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Differential diagnosis between Parkinson’s disease (PD) and corticobasal syndrome (CBS) could be challenging at the early stage, due to the asymmetric onset of both diseases. Despite the clinical overlap, the anatomical circuits involved in these disorders are different. We evaluated R2 Blink Reflex Recovery Cycle (R2BRRC) and cortical thickness (CTh) in drug-naïve PD and CBS patients for characterizing pathophysiological mechanisms underlying these conditions. Patients with a clinically probable diagnosis of PD and possible CBS were recruited. R2BRRC was evaluated bilaterally at interstimulus intervals (ISIs) of 100–150–200–300–400–500–750 ms. Asymmetry index (AI) of R2BRRC for each ISI was computed. Patients underwent a structural brain MRI and hemisphere CTh and AI of MRI was calculated. Fourteen drug-naïve PD patients and 10 patients with early CBS diagnosis were enrolled. R2BRRC of PD patients showed an increased brainstem excitability for less affected side (LAS) stimulation at ISIs of 100 and 150 ms (p

in press; CA extern There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are distinct clinicopathological subtypes of frontotemporal lobar degeneration. They both have atypical parkinsonism, and they usually have distinct clinical features. The most common clinical presentation of PSP is Richardson syndrome, and the most common presentation of CBD is corticobasal syndrome. In this report, we describe a patient with a five-year history of Richardson syndrome and a family history of PSP in her mother and sister. A tau PET scan (18F-APN-1607) revealed low-to-moderate uptake in the substantia nigra, globus pallidus, thalamus and posterior cortical areas, including temporal, parietal and occipital cortices. Neuropathological evaluation revealed widespread neuronal and glial tau pathology in cortical and subcortical structures, including tufted astrocytes in the motor cortex, striatum and midbrain tegmentum. The subthalamic nucleus had mild-to-moderate neuronal loss with globose neurofibrillary tangles, consistent with PSP. On the other hand, there were also astrocytic plaques, a pathological hallmark of CBD, in the neocortex and striatum. To further characterize the mixed pathology, we applied two machine learning-based diagnostic pipelines. These models suggested diagnoses of PSP and CBD depending on the brain region - PSP in the motor cortex and superior frontal gyrus and CBD in caudate nucleus. Western blots of insoluble tau from motor cortex showed a banding pattern consistent with mixed features of PSP and CBD, whereas tau from the superior frontal gyrus showed a pattern consistent with CBD. Real-time quaking-induced conversion (RT-QuIC) using brain homogenates from the motor cortex and superior frontal gyrus showed ThT maxima consistent with PSP, while reaction kinetics were consistent with CBD. There were no pathogenic variants in MAPT with whole genome sequencing. We conclude that this patient had an unclassified tauopathy and features of both PSP and CBD. The different pathologies in specific brain regions suggests caution in diagnosis of tauopathies with limited sampling.

Corticobasal syndrome (CBS) and Parkinson's disease (PD) both present with asymmetrical extrapyramidal symptoms, often leading to a diagnostic dilemma. Patients with CBS frequently show cerebral blood flow (CBF) asymmetry alongside asymmetrical cortical atrophy. This study aimed to evaluate the clinical utility of arterial spin labeling (ASL) magnetic resonance imaging (MRI) to detect CBF asymmetry in patients with CBS.We retrospectively investigated asymmetries of regional CBF and cortical volume, measured using ASL and T1-weighted MRI, in 13 patients with CBS and 22 age-matched patients with PD. Regional CBF and cortical volume values were derived from nine brain regions on each side. CBF and volume asymmetries were calculated as %difference in each region, respectively.CBF asymmetry showed significantly greater differences in seven of nine regions, such as the perirolandic area (- 8.7% vs. - 1.4%, p 0.001) and parietal cortex (- 9.7% vs. - 1.3%, p 0.001) in patients with CBS compared with patients with PD. In contrast, significant differences in volume asymmetry were observed in three regions included within the seven regions showing CBF asymmetry, which indicated that CBF asymmetry has greater sensitivity than volume asymmetry to detect asymmetricity in CBS.ASL imaging showed significant CBF asymmetry in a wider range of brain regions in patients with CBS, which suggests that noninvasive MRI with ASL imaging is a promising tool for the diagnosis of CBS, with advantages that include the simultaneous evaluation of asymmetrical hypoperfusion in addition to focal atrophy.

Background: Corticobasal Degeneration (CBD) is a rare neurological disease caused by the pathological accumulation of tau protein. The primary pathological features of CBD include progressive neurodegenerative processes resulting in remarkable frontoparietal and basal ganglia atrophy. Objective: Like in many other neurodegenerative disorders, there is still no effective disease-modifying drug therapy in CBD. Therefore, the development of new treatment methods is of great importance. In this study, we aimed to assess the stimulating effects of high-frequency DLPFC rTMS on the motor, cognitive and behavioral disturbances in four CBD patients. Methods: Four (three females, one male) CBD patients who had been diagnosed as CBD were enrolled in this study. Patients were evaluated before and after the rTMS procedure regarding the motor, neuropsychometric and behavioral tests. The results of statistical analysis of behavioral and neuropsychometric evaluation were assessed via SPSS 18.0 package program. Data are expressed as mean, standard deviation. Before and after values of the groups were compared with the Wilcoxon sign rank test, and p Results: We have provided strong preliminary evidence that the improvement in clinical parameters was associated with the normalizations of the theta activity and glucose metabolism. Conclusion: Our current results are consistent with some previous trials showing a strong association between DLPFC targeted rTMS and electrophysiological normalizations in the left DLPFC.

Multiple pathologies may underlie corticobasal syndrome (CBS), including Alzheimer's disease (AD). Dopamine transporter density imaging with IoflupaneThe main objective of the study was to test whether a normal DaTscan in CBS patients is indicative of an underlying AD pathology, as determined by cerebrospinal fluid (CSF) biomarkers.Eighteen CBS patients were included. They were divided into patients with an AD and a non-AD disease pathology, based on their cerebrospinal fluid biochemical profile. A typical AD CSF profile was defined as an increase in total and phosphorylated at threonine 181 tau protein in addition to a decrease in amyloid-beta with 42 amino acids. DaTscan data were compared in these two groups.Eight of the 18 CBS patients (44%) had a normal DaTscan. Seven of the 18 CBS patients (39%) had an AD cerebrospinal fluid biochemical profile. Two of seven CBS patients with AD biomarker profile had abnormal DaTscans. Three of 11 CBS patients with a non-AD biomarker profile had normal DaTscans. A normal DaTscan was indicative of AD pathology with suboptimal (~70%) sensitivity and specificity. Semi-quantitative DaTscan analysis did not differentiate between AD from non-AD CSF biomarker profile in CBS.A normal DaTscan is indicative of AD in CBS, but the sensitivity and specificity of DaTscan as an in vivo marker of AD pathology is suboptimal.

