International Genetic Testing and Counseling Practices for Parkinson's Disease.

BACKGROUND: There is growing clinical and research utilization of genetic testing in Parkinson's disease (PD), including direct-to-consumer testing. OBJECTIVES: The aim is to determine the international landscape of genetic testing in PD to inform future worldwide recommendations. METHODS: A web-based survey assessing current practices, concerns, and barriers to genetic testing and counseling was administered to the International Parkinson and Movement Disorders Society membership. RESULTS: Common hurdles across sites included cost and access to genetic testing, and counseling, as well as education on genetic counseling. Region-dependent differences in access to and availability of testing and counseling were most notable in Africa. High-income countries also demonstrated heterogeneity, with European nations more likely to have genetic testing covered through insurance than Pan-American and Asian countries. CONCLUSIONS: This survey highlights not only diversity of barriers in different regions but also the shared and highly actionable needs for improved education and access to genetic counseling and testing for PD worldwide. © 2023 International Parkinson and Movement Disorder Society.

Tolerability of clobazam as add-on therapy in patients aged 50 years and older with drug-resistant epilepsy.

OBJECTIVE: To evaluate the tolerability of clobazam in patients with drug-resistant epilepsy aged 50 years and older. METHODS: We performed a single center, retrospective chart review of patients at least 50 years of age with drug resistant epilepsy of any type who started clobazam as an add on therapy. Retention rate, safety, and tolerability at 6 and 12 months and last follow-up, and the discontinuation rate due to side effects were analyzed. RESULTS: A total of 26 patients met inclusion criteria. Mean age was 62 ± 7.1 years, and 69.2% of patients were female. The mean baseline seizure frequency before initiation of clobazam was 2 (range 1-30) seizures per month. The mean total daily dose of clobazam administered was 13 (range 5 to 30) mg/day. At the 12-month follow-up visit after clobazam initiation, 40% of patients were seizure-free and an additional 45% of patients had > 50% reduction in seizure frequency. The mean seizure frequency at 12-month follow-up was 1.5 (range 0-24) seizures per month. The mean total dose of clobazam at 12-month follow-up was 14.25 (range 5 to 25) mg/day. The mean duration of clobazam at last follow was 55.2 ± 27.02 (mean ± SD months) and 18 (69.2%) patients remained on clobazam. Twenty out of 26 (76.9%) patients reported at least one side effect and 6/26 (23%) discontinued the medication within a month of initiation. At last follow-up, 40% remained seizure free on stable dosing. CONCLUSION: Clobazam can be a safe and tolerable, add-on treatment older adults with drug-resistant epilepsy. Those who responded tolerated the medication well. Discontinuation due to side effects occurred soon after initiation of therapy.

Co-Designing Digital Technologies for Improving Clinical Care in People with Parkinson's Disease: What Did We Learn?

The healthcare model is shifting towards integrated care approaches. This new model requires patients to be more closely involved. The iCARE-PD project aims to address this need by developing a technology-enabled, home-based, and community-centered integrated care paradigm. A central part of this project is the codesign process of the model of care, exemplified by the active participation of patients in the design and iterative evaluation of three sensor-based technological solutions. We proposed a codesign methodology used for testing the usability and acceptability of these digital technologies and present initial results for one of them, MooVeo. Our results show the usefulness of this approach in testing the usability and acceptability as well as the opportunity to incorporate patients' feedback into the development. This initiative will hopefully help other groups incorporate a similar codesign approach and develop tools that are well adapted to patients' and care teams' needs.

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

OBJECTIVE: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. METHODS: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. RESULTS: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. INTERPRETATION: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94.

Sleep disturbance in movement disorders: insights, treatments and challenges.

