Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.

A single ALS center experience with clinical use of sodium phenylbutyrate-taurursodiol.

INTRODUCTION/AIMS: The aim of this study was to examine clinical utilization and discontinuation rates of sodium phenylbutyrate-taurursodiol (PB-TURSO) in a single Amyotrophic Lateral Sclerosis (ALS) center. PB-TURSO was approved by the United States Food and Drug Administration (FDA) in September 2022. Prior experience has been limited to clinical trials or expanded access protocols. In this manuscript, we discuss insurance approval rates, patient uptake, and discontinuation of PB-TURSO in a large academic center. METHODS: Records of patients seen for clinical visits between January 2022 and May 2023 were reviewed. Demographic and clinical characteristics of our clinic population and those initiating PB-TURSO were obtained from our clinical database. RESULTS: A total of 228 patients were seen during the observation period and 122 requested PB-TURSO prescriptions. 77% (94) were approved by insurance. 66% (65) of those who were approved or received free drug chose to start medication. 51% (34) of those who initiated PB-TURSO continued to take it through the end of the observation period. Four patients discontinued due to death during the observation period. Of the 29 patients who survived and discontinued, the main reasons for discontinuation were GI symptoms (17, 58.6%) and taste (8, 29.6%). DISCUSSION: PB-TURSO was approved by insurance for most patients. The discontinuation rate was high and was driven largely by GI side effects and taste. Future considerations would include deeper examination of demographic trends, patient costs, side effects, and potential benefits in clinical practice.

Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies.

TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterize TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n = 126), amyotrophic lateral sclerosis (ALS, n = 141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer's disease (n = 304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating individuals with and without Alzheimer's disease and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies.

Elevated Plasma Phosphorylated Tau 181 in Amyotrophic Lateral Sclerosis.

OBJECTIVE: Plasma phosphorylated tau (p-tau181 ) is reliably elevated in Alzheimer's disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here, we find novel evidence that plasma p-tau181 is elevated in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed evaluation to identify the clinical correlates of elevated p-tau181 in ALS. METHODS: Patients were clinically or pathologically diagnosed with ALS (n = 130) or AD (n = 79), or were healthy non-impaired controls (n = 26). Receiver operating characteristic (ROC) curves were analyzed and area under the curve (AUC) was used to discriminate AD from ALS. Within ALS, Mann-Whitney-Wilcoxon tests compared analytes by presence/absence of upper motor neuron and lower motor neuron (LMN) signs. Spearman correlations tested associations between plasma p-tau181 and postmortem neuron loss. RESULTS: A Wilcoxon test showed plasma p-tau181 was higher in ALS than controls (W = 2,600, p = 0.000015), and ROC analyses showed plasma p-tau181 poorly discriminated AD and ALS (AUC = 0.60). In ALS, elevated plasma p-tau181 was associated with LMN signs in cervical (W = 827, p = 0.0072), thoracic (W = 469, p = 0.00025), and lumbosacral regions (W = 851, p = 0.0000029). In support of LMN findings, plasma p-tau181 was associated with neuron loss in the spinal cord (rho = 0.46, p = 0.017), but not in the motor cortex (p = 0.41). Cerebrospinal spinal fluid p-tau181 and plasma neurofilament light chain were included as reference analytes, and demonstrate specificity of findings. INTERPRETATION: We found strong evidence that plasma p-tau181 is elevated in ALS and may be a novel marker specific to LMN dysfunction. ANN NEUROL 2022;92:807-818.

