Genetic Testing for Early-Onset Alzheimer Disease

ABSTRACT The availability of testing for identified risk genes for Alzheimer disease (AD) in patients with clinically probable AD or their at-risk family members raises important questions for the neurologist. Because the potential benefits and risks of testing vary for each patient, physicians need to evaluate whether it is appropriate on a case-by-case basis. This article outlines the testing decision process and serves as a guide to assist clinicians with associated counseling and result disclosure. Because genetic testing is relatively new and preventive and therapeutic options for AD remain limited, it is important to remain sensitive to and understand the specific challenges associated with obtaining these tests in the routine clinical setting. Case NOTE: This is a hypothetical case. A 60-year-old man is brought by his family for evaluation of several years of progressive memory loss and apathy. He recently became unable to balance his checkbook and has had several episodes of being unable to remember where he parked his car. His family history is notable for a paternal cousin and a maternal aunt who, by report, were also diagnosed with dementia (unknown ages). The patient and his family would like to clarify the diagnosis but are concerned because they have read about early-onset Alzheimer disease and its genetic linkages, and they are unsure whether genetic testing should be performed. Upon examination, the patient's speech is slow but fluent with some secondary naming errors (ie, referring to more specific parts of objectsVthe patient properly identified the wrist band of a watch but was unable to name the buckle of a belt) and normal repetition. His performance on the Trail-Making Test Part B is slow but accurate. The patient is unable to perform the serial 7's or serial 3's tasks and scores below normal when asked to name words beginning with the letters F, A, and S. He is able to follow two-step but not three-step commands. His abilities in both figure copying and clock drawing are inaccurate. The results of his routine dementia laboratory studies are normal, and the neurologist confirms that the presentation is most consistent with Alzheimer disease (AD). Should genetic testing be pursued? DISCUSSION Genetic Risk Factors Several genetic risk factors for AD have been identified. The major susceptibility genes for early-onset AD (less than 65 years of age) are PSEN1, PSEN2, and APP. Mutations in each gene alter APP metabolism, resulting in increased production of a toxic form of the amyloid-" peptide. 2 Additionally, several common genes are linked to the development of AD, but individually hold less predictive value. 3 For people who live a normal lifespan, PSEN1 or APP mutations are associated with complete penetrance, and PSEN2 mutation is associated with 95% penetrance. 4,5 Genetic Testing Because AD treatment is currently focused on managing clinical symptoms rather than on affecting a cure, the issue of genetic testing is controversial. Physicians must evaluate the risk-to-benefit ratio of genotyping for patients and their families on a case-by-case basis. In the case example, it would first be important to obtain a detailed, three-generational family history to help determine whether a familial inheritance pattern exists. Generally, testing is conducted when there is evidence of autosomal dominant inheritance, as mutations are otherwise unlikely to be easily detected. Testing is preferred for symptomatic patients, such as the patient described in the case, rather than for those who are asymptomatic or only mildly symptomatic. Similarly, predictive testing is somewhat uncommon. Genetic tests are rarely used diagnostically because a positive autosomal dominant test can only confirm diagnosis in an affected patient. A negative test does not necessarily exclude disease, as tests can produce false negatives and positive biomarkers are not a prerequisite for AD diagnosis. Because both known and presumed unknown mutations associated with AD exist, a negative test does not rule out genetic components to the dementia. A typical genetic test examines the three known autosomal dominant AD genes: PSEN1, PSEN2, and APP. APOE gene testing is generally not performed, as a mutation in this gene is neither necessary nor sufficient to cause AD, the testing has low sensitivity and specificity, and the role of APOE*E4 has not been fully elucidated and is not subject to mitigation strategies. 