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Introduction: Determining disease severity and predicting prognosis in younger onset-dementia (YOD) remains challenging. Whether CSF biomarkers neurofilament light (NfL), tau and amyloidβ 42 (Aβ42) can help provide such information has been underexplored., Methods: Patients with YOD and CSF analysis were identified. We compared baseline NfL, tau and Aβ42 concentrations with contemporaneous Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG) scores to assess their association with severity of cognitive impairment. Cognitive decline, as measured by longitudinal NUCOG assessment, was correlated against baseline biomarker levels to assess their utility in predicting the rate of cognitive decline., Results: 78 patients with YOD (mean age = 56 years, SD = 8) and CSF analysis were identified. Dementia types included Alzheimer's disease, behavioural variant frontotemporal dementia, dementia not-otherwise-specified and other. Tau was associated with contemporaneous memory dysfunction (r = -0.556, 95% CI:[-0.702,-0.393], p < .001). 21 patients had longitudinal cognitive assessment up to 82 months from CSF sampling. NfL was associated with the rate of executive function decline (r = 0.755, 95% CI:[0.259,0.937], p < .001). Aβ42 was associated with the rate of memory decline (r = -0.582, 95% CI:[-0.855,-0.274], p = .007) and rate of total NUCOG decline (r = -0.515, 95% CI: [-0.809, -0.227], p = .017)., Conclusion: CSF tau is related to contemporaneous memory impairment in YOD. NfL and Aβ42 levels are associated with the rate of executive function and memory decline, respectively, and may have a role in prognostication in YOD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The prion protein (PrP) has a central role in the pathogenesis of transmissible spongiform encephalopathies (TSE). Accumulating evidence suggests that normal cellular PrP (PrP(c)) may be involved in copper homeostasis and modulation of copper/zinc superoxide dismutase (Cu/ZnSOD) activity in neurons. Hydrogen peroxide (H(2)O(2)) is a toxic reactive oxygen species generated through normal cellular respiration, and neurons contain two important peroxide detoxifying systems (glutathione pathway and catalase). To determine whether PrP expression affects neuronal resistance to H(2)O(2), we exposed primary cerebellar granule neuron cultures derived from PrP knockout (PrP(-/-)) and wild-type (WT) mice to H(2)O(2) for 3, 6, and 24 hours. The PrP(-/-) neurons were significantly more susceptible to H(2)O(2) toxicity than WT neurons after 6 and 24 hours' exposure. The increased H(2)O(2) toxicity may be related to a significant decrease in glutathione reductase activity measured in PrP(-/-) neurons both in vitro and in vivo. This was supported by the finding that inhibition of GR activity with 1,3-bis(2-chloroethyl)-1-nitrosurea (BCNU) increased H(2)O(2) toxicity in WT neurons over the same exposure period. The PrP toxic peptide PrP106-126 significantly reduced neuronal glutathione reductase activity and increased susceptibility to H(2)O(2) toxicity in neuronal cultures suggesting that PrP toxicity in vivo may involve altered glutathione reductase activity. Our results suggest the pathophysiology of prion diseases may involve perturbed PrP(c) function with increased vulnerability to peroxidative stress.

alpha-Synuclein (alphaSN), also termed the precursor of the non-Abeta component of Alzheimer's disease (AD) amyloid (NACP), is a major component of Lewy bodies and Lewy neurites pathognomonic of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). A fragment of alphaSN termed the non-Abeta component of AD amyloid (NAC) had previously been identified as a constituent of AD amyloid plaques. To clarify the relationship of NAC and alphaSN with Abeta plaques, antibodies were raised to three domains of alphaSN. All antibodies produced punctate labeling of human cortex and strong labeling of Lewy bodies. Using antibodies to alphaSN(75-91) to label cortical and hippocampal sections of pathologically proven AD cases, we found no evidence for NAC in Abeta amyloid plaques. Double labeling of tissue sections in mixed DLB/AD cases revealed alphaSN in dystrophic neuritic processes, some of which were in close association with Abeta plaques restricted to the CA1 hippocampal region. In brain homogenates alphaSN was predominantly recovered in the cytosolic fraction as a 16-kd protein on Western analysis; however, significant amounts of aggregated and alphaSN fragments were also found in urea extracts of SDS-insoluble material from DLB and PD cases. NAC antibodies identified an endogenous fragment of 6 kd in the cytosolic and urea-soluble brain fractions. This fragment may be produced as a consequence of alphaSN aggregation or alternatively may accelerate aggregation of the full-length alphaSN.