Signature laminar distributions of pathology in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregional laminar pathology display patterns unique to proteinopathy or clinical syndrome. We hypothesized that FTLD-tau and FTLD-TDP accumulate pathology in relatively distinct cortical layers independent of clinical syndrome, with greater involvement of lower layers in FTLD-tau. The current study examined 170 patients with either FTLD-tau (n = 73) or FTLD-TDP (n = 97) spanning dementia and motor phenotypes in the FTD spectrum. We digitally measured the percent area occupied by tau and TDP-43 pathology in upper layers (I-III), lower layers (IV-VI), and juxtacortical white matter (WM) from isocortical regions in both hemispheres where available. Linear mixed-effects models compared ratios of upper to lower layer pathology between FTLD groups and investigated relationships with regions, WM pathology, and global cognitive impairment while adjusting for demographics. We found lower ratios of layer pathology in FTLD-tau and higher ratios of layer pathology in FTLD-TDP, reflecting lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology, respectively (p < 0.001). FTLD-tau displayed lower ratios of layer pathology related to greater WM tau pathology (p = 0.002) and to earlier involved/severe pathology regions (p = 0.007). In contrast, FTLD-TDP displayed higher ratios of layer pathology not related to either WM pathology or regional severity. Greater cognitive impairment was associated with higher ratios of layer pathology in FTLD-tau (p = 0.018), but was not related to ratios of layer pathology in FTLD-TDP. Lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology are proteinopathy-specific, regardless of clinical syndromes or regional networks that define these syndromes. Thus, patterns of laminar change may provide a useful anatomical framework for investigating how degeneration of select cells and corresponding laminar circuits influence large-scale networks and clinical symptomology in FTLD.

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.

INTRODUCTION/AIMS: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD. METHODS: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated. RESULTS: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions. DISCUSSION: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.

TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy.

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well understood. Here, we investigated the influence of genotypes at TMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)-allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. To elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.

Temporal trends and yield of clinical diagnostic genetic testing in adult neurology.

While genetics evaluation is increasingly utilized in adult neurology patients, its usage and efficacy are not well characterized. Here, we report our experience with 1461 consecutive patients evaluated in an adult neurogenetics clinic at a large academic medical center between January 2015 and March 2020. Of the 1461 patients evaluated, 1215 patients were referred for the purposes of identifying a genetic diagnosis for an undiagnosed condition, 90.5% of whom underwent genetic testing. The modalities of genetic testing utilized varied across referral diagnostic categories, including a range of utilization of whole exome sequencing (WES) as an initial test in 13.9% of neuromuscular patients to 52.9% in white matter disorder patients. The usage of WES increased over time, from 7.7% of initial testing in 2015 to a peak of 27.3% in 2019. Overall, genetic testing yielded a causal genetic diagnosis in 30.7% of patients. This yield was higher in certain referring diagnosis categories, such as neuromuscular (39.0%) and epilepsy (29.8%). Our study demonstrates that evaluation at an adult neurogenetics referral center can yield diagnoses in a substantial fraction of patients. Additional research will be needed to determine optimal genetic testing strategies and cost effectiveness of adult neurogenetics evaluation.

Degeneration of the locus coeruleus is a common feature of tauopathies and distinct from TDP-43 proteinopathies in the frontotemporal lobar degeneration spectrum.

Neurodegeneration of the locus coeruleus (LC) in age-related neurodegenerative diseases such as Alzheimer's disease (AD) is well documented. However, detailed studies of LC neurodegeneration in the full spectrum of frontotemporal lobar degeneration (FTLD) proteinopathies comparing tauopathies (FTLD-tau) to TDP-43 proteinopathies (FTLD-TDP) are lacking. Here, we tested the hypothesis that there is greater LC neuropathology and neurodegeneration in FTLD-tau compared to FTLD-TDP. We examined 280 patients including FTLD-tau (n = 94), FTLD-TDP (n = 135), and two reference groups: clinical/pathological AD (n = 32) and healthy controls (HC, n = 19). Adjacent sections of pons tissue containing the LC were immunostained for phosphorylated TDP-43 (1D3-p409/410), hyperphosphorylated tau (PHF-1), and tyrosine hydroxylase (TH) to examine neuromelanin-containing noradrenergic neurons. Blinded to clinical and pathologic diagnoses, we semi-quantitatively scored inclusions of tau and TDP-43 both inside LC neuronal somas and in surrounding neuropil. We also digitally measured the percent area occupied of neuromelanin inside of TH-positive LC neurons and in surrounding neuropil to calculate a ratio of extracellular-to-intracellular neuromelanin as an objective composite measure of neurodegeneration. We found that LC tau burden in FTLD-tau was greater than LC TDP-43 burden in FTLD-TDP (z = - 11.38, p < 0.0001). Digital measures of LC neurodegeneration in FTLD-tau were comparable to AD (z = - 1.84, p > 0.05) but greater than FTLD-TDP (z = - 3.85, p < 0.0001) and HC (z = - 4.12, p < 0.0001). Both tau burden and neurodegeneration were consistently elevated in the LC across pathologic and clinical subgroups of FTLD-tau compared to FTLD-TDP subgroups. Moreover, LC tau burden positively correlated with neurodegeneration in the total FTLD group (rho = 0.24, p = 0.001), while TDP-43 burden did not correlate with LC neurodegeneration in FTLD-TDP (rho = - 0.01, p = 0.90). These findings suggest that patterns of disease propagation across all tauopathies include prominent LC tau and neurodegeneration that are relatively distinct from the minimal degenerative changes to the LC in FTLD-TDP and HC. Antemortem detection of LC neurodegeneration and/or function could potentially improve antemortem differentiation of underlying FTLD tauopathies from clinically similar FTLD-TDP proteinopathies.