6Y9 However, the public seems to have an interest in this type of genotypingV15% of primary care physicians receive APOE genotyping requests from their patients with AD. Genetic Testing for Alzheimer Disease Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. eligible for therapeutic research studies, thereby allowing them the opportunity to contribute to general AD research. A plethora of additional concerns need to be considered when advising on whether a patient should undergo testing. Results are not straightforward, as multiple genes are known to be associated with AD. The presence or absence of a mutation cannot serve to singularly confirm or exclude a disease diagnosis. Variability regarding phenotypic changes, age of onset, and disease course cannot be definitively explained or predicted by genetic testing. Further, the expense of testing, compounded with a general lack of insurance coverage for the tests, creates financial barriers to genotyping. Although the 2008 Genetic Information Nondiscriminatory Act (GINA) offers protection against genetic discrimination in relation to employment and health insurance, clinical testing is still relatively new, and problems with application of the law continue to exist. Genetic Counseling Physicians should always pair testing with genetic counseling. Sometimes, patients and their families may benefit from receiving such counseling even before the tests are performed. This facilitates a thorough discussion of all the risks and benefits and clarifies that there are currently no established methods for preventing the onset or halting the progression of AD. Clinicians are encouraged to serve as a source of information regarding progress with AD research and established and experimental treatments. It is beneficial to have at least one family member present for the patient's counseling, as informed consent for testing is required and decisions are likely to be especially difficult for patients with dementia. 12 Furthermore, positive test results may implicate family members as being at risk, and this impact should be discussed. Patients should be advised to consider their course of action for each potential outcome, including how they will communicate the results to their family members. Physicians are advised to keep in mind that results cannot be rescinded and to thoroughly assess the psychosocial impact of testing. Testing positive for a genetic mutation may be especially overwhelming for patients or family members not experiencing disease symptoms. A follow-up appointment should be scheduled before initiating testing so that the patients will be assured that they have the opportunity to discuss next steps. Disclosure of Results Clinicians face social and ethical challenges when disclosing test results to patients. People who learn that they are genetically predisposed to developing AD may become anxious or depressed. They may undertake risky lifestyle changes, such as pursuing unsupported prevention or treatment efforts. Also, patients who test positive for APOE mutations have been recognized as being nearly 6 times more likely to alter their long-term care insurance than those who remain unaware of genotyping results. Physicians should be aware that their patients are likely to fear AD. A surveybased study conducted by the MetLife Foundation found that Americans fear AD more than heart disease, diabetes, and stroke. 14 For Americans of at least 55 years of age, AD is the most feared disease. The results can be beneficial when disclosure is handled properly; some studies indicate a lack of emotional distress in subjects who learn of their results. For example, in one study, PSEN1, PSEN2, and TAU genes were analyzed in 22 subjects at risk for AD or frontotemporal dementia. 16 The REVEAL methodology is a model for the AD community concerning the disclosure of results. It successfully demonstrates that separating education about the risks and benefits of disclosure from the actual disclosure, monitoring mood and anxiety after disclosure, requiring an emergency contact, and referring participants to mental health professionals when appropriate are all critical factors. CONCLUSIONS Given the current general lack of therapeutic benefit from genetic testing, and the uncertain implications of results for patients and their families, the decision of whether to conduct testing for a patient who is clinically probable for AD remains uncertain. In the case example, depending on the perceptions of the patient and his family, a decision to either proceed or defer testing might be reasonable. The decision to proceed should be coupled with appropriate genetic counseling. The potential for future improvements in test sensitivity, specificity, and clinical utility holds promise for an increased understanding of AD mechanisms and application of genotyping efforts. ACKNOWLEDGMENT The author wishes to thank Briana Perry, BA for substantial contributions to this article