Background and purpose: Patients with a corticobasal syndrome (CBS) present a rare form of atypical parkinsonism characterized by asymmetric clinical symptoms and progressive motor and nonmotor impairment, such as apraxia, alien limb phenomenon, aphasia, myoclonus, dystonia, and cognitive impairment. At early stages, clinical differentiation between CBS and idiopathic Parkinson's disease (IPD) can be challenging.Methods: Using high-resolution T1-weighted images and voxel-based morphometry (VBM), we sought to identify disease-specific patterns of brain atrophy in a small sample of CBS and IPD patients at early stages of disease. We acquired MR images of 17 patients diagnosed with CBS and compared them with MR images of 17 subjects affected by IPD. Images were preprocessed and analyzed using VBM.Results: When compared to each other, the CBS and IPD patients of our cohort showed differences in regional gray and white matter volume depending on the diagnosis, specifically in the superior longitudinal fascicle.Conclusions: In our small patients' group, VBM was able to detect changes in regional gray and white matter volume between patients affected by CBS and patients with IPD as early as 1.5-2 years after the onset of the first motor symptoms.Keywords: Corticobasal syndrome; brain atrophy; idiopathic Parkinson syndrome; voxel-based morphometry.

The lecture considers the issues of early clinical, biochemical, genetic and instrumental diagnosis of Parkinson’s disease at the present level. The main degenerative diseases, whose initial clinical symptoms are close to that of parkinsonism, are presented synoptically. The international classification of degenerative diseases with symptoms of parkinsonism on the basis of violations of metabolic proteins (tauopathy, synucleopathy et al.) is provided. The issues of treatment for Parkinson’s disease and its phenocopies are considered. The lecture is intended for an audience of neurologists undergoing refresher and pre-certification courses, and can also be used as a training and research material in the preparation of postgraduate students, medical residents, doctoral students., В лекции на современном уровне рассматриваются вопросы ранней клинической, биохимической, генетической и инструментальной диагностики болезни Паркинсона. В конспективном виде представлены основные дегенеративные заболевания, которые в своей начальной клинической картине проявляются симптоматикой, близкой к паркинсонизму. Приводится международная классификация дегенеративных заболеваний с симптоматикой паркинсонизма на основе нарушений обменных белков (таупатии, синуклеопатии и др.). Рассматриваются вопросы терапии болезни Паркинсона и ее фенокопий. Лекция рассчитана на аудиторию неврологов, проходящих курсы усовершенствования и предаттестационные циклы, а также может быть использована как учебный и научно-исследовательский материал в подготовке аспирантов, клинических ординаторов, докторантов., У лекції на сучасному рівні розглядаються питання ранньої клінічної, біохімічної, генетичної та інструментальної діагностики хвороби Паркінсона. У конспективному вигляді представлені основні дегенеративні захворювання, що у своїй початковій клінічній картині проявляються симптоматикою, близькою до паркінсонізму. Наводиться міжнародна класифікація дегенеративних захворювань із симптоматикою паркінсонізму на основі порушень обмінних білків (таупатії, синуклеопатії та ін.). Розглядаються питання терапії хвороби Паркінсона та її фенокопій. Лекція розрахована на аудиторію неврологів, які проходять курси удосконалення та передатестаційні цикли, а також може бути використана як навчальний та науково-дослідний матеріал у підготовці аспірантів, клінічних ординаторів, докторантів.

Introduction: We estimated the point prevalence of progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) at regional and national levels in Scotland, UK, as there are few high-quality prevalence studies of these conditions. Methods: Nationally, multiple methods of case ascertainment were used including clinician and nurse specialist referral, searches of ICD-10 diagnostic coding in routinely collected electronic health data (Scottish Morbidity Record), and patient self-referral. In one region, we also searched GP databases and unselected hospital correspondence. Cases were verified by clinical examination or medical record review. National and regional total and age-sex-stratified crude prevalence rates on December 31, 2018, were calculated. Results: The regional crude point prevalence was 4.28 per 100,000 (95% CI 2.90, 6.31) for PSP and 2.05 per 100,000 (95% CI 1.17, 3.59) for CBS. The national crude prevalence rates were lower due to the greater reliance on passive case ascertainment. There were no clear sex differences. At a national level, the peak crude prevalence rate for both PSP and CBS was in the 70–79 age group. Discussion: The prevalence rates of PSP and CBS were similar to previous estimates with little change over the past 20 years.

The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer’s type due to Alzheimer’s disease (DAT-AD), but less is known about the susceptibility of the DG to other tauopathies. Here, we report stereologic densities of total DG neurons and tau inclusions in thirty-two brains of human participants with autopsy-confirmed tauopathies with distinct isoform profiles—3R Pick’s disease (PiD, N = 8), 4R corticobasal degeneration (CBD, N = 8), 4R progressive supranuclear palsy (PSP, N = 8), and 3/4R AD (N = 8). All participants were diagnosed during life with primary progressive aphasia (PPA), an aphasic clinical dementia syndrome characterized by progressive deterioration of language abilities with spared non-language cognitive abilities in early stages, except for five patients with DAT-AD as a comparison group. 51% of total participants were female. All specimens were stained immunohistochemically with AT8 to visualize tau pathology, and PPA cases were stained for Nissl substance to visualize neurons. Unbiased stereological analysis was performed in granule and hilar DG cells, and inclusion-to-neuron ratios were calculated. In the PPA group, PiD had highest mean total (granule + hilar) densities of DG tau pathology (p

Introduction: Neuroimaging plays an increasingly important role in the diagnosis of parkinsonian syndromes. Aim of the study: In this paper, the authors elaborate on the necessity of using magnetic resonance imaging (MRI) in Parkinson’s Disease (PD) and its potential role in differential diagnosis versus other neurodegenerative parkinsonian syndromes such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy and corticobasal syndrome. State of the art: The currently known characteristic abnormalities are listed and tabulated, current recommendations are summarised and sample images are provided. As routine MRI scanning in PD remains controversial, the authors’ aim is to show the pros and cons in clinical practice. Additionally, the rationale for functional imaging examination, including [123I]-FP-CIT SPECT (DaTSCAN) and [99mTc]- HMPAO-SPECT, [18F]-FDG-PET, [123I]-mIBG-SPECT is discussed. Clinical vignette: This paper is accompanied by two illustrative clinical cases in which neuroimaging studies played a key role in diagnosis and further management. Conclusions: Neuroimaging can be helpful in differentiating PD from both atypical and symptomatic parkinsonism. Nevertheless, extensive neurological assessment in a majority of PD cases is sufficient to make a diagnosis. A network of specialists in movement disorders should be established in order to enable better, faster and more precise diagnosis of parkinsonism.

An 81-year-old woman was diagnosed with corticobasal degeneration (cognitive decline and left hand posturing). Hyponatremia and bilateral faciobrachial dystonic seizures (FBDS) ensued. Neurologic examination (figure, A; video) revealed persistent involuntary continuous left 3rd and 4th finger flexor activation and delayed relaxation. EMG revealed high-frequency spontaneous discharges, including neuromyotonia and fast myokymia of the left flexor digitorum superficialis and pronator teres (figure, B). LGI1 immunoglobulin G (IgG)1 was detected, but not CASPR2-IgG (figure, C–E). Oncologic evaluation revealed breast ductal carcinoma in situ. Encephalopathy and FBDS resolved after IV immunoglobulin. Encephalopathy coexisting with peripheral nerve hyperexcitability can mimic neurodegeneration, and should prompt exclusion of LGI1/CASPR2 autoimmunity.2

Parkinson's disease (PD) is one of the most common neurodegenerative disorders. The cardinal neuropathological features of PD include selective and progressive loss of pigmented neurons in the substantia nigra, deficiencies in dopaminergic signaling in the striatum, and occurrence of phosphorylated α-synuclein-identified Lewy bodies in the nervous system. Parkinsonism, the clinical presentation of movement disorders seen in PD, is a feature shared commonly by other pathologically distinct neurodegenerative diseases, such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA). Consequently, it is sometimes difficult to distinguish PD from such parkinsonism-related neurological disorders. In addition, parkinsonism is not always a feature of certain neurodegenerative diseases, and it can sometimes develop as a result of various forms of drug intoxication or cerebrovascular disease. Here, we describe the clinicopathological features of three patients (cases 1, 2, and 3) diagnosed as having PSP, MSA, and PD, respectively, in each of whom the postmortem histopathological diagnosis differed from the final clinical diagnosis. Neuropathologically, they had suffered from coexistent disorders: PD, MSA, and argyrophilic grain disease (case 1); PD (case 2); and vascular parkinsonism (case 3). The variety of patients showing features of parkinsonism underlines the importance of careful long-term follow up followed by postmortem neuropathological evaluation.

