Research Priorities on the Role of α-Synuclein in Parkinson's Disease Pathogenesis.

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Prediction of motor and non-motor Parkinson's disease symptoms using serum lipidomics and machine learning: a 2-year study.

Identifying biological factors which contribute to the clinical progression of heterogeneous motor and non-motor phenotypes in Parkinson's disease may help to better understand the disease process. Several lipid-related genetic risk factors for Parkinson's disease have been identified, and the serum lipid signature of Parkinson's disease patients is significantly distinguishable from controls. However, the extent to which lipid profiles are associated with clinical outcomes remains unclear. Untargeted high-performance liquid chromatography-tandem mass spectrometry identified >900 serum lipids in Parkinson's disease subjects at baseline (n = 122), and the potential for machine learning models using these lipids to predict motor and non-motor clinical scores after 2 years (n = 67) was assessed. Machine learning models performed best when baseline serum lipids were used to predict the 2-year future Unified Parkinson's disease rating scale part three (UPDRS III) and Geriatric Depression Scale scores (both normalised root mean square error = 0.7). Feature analysis of machine learning models indicated that species of lysophosphatidylethanolamine, phosphatidylcholine, platelet-activating factor, sphingomyelin, diacylglycerol and triacylglycerol were top predictors of both motor and non-motor scores. Serum lipids were overall more important predictors of clinical outcomes than subject sex, age and mutation status of the Parkinson's disease risk gene LRRK2. Furthermore, lipids were found to better predict clinical scales than a panel of 27 serum cytokines previously measured in this cohort (The Michael J. Fox Foundation LRRK2 Clinical Cohort Consortium). These results suggest that lipid changes may be associated with clinical phenotypes in Parkinson's disease.

An attentional and working memory theory of hallucination vulnerability in frontotemporal dementia.

The rate and prevalence of hallucinations in behavioural variant frontotemporal dementia is well established. The mechanisms for underlying vulnerability however are the least well described in FTD compared with other neuropsychiatric conditions, despite the presence of these features significantly complicating the diagnostic process. As such, this present study aimed to provide a detailed characterization of the neural, cognitive and behavioural profile associated with a predisposition to hallucinatory experiences in behavioural variant frontotemporal dementia. In total, 153 patients with behavioural variant frontotemporal dementia were recruited sequentially for this study. A group of patients with well characterized hallucinations and good-quality volumetric MRI scans (n = 23) were genetically and demographically matched to a group without hallucinations (n = 23) and a healthy control cohort (n = 23). All patients were assessed at their initial visit by means of a detailed clinical interview, a comprehensive battery of neuropsychological tests and MRI. Data were analysed according to three levels: (i) the relationship between neural structures, cognition, behaviour and hallucinations in behavioural variant frontotemporal dementia; (ii) the impact of the C9orf72 expansion; and (iii) hallucination subtype on expression of hallucinations. Basic and complex attentional (including divided attention and working memory) and visual function measures differed between groups (all P < 0.001) with hallucinators demonstrating poorer performance, along with evidence of structural changes centred on the prefrontal cortex, caudate and cerebellum (corrected for False Discovery Rate at P < 0.05 with a cluster threshold of 100 contiguous voxels). Attentional processes were also implicated in C9orf72 carriers with hallucinations with structural changes selectively involving the thalamus. Patients with visual hallucinations in isolation showed a similar pattern with emphasis on cerebellar atrophy. Our findings provided novel insights that attentional and visual function subsystems and related distributed brain structures are implicated in the generation of hallucinations in behavioural variant frontotemporal dementia, that dissociate across C9orf72, sporadic behavioural variant frontotemporal dementia and for the visual subtype of hallucinations. This loading on attentional and working memory measures is in line with current mechanistic models of hallucinations that frequently suggest a failure of integration of cognitive and perceptual processes. We therefore propose a novel cognitive and neural model for hallucination predisposition in behavioural variant frontotemporal dementia that aligns with a transdiagnostic model for hallucinations across neurodegeneration and psychiatry.

MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration.

Parkinson's disease (PD) is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. The activity of DA neurons is likely altered in PD, but we understand little about if or how chronic changes in activity may contribute to degeneration. To address this question, we developed a chemogenetic (DREADD) mouse model to chronically increase DA neuron activity, and confirmed this increase using ex vivo electrophysiology. Chronic hyperactivation of DA neurons resulted in prolonged increases in locomotor activity during the light cycle and decreases during the dark cycle, consistent with chronic changes in DA release and circadian disturbances. We also observed early, preferential degeneration of SNc projections, recapitulating the PD hallmarks of selective vulnerability of SNc axons and the comparative resilience of ventral tegmental area axons. This was followed by eventual loss of midbrain DA neurons. Continuous DREADD activation resulted in a sustained increase in baseline calcium levels, supporting an important role for increased calcium in the neurodegeneration process. Finally, spatial transcriptomics from DREADD mice examining midbrain DA neurons and striatal targets, and cross-validation with human patient samples, provided insights into potential mechanisms of hyperactivity-induced toxicity and PD. Our results thus reveal the preferential vulnerability of SNc DA neurons to increased neural activity, and support a potential role for increased neural activity in driving degeneration in PD.

