Stiff person syndrome.

Stiff Person syndrome (SPS) is a rare autoimmune disorder of the central nervous system characterized by stiffness and spasms in the lumbar and proximal lower limb muscles. Nonmotor symptoms include phobias, anxiety, and depression. SPS exists on a spectrum ranging from a focal disease known as the stiff limb syndrome to progressive encephalomyelitis with rigidity and myoclonus. Collectively, these conditions may be referred to as stiff person spectrum disorders, as they share similar core clinical features and autoantibodies against several neuronal proteins, which are involved in modulating central hyperexcitability. Antibodies against the glutamic acid decarboxylase enzyme are most frequently associated with SPS but their role in disease pathogenesis remains uncertain. Other antibodies associated with SPS now include those against the glycine receptor, amphiphysin, dipeptidyl-peptidase-like protein 6, gephyrin, γ-aminobutyric acid receptor A (GABAAR), and the GABAAR-associated protein. First-line treatments for SPS include diazepam and baclofen. Patients who do not respond adequately may benefit from immunotherapy. Intravenous immunoglobulin has the most supporting evidence, and while several other immunotherapies are used, further trials are required to determine their efficacy. Further studies to establish the precise role of autoantibodies in the pathogenesis of SPS are also needed to better understand and manage this disabling condition.

Neuropathologic Validation and Diagnostic Accuracy of Presynaptic Dopaminergic Imaging in the Diagnosis of Parkinsonism.

BACKGROUND AND OBJECTIVES: Degeneration of the presynaptic nigrostriatal dopaminergic system is one of the main biological features of Parkinson disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), which can be measured using single-photon emission CT imaging for diagnostic purposes. Despite its widespread use in clinical practice and research, the diagnostic properties of presynaptic nigrostriatal dopaminergic (DAT) imaging in parkinsonism have never been evaluated against the diagnostic gold standard of neuropathology. The aim of this study was to evaluate the diagnostic parameters of DAT imaging compared with pathologic diagnosis in patients with parkinsonism. METHODS: Retrospective cohort study of patients with DAT imaging for the investigation of a clinically uncertain parkinsonism with brain donation between 2010 and 2021 to the Queen Square Brain Bank (London). Patients with DAT imaging for investigation of pure ataxia or dementia syndromes without parkinsonism were excluded. Those with a pathologic diagnosis of PD, MSA, PSP, or CBD were considered presynaptic dopaminergic parkinsonism, and other pathologies were considered postsynaptic for the analysis. DAT imaging was performed in routine clinical practice and visually classified by hospital nuclear medicine specialists as normal or abnormal. The results were correlated with neuropathologic diagnosis to calculate diagnostic accuracy parameters for the diagnosis of presynaptic dopaminergic parkinsonism. RESULTS: All of 47 patients with PD, 41 of 42 with MSA, 68 of 73 with PSP, and 6 of 10 with CBD (sensitivity 100%, 97.6%, 93.2%, and 60%, respectively) had abnormal presynaptic dopaminergic imaging. Eight of 17 patients with presumed postsynaptic parkinsonism had abnormal scans (specificity 52.9%). DISCUSSION: DAT imaging has very high sensitivity and negative predictive value for the diagnosis of presynaptic dopaminergic parkinsonism, particularly for PD. However, patients with CBD, and to a lesser extent PSP (of various phenotypes) and MSA (with predominant ataxia), can show normal DAT imaging. A range of other neurodegenerative disorders may have abnormal DAT scans with low specificity in the differential diagnosis of parkinsonism. DAT imaging is a useful diagnostic tool in the differential diagnosis of parkinsonism, although clinicians should be aware of its diagnostic properties and limitations. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that DAT imaging does not accurately distinguish between presynaptic dopaminergic parkinsonism and non-presynaptic dopaminergic parkinsonism.

Tau filaments with the Alzheimer fold in cases with MAPT mutations V337M and R406W.

Frontotemporal dementia (FTD) and Alzheimer's disease are the most common forms of early-onset dementia. Dominantly inherited mutations in MAPT, the microtubule-associated protein tau gene, cause FTD and parkinsonism linked to chromosome 17 (FTDP-17). Individuals with FTDP-17 develop abundant filamentous tau inclusions in brain cells. Here we used electron cryo-microscopy to determine the structures of tau filaments from the brains of individuals with MAPT mutations V337M and R406W. Both mutations gave rise to tau filaments with the Alzheimer fold, which consisted of paired helical filaments in all V337M and R406W cases and of straight filaments in two V337M cases. We also identified a new assembly of the Alzheimer fold into triple tau filaments in a V337M case. Filaments assembled from recombinant tau(297-391) with mutation V337M had the Alzheimer fold and showed an increased rate of assembly.