Background Progressive supranuclear palsy (PSP) may present as a speech/language disorder (PSP-SL). Objective We assessed pathological correlates of patients with PSP-SL who retained the suggestive of PSP-SL (s.o. PSP-SL) diagnosis versus those who progressed to possible/probable (poss./prob.) PSP. Methods Thirty-four prospectively recruited patient with s.o. PSP-SL completed comprehensive speech/language and neurological assessments longitudinally, died, and underwent autopsy. Results Twelve patients (35%) evolved to poss./prob PSP, while 22 (65%) remained as s.o. PSP-SL. Pathological diagnoses differed across the groups (P = 0.025). Patients with s.o. PSP-SL had four different neuropathologies (corticobasal degeneration [59%], PSP [13%], Pick's disease [14%], and frontotemporal lobar degeneration with TDP-43 [14%]), while all patients with poss./prob. PSP had a 4R-tauopathy (PSP [67%] and corticobasal degeneration [33%]). Development of poss./prob. PSP increased the chance of having PSP pathology by 2.38 times. Conclusions PSP-SL is associated with heterogenous pathologies. Evolution of PSP-SL into poss./prob. PSP is more predictive of underlying PSP pathology than s.o. PSP-SL. © 2021 International Parkinson and Movement Disorder Society.

To study correlations between oxidative stress (OS) and clinical changes in patients with neurodegenerative Parkinson's and to identify clinical/biochemical subtypes of the disease.One hundred and nine people were studied, including 91 patients with neurodegenerative Parkinson's (72 patients with Parkinson's disease (PD); 10 with multiple system atrophy (MSA); 9 with corticobasal degeneration (CBD), average age 61.1±7.2 years), and 18 clinically healthy people (average age 55.1±9.2). OS indexes were detected for scoring of redox state in peripheral blood of patients with PD and healthy people (control group). Detection of biochemical indexes was performed in erythrocytes and mononuclear fraction and blood. The activity of glutathione reductase (GR), myeloperoxidase (MPO) and content of reduced glutathione (GSH) was estimated.OS is a universal mechanism and is observed in many neurodegenerative diseases. However it is possible to identify quite typical changes of redox state with group selection and their correlations with definite subtypes and PD progress, it gives opportunity, in particular, to make the differential diagnosis with atypical Parkinsonism.Изучение связи показателей окислительного стресса и клинических изменений у пациентов с нейродегенеративным паркинсонизмом и выделение клинико-биохимических подтипов заболевания.В исследование включены 109 человек, из них 91 пациент с нейродегенеративным паркинсонизмом (72 пациента с болезнью Паркинсона (БП), 10 — с мультисистемной атрофией (МСА), 9 — с кортикобазальной дегенерацией; средний возраст — 61,1±7,2 года) и 18 клинически здоровых людей, средний возраст — 55,1±9,2 года. Для оценки редокс-статуса в периферической крови пациентов с БП и здоровых лиц определяли показатели окислительного стресса. Определение биохимических показателей проводили в эритроцитах и мононуклеарной фракции крови. Оценивалась активность глутатионредуктазы (GR) и миелопероксидазы (MPO), содержание восстановленного глутатиона.Окислительный стресс является универсальным механизмом и наблюдается при многих нейродегенеративных заболеваниях. Тем не менее возможно выявить достаточно характерные изменения редокс-баланса с выделением групп и их корреляций с определенными подтипами и течением БП, что дает возможность проводить дифференциальный диагноз с атипичным паркинсонизмом.

Ordered assembly of the tau protein into filaments characterizes multiple neurodegenerative diseases, which are called tauopathies. We previously reported that by electron cryo-microscopy (cryo-EM), tau filament structures from Alzheimer’s disease (1,2), chronic traumatic encephalopathy (CTE) (3), Pick’s disease (4) and corticobasal degeneration (CBD) (5) are distinct. Here we show that the structures of tau filaments from typical and atypical progressive supranuclear palsy (PSP), the most common tauopathy after Alzheimer’s disease, define a previously unknown, three-layered fold. Moreover, the tau filament structures from globular glial tauopathy (GGT, Types I and II) are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs from the above and resembles the four-layered CBD fold. The majority of tau filaments from aging-related tau astrogliopathy (ARTAG) also have the AGD fold. Surprisingly, tau protofilament structures from inherited cases with mutations +3/+16 in intron 10 of MAPT, the microtubule-associated protein tau gene, are identical to those from AGD, suggesting that a relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, tau filament structures from cases of familial British dementia (FBD) and familial Danish dementia (FDD) are the same as those from Alzheimer’s disease and primary age-related tauopathy (PART). These structures provide the basis for a classification of tauopathies that also allows identification of new entities, as we show here for a case diagnosed as PSP, but with abundant spherical 4R tau inclusions in limbic and other brain areas. The structures of the tau fold of this new disease (Limbic-predominant Neuronal inclusion body 4R Tauopathy, LNT) were intermediate between those of GGT and PSP.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are 4-repeat tauopathies with overlapping, but also morphologically distinct tau immunoreactive lesions that vary in count by brain region. 18F-flortaucipir positron emission tomography uptake has been reported to correlate with overall tau burden, and in one CBD case to have greater affinity to threads than tangles. We determine whether 18F-flortaucipir uptake is associated with histologic lesion type in 4-repeat tauopathies. Methods: We performed semi-quantitative regional lesion counts on pretangles/neurofibrillary tangles, threads, oligodendroglial coiled bodies, tufted astrocytes, and astrocytic plaques in 29 autopsied 4-repeat tauopathies (PSP = 16; CBD=13). Regression models were used for statistical analyses. Results:18F-flortaucipir uptake marginally correlated with threads in the precentral cortex (P = 0.04) and with astrocytic lesions in the red nucleus (P = 0.05). Conclusion: The findings do not support 18F-flortaucipir having differential affinity to any 4-repeat tau lesion type.

The phenomenon of ‘prion-like propagation’ in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein tau (MAPT) contains a microtubule-binding domain that consists of three or four repeats (3R/4R) due to alternative mRNA splicing of transcripts for the MAPT gene. Although a number of models for tau propagation have been reported, most use 4R human tau transgenic mice or adult wild-type mice expressing only endogenous 4R tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3R and 4R tau accumulate simultaneously, or that of Pick’s disease in which only 3R tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3R and 4R tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer’s disease (3R and 4R tauopathy), corticobasal degeneration (4R tauopathy) or Pick’s disease (3R tauopathy). At 8–9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3R and 4R tau in Alzheimer’s disease-injected brains, 4R tau only in corticobasal degeneration-injected brains and 3R tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick’s body-like inclusions were observed in Pick’s disease-injected mice, and accumulations characteristic of Pick’s disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick’s disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3R and 4R isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.