Reliable and efficient scale to assess upper motor neuron disease burden in amyotrophic lateral sclerosis.

BACKGROUND: Validation of biomarkers of upper motor neuron (UMN) impairment in amyotrophic lateral sclerosis (ALS) requires a reliable clinical assessment of UMN findings. The Penn Upper Motor Neuron Score© (PUMNS) is a standardized measure of UMN signs in ALS. Our aims were to evaluate its intra- and inter-rater reliability, and to examine inter-item reliability as a proxy for item relatedness and scale efficiency. METHODS: Study procedures were performed during routine clinic visits. We calculated intra and inter-rater reliability using Pearson's correlation coefficient and inter-item reliability using Cronbach's alpha. RESULTS: PUMNS had high intra and inter-rater reliability. Total and sub-score correlation coefficients were all ≥0.96. The inter-item reliability indicated appropriate item relatedness with reasonable efficiency and sub-score correlation coefficients between 0.68 and 0.85. CONCLUSIONS: PUMNS is a reliable measure of UMN signs in ALS and would be a useful tool in validating imaging and laboratory biomarkers of UMN injury in ALS.

Primary lateral sclerosis (PLS) functional rating scale: PLS-specific clinimetric scale.

INTRODUCTION: Our research aim was to develop a novel clinimetric scale sensitive enough to detect disease progression in primary lateral sclerosis (PLS). METHODS: A prototype of the PLS Functional Rating Scale (PLSFRS) was generated. Seventy-seven participants with PLS were enrolled and evaluated at 21 sites that comprised the PLSFRS study group. Participants were assessed using the PLSFRS, Neuro-Quality of Life (QoL), Schwab-England Activities of Daily Living (ADL), and the Clinical Global Impression of Change scales. Participants completed telephone assessments at 12, 24, and 48 weeks after enrollment. RESULTS: The PLSFRS demonstrated internal consistency as well as intrarater, interrater, telephone test-retest reliability, and construct validity. Significant changes in disease progression were detected at 6 and 12 months; changes measured by the PLSFRS vs the ALSFRS-R were significantly higher. DISCUSSION: The PLSFRS is a valid tool to assess the natural history of PLS in a shorter study period.

Classifying Patients with Amyotrophic Lateral Sclerosis by Changes in FVC. A Group-based Trajectory Analysis.

Rationale: A model for stratifying progression of respiratory muscle weakness in amyotrophic lateral sclerosis (ALS) would identify disease mechanisms and phenotypes suitable for future investigations. This study sought to categorize progression of FVC after presentation to an outpatient ALS clinic.Objectives: To identify clinical phenotypes of ALS respiratory progression based on FVC trajectories over time.Methods: We derived a group-based trajectory model from a single-center cohort of 837 patients with ALS who presented between 2006 and 2015. We applied our model to the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7,461 patients with ALS. Baseline characteristics at first visit were used as predictors of trajectory group membership. The primary outcome was trajectory of FVC over time in months.Measurements and Main Results: We found three trajectories of FVC over time, termed "stable low," "rapid progressor," and "slow progressor." Compared with the slow progressors, the rapid progressors had shorter diagnosis delay, more bulbar-onset disease, and a lower ALS Functional Rating Scale-Revised (ALSFRS-R) total score at baseline. The stable low group had a shorter diagnosis delay, lower body mass index, more bulbar-onset disease, lower ALSFRS-R total score, and were more likely to have an ALSFRS-R orthopnea score lower than 4 compared with the slow progressors. We found that projected group membership predicted respiratory insufficiency in the PRO-ACT cohort (concordance statistic = 0.78, 95% CI, 0.76-0.79).Conclusions: We derived a group-based trajectory model for FVC progression in ALS, which validated against the outcome of respiratory insufficiency in an external cohort. Future studies may focus on patients predicted to be rapid progressors.

