Primary age-related tauopathy (PART) in the general autopsy setting: Not just a disease of the elderly.

Primary age-related tauopathy (PART) is generally considered a diagnosis of the elderly. In this letter, the authors present data showing that the pathologic changes of PART can occur in the general autopsy population significantly earlier than largely reported in the recent literature, particularly in woman.

Failure to Inactivate Nuclear GSK3ß by Ser389-Phosphorylation Leads to Focal Neuronal Death and Prolonged Fear Response.

GSK3ß plays an essential role in promoting cell death and is emerging as a potential target for neurological diseases. Understanding the mechanisms that control neuronal GSK3ß is critical. A ubiquitous mechanism to repress GSK3ß involves Akt-mediated phosphorylation of Ser9. Here we show that phosphorylation of GSK3ß on Ser389 mediated by p38 MAPK specifically inactivates nuclear GSK3ß in the cortex and hippocampus. Using GSK3ß Ser389 to Ala mutant mice, we show that failure to inactivate nuclear GSK3ß by Ser389 phosphorylation causes neuronal cell death in subregions of the hippocampus and cortex. Although this focal neuronal death does not impact anxiety/depression-like behavior or hippocampal-dependent spatial learning, it leads to an amplified and prolonged fear response. This phenotype is consistent with some aspects of post-traumatic stress disorder (PTSD). Our studies indicate that inactivation of nuclear GSK3ß by Ser389 phosphorylation plays a key role in fear response, revealing new potential therapeutic approaches to target PTSD.

Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors.

A novel combined imaging/morphometrical method for the analysis of human sural nerve biopsies for clinical diagnosis.

Nerve Morphometry is one tool employed in the clinical assessment of peripheral sural nerve pathological abnormalities. A new method is presented in this chapter incorporating an unbiased approach to quantitative sural nerve evaluation. Using conventional epoxy embedded nerves processed for electron microscopy, confocal microscopy, and interactive digital assessment, this method produces a rigorous, accurate reproducible record for use in clinical diagnosis.

Immunoglobulin derived depositions in the nervous system: novel mass spectrometry application for protein characterization in formalin-fixed tissues.

Proteinaceous deposits are occasionally encountered in surgically obtained biopsies of the nervous system. Some of these are amyloidomas, although the precise nature of other cases remains uncertain. We studied 13 cases of proteinaceous aggregates in clinical specimens of the nervous system. Proteins contained within laser microdissected areas of interest were identified from tryptic peptide sequences by liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS). Immunohistochemical studies for immunoglobulin heavy and light chains and amyloidogenic proteins were performed in all cases. Histologically, the cases were classified into three groups: 'proteinaceous deposit not otherwise specified' (PDNOS) (n=6), amyloidoma (n=5), or 'intracellular crystals' (n=2). LC-MS/MS demonstrated the presence of lambda, but not kappa, light chain as well as serum amyloid P in all amyloidomas. lambda-Light-chain immunostaining was noted in amyloid (n=5), although demonstrable monotypic lymphoplasmacytic cells were seen in only one case. Conversely, in PDNOS kappa, but not lambda, was evident in five cases, both light chains being present in a single case. In three cases of PDNOS, a low-grade B-cell lymphoma consistent with marginal zone lymphoma was present in the brain specimen (n=2) or spleen (n=1). Lastly, in the 'intracellular crystals' group, the crystals were present within CD68+ macrophages in one case wherein kappa-light chain was found by LC-MS/MS only; the pathology was consistent with crystal-storing histiocytosis. In the second case, the crystals contained immunoglobulin G within CD138+ plasma cells. Our results show that proteinaceous deposits in the nervous system contain immunoglobulin components and LC-MS/MS accurately identifies the content of these deposits in clinical biopsy specimens. LC-MS/MS represents a novel application for characterization of these deposits and is of diagnostic utility in addition to standard immunohistochemical analyses.