Corticobasal syndrome (CBS) is one of the Parkinson-plus disorders. While initially defined as a movement disorder rather than cognition, it is now known that CBS is related to various psychiatric symptoms. We describe a patient clinically diagnosed with CBS whose initial presentation was psychiatric and rather atypical. His clinical picture included psychotic depression and delusional jealousy. Misdiagnosing these syndromes may delay the initiation of the treatment and worsen the patients' condition, as well as increase the burden of the caretakers. Finally, COVID-19-related changes in the organization of health services complicated the diagnosis and follow-up processes of this patient.

The differential diagnosis of parkinsonism (tremor, rigidity, bradykinesia, and gait difficulty/postural instability) is broad and includes two neurodegenerative conditions that exist on a clinicopathologic spectrum: progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). Early in their clinical course, PSP and CBS may be difficult to distinguish from Parkinson disease and several other illnesses, but it is crucial to do so because of implications for management and prognosis.Early accurate diagnosis of PSP and CBS remains a challenge because of heterogeneity in presenting symptoms and high frequency of coexisting pathologies (especially Alzheimer disease and vascular disease). It is increasingly recognized that patients with PSP, CBS, and other parkinsonian disorders require multidisciplinary care for optimal outcomes. With the recent proliferation of biomarker studies and therapeutic trials for tauopathies, there is growing hope that better treatments for PSP and CBS are on the horizon.Although PSP and CBS currently lack disease-modifying therapies, it is important to diagnose them as early as possible so that the patient can benefit from the many available symptomatic therapies, support groups, and a growing number of clinical trials.

The first candidate PI-2014 was tested in healthy controls and subjects with Alzheimer's disease (AD). As PI-2014 displayed off-target binding to monoamine oxidase A (MAO-A), a new lead with improved binding to Tau and decreased MAO-A binding was required. For compound optimization, Tau binding assays based on both human AD brain homogenate and Tau-paired helical filaments were employed. Furthermore, two MAO-A screening assays based on (1) human-recombinant MAO-A and (2) displacement of 2-fluoro-ethyl-harmine from mouse brain homogenate were employed. Removing the N-methyl group from the tricyclic core resulted in compounds displaying improved Tau binding. For the final round of optimization, the cyclic amine substituents were replaced by pyridine derivatives. PI-2620 (2-(2-fluoropyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine) emerged as a best candidate displaying high Tau binding, low MAO-A binding, high brain uptake, and fast and complete brain washout. Furthermore, PI-2620 showed Tau binding on brain sections from corticobasal degeneration, progressive supranuclear palsy, and Pick's disease.

Creutzfeld-Jakob Disease (CJD) is a rare disease but a common cause of rapidly progressive neurodegeneration. Although the "classic" presentation involves early dementia or behavioral changes, there are well-described atypical variants with less prominent cognitive symptoms at onset. One such variant is Corticobasal Syndrome (CBS), which may be seen with other underlying neurodegenerative processes, but when due to prion disease pathology involves much more rapid progression and certain characteristic imaging findings. This report presents a case presenting as CBS without cognitive or behavioral changes at onset, which rapidly progressed and was determined ultimately to be due to underlying CJD. This case illustrates the need for a high index of suspicion for CJD in order to drive appropriate diagnostic testing and careful review of imaging and EEG findings, which may be subtle in early disease.

Neurodegenerative disorders involving preferentially the globus pallidus, its efferet and afferent circuits and/or related neuronal systems are rare. They include a variety of both familial and sporadic progressive movement disorders, clinically manifesting as choreoathetosis, dystonia, Parkinsonism, akinesia or myoclonus, often associated with seizures, mental impairment and motor or cerebellar symptoms. Based on the involved neuronal systems, this heterogenous group has been classified into several subgroups: "pure" pallidal atrophy (PPA) and extended forms, pallidonigral and pallidonigrospinal degeneration (PND, PNSD), pallidopyramidal syndrome (PPS), a highly debatable group, pallidopontonigral (PPND), nigrostriatal-pallidal-pyramidal degeneration (NSPPD) (Kufor-Rakeb syndrome /KRS), pallidoluysian degeneration (PLD), pallidoluysionigral degeneration (PLND), pallidoluysiodentate atrophy (PLDA), the more frequent dentatorubral-pallidoluysian atrophy (DRPLA), and other hereditary multisystem disorders affecting these systems, e.g., neuroferritinopathy (NF). Some of these syndromes are sporadic, others show autosomal recessive or dominant heredity, and for some specific gene mutations have been detected, e.g., ATP13A2/PARK9 (KRS), FTL1 or ATP13A2 (neuroferritinopathy), CAG triple expansions in gene ATN1 (DRPLA) or pA152T variant in MAPT gene (PNLD). One of the latter, and both PPND and DRPLA are particular subcortical 4-R tauopathies, related to progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and frontotemporal lobe degeneration-17 (FTLD-17), while others show additional 3-R and 4-R tauopathies or TDP-43 pathologies. The differential diagnosis includes a large variety of neurodegenerations ranging from Huntington and Joseph-Machado disease, tauopathies (PSP), torsion dystonia, multiple system atrophy, neurodegeneration with brain iron accumulation (NBIA), and other extrapyramidal disorders. Neuroimaging data and biological markers have been published for only few syndromes. In the presence of positive family histories, an early genetic counseling may be effective. The etiology of most phenotypes is unknown, and only for some pathogenic mechanisms, like polyglutamine-induced oxidative stress and autophagy in DRPLA, mitochondrial dysfunction induced by oxidative stress in KRS or ferrostasis/toxicity and protein aggregation in NF, have been discussed. Currently no disease-modifying therapy is available, and symptomatic treatment of hypo-, hyperkinetic, spastic or other symptoms may be helpful.

The hot cross bun (HCB) sign encompasses a cross-shaped hyperintensity area in the pons on axial T2-weighted magnetic resonance imaging (MRI). The HCB sign is characteristic of multiple system atrophy (MSA) and has occasionally been observed in other neurological disorders. Here, we report an autopsied case of corticobasal degeneration (CBD) that showed the HCB sign. A female patient presented with progressive gait disturbance and cognitive impairment at the age of 60 years. A neurological examination revealed dysarthria, muscle rigidity of the limbs, akinesia, truncal ataxia, urinary incontinence, and dementia. The HCB sign was observed on a brain MRI at the age of 65 years, and a clinical diagnosis of possible MSA was made. She died of pneumonia at the age of 67 years. A postmortem observation, provided neuropathological findings characteristic of CBD, including the presence of astrocytic plaques, pretangles, neuropil threads, and ballooned neurons in association with four-repeat-tau aggregation. Interestingly, the pons displayed severe neuronal loss and astrogliosis that were prominent in the pontine and raphe nuclei. Myelin sheath depletion was prominent in the transverse fibers of the pontine base and the myelinated fibers of the pontine tegmentum in contrast to relative sparing of the pontine corticospinal tract and medial lemniscus. The cerebellar dentate nucleus exhibited neuronal loss and grumose degeneration. Western blot analysis of sarkosyl-insoluble fractions from brain tissue lysates using an anti-phosphorylated tau antibody identified immunoreactive signal bands in approximately 37-40, 43, 64, and 68 kDa, consistent with CBD. Genetic analysis did not reveal any known pathogenic mutations in the microtubule-associated protein tau gene (MAPT). Our case was characterized by the HCB sign and concordant neuropathological changes in the pons. CBD should be considered an underlying pathology of the HCB sign, even though the pontocerebellar changes would be unusual in CBD cases.