Development of a prognostic model of respiratory insufficiency or death in amyotrophic lateral sclerosis.

A clinically useful model to prognose onset of respiratory insufficiency in amyotrophic lateral sclerosis (ALS) would inform disease interventions, communication and clinical trial design. We aimed to derive and validate a clinical prognostic model for respiratory insufficiency within 6 months of presentation to an outpatient ALS clinic.We used multivariable logistic regression and internal cross-validation to derive a clinical prognostic model using a single-centre cohort of 765 ALS patients who presented between 2006 and 2015. External validation was performed using the multicentre Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database with 7083 ALS patients. Predictors included baseline characteristics at first outpatient visit. The primary outcome was respiratory insufficiency within 6 months, defined by initiation of noninvasive ventilation, forced vital capacity (FVC) <50% predicted, tracheostomy, or death.Of 765 patients in our centre, 300 (39%) had respiratory insufficiency or death within 6 months. Six baseline characteristics (diagnosis age, delay between symptom onset and diagnosis, FVC, symptom onset site, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R) total score and ALSFRS-R dyspnoea score) were used to prognose the risk of the primary outcome. The derivation cohort c-statistic was 0.86 (95% CI 0.84-0.89) and internal cross-validation produced a c-statistic of 0.86 (95% CI 0.85-0.87). External validation of the model using the PRO-ACT cohort produced a c-statistic of 0.74 (95% CI 0.72-0.75).We derived and externally validated a clinical prognostic rule for respiratory insufficiency in ALS. Future studies should investigate interventions on equivalent high-risk patients.

Rasagiline for amyotrophic lateral sclerosis: A randomized, controlled trial.

INTRODUCTION: Rasagiline is a monoamine oxidase B (MAO-B) inhibitor with possible neuroprotective effects in patients with amyotrophic lateral sclerosis (ALS). METHODS: We performed a randomized, double-blind, placebo-controlled trial of 80 ALS participants with enrichment of the placebo group with historical controls (n = 177) at 10 centers in the United States. Participants were randomized in a 3:1 ratio to 2 mg/day rasagiline or placebo. The primary outcome was average slope of decline on the ALS Functional Rating Scale-Revised (ALSFRS-R). Secondary measures included slow vital capacity, survival, mitochondrial and molecular biomarkers, and adverse-event reporting. RESULTS: There was no difference in the average 12-month ALSFRS-R slope between rasagiline and the mixed placebo and historical control cohorts. Rasagiline did not show signs of drug-target engagement in urine and blood biomarkers. Rasagiline was well tolerated with no serious adverse events. DISCUSSION: Rasagiline did not alter disease progression compared with controls over 12 months of treatment. Muscle Nerve 59:201-207, 2019.

Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-ß, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-ß common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-ß (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-ß, α-synuclein and TDP-43.

Elevated CSF GAP-43 is Alzheimer's disease specific and associated with tau and amyloid pathology.

INTRODUCTION: The level of the presynaptic protein growth-associated protein 43 (GAP-43) in cerebrospinal fluid (CSF) has previously been shown to be increased in Alzheimer's disease (AD) and thus may serve as an outcome measure in clinical trials and facilitate earlier disease detection. METHODS: We developed an enzyme-linked immunosorbent assay for CSF GAP-43 and measured healthy controls (n = 43), patients with AD (n = 275), or patients with other neurodegenerative diseases (n = 344). In a subpopulation (n = 93), CSF GAP-43 concentrations from neuropathologically confirmed cases were related to Aß plaques, tau, α-synuclein, and TDP-43 pathologies. RESULTS: GAP-43 was significantly increased in AD compared to controls and most neurodegenerative diseases and correlated with the magnitude of neurofibrillary tangles and Aß plaques in the hippocampus, amygdala, and cortex. GAP-43 was not associated to α-synuclein or TDP-43 pathology. DISCUSSION: The presynaptic marker GAP-43 is associated with both diagnosis and neuropathology of AD and thus may be useful as a sensitive and specific biomarker for clinical research.

