A case report of a patient with primary familial brain calcification with a genetic variant.

Fahr's disease, or primary familial brain calcification (PFBC), is a rare genetic neurologic disease characterized by abnormal calcification of the basal ganglia, subcortical white matter and cerebellum. Common clinical features include parkinsonism, neuropsychiatric symptoms, and cognitive decline. Genes implicated in Fahr's disease include , , , , , and .

Challenging Cases of Neurocognitive Disorders.

Dementia is broadly defined by DSM-V as cognitive decline from a previous level that impacts the patient's functioning at work or play. This broad definition does not provide information about the underlying disease process, an aspect of clinical care that is of increasing importance, as therapeutic development inches closer to effective disease-modifying treatments. The most common neurodegenerative dementias include Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, and Parkinson's disease dementia.

A Novel Variant (Lys694del) Presenting With Corticobasal Syndrome in a Family With FTD-ALS Spectrum Diseases: Case Report.

Several variants of the TANK-Binding Kinase 1 () gene have been associated with frontotemporal dementia - amyotrophic lateral sclerosis (FTD-ALS) spectrum diseases. Corticobasal syndrome (CBS) is characterized by asymmetric limb rigidity, dystonia or myoclonus, in association with speech or limb apraxia, cortical sensory deficit, and/or alien limb. It can result from a variety of underlying pathologies and although typically sporadic, it has been occasionally associated with and variants.

Generation of human chronic wasting disease in transgenic mice.

Chronic wasting disease (CWD) is a cervid prion disease caused by the accumulation of an infectious misfolded conformer (PrP) of cellular prion protein (PrP). It has been spreading rapidly in North America and also found in Asia and Europe. Although bovine spongiform encephalopathy (i.

An atypical presentation of primary central nervous system lymphoma: A case report.

Rationale: Primary central nervous system lymphoma (PCNSL) involving the choroid plexus is exceedingly rare. The differential diagnosis for choroid plexus enhancing lesions in addition to lymphoma includes infections, sarcoidosis, tuberculosis, papilloma, meningioma, subependymoma, and metastatic lesions.

Patient Concerns: A 71-year-old man presented with 3 days of episodic memory loss and gait disturbance.

"Dual Disease" TgAD/GSS mice exhibit enhanced Alzheimer's disease pathology and reveal PrP-dependent secretion of Aβ.

To address the question of cross-talk between prion protein (PrP) and Alzheimer's disease (AD), we generated TgAD/GSS mice that develop amyloid-β (Aβ) plaques of AD and PrP (specifically mutated PrP) plaques of Gerstmann-Sträussler-Scheinker disease (GSS) and compared plaque-related features in these mice to AD mice that express normal (TgAD), high (TgAD/HuPrP), or no (TgAD/PrP) PrP. In contrast to PrP, PrP weakly co-localized to Aβ plaques, did not co-immunoprecipitate with Aβ, and poorly bound to Aβ in an ELISA-based binding assay. Despite the reduced association of PrP with Aβ, TgAD/GSS and TgAD/HuPrP mice that express comparable levels of PrP and PrP respectively, displayed similar increases in Aβ plaque burden and steady state levels of Aβ and its precursor APP compared with TgAD mice.

Anle138b prevents PrP plaque accumulation in Tg(PrP-A116V) mice but does not mitigate clinical disease.

Anle138b is an anti-aggregating compound previously shown to delay the onset of scrapie, a transmissible prion disease, although its in vivo efficacy against other prion disease subtypes has not been fully assessed. TgGSS mice that model Gerstmann-Sträussler-Scheinker disease (GSS) via expression of mouse PrP accumulate PrP amyloid plaques in their brains and develop progressive ataxia leading to death in ~160 days. When allowed to feed on food pellets containing anle138b from weaning until death, the brains of TgGSS mice displayed significant reductions in PrP plaque burden, insoluble PrP, and proteinase K-resistant PrP at end stage, compared with TgGSS mice allowed to feed on placebo food pellets.

Impaired transmissibility of atypical prions from genetic CJD.

Objective: To describe the clinicopathologic, molecular, and transmissible characteristics of genetic prion disease in a young man carrying the -G114V variant.

Methods: We performed genetic, histologic, and molecular studies, combined with in vivo transmission studies and in vitro replication studies, to characterize this genetic prion disease.

Results: A 24-year-old American man of Polish descent developed progressive dementia, aphasia, and ataxia, leading to his death 5 years later.

IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease.

Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti-Aβ autoantibodies that might be able to treat Alzheimer's disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases.

Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy.

Prion diseases are linked to the accumulation of a misfolded isoform (PrP(Sc)) of prion protein (PrP). Evidence suggests that lysosomes are degradation endpoints and sites of the accumulation of PrP(Sc). We questioned whether lysosomes participate in the early quality control of newly generated misfolded PrP.

In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease.

Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid-rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD.

Systemic transthyretin amyloidosis in a patient with bent spine syndrome.