Pathology of neurodegenerative disease for the general neurologist.

Neurodegeneration refers to progressive dysfunction or loss of selectively vulnerable neurones from brain and spinal cord regions. Despite important advances in fluid and imaging biomarkers, the definitive diagnosis of most neurodegenerative diseases still relies on neuropathological examination. Not only has careful clinicopathological correlation shaped current clinical diagnostic criteria and informed our understanding of the natural history of neurodegenerative diseases, but it has also identified conditions with important public health implications, including variant Creutzfeldt-Jakob disease, iatrogenic amyloid-ß and chronic traumatic encephalopathy. Neuropathological examination may also point to previously unsuspected genetic diagnoses with potential implications for living relatives. Moreover, detailed neuropathological assessment is crucial for research studies that rely on curated postmortem tissue to investigate the molecular mechanisms responsible for neurodegeneration and for biomarker discovery and validation. This review aims to elucidate the hallmark pathological features of neurodegenerative diseases commonly seen in general neurology clinics, such as Alzheimer's disease and Parkinson's disease; rare but well-known diseases, including progressive supranuclear palsy, corticobasal degeneration and multiple system atrophy and more recently described entities such as chronic traumatic encephalopathy and age-related tau astrogliopathy.

Late Presentation of Chronic Traumatic Encephalopathy in a Former Association Football Player.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by widespread accumulation of hyperphosphorylated tau that typically occurs in people who have suffered repetitive head impacts. To date, very few cases have been reported in association football players. Objectives: To describe the clinicopathological features of a case of CTE in an 84-year-old former football player who was clinically diagnosed as having dementia with Lewy bodies (DLB). Methods: A retrospective review of the patient's primary care and hospital medical records was performed along with a comprehensive neuropathological examination. Results: This patient presented at age 84 with symmetrical parkinsonism and cognitive impairment that was exacerbated by prochlorperazine. His condition was rapidly progressive with recurrent falls within 1 year. Other features included headaches, depression, anxiety, suicidal ideation, disturbed sleep and aggression. He received a clinical diagnosis of DLB and died approximately 2 years after the onset of symptoms. A post-mortem examination revealed stage 4 CTE. Conclusions: While the contemporaneous onset of parkinsonism and cognitive symptoms in the context of possible neuroleptic sensitivity is suggestive of DLB, the additional symptoms of aggressive behavior, depression and suicidality in a former football player are consistent with the neuropathological diagnosis of CTE. This case, which is notable for the late presentation, demonstrates that CTE may masquerade as other dementias and highlights the importance of seeking a history of repetitive head impacts.

Globular glial tauopathy type II.

The globular glial tauopathies (GGTs) are a rare group of neurodegenerative diseases with fewer than 90 autopsy-confirmed cases reported in the literature. Although there has been some uncertainty about whether GGT is entirely distinct from progressive supranuclear palsy, a recent study of tau filament structures supports the definition of GGT as a separate neuropathological entity. We present a sporadic case of GGT type II presenting with a progressive corticobasal-primary lateral sclerosis overlap syndrome in a 74-year-old woman. Neuropathological examination identified neuronal and glial tau inclusions, including globular astrocytic and oligodendroglial inclusions. We also discuss the clinical features and molecular pathophysiology of GGT. Increased awareness of this condition could become more important as patients with GGT may be candidates for anti-tau therapies currently undergoing clinical evaluation in patients with other tauopathies.

Type 2 Diabetes and Parkinson's Disease: A Focused Review of Current Concepts.

Highly reproducible epidemiological evidence shows that type 2 diabetes (T2D) increases the risk and rate of progression of Parkinson's disease (PD), and crucially, the repurposing of certain antidiabetic medications for the treatment of PD has shown early promise in clinical trials, suggesting that the effects of T2D on PD pathogenesis may be modifiable. The high prevalence of T2D means that a significant proportion of patients with PD may benefit from personalized antidiabetic treatment approaches that also confer neuroprotective benefits. Therefore, there is an immediate need to better understand the mechanistic relation between these conditions and the specific molecular pathways affected by T2D in the brain. Although there is considerable evidence that processes such as insulin signaling, mitochondrial function, autophagy, and inflammation are involved in the pathogenesis of both PD and T2D, the primary aim of this review is to highlight the evidence showing that T2D-associated dysregulation of these pathways occurs not only in the periphery but also in the brain and how this may facilitate neurodegeneration in PD. We also discuss the challenges involved in disentangling the complex relationship between T2D, insulin resistance, and PD, as well as important questions for further research. © 2022 International Parkinson and Movement Disorder Society.

