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There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers.

Psychologists have been applying neurorehabilitation models of care for many years. These practitioners come from different training backgrounds and use a variety of titles to refer to themselves despite considerable overlap in practice patterns, professional identification, and salary. Titles like 'neurorehabilitation psychologist' and 'rehabilitation neuropsychologist' are sometimes used by practitioners in the field to indicate their specialty area, but are not formally recognized by the American Psychological Association, the American Board of Professional Psychology, or by training councils in clinical neuropsychology (CN) or rehabilitation psychology (RP). Neither the CN or RP specialties alone fully address or define the competencies, skill sets, and clinical experiences required to provide high quality, comprehensive neurorehabilitation psychology services across settings. Therefore, irrespective of practice setting, we believe that both clinical neuropsychologists and rehabilitation psychologists should ideally have mastery of specific, overlapping competencies and a philosophical approach to care that we call neurorehabilitation psychology in this paper. Trainees and early career professionals who aspire to practice in this arena are often pressured to prioritize either CN or RP pathways over the other, with anxiety about perceived and real potential for falling short in their training goals. In the absence of an explicit training path or formal guidelines, these professionals emerge only after the opportunity, privilege, or frank luck of working with specific mentors or in exceptional patient care settings that lend themselves to obtaining integrated competencies in neurorehabilitation psychology. This paper reflects the efforts of 7 practitioners to preliminarily define the practice and philosophies of neurorehabilitation psychology, the skill sets and competencies deemed essential for best practice, and essential training pathway elements. We propose competencies designed to maximize the integrity of training and provide clear guideposts for professional development. [ABSTRACT FROM AUTHOR]

Objective: To critically review contemporary theoretical models, diagnostic approaches, clinical features, and assessment findings in Functional Cognitive Disorder (FCD), and make recommendations for neuropsychological evaluation of this condition. Method: Narrative review. Results: FCD is common in neuropsychological practice. It is characterized by cognitive symptoms that are not better explained by another medical or psychiatric disorder. The cognitive symptoms are associated with distress and/or limitations in daily functioning, but are potentially reversible with appropriate identification and treatment. Historically, a variety of diagnostic frameworks have attempted to capture this condition. A contemporary conceptualization of FCD positions it as a subtype of Functional Neurological Disorder, with shared and unique etiological factors. Patients with FCD tend to perform normally on neuropsychological testing or demonstrate relatively weak memory acquisition (e.g. list learning trials) in comparison to strong attention and delayed recall performance. Careful history-taking and behavioral observations are essential to support the diagnosis of FCD. Areas of ongoing controversy include operationalizing "internal inconsistencies" and the role of performance validity testing. Evidence for targeted interventions remains scarce. Conclusions: Neuropsychologists familiar with FCD can uniquely contribute to the care of patients with this condition by improving diagnostic clarity, richening case formulation, communicating effectively with referrers, and leading clinical management. Further research is needed to refine diagnosis, prognosis, and treatment. [ABSTRACT FROM AUTHOR]

Patients with psychogenic nonepileptic seizure (PNES) who fail performance validity testing (PVT) may appear to produce non-valid cognitive profiles. Consequently, they may not get referred to treatment and events persist, with worsening disability and high resource utilization. As a result, we report pre- and post-treatment neuropsychological evaluation findings in a 59-year-old woman with a confirmed diagnosis of PNES established using video-EEG monitoring. At pre-treatment baseline neuropsychological evaluation, PNES events occurred weekly to daily. Performance was impaired across PVTs and across multiple cognitive domains. After behavioral intervention specific to PNES, these events substantially reduced in frequency to rare stress-induced flares. Post-treatment neuropsychological evaluation revealed marked improvement of most cognitive and behavioral scores from baseline, and valid PVT scores. We review predisposing, precipitating, and perpetuating factors for PNES and cognitive impairment in this case and discuss the patient's outcome from treatment. Effectively managing PNES events and dissociative tendencies while reducing unnecessary pharmacological interventions appears to have allowed this patient to function closer to her optimal state. This case illustrates the complexity of Functional Neurologic Disorder (FND) clinical presentation and challenges the assumption that suboptimal neuropsychological performance predicts poor treatment engagement and outcome. We showcase the reversibility of PNES and cognitive manifestations of FND using targeted psychotherapeutic interventions, which resulted in reduced disability and associated healthcare costs, as well as re-engagement in life. [ABSTRACT FROM AUTHOR]

Introduction: The neuropsychological profile of CSF1R-related leukoencephalopathy (CRL) is undefined. This study defines the profile, contrasts it with that of other dementia syndromes, and highlights measures sensitive to cognitive impairment. Methods: We administered a standardized battery of neuropsychological tests to five consecutive CRL cases. Results: The neuropsychological profile of CRL reflects impaired general cognitive function, processing speed, executive function, speeded visual problem solving, verbal fluency, and self-reported depression and anxiety. Confrontation naming and memory are preserved. Within cognitive domains, certain measures more frequently identified impairment than others. Discussion: CRL impairs general cognitive function, processing speed, executive function. Language and visual problem solving may be impaired if processing speed is required. Confrontation naming and memory are uniquely preserved, contrasting CRL to other dementia syndromes. Cognitive screens excluding processing speed and executive function may not detect CRL cognitive manifestations. Findings sharply define cognitive impairment of CRL and inform cognitive test selection. [ABSTRACT FROM AUTHOR]