Genetic test utilization and diagnostic yield in adult patients with neurological disorders.

To determine the diagnostic yield of different genetic test modalities in adult patients with neurological disorders, we evaluated all adult patients seen for genetic diagnostic evaluation in the outpatient neurology practice at the University of Pennsylvania between January 2016 and April 2017 as part of the newly created Penn Neurogenetics Program. Subjects were identified through our electronic medical system as those evaluated by the Program's single clinical genetic counselor in that period. A total of 377 patients were evaluated by the Penn Neurogenetics Program in different settings and genetic testing recommended. Of those, 182 (48%) were seen in subspecialty clinic setting and 195 (52%) in a General Neurogenetics Clinic. Genetic testing was completed in over 80% of patients in whom it was recommended. The diagnostic yield was 32% across disease groups. Stratified by testing modality, the yield was highest with directed testing (50%) and array comparative genomic hybridization (45%), followed by gene panels and exome testing (25% each). In conclusion, genetic testing can be successfully requested in clinic in a large majority of adult patients. Age is not a limiting factor for a genetic diagnostic evaluation and the yield of clinical testing across phenotypes (almost 30%) is consistent with previous phenotype-focused or research-based studies. These results should inform the development of specific guidelines for clinical testing and serve as evidence to improve reimbursement by insurance payers.

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology.

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer's disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson's disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid ß (Aß), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aß neuritic plaque (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with ß-amyloid plaque pathology.

Amyotrophic lateral sclerosis-specific quality of life-short form (ALSSQOL-SF): A brief, reliable, and valid version of the ALSSQOL-R.

INTRODUCTION: The Amyotrophic Lateral Sclerosis (ALS)-Specific Quality of Life instrument and its revised version (ALSSQOL and ALSSQOL-R) have strong psychometric properties, and have demonstrated research and clinical utility. In this study we aimed to develop a short form (ALSSQOL-SF) suitable for limited clinic time and patient stamina. METHODS: The ALSSQOL-SF was created using Item Response Theory and confirmatory factor analysis on 389 patients. A cross-validation sample of 162 patients assessed convergent, divergent, and construct validity of the ALSSQOL-SF compared with psychosocial and physical functioning measures. RESULTS: The ALSSQOL-SF consisted of 20 items. Compared with the ALSSQOL-R, optimal precision was retained, and completion time was reduced from 15-25 minutes to 2-4 minutes. Psychometric properties for the ALSSQOL-SF and its subscales were strong. DISCUSSION: The ALSSQOL-SF is a disease-specific global QOL instrument that has a short administration time suitable for clinical use, and can provide clinically useful, valid information about persons with ALS. Muscle Nerve 58: 646-654, 2018.

Cerebrospinal fluid α-synuclein contributes to the differential diagnosis of Alzheimer's disease.

INTRODUCTION: The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid ß peptide 1-42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF α-synuclein [α-syn] for Lewy body pathology) may be needed to further improve the differential diagnosis. METHODS: CSF total α-syn, phosphorylated α-syn at Ser129, and AD CSF biomarkers were evaluated with Luminex immunoassays in 367 participants, followed by validation in 74 different neuropathologically confirmed cases. RESULTS: CSF total α-syn, when combined with amyloid ß peptide 1-42 and either total tau or phosphorylated tau, improved the differential diagnosis of AD versus frontotemporal dementia, Lewy body disorders, or other neurological disorders. The diagnostic accuracy of the combined models attained clinical relevance (area under curve ∼0.9) and was largely validated in neuropathologically confirmed cases. DISCUSSION: Combining CSF biomarkers representing AD and Lewy body pathologies may have clinical value in the differential diagnosis of AD.