Neuroimaging and Neuropsychological Studies in Sports-Related Concussions in Adolescents: Current State and Future Directions

Sports-related concussion, is a serious neurological concern that many adolescent athletes will face during their athletic careers. In some instances, the effects of sports-related head injury are long-lasting. Due to their still-developing brains, adolescents appear to be more vulnerable to long-term repercussions of these injuries. As all sports-related concussions are mild traumatic brain injuries (mTBI), this review we will examine the pathophysiology of mTBI, its acute effects and long-term risks from sustaining injury, and current and needed advancements in the areas of neuropsychological testing, accelerometer telemetry, and neuroimaging. Current methods do not adequately measure the extent of an injury that an athlete may sustain, potentially putting these athletes at a much greater risk for long-term effects. To better understand mTBI, neuropsychological testing best practices need to be developed, standardized, and implemented based on sound scientific evidence in order to be propagated as clinical guidelines. Wearable accelerometers can be used to assess thresholds for mTBI and cumulative effects of concussive and subconcussive injuries. Novel neuroimaging methods that can detect anatomical abnormalities and functional deficits with more specificity and sensitivity should be developed. Young athletes are particularly a vulnerable population warranting immediate and significant research aimed at protecting them against sports related injury and mitigating their long-term deficits

Virtual Integration Environment as an Advanced Prosthetic Limb Training Platform

Background: Despite advances in prosthetic development and neurorehabilitation, individuals with upper extremity (UE) loss continue to face functional and psychosocial challenges following amputation. Recent advanced myoelectric prostheses offer intuitive control over multiple, simultaneous degrees of motion and promise sensory feedback integration, but require complex training to effectively manipulate. We explored whether a virtual reality simulator could be used to teach dexterous prosthetic control paradigms to individuals with UE loss.Methods: Thirteen active-duty military personnel with UE loss (14 limbs) completed twenty, 30-min passive motor training sessions over 1–2 months. Participants were asked to follow the motions of a virtual avatar using residual and phantom limbs, and electrical activity from the residual limb was recorded using surface electromyography. Eight participants (nine limbs), also completed twenty, 30-min active motor training sessions. Participants controlled a virtual avatar through three motion sets of increasing complexity (Basic, Advanced, and Digit) and were scored on how accurately they performed requested motions. Score trajectory was assessed as a function of time using longitudinal mixed effects linear regression.Results: Mean classification accuracy for passive motor training was 43.8 ± 10.7% (14 limbs, 277 passive sessions). In active motor sessions, >95% classification accuracy (which we used as the threshold for prosthetic acceptance) was achieved by all participants for Basic sets and by 50% of participants in Advanced and Digit sets. Significant improvement in active motor scores over time was observed in Basic and Advanced sets (per additional session: β-coefficient 0.125, p = 0.022; β-coefficient 0.45, p = 0.001, respectively), and trended toward significance for Digit sets (β-coefficient 0.594, p = 0.077).Conclusions: These results offer robust evidence that a virtual reality training platform can be used to quickly and efficiently train individuals with UE loss to operate advanced prosthetic control paradigms. Participants can be trained to generate muscle contraction patterns in residual limbs that are interpreted with high accuracy by computer software as distinct active motion commands. These results support the potential viability of advanced myoelectric prostheses relying on pattern recognition feedback or similar controls systems

Clinical Trial of the Virtual Integration Environment to Treat Phantom Limb Pain With Upper Extremity Amputation