Corticobasal syndrome is a disorder of movement, cognition and behaviour with several possible underlying pathologies, including corticobasal degeneration. It presents insidiously and is slowly progressive. Clinicians should consider the diagnosis in people presenting with any combination of extrapyramidal features (with poor response to levodopa), apraxia or other parietal signs, aphasia and alien-limb phenomena. Neuroimaging showing asymmetrical perirolandic cortical changes supports the diagnosis, while advanced neuroimaging may give insight into the underlying pathology. Identifying corticobasal syndrome carries some management implications (especially if protein-based treatments arise in the future) and prognostic significance. Its treatment is largely symptomatic and is best undertaken within a multidisciplinary setting, including a neurologist, physiotherapist, occupational therapist, speech language therapist, psychiatrist and, ultimately, a palliative care clinician. Corticobasal syndrome can be a confusing entity for neurologists, not least because it has over time evolved from being considered predominantly as a movement disorder to a condition spanning a wide range of cognitive and motor manifestations. In this practical review, we attempt to disentangle this syndrome and provide clarity around diagnosis, its underlying pathological substrates, key clinical features and potential treatments.

Introduction Apraxia is a core clinical feature of corticobasal syndrome (CBS). Among the subtypes of apraxia, ideomotor and imitation apraxia are frequently found in CBS. However, little is known about the brain networks that are characteristic of each apraxia subtype or their clinical implication. In this study, we used 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to explore the specific patterns of glucose hypometabolism that are characteristic of apraxia subtypes by focusing on ideomotor and imitation apraxia. Methods We compared the areas of glucose hypometabolism in the brains of 52 patients with CBS and 13 healthy controls, both as a whole and according to apraxia subtypes. In addition, we investigated the relationship between the apraxia subtypes and the clinical phenotype of CBS. Results In patients with CBS, common hypometabolism was observed in the frontal gyrus, precentral gyrus and caudate regardless of apraxia subtypes. In particular, ideomotor apraxia was associated with hypometabolism in the angular gyrus, while imitation apraxia was associated with hypometabolism in the posterior part including the postcentral gyrus, precuneus, and posterior cingulate gyrus. Patients who showed both ideomotor and imitation apraxia were more likely to show the typical features of CBS and progressive supranuclear palsy compared with patients showing only one type of apraxia. Conclusion Group comparison analysis using FDG-PET revealed distinct pathways of ideomotor and imitation apraxia in CBS. These findings add to our understanding of the brain networks underlying apraxia in association with the clinical features of CBS.

In human neurodegenerative diseases associated with the intracellular aggregation of Tau protein, the ordered cores of Tau filaments adopt distinct folds. Here, we analyze Tau filaments isolated from the brain of individuals affected by Prion-Protein cerebral amyloid angiopathy (PrP-CAA) with a nonsense mutation in the PRNP gene that leads to early termination of translation of PrP (Q160Ter or Q160X), and Gerstmann–Sträussler–Scheinker (GSS) disease, with a missense mutation in the PRNP gene that leads to an amino acid substitution at residue 198 (F198S) of PrP. The clinical and neuropathologic phenotypes associated with these two mutations in PRNP are different; however, the neuropathologic analyses of these two genetic variants have consistently shown the presence of numerous neurofibrillary tangles (NFTs) made of filamentous Tau aggregates in neurons. We report that Tau filaments in PrP-CAA (Q160X) and GSS (F198S) are composed of 3-repeat and 4-repeat Tau isoforms, having a striking similarity to NFTs in Alzheimer disease (AD). In PrP-CAA (Q160X), Tau filaments are made of both paired helical filaments (PHFs) and straight filaments (SFs), while in GSS (F198S), only PHFs were found. Mass spectrometry analyses of Tau filaments extracted from PrP-CAA (Q160X) and GSS (F198S) brains show the presence of post-translational modifications that are comparable to those seen in Tau aggregates from AD. Cryo-EM analysis reveals that the atomic models of the Tau filaments obtained from PrP-CAA (Q160X) and GSS (F198S) are identical to those of the Tau filaments from AD, and are therefore distinct from those of Pick disease, chronic traumatic encephalopathy, and corticobasal degeneration. Our data support the hypothesis that in the presence of extracellular amyloid deposits and regardless of the primary amino acid sequence of the amyloid protein, similar molecular mechanisms are at play in the formation of identical Tau filaments.

Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein tau (MAPT), which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in MAPT pre-mRNA produces equal amounts of protein isoforms with either three (3R) or four (4R) microtubule binding domains. Imbalance in the 3R:4R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal. Here we report motor coordination impairments in the htau mouse model of tauopathy which harbour abnormal 3R:4R tau isoforms content, and in contrast to TauKO mice, are unresponsive to l-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses indicated the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results suggest that abnormal striatal tau isoform content might lead to parkinsonian-like phenotypes and demonstrate a proof of concept that modulation of tau mis-splicing is a plausible disease-modifying therapy for some primary tauopathies.

Tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) exhibit characteristic neuronal and glial inclusions of hyperphosphorylated Tau (pTau). Although the astrocytic pTau phenotype upon neuropathological examination is the most guiding feature in distinguishing both diseases, regulatory mechanisms controlling their transitions into disease-specific states are poorly understood to date. Here, we provide accessible chromatin data of more than 45,000 single nuclei isolated from the frontal cortex of PSP, CBD, and control individuals. We found a strong association of disease-relevant molecular changes with astrocytes and demonstrate that tauopathy-relevant genetic risk variants are tightly linked to astrocytic chromatin accessibility profiles in the brains of PSP and CBD patients. Unlike the established pathogenesis in the secondary tauopathy Alzheimer disease, microglial alterations were relatively sparse. Transcription factor (TF) motif enrichments in pseudotime as well as modeling of the astrocytic TF interplay suggested a common pTau signature for CBD and PSP that is reminiscent of an inflammatory immediate-early response. Nonetheless, machine learning models also predicted discriminatory features, and we observed marked differences in molecular entities related to protein homeostasis between both diseases. Predicted TF involvement was supported by immunofluorescence analyses in postmortem brain tissue for their highly correlated target genes. Collectively, our data expand the current knowledge on risk gene involvement (e.g., MAPT, MAPK8, and NFE2L2) and molecular pathways leading to the phenotypic changes associated with CBD and PSP.

We present a case report of a patient with a history of renal cell carcinoma in which corticobasal syndrome had been diagnosed ante-mortem. However, distinguishing features of corticobasal degeneration pathology were absent at post-mortem. Instead, neuropathological examination revealed features consistent with the patient's history of renal cell carcinoma: micrometastatic renal cell carcinoma in cerebellar and cerebral white matter, including within the gyral white matter of the primary motor and somatosensory cortices. There was also Purkinje cell loss and mild lymphocytic inflammation in the cerebellum, but the significance of this was unclear. A number of "corticobasal degeneration mimics" have been described in the literature, but micrometastatic carcinoma causing corticobasal syndrome is a novel finding. This case expands the range of clinical disorders which may mimic corticobasal degeneration to include micrometastatic carcinoma.