Wild-type and mutant transthyretin (TTR) are implicated in systemic amyloidosis (ATTR). Myopathy is a rare complication of ATTR amyloidosis, however no patient with bent spine syndrome secondary to ATTR amyloidosis has been reported so far. We present the first case of bent spine syndrome in a patient with wild-type ATTR amyloidosis who also had concomitant Alzheimer's disease.

Acute encephalopathy as the initial manifestation of CADASIL.

A 29-year-old right-handed G1P1 Caucasian woman presented with acute bifrontal headache (which resolved within 1 day), confusion, and difficulty using her right hand on postpartum day 10. She did not report nausea, vomiting, or visual complaints. The patient was previously healthy except for her recent preeclampsia, which required emergent cesarean section.

Rapamycin delays disease onset and prevents PrP plaque deposition in a mouse model of Gerstmann-Sträussler-Scheinker disease.

Autophagy is a cell survival response to nutrient deprivation that delivers cellular components to lysosomes for digestion. In recent years, autophagy has also been shown to assist in the degradation of misfolded proteins linked to neurodegenerative disease (Ross and Poirier, 2004). In support of this, rapamycin, an autophagy inducer, improves the phenotype of several animal models of neurodegenerative disease.

Tunicamycin produces TDP-43 cytoplasmic inclusions in cultured brain organotypic slices.

The cellular distribution of TAR DNA binding protein (TDP-43) is disrupted in several neurodegenerative disorders, including frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U subtype) and amyotrophic lateral sclerosis (ALS). In these conditions, TDP-43 is found in neuronal cytoplasmic inclusions, with loss of the normal nuclear expression. The mechanisms leading to TDP-43 redistribution and its role in disease pathophysiology remain unknown.

Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype.

Objective: To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP).

Methods: Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation.

Generation of a new form of human PrP(Sc) in vitro by interspecies transmission from cervid prions.

Prion diseases are infectious neurodegenerative disorders that affect humans and animals and that result from the conversion of normal prion protein (PrP(C)) into the misfolded prion protein (PrP(Sc)). Chronic wasting disease (CWD) is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. Determining the risk of transmission of CWD to humans is of utmost importance, considering that people can be infected by animal prions, resulting in new fatal diseases.

The prion diseases.

The prion diseases are a family of rare neurodegenerative disorders that result from the accumulation of a misfolded isoform of the prion protein (PrP), a normal constituent of the neuronal membrane. Five subtypes constitute the known human prion diseases; kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal insomnia (FI), and variant CJD (vCJD). These subtypes are distinguished, in part, by their clinical phenotype, but primarily by their associated brain histopathology.

Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein.

Objective: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV).

Methods: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics.

The genetics of prion diseases.

Prion diseases are a rare group of fatal neurodegenerative disorders of humans and animals that manifest primarily as progressive dementia and ataxia. Unique to these diseases is the prion, a misfolded isoform of the prion protein that can transmit disease from cell to cell or host to host by associating with, and transforming, normal prion protein into the misfolded isoform (the pathogenic scrapie-inducing form). Although the majority of cases occur on a sporadic basis, and rarely result from exposure to prions, such as mad cow disease, 10-15% are attributable to the presence of an autosomal dominant mutation of the prion protein gene (PRNP).

Live cell fluorescence resonance energy transfer predicts an altered molecular association of heterologous PrPSc with PrPC.

Prion diseases result from the accumulation of a misfolded isoform (PrP(Sc)) of the normal host prion protein (PrP(C)). PrP(Sc) propagates by templating its conformation onto resident PrP(C) to generate new PrP(Sc). Although the nature of the PrP(Sc)-PrP(C) complex is unresolved, certain segments or specific residues are thought to feature critically in its formation.

A New Transgenic Mouse Model of Gerstmann-Straussler-Scheinker Syndrome Caused by the A117V Mutation of PRNP.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a genetic prion disease typified clinically by the development of progressive ataxia and dementia, and histopathologically by the presence of prion protein (PrP) amyloid plaques in the CNS, especially within the cerebellum. Several mutations of the PrP gene (PRNP) are associated with GSS, but only the P102L mutation has been convincingly modeled in transgenic (Tg) mice. To determine whether other mutations carry specific GSS phenotypic information, we constructed Tg mice that express PrP carrying the mouse homolog of the GSS-associated A117V mutation.

Identifying key components of the PrPC-PrPSc replicative interface.

In prion disease, direct interaction between the cellular prion protein (PrP(C)) and its misfolded disease-associated conformer PrP(Sc) is a crucial, although poorly understood step promoting the formation of nascent PrP(Sc) and prion infectivity. Recently, we hypothesized that three regions of PrP (corresponding to amino acid residues 23-33, 98-110, and 136-158) interacting specifically and robustly with PrP(Sc), likely represent peptidic components of one flank of the prion replicative interface. In this study, we created epitope-tagged mouse PrP(C) molecules in which the PrP sequences 23-33, 98-110, and 136-158 were modified.