Synaptic organization of monosynaptic connections from mesencephalic trigeminal nucleus neurons to hypoglossal motoneurons in the rat.

Synaptological characteristics of synapses between axonal boutons of the trigeminal mesencephalic nucleus (Vme) neurons and the hypoglossal nucleus (XII) motoneurons (MNs) were studied using biotinylated dextran amine (BDA) anterograde labeling combined with horseradish peroxidase (HRP) retrograde transport in the rat. BDA was initially iontophoresed into Vme unilaterally and 7 days later HRP was injected into the anterior two-thirds of the ipsilateral tongue. After histochemical reactions, BDA anterogradely labeled boutons were seen to appose closely to somata and dendrites of HRP retrogradely labeled MNs in XII by light microscopy. A total of 212 BDA-labeled Vme boutons were examined ultrastructurally, which had an average diameter of 1.3 +/- 0.4 microm and contain small clear spherical vesicles. Eighty-eight percent of Vme boutons (187/212) synapsed on dendrites of HRP-labeled XII MNs. Twenty-five Vme boutons (25/212, 12%) made synapses with somata of HRP-labeled XII MNs. Thirty-five percent (74/212) of BDA-labeled Vme boutons were also contacted by unlabeled P-type terminals. Presynaptic P-type terminals contained spherical (47%, 35/74), pleomorphic (43%, 32/74), and flattened (10%, 7/74) synaptic vesicles. Thus, P-type terminals (as a presynaptic element), BDA-labeled Vme boutons, and XII MNs constitute axoaxodendritic and axoaxosomatic synaptic triads. There are four types of synaptic microcircuits in XII neuropil: synaptic convergence, synaptic divergence, presynaptic inhibition synaptic circuits, and feedforward regulation circuits. This detailed ultrastructure examination of the synaptic organization between Vme neurons and XII MNs provides insights into the synaptic mechanisms of the trigeminal proprioceptive afferents involved in the jaw-tongue reflex and coordination during oral motor behaviors.

Chronic inflammatory demyelinating polyradiculoneuropathy in diabetic patients.

This retrospective analysis was undertaken to determine whether a subset of diabetic patients with demyelinating polyneuropathy were similar to patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Ten patients meeting the clinical criteria for idiopathic CIDP were compared to nine patients with diabetes and demyelinating polyneuropathy. The diabetic patients with demyelinating polyneuropathy displayed clinical, electrophysiologic, and histologic features that were similar to those in CIDP patients. All six patients with diabetes and demyelinating polyneuropathy who were treated with immunomodulatory therapy showed a favorable response. Our study highlights the importance of investigating diabetic patients with polyneuropathy in an attempt to identify patients with demyelinating polyneuropathy, because of the likelihood of benefit in these patients from immunomodulatory treatment.

Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2.

This is the first description of slowly progressive Niemann-Pick disease type C (NPC) without the typical lysosomal storage in bone marrow and viscera in two descendants of a group of 17th century French-Canadians. The index patient was a married 43-year-old woman with onset of dementia in her thirties, later followed by the development of ataxia and athetoid movements. Her autopsy disclosed frontal lobe atrophy, neurolysosomal storage with oligolamellar inclusion and tau-positive neurofibrillary tangles. Of the 119 family members screened, only a married 42-year-old sister displayed symptoms of a dementia. Both women displayed vertical supranuclear ophthalmoplegia; expressive aphasia; concrete, stimulus-bound, perseverative behavior; and impaired conceptualization and planning. Cultured fibroblasts showed decreased cholesterol esterification and positive filipin staining, but no mutation was detected in coding or promoter regions of the NPC1 gene using conformation sensitive gel electrophoresis and sequencing. Sequencing showed a homozygous gene mutation that is predicted to result in an amino acid substitution, V39M, in the cholesterol binding protein HE1 (NPC2). Adult-onset NPC2 with lysosomal storage virtually restricted to neurons represents a novel phenotypic and genotypic variant with diffuse cognitive impairment and focal frontal involvement described for the first time.