Parkinson’s disease and related disorders (PDRD) are the second most common neurodegenerative disease and a leading cause of death. However, patients with PDRD receive less end-of-life palliative care (hospice) than other illnesses, including other neurologic illnesses. Identification of predictors of PDRD mortality may aid in increasing appropriate and timely referrals. To systematically review the literature for causes of death and predictors of mortality in PDRD to provide guidance regarding hospice/end-of-life palliative care referrals. We searched MEDLINE, PubMed, EMBASE and CINAHL databases (1970–2020) of original quantitative research using patient-level, provider-level or caregiver-level data from medical records, administrative data or survey responses associated with mortality, prognosis or cause of death in PDRD. Findings were reviewed by an International Working Group on PD and Palliative Care supported by the Parkinson’s Foundation. Of 1183 research articles, 42 studies met our inclusion criteria. We found four main domains of factors associated with mortality in PDRD: (1) demographic and clinical markers (age, sex, body mass index and comorbid illnesses), (2) motor dysfunction and global disability, (3) falls and infections and (4) non-motor symptoms. We provide suggestions for consideration of timing of hospice/end-of-life palliative care referrals. Several clinical features of advancing disease may be useful in triggering end-of-life palliative/hospice referral. Prognostic studies focused on identifying when people with PDRD are nearing their final months of life are limited. There is further need for research in this area as well as policies that support need-based palliative care for the duration of PDRD.

Though distinct pathological entities, corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) share multiple biochemical and genetic features suggesting overlapping pathophysiolog...

Neurodegenerative disorders may demonstrate typical lobar and regional patterns of volume loss with corresponding decreased glucose metabolism. In this retrospective study, we correlated semi-quantitative volumetric changes utilizing NeuroQuant morphometric analysis with decreased fluorodeoxyglucose (FDG) uptake age-matched calculated z-scores utilizing 18F-FDG positron emission tomography/magnetic resonance imaging (PET/MRI). Eighty-nine patients (mean age 71.4) with clinical findings suggestive of various subtypes of dementia underwent PET/MR brain imaging. Cases were categorized as follows: Alzheimer's dementia (AD), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), and corticobasal degeneration (CBD). NeuroQuant software provided semi-quantitative assessment of lobar-specific patterns of volume loss compared to age-matched controls. MIMneuro software provided semi-quantitative FDG uptake data, with metabolic z-scores generated in comparison to age-matched controls. Volumetric and metabolic data were then correlated for statistical significance. In 29 AD cases, Pearson correlation coefficient between z-score and lobar volume was 0.3 (P = 0.120) and 0.38 (P < 0.05), for parietal and temporal lobes, respectively. In 34 FTLD cases, it was 0.35 (P = 0.051) and 0.02 (P = 0.916), for frontal and temporal lobes, respectively. In 14 DLB cases, it was 0.42 (P = 0.130), 0.5 (P = 0.067), and 0.22 (P = 0.447) for the occipital lobes, middle occipital gyrus, and parietal lobes, respectively. In 12 CBD cases, it was 0.58 (P < 0.05) for the superior parietal lobule. Semi-quantitative (F18)-FDG PET/MRI analysis demonstrated a positive relationship between volumetric loss and hypometabolism within certain lobar-specific regions, depending on neurodegenerative disorder subtype. Our findings may add diagnostic confidence in the accurate imaging diagnosis of neurodegenerative disease.

Tauopathies are neurological disorders characterized by intracellular tau deposits forming neurofibrillary tangles, neuropil threads, or other disease-specific aggregates composed of the protein tau. Tauopathy disorders include frontotemporal lobar degeneration, corticobasal degeneration, Pick’s disease, and the largest cause of dementia, Alzheimer’s disease. The lack of disease-modifying therapeutic strategies to address tauopathies remains a critical unmet need in dementia care. Thus, novel broad-spectrum tau-targeted therapeutics could have a profound impact in multiple tauopathy disorders, including Alzheimer’s disease. Here we have designed a drug discovery paradigm to identify inhibitors of the pathological tau-enabling protein, MSUT2. We previously showed that activity of the RNA-binding protein MSUT2 drives tauopathy, including tau-mediated neurodegeneration and cognitive dysfunction, in mouse models. Thus, we hypothesized that MSUT2 inhibitors could be therapeutic for tauopathy disorders. Our pipeline for MSUT2 inhibitory compound identification included a primary AlphaScreen, followed by dose–response validation, a secondary fluorescence polarization orthogonal assay, a tertiary specificity screen, and a preliminary toxicity screen. Our work here serves as a proof-of-principle methodology for finding specific inhibitors of the poly(A) RNA-binding protein MSUT2 interaction. Here we identify 4,4′-diisothiocyanostilbene-2,2′-sulfonic acid (DIDS) as a potential tool compound for future work probing the mechanism of MSUT2-induced tau pathology.

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.

Aim of the study. To examine possible features of neuroinflammation in progressive supranuclear palsy — Richardson syndrome and corticobasal syndrome (CBS). Clinical rationale for the study. Neutrophil-to-lymphocyte ratio (NLR) is a parameter reflecting inflammation used in numerous branches of medicine. The search for pathogenesis of the diseases partly related to inflammatory processes confirms the need to obtain possible factors which could be relatively easily verified. NLR is a benchmark routinely evaluated in most hospitalised patients. Materials and methods. 23 patients with a clinical diagnosis of PSP-RS, 18 patients with CBS, and 32 healthy controls, were included in the study. Blood samples were assessed in the context of neutrophil and lymphocyte rates. Subsequently, the results were transformed into neutrophil-to-lymphocyte ratio (NLR). The NLRs from each group were statistically assessed using a Kruskal-Wallis test and post-hoc analysis. Results. Statistical analysis confirmed significant differences in NLR between PSP-RS and control group. No other significant differences were observed. Clinical implications. The possible use of NLR in the additional examination of atypical parkinsonisms. Conclusions. To the best of our knowledge, this is the first study comparing this aspect of neuroinflammation in PSP and CBS. It presents NLR as a promising non-specific parameter in neurodegenerative diseases.

Background: Various cerebrospinal fluid (CSF) biomarkers are studied in Parkinson’s disease (PD) and atypical parkinsonian syndromes (APS). Several studies found reduced 5-hydroxyindoleacetic acid (5-HIAA), the main serotonin metabolite, in PD. There is little evidence regarding its levels in APS. Methods: We measured 5-HIAA in the CSF of 90 PD patients, 16 MSA patients, 26 progressive supranuclear palsy (PSP) patients, 11 corticobasal syndrome (CBS) patients, and 31 controls. We also compared the values in depressed and nondepressed patients. Results: There was a statistically significant difference in CSF 5-HIAA in PD and MSA compared to the control group (median in PD 15.8 μg/L, in MSA 13.6 μg/L vs. 24.3 μg/L in controls; p = 0.0008 in PD, p = 0.006 in MSA). There was no statistically significant difference in CSF 5-HIAA in PSP and CBS compared to the control group (median in PSP 22.7 μg/L, in CBS 18.7 μg/L vs. 24.3 μg/L in controls; p = 1 in both PSP and CBS). CSF 5-HIAA levels were lower in PD patients with depression compared to PD patients without depression (median 8.34 vs. 18.48, p < 0.0001). Conclusions: CSF 5-HIAA is decreased in PD and MSA. The CSF 5-HIAA levels in PSP and CBS did not differ from those of the control group. There was a tendency toward lower CSF 5-HIAA in MSA than in PD; however, the results did not reach statistical significance. These results may be explained by more severe damage of the serotonergic system in synucleinopathies (PD and MSA) than in tauopathies (PSP and CBS).