Background: Phantom limb pain (PLP) is commonly seen following upper extremity (UE) amputation. Use of both mirror therapy, which utilizes limb reflection in a mirror, and virtual reality therapy, which utilizes computer limb simulation, has been used to relieve PLP. We explored whether the Virtual Integration Environment (VIE), a virtual reality UE simulator, could be used as a therapy device to effectively treat PLP in individuals with UE amputation.Methods: Participants with UE amputation and PLP were recruited at Walter Reed National Military Medical Center (WRNMMC) and instructed to follow the limb movements of a virtual avatar within the VIE system across a series of study sessions. At the end of each session, participants drove virtual avatar limb movements during a period of “free-play” utilizing surface electromyography recordings collected from their residual limbs. PLP and phantom limb sensations were assessed at baseline and following each session using the Visual Analog Scale (VAS) and Short Form McGill Pain Questionnaire (SF-MPQ), respectively. In addition, both measures were used to assess residual limb pain (RLP) at baseline and at each study session. In total, 14 male, active duty military personnel were recruited for the study.Results: Of the 14 individuals recruited to the study, nine reported PLP at the time of screening. Eight of these individuals completed the study, while one withdrew after three sessions and thus is not included in the final analysis. Five of these eight individuals noted RLP at baseline. Participants completed an average of 18, 30-min sessions with the VIE leading to a significant reduction in PLP in seven of the eight (88%) affected limbs and a reduction in RLP in four of the five (80%) affected limbs. The same user reported an increase in PLP and RLP across sessions. All participants who denied RLP at baseline (n = 3) continued to deny RLP at each study session.Conclusions: Success with the VIE system confirms its application as a non-invasive and low-cost therapy option for PLP and phantom limb symptoms for individuals with upper limb loss

Hand-to-Face Remapping But No Differences in Temporal Discrimination Observed on the Intact Hand Following Unilateral Upper Limb Amputation

Unilateral major limb amputation causes changes in sensory perception. Changes may occur within not only the residual limb but also the intact limb as well as the brain. We tested the hypothesis that limb amputation may result in the detection of hand sensation during stimulation of a non-limb-related body region. We further investigated the responses of unilateral upper limb amputees and individuals with all limbs intact to temporally based sensory tactile testing of the fingertips to test the hypothesis that changes in sensory perception also have an effect on the intact limb. Upper extremity amputees were assessed for the presence of referred sensations (RSs)—experiencing feelings in the missing limb when a different body region is stimulated, to determine changes within the brain that occur due to an amputation. Eight of 19 amputees (42.1%) experienced RS in the phantom limb with manual tactile mapping on various regions of the face. There was no correlation between whether someone had phantom sensations or phantom limb pain and where RS was found. Six of the amputees had either phantom sensation or pain in addition to RS induced by facial stimulation. Results from the tactile testing showed that there were no significant differences in the accuracy of participants in the temporal order judgment tasks (p = 0.702), whereby participants selected the digit that was tapped first by a tracking paradigm that resulted in correct answers leading to shorter interstimulus intervals (ISIs) and incorrect answers increasing the ISI. There were also no significant differences in timing perception, i.e., the threshold accuracy of the duration discrimination task (p = 0.727), in which participants tracked which of the two digits received a longer stimulus. We conclude that many, but not all, unilateral upper limb amputees experience phantom hand sensation and/or pain with stimulation of the face, suggesting that there could be postamputation changes in neuronal circuitry in somatosensory cortex. However, major unilateral limb amputation does not lead to changes in temporal order judgment or timing perception tasks administered via the tactile modality of the intact hand in upper limb amputees

Expression of the neuroprotective slow Wallerian degeneration (WldS) gene in non-neuronal tissues