A protective role of ABCA5 in response to elevated sphingomyelin levels in Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder that affects the motor system. Increasing evidence indicates that lysosomal dysfunction is pivotal in the pathogenesis of PD, typically characterized by dysregulation of sphingolipids in lysosomes. ATP-binding cassette subfamily A member 5 (ABCA5) is a lysosomal transporter that mediates the removal of excess sphingomyelin from lysosomes. We therefore investigated whether the expression levels of ABCA5 are associated with sphingomyelin levels and α-synuclein pathology in PD. Firstly, we undertook a comprehensive assessment of the six sphingolipid classes that are part of the lysosomal salvage pathway in the disease-affected amygdala and disease-unaffected visual cortex using liquid chromatography-mass spectrometry. We found that sphingomyelin levels were significantly increased in PD compared to controls and correlated with disease duration only in the amygdala, whereas, the five other sphingolipid classes were slightly altered or unaltered. Concomitantly, the expression of ABCA5 was upregulated in the PD amygdala compared to controls and correlated strongly with sphingomyelin levels. Using neuronal cells, we further verified that the expression of ABCA5 was dependent on cellular levels of sphingomyelin. Interestingly, sphingomyelin levels were strongly associated with α-synuclein in the amygdala and were related to α-synuclein expression. Finally, we revealed that sphingomyelin levels were also increased in PD plasma compared to controls, and that five identical sphingomyelin species were increased in both the brain and the plasma. When put together, these results suggest that in regions accumulating α-synuclein in PD, ABCA5 is upregulated to reduce lysosomal sphingomyelin levels potentially as a protective measure. This process may provide new targets for therapeutic intervention and biomarker development for PD.

A potential patient stratification biomarker for Parkinson´s disease based on LRRK2 kinase-mediated centrosomal alterations in peripheral blood-derived cells.

Parkinson´s disease (PD) is a common neurodegenerative movement disorder and leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for disease intervention. However, the ability to stratify patients who will benefit from such treatment modalities based on shared etiology is critical for the success of disease-modifying therapies. Ciliary and centrosomal alterations are commonly associated with pathogenic LRRK2 kinase activity and can be detected in many cell types. We previously found centrosomal deficits in immortalized lymphocytes from G2019S-LRRK2 PD patients. Here, to investigate whether such deficits may serve as a potential blood biomarker for PD which is susceptible to LRKK2 inhibitor treatment, we characterized patient-derived cells from distinct PD cohorts. We report centrosomal alterations in peripheral cells from a subset of early-stage idiopathic PD patients which is mitigated by LRRK2 kinase inhibition, supporting a role for aberrant LRRK2 activity in idiopathic PD. Centrosomal defects are detected in R1441G-LRRK2 and G2019S-LRRK2 PD patients and in non-manifesting LRRK2 mutation carriers, indicating that they accumulate prior to a clinical PD diagnosis. They are present in immortalized cells as well as in primary lymphocytes from peripheral blood. These findings indicate that analysis of centrosomal defects as a blood-based patient stratification biomarker may help nominate idiopathic PD patients who will benefit from LRRK2-related therapeutics.

Transitioning from Subtyping to Precision Medicine in Parkinson's Disease: A Purpose-Driven Approach.

The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Predicting neurodegeneration from sleep related biofluid changes.

Sleep-wake disturbances are common in neurodegenerative diseases and may occur years before the clinical diagnosis, potentially either representing an early stage of the disease itself or acting as a pathophysiological driver. Therefore, discovering biomarkers that identify individuals with sleep-wake disturbances who are at risk of developing neurodegenerative diseases will allow early diagnosis and intervention. Given the association between sleep and neurodegeneration, the most frequently analyzed fluid biomarkers in people with sleep-wake disturbances to date include those directly associated with neurodegeneration itself, such as neurofilament light chain, phosphorylated tau, amyloid-beta and alpha-synuclein. Abnormalities in these biomarkers in patients with sleep-wake disturbances are considered as evidence of an underlying neurodegenerative process. Levels of hormonal sleep-related biomarkers such as melatonin, cortisol and orexin are often abnormal in patients with clinical neurodegenerative diseases, but their relationships with the more standard neurodegenerative biomarkers remain unclear. Similarly, it is unclear whether other chronobiological/circadian biomarkers, such as disrupted clock gene expression, are causal factors or a consequence of neurodegeneration. Current data would suggest that a combination of fluid biomarkers may identify sleep-wake disturbances that are most predictive for the risk of developing neurodegenerative disease with more optimal sensitivity and specificity.