Context.— Postmortem evaluation for neurodegenerative disease is expensive in time and materials. These challenges can be met by implementing simpler sampling protocols while preserving anatomic relations. Objective.— To determine the diagnostic effectiveness and cost-effectiveness of a simplified brain blocking protocol compared with the standard blocking protocol used in our Alzheimer's Disease Research Center (ADRC). Design.— We prospectively compared the neuropathologic diagnoses established from our standard 19-cassette/19 brain sites ADRC protocol to a simplified 6-cassette/12 brain sites protocol in 52 consecutive cases. The simplified protocol generated 14 slides for comparison to 52 slides from our standard protocol. Results.— Compared with the ADRC protocol the simplified protocol produced Alzheimer Disease Neuropathologic Changes probability scores that were the same in 50 of 52 cases (r = 0.99). Staging for Lewy pathology was equivalent in 45 of 52 (r = 0.98), scoring for cerebral amyloid angiopathy was equivalent in 48 of 52 (r = 0.97), and grading for arteriolosclerosis was the same in 45 of 52 cases (r = 0.92). Progressive supranuclear palsy (n = 4), multiple system atrophy (n = 2), and corticobasal degeneration (n = 1) could be diagnosed by either protocol independently. The estimated savings per case was 72% or $1744.89 ($2436.37 [ADRC] versus $691.48 [simplified]). Conclusions.— The diagnosis of neurodegenerative disease at autopsy can be done accurately with a less expensive, simplified protocol. Our protocol is similar to those of previously published approaches, but it has a simpler organization scheme. This method should be valuable to institutions where autopsy cost considerations may be important.

Importance: The accurate diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is hampered by imperfect clinical-pathological correlations. Objective: To assess and compare the diagnostic value of the magnetic resonance parkinsonism index (MRPI) and other magnetic resonance imaging-based measures of cerebral atrophy to differentiate between PSP, CBD, and other neurodegenerative diseases. Design, setting, and participants: This prospective diagnostic study included participants with 4-repeat tauopathies (4RT), PSP, CBD, other neurodegenerative diseases and available MRI who appeared in the University of California, San Francisco, Memory and Aging Center database. Data were collected from October 27, 1994, to September 29, 2019. Data were analyzed from March 1 to September 14, 2021. Main outcomes and measures: The main outcome of this study was the neuropathological diagnosis of PSP or CBD. The clinical diagnosis at the time of the MRI acquisition was noted. The imaging measures included the MRPI, cortical thickness, subcortical volumes, including the midbrain, pons, and superior cerebellar peduncle volumes. Multinomial logistic regression models (MLRM) combining different cortical and subcortical regions were defined to discriminate between PSP, CBD, and other pathologies. The areas under the receiver operating characteristic curves (AUROC) and cutoffs were calculated to differentiate between PSP, CBD, and other diseases. Results: Of the 326 included participants, 176 (54%) were male, and the mean (SD) age at MRI was 64.1 (8.0) years. The MRPI showed good diagnostic accuracy for the differentiation between PSP and all other pathologies (accuracy, 87%; AUROC, 0.90; 95% CI, 0.86-0.95) and between 4RT and other pathologies (accuracy, 80%; AUROC, 0.82; 95% CI, 0.76-0.87), but did not allow the discrimination of participants with CBD. Its diagnostic accuracy was lower in the subgroup of patients without the canonical PSP-Richardson syndrome (PSP-RS) or probable corticobasal syndrome (CBS) at MRI. MLRM combining cortical and subcortical measurements showed the highest accuracy for the differentiation between PSP and other pathologies (accuracy, 95%; AUROC, 0.98; 95% CI, 0.97-0.99), CBD and other pathologies (accuracy, 83%; AUROC, 0.86; 95% CI, 0.81-0.91), 4RT and other pathologies (accuracy, 89%; AUROC, 0.94; 95% CI, 0.92-0.97), and PSP and CBD (accuracy, 91%; AUROC, 0.95; 95% CI, 0.91-0.99), even in participants without PSP-RS or CBS at MRI. Conclusions and relevance: In this study, the combination of widely available cortical and subcortical measures of atrophy on MRI discriminated between PSP, CBD, and other pathologies and could be used to support the diagnosis of 4RT in clinical practice.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are tauopathies that clinically present with atypical parkinsonism. Autonomic dysfunction is known to occur in synucleinopathies, particularly in cases of multiple system atrophy; however, the frequency and features of autonomic dysfunction in patients with tauopathies remain unclear. Recent studies have reported that urinary dysfunction and constipation are common and affect the prognosis of patients with PSP. In contrast, neurogenic orthostatic hypotension is rare in PSP, which is useful to distinguish PSP from multiple system atrophy and Lewy body disease. Urinary dysfunction is also commonly observed in patients with CBD and serves as an inclusion criterion for PSP syndrome in patients with CBD. However, this finding is not validated in other cohorts; therefore, further studies are warranted to confirm the usefulness of this criterion.

Background The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. Methods We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. Results There were 257 unique parkinsonian patients with autopsy-based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy-confirmed PD, 52.0% (13/25) of those with autopsy-confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy-confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy-confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. Conclusion A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society.

Sleep complaints are the most prevalent syndromes in older adults, particularly in women. Moreover, they are frequently accompanied with a high level of depression and stress. Although several diffusion tensor imaging (DTI) studies reported associations between sleep quality and brain white matter (WM) microstructure, it is still unclear whether gender impacts the effect of sleep quality on structural alterations, and whether these alterations mediate the effects of sleep quality on emotional regulation. We included 389 older participants (176 females, age = 65.5 ± 5.5 years) from the 1000BRAINS project. Neuropsychological examinations covered the assessments of sleep quality, depressive symptomatology, current stress level, visual working memory, and selective attention ability. Based on the DTI dataset, the diffusion parameter maps, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were calculated and normalized to a population-specific FA template. According to the global Pittsburgh Sleep Quality Index (PSQI), 119 poor sleepers (PSQI: 10∼17) and 120 good sleepers (PSQI: 3∼6) were identified. We conducted a two by two (good sleepers/poor sleepers) × (males/females) analysis of variance by using tract-based spatial statistics (TBSS) and JHU-ICBM WM atlas-based comparisons. Moreover, we performed a voxel-wise correlation analysis of brain WM microstructure with the neuropsychological tests. Finally, we applied a mediation analysis to explore if the brain WM microstructure mediates the relationship between sleep quality and emotional regulation. No significant differences in brain WM microstructure were detected on the main effect of sleep quality. However, the MD, AD, and RD of pontine crossing tract and bilateral inferior cerebellar peduncle were significant lower in the males than females. Voxel-wise correlation analysis revealed that FA and RD values in the corpus callosum were positively related with depressive symptomatology and negatively related with current stress levels. Additionally, we found a significantly positive association between higher FA values in visual-related WM tracts and better outcomes in a visual pattern recognition test. Furthermore, a mediation analysis suggested that diffusion metrics within the corpus callosum partially mediated the associations between poor sleep quality/high stress and depressive symptomatology.

