[Cortico-basal syndrome and cortico-basal degeneration: From the clinical diagnosis to the lesional substrate for an adapted care]. / Le syndrome cortico-basal et la dégénérescence cortico-basale : du diagnostic clinique au substrat lésionnel pour une prise en charge adaptée.

Cortico-basal degeneration is a relatively uncommon cause of degenerative parkinsonism in the elderly. From a clinical point of view, it manifests as a cortico-basal syndrome (CBS), featuring a highly asymmetrical akinetic-rigid syndrome, dystonia, myoclonus and cognitive-behavioral impairment with predominant apraxia. Other clinical phenotypes are possible, including variants with mainly language or behavioral impairment, or with axial, symmetrical parkinsonism resembling progressive supranuclear palsy (PSP). Current diagnostic criteria take into account the heterogeneity of clinical presentations. However, a diagnosis of certainty can only be reached by a pathological study, with the evidence of TAU-positive intraneuronal inclusions. Indeed SCB may be underpinned by other lesional substrates, ranging from frontotemporal degeneration to Alzheimer's disease. Symptom management must be early, multidisciplinary and adapted to the progression of the disorder. The identification of the pathological substrate is an essential prerequisite for pathophysiological therapeutic trials.

Purpose in Life and Its Association to Parkinsonism.

OBJECTIVES: Purpose in life has been associated with diverse health outcomes; however, few studies have examined its associations with progressive motor decline in older adults. We tested if higher purpose would be associated with lower likelihood of incident parkinsonism as well as with lower levels and slower rates of increase in parkinsonian signs. METHODS: Participants were 2,626 older adults from the Rush Memory and Aging Project and Minority Aging Research Study followed for an average of 7.2 years (standard deviation [SD] = 4.6). Purpose was measured using the purpose in life subscale of the modified Ryff's and Keyes's measure of psychological well-being. Four parkinsonian signs (i.e., parkinsonian gait, rigidity, bradykinesia, and tremor) were assessed using the United Parkinson's Disease Rating Scale. We examined purpose with risk of developing incident parkinsonism using Cox proportional hazards models. We also used linear mixed-effect models to assess the association between purpose and parkinsonian sign trajectories. RESULTS: After including demographics, health conditions, and health behaviors in the model, for a 1-SD increase in purpose, the hazards ratio for incident parkinsonism was 0.88 (95% confidence interval [CI] 0.80, 0.97). A 1-SD increase in purpose was associated with a -0.19 (95% CI -0.24, -0.15) point lower score in the global parkinsonian summary score at baseline but no differences in rate of change were evident. DISCUSSION: Higher purpose was associated with lower hazards of incident parkinsonism and lower levels of parkinsonian signs at baseline. Associations were seen even after adjustment for a wide range of covariates. Findings suggest higher purpose may contribute to maintenance of healthy physical function among older adults.

Putaminal T1/T2-weighted ratio is increased in PSP compared to PD and healthy controls, a multi-cohort study.

INTRODUCTION: Differentiating Parkinson's disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is a common clinical problem. We aimed to apply the T1-/T2-weighted ratio imaging technique, based on standard clinical MRI, to reveal differences in neurodegeneration in three large cohorts. METHODS: Three cohorts, with a total of 405 participants (269 PD, 44 PSP, 38 MSA, 54 controls), were combined and T1/T2-weighted ratio image analyses were carried out. A combination of automatic segmentation and atlas-based ROI were used in this study. The cohorts were combined using the ComBat batch correction procedure. RESULTS: Group differences were found in the putamen (p = 0.040), with higher T1/T2-weighted ratio in this region in PSP compared to PD and healthy controls (p-values 0.010 and 0.007 respectively). Using putaminal T1/T2-weighted ratio for diagnostic separation, a fair performance was found in separating PSP from healthy controls, with an area under the receiver operating characteristic curve of 0.701. CONCLUSION: Different patterns of T1/T2-weighted ratio, reflecting differences in underlying pathophysiology, were found between the groups. Since T1/T2-weighted ratio can be applied to standard clinical MRI sequences to allow more quantitative analyses, this seems to be a promising biomarker for diagnostics and treatment evaluation of parkinsonian disorders for clinical trials.

