This study aims to use the whole brain structural connectome (SC) to gain insights into the underlying disconnectivity which may be implicated in the clinical features of PSP-RS. METHODS: Sixteen patients of PSP-RS and 12 healthy controls were recruited. Disease severity was quantified using PSP rating scale (PSPRS), and mini-mental scale was applied to evaluate cognition. Thirty-two direction diffusion MRIs were acquired and used to compute the structural connectome of the whole brain using deterministic fiber tracking. Group analyses were performed at the edge-wise, nodal, and global levels. Age and gender were used as nuisance covariates for all the subsequent analyses, and FDR correction was applied. RESULTS: Network-based statistics revealed a 34-edge network with significantly abnormal edge-wise connectivity in the patient group. Of these, 25 edges were cortical connections, of which 68% were frontal connections. Abnormal deep gray matter connections were predominantly comprised of connections between structures of the basal ganglia. The characteristic path length of the SC was lower in PSP-RS, and nodal analysis revealed abnormal degree, strength, local efficiency, betweenness centrality, and participation coefficient in several nodes. CONCLUSIONS: Significant alterations in the structural connectivity of the whole brain connectome were observed in PSP-RS. The higher degree of abnormality observed in nodes belonging to the frontal lobe and basal ganglia substantiates the predominant frontal dysfunction and parkinsonism observed in PSP-RS. The findings of this study support the concept that PSP-RS may be a network-based disorder.

The evolution of parkinsonism in primary progressive apraxia of speech: A 6-year longitudinal study.

INTRODUCTION: Primary progressive apraxia of speech (PPAOS) is a neurodegenerative syndrome in which patients present with an isolated motor speech disorder. Some PPAOS patients develop parkinsonism and other features of progressive supranuclear palsy (PSP) and/or corticobasal syndrome (CBS) over time. We aimed to assess the evolution of parkinsonian characteristics in PPAOS patients who had been followed yearly for at least six years. METHODS: From a large cohort of 46 PPAOS patients, eight were followed yearly for > 6-years in multiple NIH-funded grants. Parkinsonian and other features, including bradykinesia, tremor, rigidity, postural instability, apraxia, ocular motor function and cognition were assessed at each visit, and research criteria applied for PSP and CBS diagnosis. Neurological, speech-language test scores, and [18F]fluorodeoxyglucose PET (FDG-PET) and MRI midbrain volumes were assessed. RESULTS: A Parkinson's plus syndrome developed in all eight patients (100%). Bradykinesia was the earliest feature, followed by rigidity and postural instability. Tremor was not a significant feature. Parkinsonism, limb apraxia and ocular motor impairment tended to develop four-to-five years after onset with some patients having slight asymmetric parkinsonism. Six patients (75%) met research criteria for probable PSP, although only one for PSP-Richardson's syndrome; three patients met criteria for possible CBS. Slightly asymmetric, left-sided, hypometabolism was observed on FDG-PET, not matching asymmetry of Parkinsonism. Midbrain hypometabolism was absent-minimal. Three patients had progressive midbrain volumes in the PSP-Richardson's syndrome range. CONCLUSIONS: A Parkinson's plus syndrome may inevitably develop in PPAOS supporting PPAOS as an early presentation of a Parkinson's plus disorder.

Neural correlates of naming errors across different neurodegenerative diseases: An FDG-PET study.

OBJECTIVE: To investigate the types of errors produced in a picture naming task by patients with neurodegenerative dementia due to different etiologies and their neural correlates. METHODS: The same standardized picture naming test was administered to a consecutive sample of patients (n = 148) who had been studied with [18F] FDG-PET. The errors were analyzed in 3 categories (visual, semantic, and phonologic). The PET data were analyzed using an optimized single-subject procedure, and the statistical parametric mapping multiple regression design was used to explore the correlation between each type of error and brain hypometabolism in the whole group. Metabolic connectivity analyses were run at the group level on 7 left hemisphere cortical areas corresponding to an a priori defined naming network. RESULTS: Semantic errors were predominant in most patients, independent of clinical diagnosis. In the whole group analysis, visual errors correlated with hypometabolism in the right inferior occipital lobe and in the left middle occipital lobe. Semantic errors correlated with hypometabolism in the left fusiform gyrus, the inferior and middle temporal gyri, and the temporal pole. Phonologic errors were associated with hypometabolism in the left superior and middle temporal gyri. Both positive (occipital-posterior fusiform) and negative (anterior fusiform gyrus and the superior anterior temporal lobe) connectivity changes were associated with semantic errors. CONCLUSIONS: Naming errors reflect the dysfunction of separate stages of the naming process and are specific markers for different patterns of brain involvement. These correlations are not limited to primary progressive aphasia but extend to other neurodegenerative dementias.