Enhancing of cerebral Abeta clearance by modulation of ABC transporter expression: a review of experimental approaches.

Clearance of amyloid-beta (Aß) from the brain is impaired in both early-onset and late-onset Alzheimer's disease (AD). Mechanisms for clearing cerebral Aß include proteolytic degradation, antibody-mediated clearance, blood brain barrier and blood cerebrospinal fluid barrier efflux, glymphatic drainage, and perivascular drainage. ATP-binding cassette (ABC) transporters are membrane efflux pumps driven by ATP hydrolysis. Their functions include maintenance of brain homeostasis by removing toxic peptides and compounds, and transport of bioactive molecules including cholesterol. Some ABC transporters contribute to lowering of cerebral Aß. Mechanisms suggested for ABC transporter-mediated lowering of brain Aß, in addition to exporting of Aß across the blood brain and blood cerebrospinal fluid barriers, include apolipoprotein E lipidation, microglial activation, decreased amyloidogenic processing of amyloid precursor protein, and restricting the entrance of Aß into the brain. The ABC transporter superfamily in humans includes 49 proteins, eight of which have been suggested to reduce cerebral Aß levels. This review discusses experimental approaches for increasing the expression of these ABC transporters, clinical applications of these approaches, changes in the expression and/or activity of these transporters in AD and transgenic mouse models of AD, and findings in the few clinical trials which have examined the effects of these approaches in patients with AD or mild cognitive impairment. The possibility that therapeutic upregulation of ABC transporters which promote clearance of cerebral Aß may slow the clinical progression of AD merits further consideration.

Approaches for Increasing Cerebral Efflux of Amyloid-ß in Experimental Systems.

Amyloid protein-ß (Aß) concentrations are increased in the brain in both early onset and late onset Alzheimer's disease (AD). In early onset AD, cerebral Aß production is increased and its clearance is decreased, while increased Aß burden in late onset AD is due to impaired clearance. Aß has been the focus of AD therapeutics since development of the amyloid hypothesis, but efforts to slow AD progression by lowering brain Aß failed until phase 3 trials with the monoclonal antibodies lecanemab and donanemab. In addition to promoting phagocytic clearance of Aß, antibodies lower cerebral Aß by efflux of Aß-antibody complexes across the capillary endothelia, dissolving Aß aggregates, and a "peripheral sink" mechanism. Although the blood-brain barrier is the main route by which soluble Aß leaves the brain (facilitated by low-density lipoprotein receptor-related protein-1 and ATP-binding cassette sub-family B member 1), Aß can also be removed via the blood-cerebrospinal fluid barrier, glymphatic drainage, and intramural periarterial drainage. This review discusses experimental approaches to increase cerebral Aß efflux via these mechanisms, clinical applications of these approaches, and findings in clinical trials with these approaches in patients with AD or mild cognitive impairment. Based on negative findings in clinical trials with previous approaches targeting monomeric Aß, increasing the cerebral efflux of soluble Aß is unlikely to slow AD progression if used as monotherapy. But if used as an adjunct to treatment with lecanemab or donanemab, this approach might allow greater slowing of AD progression than treatment with either antibody alone.

Antibody-Mediated Clearance of Brain Amyloid-ß: Mechanisms of Action, Effects of Natural and Monoclonal Anti-Aß Antibodies, and Downstream Effects.