A Blinded Evaluation of Brain Morphometry for Differential Diagnosis of Atypical Parkinsonism.

BACKGROUND: Advanced imaging techniques have been studied for differential diagnosis between PD, MSA, and PSP. OBJECTIVES: This study aims to validate the utility of individual voxel-based morphometry techniques for atypical parkinsonism in a blinded fashion. METHODS: Forty-eight healthy controls (HC) T1-WI were used to develop a referential dataset and fit a general linear model after segmentation into gray matter (GM) and white matter (WM) compartments. Segmented GM and WM with PD (n = 96), MSA (n = 18), and PSP (n = 20) were transformed into z-scores using the statistics of referential HC and individual voxel-based z-score maps were generated. An imaging diagnosis was assigned by two independent raters (trained and untrained) blinded to clinical information and final diagnosis. Furthermore, we developed an observer-independent index for ROI-based automated differentiation. RESULTS: The diagnostic performance using voxel-based z-score maps by rater 1 and rater 2 for MSA yielded sensitivities: 0.89, 0.94 (95% CI: 0.74-1.00, 0.84-1.00), specificities: 0.94, 0.80 (0.90-0.98, 0.73-0.87); for PSP, sensitivities: 0.85, 0.90 (0.69-1.00, 0.77-1.00), specificities: 0.98, 0.94 (0.96-1.00, 0.90-0.98). Interrater agreement was good for MSA (Cohen's kappa: 0.61), and excellent for PSP (0.84). Receiver operating characteristic analysis using the ROI-based new index showed an area under the curve (AUC): 0.89 (0.77-1.00) for MSA, and 0.99 (0.98-1.00) for PSP. CONCLUSIONS: These evaluations provide support for the utility of this imaging technique in the differential diagnosis of atypical parkinsonism demonstrating a remarkably high differentiation accuracy for PSP, suggesting potential use in clinical settings in the future.

Kinect-based objective assessment of the acute levodopa challenge test in parkinsonism: a feasibility study.

INTRODUCTION: The acute levodopa challenge test (ALCT) is an important and valuable examination but there are still some shortcomings with it. We aimed to objectively assess ALCT based on a depth camera and filter out the best indicators. METHODS: Fifty-nine individuals with parkinsonism completed ALCT and the improvement rate (IR, which indicates the change in value before and after levodopa administration) of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS III) was calculated. The kinematic features of the patients' movements in both the OFF and ON states were collected with an Azure Kinect depth camera. RESULTS: The IR of MDS-UPDRS III was significantly correlated with the IRs of many kinematic features for arising from a chair, pronation-supination movements of the hand, finger tapping, toe tapping, leg agility, and gait (rs = - 0.277 ~ - 0.672, P < 0.05). Moderate to high discriminative values were found in the selected features in identifying a clinically significant response to levodopa with sensitivity, specificity, and area under the curve (AUC) in the range of 50-100%, 47.22%-97.22%, and 0.673-0.915, respectively. The resulting classifier combining kinematic features of toe tapping showed an excellent performance with an AUC of 0.966 (95% CI = 0.922-1.000, P < 0.001). The optimal cut-off value was 21.24% with sensitivity and specificity of 94.44% and 87.18%, respectively. CONCLUSION: This study demonstrated the feasibility of measuring the effect of levodopa and objectively assessing ALCT based on kinematic data derived from an Azure Kinect-based system.

Under-Diagnosis of Dementia with Lewy Bodies in Individuals Racialized as Black: Hypotheses Regarding Potential Contributors.