Background Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome related to multiple underlying pathologies. Objective To investigate if individual brain [18 F]fluorodeoxyglucose-positron emission tomography (FDG-PET) patterns could distinguish CBS due to Alzheimer's disease (AD) from other pathologies based on [11 C]Pittsburgh Compound-B (PIB)-PET. Methods Forty-five patients with probable CBS were prospectively evaluated regarding cognitive and movement disorders profile. They underwent FDG-PET and were distributed into groups: likely related to AD (CBS FDG-AD) or likely non-AD (CBS FDG-nonAD) pathology. Thirty patients underwent PIB-PET on a hybrid PET-magnetic resonance imaging equipment to assess their amyloid status. FDG and PIB-PET images were classified individually based on visual and semi-quantitative analysis, blinded to each other. Quantitative group analyses were also performed. Results CBS FDG-AD group demonstrated worse cognitive performances, mostly concerning attention, memory, visuospatial domains, and displayed more myoclonus and hallucinations. The non-AD metabolic group presented more often limb dystonia, ocular motor dysfunction, motor perseveration, and dysarthria. All patients classified as CBS FDG-AD tested positive at PIB-PET compared to 3 of 20 in the non-AD group. The individual FDG-PET classification demonstrated 76.92% of sensitivity, 100% of specificity and positive predictive value and 88.5% of balanced accuracy to detect positive PIB-PET scans. Individuals with positive and negative PIB-PET showed hypometabolism in posterior temporoparietal areas and in thalamus and brainstem, respectively, mainly contralateral to most affected side, disclosing possible metabolic signatures of CBS variants. Conclusion FDG-PET was useful to predict AD and non-AD CBS variants depicting their specific degeneration patterns, different clinical features, and brain amyloid deposition. © 2020 International Parkinson and Movement Disorder Society.

Purpose This systematic review aimed to establish language and speech markers to support the clinical diagnosis of primary progressive aphasia (PPA) and its clinical phenotypes. Our first objective was to identify behavioral language and speech markers of early-stage PPA. Our second objective was to identify the electrophysiological correlates of the language and speech characteristics in PPA. Method The databases MEDLINE, Web of Science, and Embase were searched for relevant articles. To identify behavioral markers, the initial subjective complaints and the language and speech deficits detected during the initial diagnostic evaluation were summarized for PPA in general and each clinical variant according to the 2011 consensus diagnostic criteria (nonfluent variant [NFV], semantic variant, and logopenic variant [LV]). To identify electrophysiological markers, the studies in which event-related potentials (ERPs) were elicited by a language or speech paradigm in patients with PPA were included. Results In total, 114 relevant studies were identified, including 110 behavioral studies and only four electrophysiological studies. This review suggests that patients with the semantic variant could be accurately differentiated from the NFV and LV in the initial stages based on the consensus criteria. Nonetheless, the early differentiation between the NFV and LV is not straightforward. In the four electrophysiological studies, differences in the latency, amplitude, and topographical distribution of the semantic N400 component were found between patients with PPA and healthy controls. Conclusions To accurately differentiate the NFV from the LV, it could be important to assess the language and speech degeneration by more specific assessments and by more objective diagnostic methods that offer insights into the language-related processes. Electrophysiological markers of PPA were not identified in this review due to the low number of studies that investigated language-related ERPs. More controlled ERP studies in larger patient cohorts are needed to investigate the diagnostic applicability of language-related ERPs in PPA. Supplemental Material https://doi.org/10.23641/asha.12798080

Corticobasal degeneration (CBD) is a pathology of low incidence and prevalence worldwide; it is accompanied by symptoms such as dystonia, rigid akinetic syndrome (bradykinesia), gait disturbances, neurological deterioration associated with severe cortical subcortical atrophy, and progressive to moderate to severe neurocognitive deficits, especially in immediate verbal memory and dorsolateral or dysexecutive syndrome. We identified neurocognitive impairment and neuropsychiatric symptoms in a patient diagnosed with CBD. Participant was a 70-year-old female patient, single; she presented progressive memory loss of an immediate verbal nature. Initially, she was diagnosed with Alzheimer’s disease and Lewy body dementia, finding that she had no characteristic signs and symptoms of these pathologies. The patient presented conciliation insomnia, gait disturbances, and severe neurocognitive deficit, especially in executive functions, immediate verbal memory, and visuospatial functioning. It was found that the patient presented neurocognitive alterations of the executive type (frontal lobe) such as decision making, planning, inhibition and operative memory, correlated with a severe alteration in her basic, instrumental and advanced activities of daily life, with a high risk factor for developing dementia. It is necessary to diagnose in an assertive and timely manner in order to generate functional neurorehabilitation plans in people diagnosed with CBD, with the main objective of positively impacting quality of life, at the individual, family, and social level.

Few studies have evaluated the relationship between in vivo18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34–76); eight female; median PET-to-autopsy interval of 30 months (range 4–59 months)]. Eight patients had primary Alzheimer’s disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration. Using an inferior cerebellar grey matter reference, 80–100-min 18F-flortaucipir PET standardized uptake value ratio (SUVR) images were created. Mean SUVRs were calculated for progressive supranuclear palsy, corticobasal degeneration, and neurofibrillary tangle Braak stage regions of interest, and these values were compared to SUVRs derived from young, non-autopsy, cognitively normal controls used as a standard for tau negativity. W-score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. There was excellent correspondence between areas of 18F-flortaucipir retention, on both SUVR images and W-score maps, and neurofibrillary tangle distribution in patients with primary Alzheimer’s disease neuropathology. Patients with non-Alzheimer tauopathies and non-tau frontotemporal lobar degeneration showed a range of tracer retention that was less than Alzheimer’s disease, though higher than age-matched, cognitively normal controls. Overall, binding across both tau-positive and tau-negative non-Alzheimer disorders did not reliably correspond with post-mortem tau pathology. 18F-flortaucipir SUVRs in subcortical regions were higher in autopsy-confirmed progressive supranuclear palsy and corticobasal degeneration than in controls, but were similar to values measured in Alzheimer’s disease and tau-negative neurodegenerative pathologies. Quantification of 18F-flortaucipir SUVR images at Braak stage regions of interest reliably detected advanced Alzheimer’s (Braak VI) pathology. However, patients with earlier Braak stages (Braak I–IV) did not show elevated tracer uptake in these regions compared to young, tau-negative controls. In summary, PET-to-autopsy comparisons confirm that 18F-flortaucipir PET is a reliable biomarker of advanced Braak tau pathology in Alzheimer’s disease. The tracer cannot reliably differentiate non-Alzheimer tauopathies and may not detect early Braak stages of neurofibrillary tangle pathology.

Tau is an evolutionary conserved protein that promotes the assembly and stabilization of microtubules in neuronal axons. Complex patterns of posttranslational modifications (PTMs) dynamically regulate tau biochemical properties and consequently its functions. An imbalance in tau PTMs has been connected with a broad spectrum of neurodegenerative conditions which are collectively known as tauopathies and include Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) among others. The hallmark of these neurological disorders is the presence in the brain of fibrillary tangles constituted of misfolded species of hyper-phosphorylated tau. The pathological events leading to tau aggregation are still largely unknown but increasing evidence suggests that neuroinflammation plays a critical role in tangle formation. Moreover, tau aggregation itself could enhance inflammation through feed-forward mechanisms, amplifying the initial neurotoxic insults. Protective effects of tau against neuroinflammation have been also documented, adding another layer of complexity to this phenomenon. Here, we will review the current knowledge on tau regulation and function in health and disease. In particular, we will address its emerging role in connecting neurodegenerative and neuroinflammatory processes.