Sleep and circadian rhythm disturbances are central features of many movement disorders, exacerbating motor and non-motor symptoms and impairing quality of life. Understanding these disturbances to sleep is clinically important and may further our understanding of the underlying movement disorder. This review evaluates the current anatomical and neurochemical understanding of normal sleep and the recognised primary sleep disorders. In addition, we undertook a systematic review of the evidence for disruption to sleep across multiple movement disorders. Rapid eye movement sleep behaviour disorder has emerged as the most reliable prodromal biomarker for the alpha synucleinopathies, including Parkinson's disease and multiple system atrophy, often preceding motor symptom onset by several years. Abnormal sleep has also been described for many other movement disorders, but further evidence is needed to determine whether this is a primary or secondary phenotypic component of the underlying condition. Medication used in the treatment of motor symptoms also affects sleep and can aggravate or cause certain sleep disorders. Within the context of movement disorders, there is also some suggestion of a shared underlying mechanism for motor and sleep pathophysiology, with evidence implicating thalamic and brainstem structures and monoaminergic neurotransmission. This review highlights the need for an understanding of normal and abnormal sleep within the movement disorder clinic, an ability to screen for specific causes of poor sleep and to treat sleep disturbance to improve quality of life. Key sleep disorders also act as important biomarkers and have implications in diagnosis, prognosis and the development of future therapies.

Neurophysiological correlates of dual tasking in people with Parkinson's disease and freezing of gait.

Freezing of gait in people with Parkinson's disease (PwP) is associated with executive dysfunction and motor preparation deficits. We have recently shown that electrophysiological markers of motor preparation, rather than decision-making, differentiate PwP with freezing of gait (FOG +) and without (FOG -) while sitting. To examine the effect of locomotion on these results, we measured behavioural and electrophysiological responses in PwP with and without FOG during a target response time task while sitting (single-task) and stepping-in-place (dual-task). Behavioural and electroencephalographic data were acquired from 18 PwP (eight FOG +) and seven young controls performing the task while sitting and stepping-in-place. FOG + had slower response times while stepping compared with sitting. However, response times were significantly faster while stepping compared with sitting for controls. Electrophysiological responses showed no difference in decision-making potentials (centroparietal positivity) between groups or conditions but there were differences in neurophysiological markers of response inhibition (N2) and motor preparation (lateralized readiness potential, LRP) in FOG + while performing a dual-task. This suggests that the addition of a second complex motor task (stepping-in-place) impacts automatic allocation of resources in FOG +, resulting in delayed response times. The impact of locomotion on the generation of the N2 and LRP potentials, particularly in freezers, indirectly implies that these functions compete with locomotion for resources. In the setting of multiple complex tasks or cognitive impairment, severe motor dysfunction may result, leading to freezing of gait.

A Rare Case of Cecal Bascule in a Child With Normal Neurodevelopment.

Cecal volvulus is a rare cause of bowel obstruction in adults and an extremely rare presentation in children. One form known as a cecal bascule has only previously been reported in children with neurodevelopmental issues or with severe chronic constipation. We present the case of a 10-year-old boy who presented with an acute history of left lower quadrant abdominal pain, who upon investigation was found to have a cecal bascule.

Cognitive Indicators of Preclinical Behavioral Variant Frontotemporal Dementia in MAPT Carriers.

OBJECTIVES: The cognitive indicators of preclinical behavioral variant Frontotemporal Dementia (bvFTD) have not been identified. To investigate these indicators, we compared cross-sectional performance on a range of cognitive measures in 12 carriers of pathogenic MAPT mutations not meeting diagnostic criteria for bvFTD (i.e., preclinical) versus 32 demographically-matched familial non-carriers (n = 44). Studying preclinical carriers offers a rare glimpse into emergent disease, environmentally and genetically contextualized through comparison to familial controls. METHODS: Evaluating personnel blinded to carrier status administered a standardized neuropsychological battery assessing attention, speed, executive function, language, memory, spatial ability, and social cognition. Results from mixed effect modeling were corrected for multiplicity of comparison by the false discovery rate method, and results were considered significant at p < .05. To control for potential interfamilial variation arising from enrollment of six families, family was treated as a random effect, while carrier status, age, gender, and education were treated as fixed effects. RESULTS: Group differences were detected in 17 of 31 cognitive scores and spanned all domains except spatial ability. As hypothesized, carriers performed worse on specific measures of executive function, and social cognition, but also on measures of attention, speed, semantic processing, and memory storage and retrieval. CONCLUSIONS: Most notably, group differences arose on measures of memory storage, challenging long-standing ideas about the absence of amnestic features on neuropsychological testing in early bvFTD. Current findings provide important and clinically relevant information about specific measures that may be sensitive to early bvFTD, and advance understanding of neurocognitive changes that occur early in the disease. (JINS, 2019, 25, 184-194).