Rationale and Design of the "DIagnostic and Prognostic Precision Algorithm for behavioral variant Frontotemporal Dementia" (DIPPA-FTD) Study: A Study Aiming to Distinguish Early Stage Sporadic FTD from Late-Onset Primary Psychiatric Disorders.

BACKGROUND: The behavioral variant of frontotemporal dementia (bvFTD) is very heterogeneous in pathology, genetics, and disease course. Unlike Alzheimer's disease, reliable biomarkers are lacking and sporadic bvFTD is often misdiagnosed as a primary psychiatric disorder (PPD) due to overlapping clinical features. Current efforts to characterize and improve diagnostics are centered on the minority of genetic cases. OBJECTIVE: The multi-center study DIPPA-FTD aims to develop diagnostic and prognostic algorithms to help distinguish sporadic bvFTD from late-onset PPD in its earliest stages. METHODS: The prospective DIPPA-FTD study recruits participants with late-life behavioral changes, suspect for bvFTD or late-onset PPD diagnosis with a negative family history for FTD and/or amyotrophic lateral sclerosis. Subjects are invited to participate after diagnostic screening at participating memory clinics or recruited by referrals from psychiatric departments. At baseline visit, participants undergo neurological and psychiatric examination, questionnaires, neuropsychological tests, and brain imaging. Blood is obtained to investigate biomarkers. Patients are informed about brain donation programs. Follow-up takes place 10-14 months after baseline visit where all examinations are repeated. Results from the DIPPA-FTD study will be integrated in a data-driven approach to develop diagnostic and prognostic models. CONCLUSIONS: DIPPA-FTD will make an important contribution to early sporadic bvFTD identification. By recruiting subjects with ambiguous or prodromal diagnoses, our research strategy will allow the characterization of early disease stages that are not covered in current sporadic FTD research. Results will hopefully increase the ability to diagnose sporadic bvFTD in the early stage and predict progression rate, which is pivotal for patient stratification and trial design.

Heterogeneity of cortical pTDP-43 inclusion morphologies in amyotrophic lateral sclerosis.

BACKGROUND: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with amyotrophic lateral sclerosis (ALS), pathological subclassification is routinely performed in the minority of patients with concomitant frontotemporal dementia (FTD). OBJECTIVE: In order to improve current understanding of the presence and relevance of pathological pTDP-43 subtypes in ALS, the present study examined the pattern of cortical pTDP-43 aggregates in 61 ALS cases without FTD. RESULTS: Based on the presence, morphology and composition of pTDP-43 pathology, three distinct ALS-TDP subtypes were delineated: (1) A predominant pattern of pTDP-43 granulofilamentous neuronal inclusions (GFNIs) and grains that were immuno-negative for p62 was identified in 18% of cases designated ALS-TDP type E; (2) neuronal cytoplasmic inclusions (NCIs) that were immuno-positive for both pTDP-43 and p62 were observed in 67% of cases assigned ALS-TDP type B; and (3) scarce cortical pTDP-43 and p62 aggregates were identified in 15% of cases coined ALS-TDP type SC (scarce cortical). Quantitative analyses revealed a significantly greater burden of pTDP-43 GFNI and grains in ALS-TDP type E. Principal component analysis demonstrated significant relationships between GFNIs, grains and ALS-TDP subtypes to support the distinction of subtypes E and B. No significant difference in age at death or disease duration was found between ALS-TDP subgroups to suggest that these subtypes represent earlier or later stages of the same disease process. Instead, a significantly higher ALS-TDP stage, indicating greater topographical spread of pTDP-43, was identified in ALS-TDP type E. Alzheimer's disease neuropathological change (ABC score ≥ intermediate) and Lewy body disease (Braak stage ≥ IV) was more prevalent in the ALS-TDP type SC cohort, which also demonstrated a significantly lower overall cognitive score. CONCLUSION: In summary, the present study demonstrates that ALS-TDP does not represent a single homogenous neuropathology. We propose the subclassification of ALS-TDP into three distinct subtypes using standard immuno-stains for pTDP-43 and p62 in the motor cortex, which is routinely sampled and evaluated for diagnostic neuropathological characterisation of ALS. We propose that future studies specify both clinicopathological group and pTDP-43 subtype to advance current understanding of the pathogenesis of clinical phenotypes in pTDP-43 proteinopathies, which will have significant relevance to the development of targeted therapies for this heterogeneous disorder.