<p>Abstract</p> <p>Background</p> <p>The slow Wallerian Degeneration (<it>Wld</it>^<it>S</it>) gene specifically protects axonal and synaptic compartments of neurons from a wide variety of degeneration-inducing stimuli, including; traumatic injury, Parkinson's disease, demyelinating neuropathies, some forms of motor neuron disease and global cerebral ischemia. The <it>Wld</it>^{<it>S </it>}gene encodes a novel Ube4b-Nmnat1 chimeric protein (Wld^Sprotein) that is responsible for conferring the neuroprotective phenotype. How the chimeric Wld^Sprotein confers neuroprotection remains controversial, but several studies have shown that expression in neurons <it>in vivo </it>and <it>in vitro </it>modifies key cellular pathways, including; NAD biosynthesis, ubiquitination, the mitochondrial proteome, cell cycle status and cell stress. Whether similar changes are induced in non-neuronal tissue and organs at a basal level <it>in vivo </it>remains to be determined. This may be of particular importance for the development and application of neuroprotective therapeutic strategies based around <it>Wld</it>^<it>S</it>-mediated pathways designed for use in human patients.</p> <p>Results</p> <p>We have undertaken a detailed analysis of non-neuronal <it>Wld</it>^{<it>S </it>}expression in <it>Wld</it>^{<it>S </it>}mice, alongside gravimetric and histological analyses, to examine the influence of <it>Wld</it>^{<it>S </it>}expression in non-neuronal tissues. We show that expression of <it>Wld</it>^{<it>S </it>}RNA and protein are not restricted to neuronal tissue, but that the relative RNA and protein expression levels rarely correlate in these non-neuronal tissues. We show that <it>Wld</it>^{<it>S </it>}mice have normal body weight and growth characteristics as well as gravimetrically and histologically normal organs, regardless of Wld^Sprotein levels. Finally, we demonstrate that previously reported <it>Wld</it>^<it>S</it>-induced changes in cell cycle and cell stress status are neuronal-specific, not recapitulated in non-neuronal tissues at a basal level.</p> <p>Conclusions</p> <p>We conclude that expression of Wld^Sprotein has no adverse effects on non-neuronal tissue at a basal level <it>in vivo</it>, supporting the possibility of its safe use in future therapeutic strategies targeting axonal and/or synaptic compartments in patients with neurodegenerative disease. Future experiments determining whether Wld^Sprotein can modify responses to injury in non-neuronal tissue are now required.</p

Cognitive-Behavior Therapy (CBT) for Panic Disorder: Relationship of Anxiety and Depression Comorbidity with Treatment Outcome

Research evaluating the relationship of comorbidity to treatment outcome for panic disorder has produced mixed results. The current study examined the relationship of comorbid depression and anxiety to treatment outcome in a large-scale, multi-site clinical trial for cognitive-behavior therapy (CBT) for panic disorder. Comorbidity was associated with more severe panic disorder symptoms, although comorbid diagnoses were not associated with treatment response. Comorbid generalized anxiety disorder (GAD) and major depressive disorder (MDD) were not associated with differential improvement on a measure of panic disorder severity, although only rates of comorbid GAD were significantly lower at posttreatment. Treatment responders showed greater reductions on measures of anxiety and depressive symptoms. These data suggest that comorbid anxiety and depression are not an impediment to treatment response, and successful treatment of panic disorder is associated with reductions of comorbid anxiety and depressive symptoms. Implications for treatment specificity and conceptual understandings of comorbidity are discussed

Impact of Select Actionable Genomic Alterations on Efficacy of Neoadjuvant Immunotherapy in Resectable Non-small Cell Lung Cancer

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs. Methods: Tumor molecular profiles were obtained from patients with stage I-IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF was defined as any progression of primary lung cancer after neoadjuvant ICI therapy in patients without surgery, radiographic and/or biopsy-proven primary lung cancer recurrence after surgery, or death from possibly treatment-related complications or from primary lung cancer since randomization. Tumors with AGAs (n=12) were compared with tumors without AGAs and non-profiled squamous cell carcinomas (non-AGAs+NP SCC, n=20). Results: With a median follow-up of 60.2 months, the overall TF rate was 34.1% (15/44). Tumor molecular profiling was retrospectively obtained in 47.7% (21/44) of patients and select AGAs were identified in 12 patients: 5 epidermal growth factor receptor (EGFR), 2 KRAS, 1 ERBB2, and 1 BRAF mutations, 2 anaplastic lymphoma kinase (ALK) and 1 RET fusions. The median time to TF in patients with AGAs was 24.7 months (95% CI: 12.6 to 40.4), compared with not reached (95% CI: not evaluable (NE)-NE) in the non-AGAs+NP SCC group. The TF risk was higher in AGAs (HR: 5.51, 95% CI: 1.68 to 18.1), and lower in former/current smokers (HR: 0.24, 95% CI: 0.08 to 0.75). The odds of major pathological response were 4.71 (95% CI: 0.49 to 45.2) times higher in the non-AGAs+NP SCC group, and the median percentage of residual viable tumor was 72.5% in AGAs compared with 33.0% in non-AGS+NP SCC tumors. Conclusions: Patients with NSCLC harboring select AGAs, including EGFR and ALK alterations, have a higher risk for TF, shorter median time to TF, and diminished pathological regression after neoadjuvant ICIs. The suboptimal efficacy of neoadjuvant chemotherapy-sparing, ICI-based regimens in this patient subset underscores the importance of tumor molecular testing prior to initiation of neoadjuvant ICI therapy in patients with resectable NSCLC