Background: Apart from the small number of iatrogenic and familial cases, the cause of most cases of Creutzfeldt-Jakob disease (CJD) is not known. We aimed to identify risk factors for sporadic CJD., Methods: In a case-control study, we compared the medical history and selected demographic characteristics of 241 definite (neuropathologically confirmed) and probable (clinically likely) patients with CJD, ascertained from the Australian National Creutzfeldt-Jakob Disease Registry between Jan 1, 1970, and October 31, 1997, and of 784 controls, recruited from the community by random telephone interview in August, 1997. Standard logistic regression was used for the comparisons., Findings: Surgical procedures were significantly associated with the development of sporadic CJD. This risk progressively increased with the number of surgical treatments to a maximum for three procedures (odds ratio 2.13 [95% Cl 1.34-3.41], p=0.002). There was also a significant association between risk of CJD and residence or employment on a farm (p<0.001) or market garden (p=0.002) for longer than 10 years. We found no significant risk associated with a history of blood transfusion, organ transplantation, major dental work, or occupation., Interpretation: Our findings accord with the hypothesis that a range of surgical treatments may serve as unrecognised contamination events and account for a proportion of cases of sporadic CJD. Possible biases in different methods and times for the acquisition of data on cases and controls suggest our findings need to be replicated in independent studies with community controls.

The consensus recommendations for the post mortem diagnosis Alzheimer's disease (AD) highlight the difficulties in establishing a pathological diagnosis in brains from clinically demented individuals with both certainty and uniformity. There is, however, a need for diagnostic guidelines that are relatively simple, inexpensive, and adaptable to general pathologists and different laboratories. The current Consortium to Establish a Registry for Alzheimer's disease (CERAD) criteria and the recommendations in the consensus document giving three probabilistic categories for diagnosis go a long way towards establishing a uniform approach for the diagnosis of AD. However, more uniformity could be adopted in the topography of sectioning to enhance diagnostic and future research comparisons. We also recommend that immunohistochemistry for beta A4 (A beta) amyloid and tau-reactive neurofibrillary changes, in addition to hematoxylin and eosin stains, should become the basis for histological diagnosis. We agree with the guidelines concerning documentation of all AD changes. Until a clearer understanding of the early changes of AD is established, strict observation and recording are the pathologists' best diagnostic skills. The ill-defined diagnostic areas of AD continue to prompt the need for a new method of detection of the underlying pathologic process.

The amyloid protein precursor (APP) of Alzheimer's disease (AD) is abundantly expressed in platelets, where its primary function remains undetermined. As an integral transmembrane protein, the release of APP from the membrane may be a critical event in AD. We examined the association of APP with human platelet membranes using a combination of alkali treatment and immunoprecipitation of the carboxyl-terminus of APP. Most of the platelet membrane-associated APP (APPMem) with molecular mass of 100 to 130 kD is removed with alkali treatment and is also truncated at the carboxyl-terminus. APPMem is present at least in part on the surface of the platelet. The full-length transmembrane form of APP, as a 140- to 150-kD minor species, is alkali resistant and is also present on the plasma membrane. In contrast, most of the APPMem from brain is full-length (possessing the carboxyl-terminus) with a molecular mass of 105 to 130 kD and is resistant to alkali treatment. Immunoelectron microscopy shows platelet APP to be localized to the alpha-granule. Activation of platelets results in a threefold increase in surface APP detectability. In plasma, the 130-kD APP-reactive band is increased in AD. We find that in the gray platelet syndrome, platelets contain reduced amounts of APP, with a corresponding reduction in plasma APP levels, suggesting that platelets are the major source of plasma APP. Our studies also identify an interaction of APP with platelet membranes which differs from that found in the brain, and raise the possibility of a receptor for APP in platelet membranes. Quantitative differences in the amounts of APPMem in platelets compared with brain also indicate regulation of the pathways that determine the cleavage of APP near its transmembrane domain. These pathways are a therapeutic target in AD, and may be easily amenable to investigation in platelets.