Complexity based measures of postural stability provide novel evidence of functional decline in fragile X premutation carriers.

BACKGROUND: Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative movement disorder characterized by tremor, ataxic gait, and balance issues resulting from a premutation of the Fragile X Mental Retardation 1 (FMR1) gene. No biomarkers have yet been identified to allow early diagnosis of FXTAS, however, recent studies have reported subtle issues in the stability of younger premutation carriers, before disease onset. This study investigates the efficacy of multiscale entropy analysis (MSE) in detecting early changes in the motor system of premutation carriers without FXTAS. METHODS: Sway complexity of 12 female Premutation carriers and 15 healthy Controls were measured under four conditions: eyes open, closed, and two dual-task conditions. A Sustained Attention Response Task (SART) and a working memory based N-Back task were employed to increase cognitive load while standing on the forceplate. A Complexity Index (Ci) was calculated for anterior-posterior (AP) and mediolateral (ML) sway. Independent t-tests were used to assess between-group differences and Oneway repeated measures ANOVA were used to assess within group differences with Bonferroni corrections to adjust for multiple comparisons. RESULTS: Group performances were comparable with eyes open and closed conditions. The Carrier group's Ci was consistent across tasks and conditions while the Control group's AP Ci increased significantly during the cognitive dual-task (p = 0.001). There was also a strong correlation between CGG repeat length and complexity for the Carrier group (p = 0.004). SIGNIFICANCE: Increased sway complexity is believed to stem from reallocation of attention to facilitate the increased cognitive demands of dual-tasks. Carriers' complexity did not change during dual-tasks, possibly indicating capacity interference and inefficient division of attention. Lower sway complexity in carriers suggests diminished adaptive capacity under stress as well as degradation of motor functioning. Therefore, sway complexity may be a useful tool in identifying early functional decline in FMR1 premutation carriers as well as monitoring progression towards disease onset.

Improving Resident Well-Being During Shiftwork: Are Casino Shifts the Answer?

PURPOSE: The objective of this study is to quantitatively evaluate the well-being of residents doing casino shifts compared with those doing standard overnight shifts while working in an academic pediatric emergency department. METHODS: A randomized prospective survey study was performed over a period of 1 year on all residents who were scheduled to complete a 28-day block. Each block (28-day period) within the year was designated as either a "standard" or "casino" block. The standard overnight shifts were scheduled from midnight to 0800 hours, and casino shifts occurred from either 2000 to 0400 hours (casino A) and 0400 to 1200 hours (casino B). Participating residents were asked to complete both a preblock and postblock survey. The primary outcome was defined as differences in resident well-being as assessed by the brief resident wellness profile (BRWP). A mood faces graphical rating item to assess overall mood was used as a secondary outcome measures as well as a 10-item survey based on World Health Organization domains for quality of life and adapted to reflect completion of shiftwork. RESULTS: A total of 124 (90%) of 138 residents completed the study and were included in the analysis. No significant difference in resident well-being measured by BRWP between those in the standard and casino shift groups (17 ± 2.5 for preblock standard and 16.9 ± 2.8 for casino, P = 0.904; 17.1 ± 2.7 for postblock standard and 17.2 ± 3.1 for casino, P = 0.817), or in the relative change of the BRWP preblock and postblock between the 2 groups (standard, 0.35 ± 2.7; casino, 0.29 ± 3.0; P = 0.926). No significant difference in the mood faces rating scale scores or the 10-item postblock survey was found. CONCLUSIONS: In the first study examining the effects of casino shifts on trainees, we found no effect of standard overnight versus casino shifts on their well-being. This counters the benefits previously seen in emergency department consultant staff and highlights the need for more studies specifically in trainees.