On the physical mechanism underlying Asymptotic Safety

We identify a simple physical mechanism which is at the heart of Asymptotic Safety in Quantum Einstein Gravity (QEG) according to all available effective average action-based investigations. Upon linearization the gravitational field equations give rise to an inverse propagator for metric fluctuations comprising two pieces: a covariant Laplacian and a curvature dependent potential term. By analogy with elementary magnetic systems they lead to, respectively, dia- and paramagnetic-type interactions of the metric fluctuations with the background gravitational field. We show that above 3 spacetime dimensions the gravitational antiscreening occurring in QEG is entirely due to a strong dominance of the ultralocal paramagnetic interactions over the diamagnetic ones that favor screening. (Below 3 dimensions both the dia- and paramagnetic effects support antiscreening.) The spacetimes of QEG are interpreted as a polarizable medium with a "paramagnetic" response to external perturbations, and similarities with the vacuum state of Yang-Mills theory are pointed out. As a by-product, we resolve a longstanding puzzle concerning the beta function of Newton's constant in 2+{\epsilon} dimensional gravity.Comment: 43 pages, 8 figures; clarifying remarks added; to appear in JHE

Peroxiredoxin 3 Is a Redox-Dependent Target of Thiostrepton in Malignant Mesothelioma Cells

Thiostrepton (TS) is a thiazole antibiotic that inhibits expression of FOXM1, an oncogenic transcription factor required for cell cycle progression and resistance to oncogene-induced oxidative stress. The mechanism of action of TS is unclear and strategies that enhance TS activity will improve its therapeutic potential. Analysis of human tumor specimens showed FOXM1 is broadly expressed in malignant mesothelioma (MM), an intractable tumor associated with asbestos exposure. The mechanism of action of TS was investigated in a cell culture model of human MM. As for other tumor cell types, TS inhibited expression of FOXM1 in MM cells in a dose-dependent manner. Suppression of FOXM1 expression and coincidental activation of ERK1/2 by TS were abrogated by pre-incubation of cells with the antioxidant N-acetyl-L-cysteine (NAC), indicating its mechanism of action in MM cells is redox-dependent. Examination of the mitochondrial thioredoxin reductase 2 (TR2)-thioredoxin 2 (TRX2)-peroxiredoxin 3 (PRX3) antioxidant network revealed that TS modifies the electrophoretic mobility of PRX3. Incubation of recombinant human PRX3 with TS in vitro also resulted in PRX3 with altered electrophoretic mobility. The cellular and recombinant species of modified PRX3 were resistant to dithiothreitol and SDS and suppressed by NAC, indicating that TS covalently adducts cysteine residues in PRX3. Reduction of endogenous mitochondrial TRX2 levels by the cationic triphenylmethane gentian violet (GV) promoted modification of PRX3 by TS and significantly enhanced its cytotoxic activity. Our results indicate TS covalently adducts PRX3, thereby disabling a major mitochondrial antioxidant network that counters chronic mitochondrial oxidative stress. Redox-active compounds like GV that modify the TR2/TRX2 network may significantly enhance the efficacy of TS, thereby providing a combinatorial approach for exploiting redox-dependent perturbations in mitochondrial function as a therapeutic approach in mesothelioma