Structures of α-synuclein filaments from human brains with Lewy pathology.

Parkinson's disease (PD) is the most common movement disorder, with resting tremor, rigidity, bradykinesia and postural instability being major symptoms1. Neuropathologically, it is characterized by the presence of abundant filamentous inclusions of α-synuclein in the form of Lewy bodies and Lewy neurites in some brain cells, including dopaminergic nerve cells of the substantia nigra2. PD is increasingly recognised as a multisystem disorder, with cognitive decline being one of its most common non-motor symptoms. Many patients with PD develop dementia more than 10 years after diagnosis3. PD dementia (PDD) is clinically and neuropathologically similar to dementia with Lewy bodies (DLB), which is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within one year from their onset4. In PDD, cognitive impairment develops in the setting of well-established PD. Besides PD and DLB, multiple system atrophy (MSA) is the third major synucleinopathy5. It is characterized by the presence of abundant filamentous α-synuclein inclusions in brain cells, especially oligodendrocytes (Papp-Lantos bodies). We previously reported the electron cryo-microscopy structures of two types of α-synuclein filament extracted from the brains of individuals with MSA6. Each filament type is made of two different protofilaments. Here we report that the cryo-electron microscopy structures of α-synuclein filaments from the brains of individuals with PD, PDD and DLB are made of a single protofilament (Lewy fold) that is markedly different from the protofilaments of MSA. These findings establish the existence of distinct molecular conformers of assembled α-synuclein in neurodegenerative disease.

Phenotypic Variability in Leukoencephalopathy with Brain Calcifications and Cysts: Case Report of Siblings from an Irish Traveller Family with a Homozygous SNORD118 Mutation.

Leukoencephalopathy with brain calcifications and cysts (LCC) is a rare cerebral microangiopathy, the cause of which was recently determined to be recessively inherited mutations in the SNORD118 gene. We report the case of a 32-year-old Irish Traveller woman who presented to the emergency department in convulsive status epilepticus with abnormal neuroimaging features characteristic of LCC. Her medical history consisted of epilepsy, intellectual impairment, previous craniotomies for excision of cerebral cysts and resection of a tibial osteogenic sarcoma. Whole exome sequencing identified a previously described homozygous variant, NR_033294.1 n.*5C>G, in the 3' UTR of the SNORD118 gene. Her sister was subsequently found to be homozygous for the same variant but with a significantly milder clinical phenotype consisting of migraine without aura and mild, non-specific, cerebral white matter changes on neuroimaging. Knowledge of the existence of LCC within this population means that targeted genetic testing for this specific mutation should be considered in Irish Traveller patients presenting with the characteristic clinical and radiological features. Given the striking phenotypic variability seen within this family, LCC should also be considered in Irish Traveller patients even in the absence of the complete radiological triad.

Gray vs. White Matter Segmentation of the Conus Medullaris: Reliability and Variability in Healthy Volunteers.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI)-derived spinal cord (SC) gray and white matter (GM/WM) volume are useful indirect measures of atrophy and neurodegeneration over time, typically obtained in the upper SC. Neuropathological evidence suggests that in certain neurological conditions, early degeneration may occur as low as the sacral SC. In this study, the feasibility of GM/WM segmentation of the conus medullaris (CM) was assessed in vivo. METHODS: Twenty-three healthy volunteers (11 female, mean age 47 years) underwent high-resolution 3T MRI of the CM using a 3-dimensional fast field echo sequence. Reproducibility of the volume measurements was assessed in 5 subjects (2 female, 25-37 years) by one rater who repeated the analysis 3 times and also with 2 additional raters working independently in order to calculate the intra- and interrater coefficient of variation (COV), respectively. Furthermore, the influence of age, gender, spine and SC metrics on tissue-specific measures of the CM was investigated. RESULTS: Volumetric CM analyses (N = 23) for the SC, GM, and WM revealed a mean (SD) total volume of CM-TV = 1746.9 (296.7) mm3 , CM-GM-TV = 731.2 (106.0) mm3 , and CM-WM-TV = 1014.6 (211.3) mm3 , respectively. The intra-rater COV for measuring the CM-TV and CM-GM-TV was 3.38% and 7.42%, respectively; the interrater COV was 3.43% and 10.80%, respectively. Using age, gender, spine and SC metrics in regression models substantially reduced group variability for CM-TV, CM-WM-TV, and CM-GM-TV by up to 39.2%, 42.7%, and 21.2%, respectively. CONCLUSIONS: The results from this study demonstrate the feasibility of obtaining tissue-specific volume measurements in the CM by means of MRI with good reproducibility and provide normative data for future applications in neurological diseases affecting the lower SC.