Identification of genetic modifiers of age-at-onset for familial Parkinson's disease.

Parkinson's disease (PD) is the most common cause of neurodegenerative movement disorder and the second most common cause of dementia. Genes are thought to have a stronger effect on age-at-onset of PD than on risk, yet there has been a phenomenal success in identifying risk loci but not age-at-onset modifiers. We conducted a genome-wide study for age-at-onset. We analysed familial and non-familial PD separately, per prior evidence for strong genetic effect on age-at-onset in familial PD. GWAS was conducted in 431 unrelated PD individuals with at least one affected relative (familial PD) and 1544 non-familial PD from the NeuroGenetics Research Consortium (NGRC); an additional 737 familial PD and 2363 non-familial PD were used for replication. In familial PD, two signals were detected and replicated robustly: one mapped to LHFPL2 on 5q14.1 (PNGRC = 3E-8, PReplication = 2E-5, PNGRC + Replication = 1E-11), the second mapped to TPM1 on 15q22.2 (PNGRC = 8E-9, PReplication = 2E-4, PNGRC + Replication = 9E-11). The variants that were associated with accelerated onset had low frequencies (<0.02). The LHFPL2 variant was associated with earlier onset by 12.33 [95% CI: 6.2; 18.45] years in NGRC, 8.03 [2.95; 13.11] years in replication, and 9.79 [5.88; 13.70] years in the combined data. The TPM1 variant was associated with earlier onset by 15.30 [8.10; 22.49] years in NGRC, 9.29 [1.79; 16.79] years in replication, and 12.42 [7.23; 17.61] years in the combined data. Neither LHFPL2 nor TPM1 was associated with age-at-onset in non-familial PD. LHFPL2 (function unknown) is overexpressed in brain tumours. TPM1 encodes a highly conserved protein that regulates muscle contraction, and is a tumour-suppressor gene.

Psychiatric symptoms in preclinical behavioural-variant frontotemporal dementia in MAPT mutation carriers.

OBJECTIVE: To characterise psychiatric symptoms in preclinical and early behavioural-variant frontotemporal dementia (bvFTD), a neurodegenerative disorder whose symptoms overlap with and are often mistaken for psychiatric illness. METHODS: The present study reports findings from a systematic, global, prospective evaluation of psychiatric symptoms in 12 preclinical carriers of pathogenic MAPT mutations, not yet meeting bvFTD diagnostic criteria, and 46 familial non-carrier controls. Current psychiatric symptoms, informant-reported symptoms and lifetime prevalence of psychiatric disorders were assessed with The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the Neuropsychiatric Inventory Questionnaire. Fisher exact test was used to compare carriers and non-carriers' lifetime prevalence of six DSM-IV disorders: major depressive disorder, panic attacks, alcohol abuse, generalised anxiety disorder, panic disorder, and depressive disorder not otherwise specified. Other DSM-IV disorders had insufficient prevalence across our sample for between-group comparisons, but are reported. RESULTS: Non-carriers had greater prevalence of mood and anxiety disorders than has been reported for a general reference population. Preclinical carriers had lower lifetime prevalence of mood and anxiety disorders than non-carriers, except for depressive disorder not otherwise specified, an atypical syndrome comprising clinically significant depressive symptoms which fail to meet criteria for major depressive disorder. CONCLUSION: Findings suggest that early psychiatric symptoms of emergent bvFTD may manifest as emotional blunting or mood changes not cleanly conforming to criteria for a DSM-defined mood disorder.

Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.

