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Background and purpose Argyrophilic grain disease (AGD) is a limbic-predominant 4R-tauopathy. AGD is thought to be an age-related disorder and is frequently detected as a concomitant pathology with other neurodegenerative conditions. There is a paucity of data on the clinical phenotype of pure AGD. In elderly patients, however, AGD pathology frequently associates with cognitive decline, personality changes, urine incontinence and cachexia. In this study, clinicopathological findings were analysed in individuals younger than 75. Methods Patients were identified retrospectively based on neuropathological examinations during 2006-2017 and selected when AGD was the primary and dominant pathological finding. Clinical data were obtained retrospectively through medical records. Results In all, 55 patients (2% of all examinations performed during that period) with AGD were identified. In seven cases (13%) AGD was the primary neuropathological diagnosis without significant concomitant pathologies. Two patients were female, median age at the time of death was 64 years (range 51-74) and the median duration of disease was 3 months (range 0.5-36). The most frequent symptoms were progressive cognitive decline, urinary incontinence, seizures and psychiatric symptoms. Brain magnetic resonance imaging revealed mild temporal atrophy. Conclusions Argyrophilic grain disease is a rarely recognized limbic tauopathy in younger individuals. Widening the clinicopathological spectrum of tauopathies may allow identification of further patients who could benefit from tau-based therapeutic strategies.

Disease-associated proteins are thought to propagate along neuronal processes in neurodegenerative diseases. To detect disease-associated prion protein (PrPSc ) in the vagus nerve in different forms and molecular subtypes of Creutzfeldt-Jakob disease (CJD), we applied 3 different anti-PrP antibodies. We screened the vagus nerve in 162 sporadic and 30 genetic CJD cases. Four of 31 VV-2 type sporadic CJD and 7 of 30 genetic CJD cases showed vagal PrPSc immunodeposits with distinct morphology. Thus, PrPSc in CJD affects the vagus nerve analogously to α-synuclein in Parkinson disease. The morphologically diverse deposition of PrPSc in genetic and sporadic CJD argues against uniform mechanisms of propagation of PrPSc . Ann Neurol 2019;85:782-787.

Cerebrospinal fluid (CSF) cytology, i.e., the cytologic evaluation of its cellular composition, forms an integral part of the neurologist's armamentarium. Total and differential cell counts provide important first information across a spectrum of pathologic conditions involving the central nervous system and its coverings. CSF samples require immediate processing, ideally within 1 hour from collection. Upon centrifugation cytology is commonly assessed on May-Grunwald-Giemsa stains. Several additional stains are available for the identification of infectious agents such as bacteria or fungi, or the further specification of neoplastic cells by immunocytochemistry. The evaluation warrants familiarity with cytologic characteristics of cells across normal and diseased states. In normal CSF, lymphocytes and monocytes are encountered. A predominance of neutrophil granulocytes suggests bacterial meningitis and prompts search for intracellular bacteria. In contrast, in viral and chronic infections lymphocytes and monocytes prevail. Upon activation lymphocytes typically enlarge and eventually differentiate into plasma cells. Similarly, monocytes differentiate into macrophages that clear cellular debris. Macrophages that contain fragments of erythrocytes or hemoglobin degradation products are referred to as erythro- or siderophages, both of which indicate prior subarachnoid hemorrhage. Likewise, the detection of tumor cells is specific for neoplastic meningitis, although false-negative CSF cytologies are frequent. In summary, detailed morphologic workup of CSF samples provides valuable diagnostic information and is mandated in all cases with elevated cell count, computed tomography-negative suspected subarachnoid hemorrhage, and neoplastic meningitis. In all cases it needs to be interpreted in the clinical context and complements other clinical and laboratory findings.

Tuberous Sclerosis Complex (TSC) is a genetic hamartoma syndrome frequently associated with severe intractable epilepsy. In some TSC patients epilepsy surgery is a promising treatment option provided that the epileptogenic zone can be precisely delineated. TSC brain lesions (cortical tubers) contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations in various proportions. However, a histological classification system has not been established for tubers. Therefore, the aim of this study was to define distinct histological patterns within tubers based on semi-automated histological quantification and to find clinically significant correlations. In total, we studied 28 cortical tubers and seven samples of perituberal cortex from 28 TSC patients who had undergone epilepsy surgery. We assessed mammalian target of rapamycin complex 1 (mTORC1) activation, the numbers of giant cells, dysmorphic neurons, neurons, and oligodendrocytes, and calcification, gliosis, angiogenesis, inflammation, and myelin content. Three distinct histological profiles emerged based on the proportion of calcifications, dysmorphic neurons and giant cells designated types A, B, and C. In the latter two types we were able to subsequently associate them with specific features on presurgical MRI. Therefore, these histopathological patterns provide consistent criteria for improved definition of the clinico-pathological features of cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC.cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC.

Background Spreading of misfolded proteins has been suggested for neurodegenerative diseases. The hierarchical distribution of protein deposits in Alzheimer's (AD) and Parkinson's disease (PD) supports this concept. Objectives To evaluate α-synuclein and tau-deposition in the optic pathway as an excellent anatomical model, which follows a strict trajectory including a cortico-geniculate feedback connection. Methods We immunostained the optic nerve, lateral geniculate nucleus (LGN), and occipital cortex for AT8 (phosphorylated tau), α-synuclein, and disease-associated prion protein (PrP) in 47 cases with tau pathology (AD type, argyrophilic grain disease, or progressive supranuclear palsy), 16 PD, and 5 Creutzfeldt-Jakob disease (CJD) cases, respectively. Results We detected immunoreactivity for all proteins along the optic pathway. The optic nerve showed immunopositivity only in cases with tau (6/8, 75%) or α-synuclein (5/7, 71%) pathology. The LGN was involved also frequently (tau: 22/47, 46.8% ; α-synuclein: 15/16, 93.7% ; PrP 5/5, 100%). The occipital cortex was variably affected by tau or α-synuclein pathology, but always showed PrP immunoreactivity in the CJD cases. Tau pathology in the LGN correlated with tau immunoreactivity in the occipital cortex and Braak stages of neurofibrillary degeneration. In tauopathies, which do not involve the occipital cortex, like argyrophilic grain disease or progressive supranuclear palsy, tau pathology was more frequently astrocytic in the LGN. Conclusions Our results have implications 1) for the understanding of disease spreading along neural pathways and 2) for the diagnostic evaluation of the visual system in neurodegenerative proteinopathies as a potential biomarker to evaluate disease progression or subgrouping of cases.

Introduction: Syncope and palpitations as the only initial manifestations of myotonic dystrophy type 1 (MD1) due to a CTG expansion of 50–100 repeats have not been reported. Case report: In a 55-year-old female with a family history of MD1 and a personal history of a single syncope, palpitations, and hyperCKemia, 70 CTG repeats were detected in the DMPK gene. Her brother had presented atypical clinical, electromyographic, and muscle biopsy features since the age of 35 but had been diagnosed with MD1 after he later developed typical distal myotonia. He died suddenly during an episode of syncope at the age of 53. A sister with clinical myotonia died suddenly during sleep at the age of 45 and a second sister with quadriparesis died from complications of intestinal rupture at age 52. A third sister committed suicide at age 40 after developing recurrent syncopes, while a fourth sister had hyperCKemia and foot-extensor weakness. The mother of these five affected children died suddenly from myocardial rupture. Conclusions: MD1 with