Immunotherapeutic efforts to slow the clinical progression of Alzheimer's disease (AD) by lowering brain amyloid-ß (Aß) have included Aß vaccination, intravenous immunoglobulin (IVIG) products, and anti-Aß monoclonal antibodies. Neither Aß vaccination nor IVIG slowed disease progression. Despite conflicting phase III results, the monoclonal antibody Aducanumab received Food and Drug Administration (FDA) approval for treatment of AD in June 2021. The only treatments unequivocally demonstrated to slow AD progression to date are the monoclonal antibodies Lecanemab and Donanemab. Lecanemab received FDA approval in January 2023 based on phase II results showing lowering of PET-detectable Aß; phase III results released at that time indicated slowing of disease progression. Topline results released in May 2023 for Donanemab's phase III trial revealed that primary and secondary end points had been met. Antibody binding to Aß facilitates its clearance from the brain via multiple mechanisms including promoting its microglial phagocytosis, activating complement, dissolving fibrillar Aß, and binding of antibody-Aß complexes to blood-brain barrier receptors. Antibody binding to Aß in peripheral blood may also promote cerebral efflux of Aß by a peripheral sink mechanism. According to the amyloid hypothesis, for Aß targeting to slow AD progression, it must decrease downstream neuropathological processes including tau aggregation and phosphorylation and (possibly) inflammation and oxidative stress. This review discusses antibody-mediated mechanisms of Aß clearance, findings in AD trials involving Aß vaccination, IVIG, and anti-Aß monoclonal antibodies, downstream effects reported in those trials, and approaches which might improve the Aß-clearing ability of monoclonal antibodies.

Experimental approaches for altering the expression of Abeta-degrading enzymes.

Cerebral clearance of amyloid ß-protein (Aß) is decreased in early-onset and late-onset Alzheimer's disease (AD). Aß is cleared from the brain by enzymatic degradation and by transport out of the brain. More than 20 Aß-degrading enzymes have been described. Increasing the degradation of Aß offers an opportunity to decrease brain Aß levels in AD patients. This review discusses the direct and indirect approaches which have been used in experimental systems to alter the expression and/or activity of Aß-degrading enzymes. Also discussed are the enzymes' regulatory mechanisms, the conformations of Aß they degrade, where in the scheme of Aß production, extracellular release, cellular uptake, and intracellular degradation they exert their activities, and changes in their expression and/or activity in AD and its animal models. Most of the experimental approaches require further confirmation. Based upon each enzyme's effects on Aß (some of the enzymes also possess ß-secretase activity and may therefore promote Aß production), its direction of change in AD and/or its animal models, and the Aß conformation(s) it degrades, investigating the effects of increasing the expression of neprilysin in AD patients would be of particular interest. Increasing the expression of insulin-degrading enzyme, endothelin-converting enzyme-1, endothelin-converting enzyme-2, tissue plasminogen activator, angiotensin-converting enzyme, and presequence peptidase would also be of interest. Increasing matrix metalloproteinase-2, matrix metalloproteinase-9, cathepsin-B, and cathepsin-D expression would be problematic because of possible damage by the metalloproteinases to the blood brain barrier and the cathepsins' ß-secretase activity. Many interventions which increase the enzymatic degradation of Aß have been shown to decrease AD-type pathology in experimental models. If a safe approach can be found to increase the expression or activity of selected Aß-degrading enzymes in human subjects, then the possibility that this approach could slow the AD progression should be examined in clinical trials.

An Euler system for GU(2, 1).

We construct an Euler system associated to regular algebraic, essentially conjugate self-dual cuspidal automorphic representations of GL 3 over imaginary quadratic fields, using the cohomology of Shimura varieties for GU ( 2 , 1 ) .

Modifiable, Non-Modifiable, and Clinical Factors Associated with Progression of Alzheimer's Disease.

There is an extensive literature relating to factors associated with the development of Alzheimer's disease (AD), but less is known about factors which may contribute to its progression. This review examined the literature with regard to 15 factors which were suggested by PubMed search to be positively associated with the cognitive and/or neuropathological progression of AD. The factors were grouped as potentially modifiable (vascular risk factors, comorbidities, malnutrition, educational level, inflammation, and oxidative stress), non-modifiable (age at clinical onset, family history of dementia, gender, Apolipoprotein E ɛ4, genetic variants, and altered gene regulation), and clinical (baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs). Although conflicting results were found for the majority of factors, a positive association was found in nearly all studies which investigated the relationship of six factors to AD progression: malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs. Whether these or other factors which have been suggested to be associated with AD progression actually influence the rate of decline of AD patients is unclear. Therapeutic approaches which include addressing of modifiable factors associated with AD progression should be considered.

Hepatitis Testing Performance of an Analyzer Integrated into Another Manufacturer's Automation System.