Dementia with Lewy bodies (DLB) is one of the most common degenerative dementias after Alzheimer's disease (AD) dementia. DLB is under-diagnosed across populations but may be particularly missed in older Black adults. The object of this review was to examine key features of DLB and potential associations with race in order to hypothesize why DLB may be under-diagnosed in Black adults in the U.S. In terms of dementia, symptoms associated with high rates of co-pathology (e.g., AD, vascular disease) in older Black adults may obscure the clinical picture that might suggest Lewy body pathology. Research also suggests that clinicians may be predisposed to give AD dementia diagnoses to Black adults, potentially missing contributions of Lewy body pathology. Hallucinations in Black adults may be misattributed to AD or primary psychiatric disease rather than Lewy body pathology. Research on the prevalence of REM sleep behavior in diverse populations is lacking, but REM sleep behavior disorder could be under-diagnosed in Black adults due to sleep patterns or reporting by caregivers who are not bed partners. Recognition of parkinsonism could be reduced in Black adults due to clinician biases, cultural effects on self-report, and potentially underlying differences in the frequency of parkinsonism. These considerations are superimposed on structural and systemic contributions to health (e.g., socioeconomic status, education, structural racism) and individual-level social exposures (e.g., social interactions, discrimination). Improving DLB recognition in Black adults will require research to investigate reasons for diagnostic disparities and education to increase identification of core symptoms in this population.

Characterization of de novo Dementia with Lewy Body with different duration of rapid eye movement sleep behavior disorder.

BACKGROUND: Cognitive disorder, parkinsonism, autonomic dysfunction (AuD) and rapid eye movement sleep behavior disorder (RBD) can occur prior to or simultaneously with Dementia with Lewy Body (DLB) onset. RBD is generally linked with progressive neurodegenerative traits. However, associations between RBD with DLB, RBD without DLB, and RBD duration effects on DLB symptoms remain unclear. OBJECTIVES: To examine DLB symptom frequency and subtypes in RBD, and explore the effects of different RBD onset times on symptoms in de novo DLB patients. METHODS: In this multicenter investigation, we consecutively recruited 271 de novo DLB patients. All had standardized clinical and comprehensive neuropsychological evaluations. Subgroup analyses, performed based on the duration of RBD confirmed by polysomnography before the DLB diagnosis, we compared the proportion of patients with cognitive impairment, parkinsonism, and AuD features between groups. RESULTS: Parkinsonism and AuD incidences were significantly elevated in DLB patients with RBD when compared with patients without RBD. Subgroup analyses indicated no significant differences in parkinsonism between DLB patients who developed RBD ≥10 years prior to the DLB diagnosis and DLB patients without RBD. The incidence of non-tremor-predominant parkinsonism and AuD was significantly higher in DLB patients whose RBD duration before the DLB diagnosis was <10 years when compared with DLB patients without RBD. CONCLUSIONS: We identified significant symptom and phenotypic variability between DLB patients with and without RBD. Also, different RBD duration effects before the DLB diagnosis had a significant impact on symptomatic phenotypes, suggesting the existence of a slowly progressive DLB neurodegenerative subtype.

Fahr's disease in a patient with recurrent pneumonias, parkinsonism and dementia.

Fahr's disease is a rare condition characterised by the presence of idiopathic familial bilateral basal ganglia calcifications, transmitted in an autosomal-dominant fashion. Diagnosis is based on clinical features of neuropsychiatric and somatic symptoms in conjunction with radiological findings. Our patient, a man in his early 50s, presented with pneumonia. History was significant for five admissions in the last 2 years for pneumonia and falls, with gradual cognitive and motor decline since his late 30s. Hypophonia, bradykinesia and dementia were noted on examination. CT of the brain revealed bilateral thalamic calcinosis, consistent with Fahr's syndrome. Further investigations and retrospective history taking, and similar radiological findings within first-degree and second-degree relatives with early deaths, transitioned the diagnosis from Fahr's syndrome to Fahr's disease. We present this case of Fahr's disease to emphasise the value of collaboration among multidisciplinary professionals to improve quality of care for such patients.

Management of lower urinary tract symptoms in Parkinsonian disorders.