SEE GANDHI AND PLUN-FAVREAU DOI101093/AWW320 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: It has been postulated that heterozygous mutations in recessive Parkinson's genes may increase the risk of developing the disease. In particular, the PTEN-induced putative kinase 1 (PINK1) p.G411S (c.1231G>A, rs45478900) mutation has been reported in families with dominant inheritance patterns of Parkinson's disease, suggesting that it might confer a sizeable disease risk when present on only one allele. We examined families with PINK1 p.G411S and conducted a genetic association study with 2560 patients with Parkinson's disease and 2145 control subjects. Heterozygous PINK1 p.G411S mutations markedly increased Parkinson's disease risk (odds ratio = 2.92, P = 0.032); significance remained when supplementing with results from previous studies on 4437 additional subjects (odds ratio = 2.89, P = 0.027). We analysed primary human skin fibroblasts and induced neurons from heterozygous PINK1 p.G411S carriers compared to PINK1 p.Q456X heterozygotes and PINK1 wild-type controls under endogenous conditions. While cells from PINK1 p.Q456X heterozygotes showed reduced levels of PINK1 protein and decreased initial kinase activity upon mitochondrial damage, stress-response was largely unaffected over time, as expected for a recessive loss-of-function mutation. By contrast, PINK1 p.G411S heterozygotes showed no decrease of PINK1 protein levels but a sustained, significant reduction in kinase activity. Molecular modelling and dynamics simulations as well as multiple functional assays revealed that the p.G411S mutation interferes with ubiquitin phosphorylation by wild-type PINK1 in a heterodimeric complex. This impairs the protective functions of the PINK1/parkin-mediated mitochondrial quality control. Based on genetic and clinical evaluation as well as functional and structural characterization, we established p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a partial dominant-negative function phenotype.

Autonomic alterations as a clinical manifestation of encephalopathy associated with autoimmune thyroid disease.

Encephalopathy associated with autoimmune thyroid disease (EAATD), also known as Hashimoto's encephalopathy, is a rare neurological condition that may occur in patients with clinical or sub-clinical autoimmune thyroid disease. The pathogenesis of EAATD has been not clearly elucidated yet. The diagnostic criteria include neurological or psychiatric symptoms, high levels of anti-thyroid antibodies, and exclusion of other possible causes of encephalopathy. In the large majority of cases, EAATD patients respond to immunosuppressant therapies, in particular to corticosteroids. We report the case of a patient with Hashimoto's thyroiditis and recurrent manifestations of encephalopathy over the previous few years responding to corticosteroid treatment. The patient presented with language and cognitive impairment, ataxia, and neurovegetative/autonomic symptoms. She was euthyroid with mildly raised anti-thyroid peroxidase antibodies. An extensive diagnostic work-up, including electroencephalogram, brain magnetic resonance, hormonal assessment, and an exhaustive panel of antibodies possibly associated with autoimmune encephalopathy, was carried out and excluded other possible etiologies of encephalopathy. The diagnosis of EAATD possibly affecting the hypothalamus and/or the neurovegetative regulatory centers was made and treatment with prednisolone was timely commenced with a dramatic and rapid improvement with progressive normalization of the symptoms. To the best of our knowledge, this is the first report of neurovegetative/autonomic alterations in the setting of EAATD.

Refractory Hypotension Caused by Prazosin Overdose Combined With Acetaminophen and Naproxen Toxicity: A Case Report and Review of the Literature.

BACKGROUND: Pediatric exposure to prazosin is unusual because it is most commonly indicated for the treatment of hypertension. Prazosin's increase in popularity as a treatment for posttraumatic stress disorder makes it important for emergency physicians to be aware of how to manage potential toxic ingestion because of prazosin overdose. CASE REPORT: A 16-year-old, 76-kg female presented after ingesting 110 mg of prazosin, 209.3 g of acetaminophen, and 55 g of naproxen. She was admitted to the pediatric intensive care unit for rapidly deteriorating hypotension (lowest blood pressure 47/19 mm Hg) refractory to aggressive fluid resuscitation and infusions of epinephrine and norepinephrine each at 0.5 mcg/kg/min. Stabilization of blood pressure was eventually achieved, and associated with use of a vasopressin infusion of 0.004 units/kg/min. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Because of the increasing exposure of children to prazosin, clinicians should be aware of the pharmacology behind alpha-1 antagonist overdose and consider treatment options, such as vasopressin, when hypotension is resistant to standard fluid and catecholamine therapy.