BACKGROUND: The capacity to integrate platforms across vendors and disciplines has become an essential feature in the design of total laboratory automation (TLA) due space and test menu constraints. However, data on its performance are lacking. We aim to evaluate an integrated third-party immunoassay platform to the TLA system for the performance of hepatitis testing using turnaround time (TAT). METHODS: We use the Beckman Power Express (PE) system with linked 2 Beckman AU5800, 2 Beckman DxI 800, 2 Abbott Architect i2000, and other accessory components. The PE system is managed and interfaced to the laboratory information system (LIS) through Beckman Remisol (middleware) and Cennexus (track software). The hepatitis tests are performed on the Abbott Architect i2000 using Abbott Instrument Manager (middleware) for test results and this is interfaced with LIS and Cennexus. Using Viewics and Microsoft Excel, the test volumes and TAT of hepatitis results were analyzed before (February 2017 to January 2018) and after (February 2018 to January 2019) integration. RESULTS: The TAT for each hepatitis test has decreased significantly, ranging from 13 to 81-minute reductions (P value <0.0001 for all tests) after instrument integration. The standard deviations of the TAT also decreased for each test. In addition, savings in labor expenditure of around 2 hours per day were observed. There were no laboratory space savings identified. Instead, 47.6 square foot more of space was utilized by the track connection lines. CONCLUSIONS: Our findings show significant improvement of TAT of hepatitis testing with the integration of the third-party Abbott Architect i2000 to Beckman PE system. In addition, the synchronization of multiple middleware for specimen management and result reporting allow the laboratory to achieve new efficiencies handling reflex tests and managing human resources.

AMBAR, an Encouraging Alzheimer's Trial That Raises Questions.

Grifols' recent Alzheimer Management by Albumin Replacement ("AMBAR") study investigated the effects of plasmapheresis with albumin replacement, plus intravenous immunoglobulin (IVIG) in some subjects, in patients with mild-to-moderate Alzheimer's disease (AD). AMBAR was a phase IIb trial in the United States and a phase III trial in Europe. There were three treatment groups (plasmapheresis with albumin replacement; plasmapheresis with low dose albumin and IVIG; plasmapheresis with high dose albumin and IVIG) and sham-treated controls. Disease progression in pooled treated patients was 66% less than control subjects based on ADAS-Cog scores (p = 0.06) and 52% less based on ADCS-ADL scores (p = 0.03). Moderate AD patients had 61% less progression, based on both ADAS-Cog and ADCS-ADL scores, than their sham-treated counterparts (p-values 0.05 and 0.002), and their CDR-Sb scores declined 53% less than their sham-treated counterparts. However, ADAS-Cog and ADCS-ADL scores were not significantly different between actively-treated and sham-treated mild AD patients, although CDR-Sb scores improved vs. baseline for treated mild AD patients. Patients administered both IVIG and albumin had less reduction in brain glucose metabolism than sham-treated patients. Questions raised by these findings include: what mechanism(s) contributed to slowing of disease progression? Is this approach as effective in mild AD as in moderate AD? Must IVIG be included in the protocol? Does age, sex, or ApoE genotype influence treatment response? Does the protocol increase the risk for amyloid-related imaging abnormalities? How long does disease progression remain slowed post-treatment? A further study should allow this approach to be optimized.

What Have We Learned from Cerebrospinal Fluid Studies about Biomarkers for Detecting LRRK2 Parkinson's Disease Patients and Healthy Subjects with Parkinson's-Associated LRRK2 Mutations?