INTRODUCTION: The aim of the study was to present a narrative review of the literature on the management of lower urinary tract symptoms (LUTS) in patients presenting Parkinsonian disorders (PD). MATERIAL AND METHODS: We carried out a literature search in PubMed and Embase database, without time restriction. We used keywords and free-text words around "Parkinsonian disorders" AND "lower urinary tracts symptoms" without language restriction. We focused mainly on papers less than 10 years old. We included all studies evaluating LUTS in patients with PD. RESULTS: For the diagnostic management, authors emphasized the importance of differentiating Parkinson's disease with symptoms of bladder overactivity from multiple system atrophy with symptoms of bladder hypoactivity. Urodynamic evaluation was noted as the key element of diagnostic management. The therapeutic management proposed was symptomatic, based on functional urology techniques for the treatment of LUTS, both with drugs (especially anticholinergics) or surgery (intradetrusor injections of botulinum toxin, neuromodulation). Moreover, it was pointed out that it is always necessary to take into account the existence of a possible associated uropathy (prostate adenoma or pelvic prolapse). CONCLUSION: Urodynamic evaluation is the cornerstone of diagnostic management of LUTS in patients with PD. Therapeutic management is above all symptomatic and must be done in a collegial way involving the urologist, neurologist, gynecologist, and physical medicine and rehabilitation physician.

Subacute Progressive Hearing Loss and Lower Body Parkinsonism in Primary Sjögren's Syndrome.

In primary Sjögren's syndrome, it is extremely rare to observe subacute progressive lower-body parkinsonism with severe sensory hearing loss responsive to corticosteroid therapy. Sjögren's syndrome can cause heterogeneous symptoms; therefore, its diagnosis and introduction of treatment are prone to be delayed, particularly in cases without sicca symptoms or seronegative cases, which are more likely to be seen in patients with neurological complications. This report may help clinicians identify atypical early neurological symptoms in primary Sjögren's syndrome.

The clinical phenotype of psychiatric-onset prodromal dementia with Lewy bodies: a scoping review.

BACKGROUND: Recent consensus research criteria have identified a 'psychiatric onset' form of prodromal dementia with Lewy bodies (DLB) characterised by prominent late-onset psychiatric symptoms. Although recognised as important to raise the index of diagnostic suspicion, evidence regarding this cohort was deemed too limited to impose formal criteria. We reviewed the published literature on psychiatric-onset DLB to identify key clinical characteristics and evidence gaps to progress our understanding of this entity. METHODS: Medline, PubMed and Embase were searched for relevant articles containing longitudinal follow-up of patients initially presenting with a psychiatric illness who subsequently developed DLB according to the diagnostic criteria available at the time. RESULTS: Two cohort studies (18 and 21 patients) along with 12 case series (13 cases) were identified totalling 52 patients (63% female). Initial psychiatric presentation occurred at a mean of 63 years (range 53-88), with depression being the most frequently reported psychiatric presentation (88%). Psychotic presentations were less common on presentation (11%) but became more prevalent throughout the prodromal period before the diagnosis of DLB (83%). Relapses of the psychiatric disease were common occurring in 94% (32/34) of patients. Parkinsonism, cognitive fluctuations, visual hallucinations, and REM sleep behaviour disorder were uncommonly reported at initial presentation (3.8%). CONCLUSIONS: Psychiatric-onset DLB is characterized by a female predominant relapsing-remitting psychiatric illness presenting with affective symptoms but later developing psychotic features prior to the onset of DLB. Additional prospective studies including other neurodegenerative cohorts with harmonised assessments are required to inform definitive diagnostic criteria for this condition.

PSP-Richardson syndrome mimics: An overview and pragmatic approach.

Progressive supranuclear palsy-Richardson syndrome (PSP-RS) is a sporadic atypical parkinsonian syndrome with levodopa-unresponsive axial-predominant parkinsonism, early postural instability, vertical supranuclear gaze palsy, dysarthria, executive dysfunction and behavioural changes. PSP-RS can be mimicked by numbers of other disorders, generally known as PSP mimics, or PSP-like syndromes. Their aetiological spectrum includes neurodegenerative (mostly genetic), vascular, infectious and drug-induced illnesses as well as other causes. Based on the available data, we have tried to create a definition of PSP-RS mimics: a syndrome resembling PSP-RS with at least one of the following red flags: 1) positive family history; 2) onset before 45 years of age; 3) rapid or stepwise progression; 4) acute or subacute onset; 5) atypical symptoms and/or signs; 6) normal or atypical brain MRI; 7) history of HIV or untreated syphilis, aortal surgery or recent therapy with dopamine-blocking agents. We have suggested a short diagnostic algorithm leading to the identification of PSP-RS mimics and the recommended diagnostic work-up. The key point of the diagnostic process is the early identification and treatment of potentially treatable PSP-RS mimics.