Live cell in situ lysosomal GCase activity correlates to alpha-synuclein levels in human differentiated neurons with LRRK2 and GBA1 mutations.

Introduction: Heterozygous mutations in GBA1, which encodes the lysosomal hydrolase glucocerebrosidase (GCase), are a common risk factor for the neurodegenerative movement disorder Parkinson's disease (PD). Consequently, therapeutic options targeting the GCase enzyme are in development. An important aspect of this development is determining the effect of potential modifying compounds on GCase activity, which can be complicated by the different methods and substrate probes that are commonly employed for this purpose. Methods: In this study, we employed the GCase substrate probe 5-(pentafluorobenzoylamino)fluorescein di-D-glucopyranoside (PFB-FDGlu) in combination with live cell imaging to measure GCase activity in situ in the lysosome. Results: The live cell assay was validated using the GCase inhibitor conduritol-B-epoxide and with GBA1 knockout neural cells and was then used to assess GCase activity in iPSC differentiated into neural stem cells and neurons that were obtained from idiopathic PD patients and PD patients with the LRRK2 G2019S and GBA N370S mutations, as well as controls (n = 4 per group). Heterogeneity in GCase activity was observed across all groups. However, a significant inverse correlation between GCase activity and levels of alpha-synuclein protein was observed. Discussion: The live cell imaging assay for GCase activity could be useful for further understanding the role of GCase in PD and screening potential modifying compounds in differentiated human cell models.

Poly-GA immunohistochemistry is a reliable tool for detecting C9orf72 hexanucleotide repeat expansions.

Poly-GA immunohistochemistry (A) on formalin fixed paraffin embedded cerebellum sections shows a similar distribution to p62 antibody (B) and reliably identifies neuronal cytoplasmic inclusions and neurites in cases with known C9orf72 repeat expansion. This is useful in the research setting where genetic testing has not been performed in life or suitable tissue is not avilable post-mortem.

A blood-based marker of mitochondrial DNA damage in Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.

Past antihypertensive medication use is associated with lower levels of small vessel disease and lower Aß plaque stage in the brains of older individuals.

AIMS: This study assesses the association of antihypertensive medication use on the severities of neuropathological cerebrovascular disease (CVD excluding lobar infarction) in older individuals. METHODS: Clinical and neuropathological data were retrieved for 149 autopsy cases >75 years old with or without CVD or Alzheimer's disease and no other neuropathological diagnoses. Clinical data included hypertension status, hypertension diagnosis, antihypertensive medication use, antihypertensive medication dose (where available) and clinical dementia rating (CDR). Neuropathological CVD severity was evaluated for differences with anti-hypertensive medication usage. RESULTS: Antihypertensive medication use was associated with less severe white matter small vessel disease (SVD, mainly perivascular dilatation and rarefaction), with a 5.6-14.4 times greater likelihood of less severe SVD if medicated. No significant relationship was detected between infarction (presence, type, number and size), lacunes or cerebral amyloid angiopathy and antihypertensive medication use. Only increased white matter rarefaction/oedema and not perivascular dilation was associated with Alzheimer's pathology, with a 4.3 times greater likelihood of reduced Aß progression through the brain if white matter rarefaction severity was none or mild. Antihypertensive medication use was associated with reduced Aß progression but only in those with moderate to severe white matter SVD. CONCLUSIONS: This histopathological study provides further evidence that antihypertensive medication use in older individuals is associated with white matter SVD and not with other CVD pathologies. This is mainly due to a reduction in white matter perivascular dilation and rarefaction/oedema. Even in those with moderate to severe white matter SVD, antihypertensive medication use reduced rarefaction and Aß propagation through the brain.

Survival in sporadic ALS is associated with lower p62 burden in the spinal cord.

The autophagy marker p62 appears as a consistent component of pathological aggregates in amyotrophic lateral sclerosis (ALS) and its modulation to facilitate protein degradation has been proposed as a potential therapeutic target. Importantly, recent studies have implicated diffuse phosphorylated TDP-43 inclusions that are immuno-negative for p62 in more rapid disease, highlighting the need for better understanding of p62 involvement in ALS pathogenesis. The present study set out to assess p62 pathology in the motor neurons of 31 patients with sporadic ALS that had either a short (<2 years) or longer (4-7 years) disease duration to determine its association with pTDP-43 pathology, motor neuron loss, and survival in sporadic disease. Our results identified significantly more cytoplasmic p62 aggregates in the spinal cord of patients with a shorter survival. Disease duration demonstrated a negative association with p62 burden and density of remaining motor neurons in the spinal cord, suggesting that survival in sporadic ALS is associated with the successful clearance of lower motor neurons with p62 aggregates. These findings implicate the autophagy pathway in ALS survival and provide support for further study of p62 as a potential prognostic biomarker in ALS.