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common known cause of autosomal dominant Parkinson's disease (PD) and sporadic PD (sPD). The clinical presentation of LRRK2 PD is similar to sPD, and except for genetic testing, no biochemical or imaging markers can differentiate LRRK2 PD from sPD. Discovery of such biomarkers could indicate neuropathological mechanisms that are unique to or increased in LRRK2 PD. This review discusses findings in 17 LRRK2 - related CSF studies found on PubMed. Most of these studies compared analyte concentrations between four diagnostic groups: LRRK2 PD patients, sPD patients, asymptomatic control subjects carrying PD-associated LRRK2 mutations (LRRK2 CTL), and healthy control subjects lacking LRRK2 mutations (CTL). Analytes examined in these studies included Aß1-42, tau, α-synuclein, oxidative stress markers, autophagy-related proteins, pteridines, neurotransmitter metabolites, exosomal LRRK2 protein, RNA species, inflammatory cytokines, mitochondrial DNA (mtDNA), and intermediary metabolites. FINDINGS: Pteridines, α-synuclein, mtDNA, 5-hydroxyindolacetic acid, ß-D-glucose, lamp2, interleukin-8, and vascular endothelial growth factor were suggested to differentiate LRRK2 PD from sPD patients; 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-isoprostane (8-ISO), 2-hydroxybutyrate, mtDNA, lamp2, and neopterin may differentiate between LRRK2 CTL and LRRK2 PD subjects; and soluble oligomeric α-synuclein, 8-OHdG, and 8-ISO might differentiate LRRK2 CTL from CTL subjects. CONCLUSIONS: The low numbers of investigations of each analyte, small sample sizes, and methodological differences limit conclusions that can be drawn from these studies. Further investigations are indicated to determine the validity of the analytes identified in these studies as possible biomarkers for LRRK2 PD patients and/or LRRK2 CTL subjects.

Influence of Normal Aging on Brain Autophagy: A Complex Scenario.

Misfolded proteins are pathological findings in some chronic neurodegenerative disorders including Alzheimer's, Parkinson's, and Huntington's diseases. Aging is a major risk factor for these disorders, suggesting that the mechanisms responsible for clearing misfolded proteins from the brain, the ubiquitin-proteasome system and the autophagy-lysosomal pathway, may decline with age. Although autophagic mechanisms have been found to decrease with age in many experimental models, whether they do so in the brain is unclear. This review examines the literature with regard to age-associated changes in macroautophagy and chaperone-mediated autophagy (CMA) in the central nervous system (CNS). Beclin 1, LC3-II, and the LC3-II/LC3-I ratio have frequently been used to examine changes in macroautophagic activity, while lamp2a and HSPA8 (also known as hsc70) have been used to measure CMA activity. Three gene expression analyses found evidence for an age-related downregulation of macroautophagy in human brain, but no published studies were found of age-related changes in CMA in human brain, although cerebrospinal fluid concentrations of HSPA8 were reported to decrease with age. Most studies of age-related changes in brain autophagy in experimental animals have found age-related declines in macroautophagy, and macroautophagy is necessary for normal lifespan in Caenorhabditis elegans, Drosophila, and mice. However, the few studies of age-related changes in brain CMA in experimental animals have produced conflicting results. Investigations of the influence of aging on macroautophagy in experimental animals in systems other than the CNS have generally found an age-related decrease in Beclin 1, but conflicting results for LC3-II and the LC3-II/LC3-I ratio, while CMA decreases with age in most models. CONCLUSION: while indirect evidence suggests that brain autophagy may decrease with normal aging, this issue has not been investigated sufficiently, particularly in human brain. Measuring autophagic activity in the brain can be challenging because of differences in basal autophagic activity between experimental models, and the inability to include lysosomal inhibitors when measuring the LC3-II/LC3-I ratio in postmortem specimens. If autophagy does decrease in the brain with aging, then pharmacological interventions and/or lifestyle alterations to slow this decline could reduce the risk of developing age-related neurodegenerative disorders.

Renal cell carcinoma presenting as epistaxis from a nasal cavity metastasis.

We present a 58-year-old gentleman who initially presented to the otolaryngology clinic with new onset epistaxis revealing a palpable facial mass that was subsequently biopsied revealing metastatic renal cell carcinoma. We hope to present an interesting case highlighting the rarity of this disease and unusual presentation in which the presence of the primary renal cell carcinoma was recognized only after biopsy.

Intraductal papillary mucinous neoplasm complicated by a gastropancreatic fistula.