The characteristic pathogenic feature of polymyositis (PM) is muscle invasion by T lymphocytes penetrating the basal lamina and displacing the sarcolemma of normal muscle fibers (T cell invasion of endomysial tubes). Active forward movement of these T cells is indicated by cell extensions interdigitating with the muscle fiber surface. Here we describe for the first time high abundance of Alzheimer amyloid protein precursor (APP) in invasive T cells contacting the border of muscle fibers in PM. These are the sites of muscle fiber displacement. The percentage of APP+ T cells at these sites is significantly higher than in other neuromuscular disorders with inflammatory infiltrates suggesting a specific pathogenic function of these cells in PM. By using a new multiparameter immunofluorescence imaging procedure and confocal laser scanning microscopy, we show that APP+ T cells in PM are invasive front cells that penetrate the basal lamina of the endomysial tube and displace the muscle fiber. Mononuclear cells behind the invasive front are negative for APP or show much lower APP levels. Front T cells either express the CD8-CD4+APP+ or CD8+CD4-APP+ phenotypes, or are CD4+CD8+APP+ T cell chimeras. The highest APP concentration is found at the tip of T cell extensions interdigitating with the fiber surface. Although normal by morphological criteria, the same fibers show intense staining for the regeneration marker NCAM. This reactivity is highest at sites contacted by the APP+ T cells. The findings indicate that APP is specifically upregulated in T cells displacing muscle fibers in PM and suggest that NCAM, which may be abnormally regulated in these fibers, is a candidate molecule for interaction with APP.

The deposition of amyloid protein aggregates in brain is the main pathological feature of Alzheimer's disease. Their principal constituent is a peptide termed beta A4, which comprises up to 43 amino acid residues. It is highly insoluble under physiological conditions and aggregates into filaments that form very dense clusters in vivo and in vitro. Based on a beta A4 prototype sequence spanning residues 10 to 42 or 43, we have designed analogues in which hydrophobic amino acid residues in position 17 to 20 were substituted by more hydrophilic residues. Depending on the kind of newly introduced amino acids and their position within the sequence, the substitution of only two residues led to variants exhibiting a broad spectrum of different properties. Common to them was a reduced beta-sheet content after solubilization in water and in the solid state. Some of the variants showed significantly reduced amyloidogenicity: although still forming filaments, they did not aggregate into the highly condensed depositions that are typical for amyloid. In addition, they could be solubilized in 200 mM-NaCl and KCl. When mixed with beta A4 peptides bearing the natural sequence, two of the analogues could inhibit the formation of filaments in vitro. These results demonstrate that a well-preserved hydrophobic core around residues 17 to 20 of beta A4 is crucial for the formation of beta-sheet structure and the amyloid properties of beta A4. The introduction of structural alterations within this region may guide the development of reagents for the therapy of Alzheimer's disease.

The deposition of amyloid beta A4 in the brain is a major pathological hallmark of Alzheimer's disease. Amyloid beta A4 is a peptide composed of 42 or 43 amino acid residues. In brain, it appears in the form of highly insoluble, filamentous aggregates. Using synthetic peptides corresponding to the natural beta A4 sequence as well as analog peptides, we demonstrate requirements for filament formation in vitro. We also determine aggregational properties and the secondary structure of beta A4. A comparison of amino-terminally truncated beta A4 peptides identifies a peptide spanning residues 10 to 43 as a prototype for amyloid beta A4. Infrared spectroscopy of beta A4 peptides in the solid state shows that their secondary structure consists of a beta-turn flanked by two strands of antiparallel beta-pleated sheet. Analog peptides containing a disulfide bridge were designed to stabilize different putative beta-turn positions. Limited proteolysis of these analogs allowed a localization of the central beta-turn at residues 26 to 29 of the entire sequence. Purified beta A4 peptides are soluble in water. Size-exclusion chromatography shows that they form dimers that, according to circular dichroism spectroscopy, adopt a beta-sheet conformation. Upon addition of salts, the bulk fraction of peptides precipitates and adopts a beta-sheet structure. Only a small fraction of peptides remains solubilized. They are monomeric and adopt a random coil conformation. This suggests that the formation of aggregates depends upon a hydrophobic effect that leads to intra- and intermolecular interactions between hydrophobic parts of the beta A4 sequence. This model is sustained by the properties of beta A4 analogs in which hydrophobic residues were substituted. These peptides show a markedly increased solubility in salt solutions and have lost the ability to form filaments. In contrast, the substitution of hydrophilic residues leads only to small deviations in the shape of filaments, indicating that hydrophilic residues contribute to the specificity of interactions between beta A4 peptides.