Incidence and risk factors of institutionalisation in Parkinson's disease and atypical parkinsonism.

INTRODUCTION: The basic epidemiology of institutionalisation (the need for long-term care in an institution) in parkinsonism is unclear. We aimed to identify the incidence of, and risk factors for, institutionalisation in Parkinson's disease (PD) and atypical parkinsonism (AP). METHODS: We analysed data from a prospective population-based incidence cohort of parkinsonism in North-East Scotland (the PINE study). 556 newly-diagnosed participants (PD, N = 200; AP, N = 98; controls, N = 258), recruited between 2002 and 2009, were prospectively followed life-long with data collection on place of residence. We determined the incidence and baseline predictors of institutionalisation using Cox regression. RESULTS: The median follow-up time was 9.3, 4.4, and 10.8 years in PD, AP, and controls respectively. 70 (35 %) PD, 53 (54 %) AP, and 43 (16 %) controls became institutionalised. The incidence rates of institutionalisation in PD, AP, and controls were 5.1, 20.8, and 1.8 per 100 person-years respectively. The median time to institutionalisation was 11.8 years in PD and 3.5 years in AP. Multivariable Cox regression showed that AP (HR versus PD = 3.05 [95 % CI 1.90,4.91]), increasing age (HR for 10-year increase = 1.82 [95 % CI 1.40,2.36]), poorer cognition (HR for MMSE<24 versus MMSE>27 = 2.62 [95 % CI 1.45, 4.73]), more-severe parkinsonian impairment (UPDRS part 3) (HR for 10-point increase = 1.25 [95 % CI 1.05, 1.48]) were independently associated with higher hazards of institutionalisation. Sex, co-morbidity, smoking history, and living alone were not associated with institutionalisation. CONCLUSION: Institutionalisation is much more frequent in parkinsonism, particularly in AP, than in controls. AP, older age, severe parkinsonian impairment, and poorer cognition were independent baseline predictors of institutionalisation.

Improved diagnostic performance of susceptibility-weighted imaging with compressed sensing-sensitivity encoding and neuromelanin-sensitive MRI for Parkinson's disease and atypical Parkinsonism.

AIM: To verify the diagnostic performance of the loss of nigrosome-1 on susceptibility-weighted imaging (SWI) with compressed sensing-sensitivity encoding (CS-SENSE) and neuromelanin on neuromelanin-sensitive (NM) magnetic resonance imaging (MRI) for the diagnosis of Parkinson's disease (PD) and atypical Parkinsonism. MATERIALS AND METHODS: A total of 195 patients who underwent MRI between October 2019 and February 2020, including SWI, with or without CS-SENSE, and NM-MRI, were reviewed retrospectively. Two neuroradiologists assessed the loss of nigrosome-1 on SWI and neuromelanin on the NM-MRI. The result of N-3-fluoropropyl-2-beta-carbomethoxy-3-beta-(4-iodophenyl) nortropane positron-emission tomography (PET) was set as the reference standard. RESULTS: When CS-SENSE was applied for nigrosome-1 imaging on SWI, the non-diagnostic scan rate was lowered significantly from 19.3% (17/88) to 5.6% (6/107; p=0.004). Diagnosis of PD and atypical Parkinsonism based on the loss of nigrosome-1 on SWI and based on NM-MRI showed good diagnostic value (area under the curve [AUC] 0.821, 95% confidence interval [CI] = 0.755-0.875: AUC 0.832, 95% CI = 0.771-0.882, respectively) with a substantial inter-reader agreement (κ = 0.791 and 0.681, respectively). Combined SWI and neuromelanin had a similar discriminatory ability (AUC 0.830, 95% CI = 0.770-0.880). Similarly, the diagnosis of PD was excellent. CONCLUSIONS: CS-SENSE may add value to the diagnostic capability of nigrosome-1 on SWI to reduce the nondiagnostic scan rates. Furthermore, loss of nigrosome-1 on SWI or volume loss of neuromelanin on NM-MRI may be helpful for diagnosing PD.