One of the rare complications of low-grade pancreatic neoplasms is fistulization into nearby structures. This often does not present clinically, but is incidentally identified in patients who have been imaged serially to monitor the progression of the disease. In this report, we present an uncommon complication of an intraductal papillary mucinous neoplasm, which developed a spontaneous gastropancreatic fistula in a patient who was conservatively managed. The clinical course, imaging features, and management of this case are discussed.

Cerebrospinal Fluid Concentration of Key Autophagy Protein Lamp2 Changes Little During Normal Aging.

Autophagy removes both functional and damaged intracellular macromolecules from cells via lysosomal degradation. Three autophagic mechanisms, namely macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy, have been described in mammals. Studies in experimental systems have found macroautophagy and CMA to decrease with normal aging, despite the fact that oxidative stress, which can activate both processes, increases with normal aging. Whether autophagic mechanisms decrease in the human brain during normal aging is unclear. The primary objective of this study was to examine the association of a major autophagy protein, lysosome-associated membrane glycoprotein (lamp2), with age in cerebrospinal fluid (CSF) samples from healthy subjects. Lamp2 consists of three isoforms, lamp2a, 2b and 2c, all of which participate in autophagy. Lamp2's CSF concentration decreases in Parkinson's disease (PD) and increases in Alzheimer's disease (AD), but whether its CSF concentration changes during normal aging has not been investigated. Our secondary objectives were to examine the associations of lamp2's CSF concentration with CSF levels of the molecular chaperone heat shock 70-kDa protein (HSPA8), which interacts with lamp2a in CMA, and oxidative stress markers 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-isoprostane (8-ISO) and Total Antioxidant Capacity (TAC) in healthy subjects. We found lamp2's observed associations with these variables to be weak, with all Kendall's tau-b absolute values ≤0.20. These results suggest that CSF lamp2 concentration changes little during normal aging and does not appear to be associated with HSPA8 or oxidative stress. Further studies are indicated to determine the relationship between CSF lamp2 concentration and brain autophagic processes.

CSF lamp2 concentrations are decreased in female Parkinson's disease patients with LRRK2 mutations.

Lysosome-associated membrane glycoprotein 2 (lamp2) plays critical roles in chaperone-mediated autophagy (CMA) and macroautophagy. Its isoform lamp2a is decreased in Parkinson's disease (PD) substantia nigra. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most known common cause of late-onset PD; although LRRK2 is thought to regulate macroautophagy, the influence of LRRK2 mutations on lamp2 concentrations in the CNS is unknown. To examine this issue we compared lamp2 levels in cerebrospinal fluid (CSF) between sporadic PD (sPD) patients (n = 31), LRRK2 PD patients (n = 20), and healthy control subjects with or without LRRK2 mutations (LRRK2 CTL = 30, CTL = 27). We also examined lamp2's correlations with age, oxidative stress, PD progression, and PD duration. Median lamp2 concentrations (pg/mL) were LRRK2 PD = 127, sPD = 333, CTL = 436, and LRRK2 CTL = 412. Log-transformed lamp2 concentrations, adjusting for gender effects (and excluding male LRRK2 PD patients because of low number), were lower in female LRRK2 PD patients than in LRRK2 CTL (p = 0.002) and CTL (p = 0.005) subjects (p = 0.06 for lamp2 comparison between female LRRK2 PD patients and sPD patients). Lamp2 did not appear to be associated with age, PD progression, or PD duration; however, three of four Spearman rho values for correlations between lamp2 and oxidative stress markers in PD subjects were ≥0.30. These findings suggest that CSF lamp2 concentrations may be decreased in female LRRK2 PD patients compared to healthy individuals with or without LRRK2 mutations.

Specific serum antibody binding to phosphorylated and non-phosphorylated tau in non-cognitively impaired, mildly cognitively impaired, and Alzheimer's disease subjects: an exploratory study.