Any explanation of the causes of Alzheimer's disease and of its unique cerebral pathologic features must take into account the distribution and ultrastructural localization of the pre-A4 amyloid proteins in tissues and organs. The authors have analyzed the expression of the pre-A4 amyloid proteins in several tissues by immunogold electron microscopy and by immunofluorescence. For this purpose, they have used a mouse monoclonal antibody and a guinea pig antiserum raised against two synthetic peptides corresponding to two different sequences common to all the full-length forms of the A4 amyloid precursors. They observed a tissue-specific distribution of the secreted and the transmembrane form of the precursors. The authors could determine that the secreted form is generated in vivo within the cytoplasm. In the salivary glands and in the adenohypophysis, all the immunoreactivity is associated with the process of secretion, whereas in the muscle, a staining pattern compatible with the presence of the pre-A4 amyloid proteins in the sarcoplasmic reticulum has been observed. This difference in the localization may reflect tissue-specific processing pathways and suggests that posttranslational modifications such as proteolytic removal of the transmembrane and cytoplasmic domains contribute to the structural and thus functional diversity of the A4 amyloid precursors.

Kuru was diagnosed in a 42-year-old Melanesian male from the Eastern Highlands Province of Papua New Guinea. The clinical features indicated predominant cerebellar degeneration together with widespread cortical neuronal dysfunction and involvement of the diencephalon, hippocampus and basal ganglia. Dementia was an early and prominent feature. The duration of clinical illness was about 12 months and atypically he spent the last 7 months in hospital allowing continuous assessment. At autopsy, spongiform encephalopathy was demonstrated, and inoculation of brain tissue into 4 squirrel monkeys and 1 capuchin monkey resulted in the development of kuru. This is the longest continuous study of kuru in a hospital setting to be recorded in the adult human subject. The virus isolated from the brain of this patient has been adopted as a standard reference strain of kuru for future use and repository.

A 16-year-old boy was stricken with a progressive neurologic disorder characterized primarily by dementia progressing to severe neurologic debility in 12 months and death 28 months following the first symptoms. Pathologic examination showed a spongiform encephalopathy, consistent witha clinical diagnosis of Creutzfeldt-Jakob disease (CJD). The noteworthy features of the case are the age of onset, the somewhat prolonged course an the amount of white matter change. These are discussed within the frame of reference of CJD and the spongiform encephalopathies of infancy and childhood. Animal inoculation studies employing post-mortem embalmed brain as inoculum are currently in progress to determine the transmissibility of this patient's disease.

Insulin treatment of virgin female rats increased the hepatic activity of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase to levels 3.4 and 1.5 fold higher than controls. The increase in glucose 6-phosphate dehydrogenase activity was attributed to increased activity of all three dimer species. Thus dimer bands, 1, 2 and 3 of insulin-treated animals were 5, 3 and 2-fold higher respectively than controls. The activity of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase decreased with fasting to 55% and 72% respectively of controls. The decrease in glucose 6-phosphate dehydrogenase activity reflected a lower activity of dimer bands 2 and 3 only, which were 62% and 39% of control activity respectively after three days fasting. A shift towards band 1 was observed under both conditions of starvation as well as under conditions of insulin treatment.