Referral practice, reporting standards, and the impact of dopamine transporter scans done in a tertiary hospital.

AIMS: We studied the referral practice, reporting standards, and the impact of 123 ioflupane single photon emission computed tomogram dopamine transporters (DAT-SPECT) scans conducted for the diagnosis and clinical management of patients. SETTINGS AND DESIGNS: The present study was a retrospective, non-interventional study. MATERIALS AND METHODS: We assessed the DAT scan referral and the official reports available from the Nuclear Medicine Department of the Mater Misericordiae University Hospital over 1 year (2013). We also assessed the impact of the DAT scan result on the management of patients by analyzing patient records. The European Association of Nuclear Medicine Neuroimaging (EANM) 2010 and the Federal Drug Administration (FDA) 2012 guidelines were taken as the standard against which the quality of our DAT scans reporting was assessed. STATISTICAL METHODS: Microsoft Excel 2010 and graphpad software were used for statistical analysis. RESULTS: Twenty five (56.2%) out of a total of 48 DAT scans were performed to confirm early Parkinson's disease, 5 (8.9%) were done to exclude drug-induced parkinsonism, and 8 (14.3%) to distinguish essential tremor from parkinsonism; 2 scans were performed to distinguish Lewy body diseases from Alzheimer's dementia, and 4 indications were outside the recommended guidelines. Twelve out of the 26 (46%) abnormal scans had bilateral abnormalities. Twenty one out of the 25 DAT scans proved the clinical diagnosis of degenerative parkinsonism to be correct. CONCLUSION: The overall compliance of the DAT imaging with the existing standard guidelines was good. DAT scan can be very useful in clinical practice because it influences the clinical diagnosis and management in 23% of the patients.

Case series of autosomal recessive hereditary spastic paraparesis with novel mutation in SPG 7 gene.

Autosomal recessive hereditary spastic paraparesis is rare.We present 4 patients with slowly progressive predominantly lower limb spasticity and ataxia. Only one patient had family history of ataxia but without any underlying diagnosis. All of them proved negative for the mutation of Spinocerebelalr ataxia genes SCA 1,2,3 and 6. All had mutation in the SPG 7 gene suggestive of autosomal recessive hereditary spastic paraparesis. One of the heterozygous mutatnts showed a novel c1617delC ,p(Val540fs) frameshift mutation in exon 12 of the SPG 7 gene. SPG7 mutation accounts for 1.5-7% of all the HSP but it is the cause of undiagnosed ataxia in 18.6% in a recent case series. SPG7 mutation should be remembered as an important cause of undiagnosed ataxia especially where next generation sequencing is not widely avaialbale or affordable.

Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations.

Tauopathies, such as Alzheimer's disease, some cases of frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy, are characterized by aggregates of the microtubule-associated protein tau, which are linked to neuronal death and disease development and can be caused by mutations in the MAPT gene. Six tau isoforms are present in the adult human brain and they differ by the presence of 3(3R) or 4(4R) C-terminal repeats. Only the shortest 3R isoform is present in foetal brain. MAPT mutations found in human disease affect tau binding to microtubules or the 3R:4R isoform ratio by altering exon 10 splicing. We have differentiated neurons from induced pluripotent stem cells derived from fibroblasts of controls and patients with N279K and P301L MAPT mutations. Induced pluripotent stem cell-derived neurons recapitulate developmental tau expression, showing the adult brain tau isoforms after several months in culture. Both N279K and P301L neurons exhibit earlier electrophysiological maturation and altered mitochondrial transport compared to controls. Specifically, the N279K neurons show abnormally premature developmental 4R tau expression, including changes in the 3R:4R isoform ratio and AT100-hyperphosphorylated tau aggregates, while P301L neurons are characterized by contorted processes with varicosity-like structures, some containing both alpha-synuclein and 4R tau. The previously unreported faster maturation of MAPT mutant human neurons, the developmental expression of 4R tau and the morphological alterations may contribute to disease development.