BACKGROUND: Tau vaccination and administration of anti-tau antibodies can prevent pathology and cognitive impairment in transgenic mouse models of tauopathy, suggesting that therapies which increase anti-tau antibodies might slow the development and/or progression of Alzheimer's disease (AD). The extent to which individuals with no cognitive impairment (NCI) possess serum anti-tau antibodies, and whether their concentrations of these antibodies differ from anti-tau antibody levels in persons with mild cognitive impairment (MCI) or AD, are unclear. Previous studies measuring these antibodies did not account for antibody polyvalent binding, which can be extensive, nor that antibody binding to phosphorylated tau peptides could be due to binding to non-phosphorylated epitopes on those peptides. METHODS: An ELISA controlling for these factors was used to measure the specific binding of serum IgG and IgM to phosphorylated ("pTau;" phosphorylated at Serine-199 and Serine-202) and non-phosphorylated ("non-pTau") tau 196-207 in subjects with NCI, MCI, or AD (n = 10/group). Between-group differences in these antibody levels were evaluated for statistical significance, and correlations were examined in pooled data from all subjects between these antibody levels and subject age, global cognitive functioning, and NFT counts. RESULTS: Specific IgG binding to pTau and non-pTau was detected in all subjects except for one NCI control. Specific IgM binding was detected to pTau in all subjects except for two AD patients, and to non-pTau in all subjects. Mean pTau IgG was increased in MCI subjects by 53% and 70% vs. AD and NCI subjects respectively (both p < 0.05), while no significant differences were found between groups for non-pTau IgG (p = 0.052), pTau IgM, or non-pTau IgM. Non-pTau IgG was negatively associated with global cognition (Spearman rho = -0.50). CONCLUSIONS: Specific binding of serum IgG and IgM to phosphorylated and non-phosphorylated tau may be present in older persons regardless of their cognitive status. Serum IgG to phosphorylated tau may be increased in individuals with MCI, but this unexpected finding requires confirmation. The approach used in this study to measure specific serum antibodies to phosphorylated tau should be useful for measuring antibodies to other post-translationally-modified proteins that are of relevance to neurodegenerative disorders.

Polyvalent immunoglobulin binding is an obstacle to accurate measurement of specific antibodies with ELISA despite inclusion of blocking agents.

Specific antibody concentrations are frequently measured in serum (and plasma and intravenous immunoglobulin) samples by enzyme-linked immunosorbent assay (ELISA). The standard negative control involves incubation of buffer alone on antigen-coated wells. The immunoreactivity that develops in antigen-coated wells in which diluted serum has been incubated is assumed to represent specific antibody binding. This approach can result in marked overestimation of specific antibody levels, because serum contains specific polyvalent antibodies which bind, primarily with low affinity, to multiple antigens (including those on ELISA plates) despite the use of blocking agents. Non-denaturing purification of serum IgG, followed by assessment of the antigen binding or antigen-binding affinity of this purified IgG, can reduce but not eliminate the problem of polyvalent antibody binding in indirect ELISAs. Alternatively, polyvalent antibody binding can be estimated by incubating a diluted serum sample on wells coated with an irrelevant protein (such as bovine serum albumin or a scrambled peptide sequence) or buffer alone, then subtracting this reactivity from the sample's binding to wells coated with the antigen of interest. Polyvalent binding of immunoglobulins must be accounted for in order to obtain accurate ELISA measurements of serum, plasma, or intravenous immunoglobulin antibodies.

Increased Oxidative Stress Markers in Cerebrospinal Fluid from Healthy Subjects with Parkinson's Disease-Associated LRRK2 Gene Mutations.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of inherited Parkinson's disease (PD). The most common PD-associated LRRK2 mutation, G2019S, induces increased production of reactive oxygen species in vitro. We therefore hypothesized that individuals with PD-associated LRRK2 mutations might have increased concentrations of oxidative stress markers and/or decreased total antioxidant capacity (TAC) in their cerebrospinal fluid (CSF). We measured two oxidative stress markers, namely 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane (8-ISO), and TAC in CSF from LRRK2 mutation-bearing PD patients (LRRK2 PD = 19), sporadic PD patients (sPD = 31), and healthy control subjects with or without these mutations (LRRK2 CTL = 30, CTL = 27). 8-OHdG and 8-ISO levels were increased in LRRK2 CTL subjects, while TAC was similar between groups. 8-ISO was negatively correlated, and TAC was positively correlated, with Montreal Cognitive Assessment scores in LRRK2 PD, LRRK2 CTL, and CTL subjects. Correlations in both groups of PD patients between the two oxidative stress markers and Unified Parkinson Disease Rating Scale Total scores were weak, while TAC was negatively correlated with these scores. These findings suggest that oxidative stress may be increased in the CNS in healthy individuals with PD-associated LRRK2 mutations. Further, TAC may decrease in the CNS with the progression of PD, and when cognitive impairment is present regardless of the presence or absence of PD.