Differentiating progressive supranuclear palsy from other movement disorders using transcranial sonography: a systematic review and meta-analysis.

Progressive supranuclear palsy (PSP) is an atypical parkinsonism that presents with different phenotypes. There are still no validated diagnostic biomarkers for early diagnosis of PSP. Transcranial sonography (TCS) is a promising tool in the differential diagnosis of parkinsonian disorders; however, there are no systematic investigations about the application of TCS in PSP patients. Therefore, we performed a systematic review and meta-analysis to discuss the role of TCS in diagnosing PSP by systematically searching PubMed, Cochrane Library, Chinese National Knowledge Infrastructure and Wan Fang databases. Of 66 obtained records, 16 articles, including 366 patients with PSP, were included. Our results showed the estimated random-effects pooled prevalence of substantia nigra hyperechogenicity in patients with PSP was 22% (95% CI 12-32%), lenticular nucleus hyperechogenicity was 70% (95% CI 52-82%), and enlarged third ventricle was 71% (95% CI 55-85%). Additionally, a normal echogenicity substantia nigra in TCS showed 70% sensitivity (95% CI 56-81%) and 86% specificity (95% CI 75-86%) to differentiate PSP from Parkinson's disease. In conclusion, TCS is an important supplementary biomarker for diagnosing PSP. At the same time, the diagnostic value of TCS in discriminating PSP from other atypical parkinsonism and between different PSP phenotypes needs further exploration.

Analysis of biomarkers in speculative CNS-enriched extracellular vesicles for parkinsonian disorders: a comprehensive systematic review and diagnostic meta-analysis.

BACKGROUND AND OBJECTIVE: Parkinsonian disorders, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), exhibit overlapping early-stage symptoms, complicating definitive diagnosis despite heterogeneous cellular and regional pathophysiology. Additionally, the progression and the eventual conversion of prodromal conditions such as REM behavior disorder (RBD) to PD, MSA, or DLB remain challenging to predict. Extracellular vesicles (EVs) are small, membrane-enclosed structures released by cells, playing a vital role in communicating cell-state-specific messages. Due to their ability to cross the blood-brain barrier into the peripheral circulation, measuring biomarkers in blood-isolated speculative CNS enriched EVs has become a popular diagnostic approach. However, replication and independent validation remain challenging in this field. Here, we aimed to evaluate the diagnostic accuracy of speculative CNS-enriched EVs for parkinsonian disorders. METHODS: We conducted a PRISMA-guided systematic review and meta-analysis, covering 18 studies with a total of 1695 patients with PD, 253 with MSA, 21 with DLB, 172 with PSP, 152 with CBS, 189 with RBD, and 1288 HCs, employing either hierarchical bivariate models or univariate models based on study size. RESULTS: Diagnostic accuracy was moderate for differentiating patients with PD from HCs, but revealed high heterogeneity and significant publication bias, suggesting an inflation of the perceived diagnostic effectiveness. The bias observed indicates that studies with non-significant or lower effect sizes were less likely to be published. Although results for differentiating patients with PD from those with MSA or PSP and CBS appeared promising, their validity is limited due to the small number of involved studies coming from the same research group. Despite initial reports, our analyses suggest that using speculative CNS-enriched EV biomarkers may not reliably differentiate patients with MSA from HCs or patients with RBD from HCs, due to their lesser accuracy and substantial variability among the studies, further complicated by substantial publication bias. CONCLUSION: Our findings underscore the moderate, yet unreliable diagnostic accuracy of biomarkers in speculative CNS-enriched EVs in differentiating parkinsonian disorders, highlighting the presence of substantial heterogeneity and significant publication bias. These observations reinforce the need for larger, more standardized, and unbiased studies to validate the utility of these biomarkers but also call for the development of better biomarkers for parkinsonian disorders.