Intramedullary amputation neuroma: a case report and review of the literature.

BACKGROUND AND IMPORTANCE: Amputation neuromas consist of non-neoplastic collections of myelinated axons and Schwann cells and typically arise in injured peripheral nerves. Rarely, however, neuromas occur within the spinal cord. Intramedullary amputation neuromas have been described both with and without a history of trauma within the peripheral nervous system. We report a rare case of an isolated intramedullary spinal cord amputation neuroma. CLINICAL PRESENTATION: This 43-year-old man presented with progressive and severe gait deterioration for ~ 7 years. Neurological exam revealed multiple positive findings consistent with cervical myelopathy, including positive Babinski and Hoffman signs, sustained clonus with patellar and Achilles reflexes, bilateral lower extremity weakness with increased muscular tone and spasticity, and inability to tandem walk. Magnetic resonance imaging demonstrated a 0.6-cm, homogeneously enhancing, intramedullary tumor with surrounding signal change at the C6 level. The lesion was excised and histologic examination revealed microscopic features compatible with an amputation neuroma. CONCLUSION: Intramedullary amputation neuromas are rare and associated with either trauma or other CNS lesions. Our case represents an amputation neuroma in an unusual location in a patient without subjective preceding history of trauma or presence of a second lesion.
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Solitary parotid metastasis 8 years after a nephrectomy for renal cell carcinoma.

Renal cell carcinoma is a common cancer, known for its aggressive behavior and ability to metastasize nearly every organ system in the body. While the cancer commonly spreads to a select few organs and metastasis usually develops within 5 years of diagnosis, there have been numerous case reports of atypical sites of metastasis and cases of relapse up to decades after treatment. We present a case a 65-year-old male who presented with right preauricular swelling 8 years after the initial diagnosis and right nephrectomy for clear cell renal cell cancer. We take a look at previous case reports with similar presentations.

Age-Related Decrease in Heat Shock 70-kDa Protein 8 in Cerebrospinal Fluid Is Associated with Increased Oxidative Stress.

Age-associated declines in protein homeostasis mechanisms ("proteostasis") are thought to contribute to age-related neurodegenerative disorders. The increased oxidative stress which occurs with aging can activate a key proteostatic process, chaperone-mediated autophagy. This study investigated age-related alteration in cerebrospinal fluid (CSF) concentrations of heat shock 70-kDa protein 8 (HSPA8), a molecular chaperone involved in proteostatic mechanisms including chaperone-mediated autophagy, and its associations with indicators of oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and 8-isoprostane) and total anti-oxidant capacity. We examined correlations between age, HSPA8, 8-OHdG, 8-isoprostane, and total antioxidant capacity (TAC) in CSF samples from 34 healthy subjects ranging from 20 to 75 years of age. Age was negatively associated with HSPA8 (ρ = -0.47; p = 0.005). An age-related increase in oxidative stress was indicated by a positive association between age and 8-OHdG (ρ = 0.61; p = 0.0001). HSPA8 was moderately negatively associated with 8-OHdG (ρ = -0.58; p = 0.0004). Age and HSPA8 were weakly associated with 8-isoprostane and TAC (range of ρ values: -0.15 to 0.16). Our findings in this exploratory study suggest that during healthy aging, CSF HSPA8 may decrease, perhaps due in part to an increase in oxidative stress. Our results also suggest that 8-OHdG may be more sensitive than 8-isoprostane for measuring oxidative stress in CSF. Further studies are indicated to determine if our findings can be replicated with a larger cohort, and if the age-related decrease in HSPA8 in CSF is reflected by a similar change in the brain.