Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.

Survey of service needs to embed genome sequencing for motor neuron disease in neurology in the English National Health Service.

All people with motor neuron disease (pwMND) in England are eligible for genome sequencing (GS), with panel-based testing. With the advent of genetically targeted MND treatments, and increasing demand for GS, it is important that clinicians have the knowledge and skills to support pwMND in making informed decisions around GS. We undertook an online survey of clinical genomic knowledge and genetic counselling skills in English clinicians who see pwMND. There were 245 respondents to the survey (160 neurology clinicians and 85 genetic clinicians). Neurology clinicians reported multiple, overlapping barriers to offering pwMND GS. Lack of time to discuss GS in clinic and lack of training in genetics were reported. Neurology clinicians scored significantly less well on self-rated genomic knowledge and genetic counselling skills than genetic clinicians. The majority of neurology clinicians reported that they do not have adequate educational or patient information resources to support GS discussions. We identify low levels of genomic knowledge and skills in the neurology workforce. This may impede access to GS and precision medicine for pwMND.

A mother and her daughter carrying a pathogenic expansion of the HTT gene with a phenotype encompassing motor neuron disease and Huntington's disease.

Recently, pathogenic expansions (range 40-64 CAG repeats) in the HTT gene have been found in patients diagnosed with pure frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). We report a mother with Huntington's disease (HD) associated with motor neuron disease (MND) signs and her daughter suffering from ALS with subtle signs of HD, both carrying a pathogenic allele of the HTT gene (i.e., >39 repeats). The co-occurrence of MND and chorea has been reported in previous cases. Subjects showing both ALS and HD signs and carrying HTT pathogenic expansions in two generations of the same kindred have never been reported so far. The study of the overlap of disease mechanisms at the cellular level between TDP-43 and Huntingtin is relevant in an era offering promising strategies of targeted treatments in neurodegenerative disorders.

Temporal course of cognitive and behavioural changes in motor neuron diseases.

BACKGROUND: Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes. METHODS: Participants with MND were recruited through the Phenotype-Genotype-Biomarker study. Every 3-6 months, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used to assess amyotrophic lateral sclerosis (ALS) specific (executive functioning, verbal fluency, language) and ALS non-specific (memory, visuospatial) functions. Informants reported on behaviour symptoms via semi-structured interview. RESULTS: Participants with neuropsychological data at ≥3 visits were included (n=237, mean age=59, 60% male), of which 18 (8%) were C9ORF72 positive. Baseline cognitive impairment was apparent in 18 (8%), typically in ALS specific domains, and associated with lower education, but not C9ORF72 status. Cognition, on average, remained stable over time, with two exceptions: (1) C9ORF72 carriers declined in all ECAS domains, (2) 8%-9% of participants with baseline cognitive impairment further declined, primarily in the ALS non-specific domain, which was associated with less education. Behavioural symptoms were uncommon. CONCLUSIONS: In this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72 status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations.

Comprehensive Analysis of a Japanese Pedigree with Biallelic ACAGG Expansions in RFC1 Manifesting Motor Neuronopathy with Painful Muscle Cramps.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive multisystem neurologic disorder caused by biallelic intronic repeats in RFC1. Although the phenotype of CANVAS has been expanding via diagnostic case accumulation, there are scant pedigree analyses to reveal disease penetrance, intergenerational fluctuations in repeat length, or clinical phenomena (including heterozygous carriers). We identified biallelic RFC1 ACAGG expansions of 1000 ~ repeats in three affected siblings having sensorimotor neuronopathy with spinocerebellar atrophy initially presenting with painful muscle cramps and paroxysmal dry cough. They exhibit almost homogeneous clinical and histopathological features, indicating motor neuronopathy. Over 10 years of follow-up, painful intractable muscle cramps ascended from legs to trunks and hands, followed by amyotrophy and subsequent leg pyramidal signs. The disease course combined with the electrophysical and imagery data suggest initial and prolonged hyperexcitability and the ensuing spinal motor neuron loss, which may progress from the lumbar to the rostral anterior horns and later expand to the corticospinal tract. Genetically, heterozygous ACAGG expansions of similar length were transmitted in unaffected family members of three successive generations, and some of them experienced muscle cramps. Leukocyte telomere length assays revealed comparatively shorter telomeres in affected individuals. This comprehensive pedigree analysis demonstrated a non-anticipating ACAGG transmission and high penetrance of manifestations with a biallelic state, especially motor neuronopathy in which muscle cramps serve as a prodromal and disease progress marker. CANVAS and RFC1 spectrum disorder should be considered when diagnosing lower dominant motor neuron disease, idiopathic muscle cramps, or neuromuscular hyperexcitability syndromes.

SOD1-Related Cerebellar Ataxia and Motor Neuron Disease: Cp Variant as Functional Modifier?

We describe a novel superoxide dismutase (SOD1) mutation-associated clinical phenotype of cerebellar ataxia and motor neuron disease with a variant in the ceruloplasmin (Cp) gene, which may have possibly contributed to a multi-factorial phenotype, supported by genetic and protein structure analyses.

Fluctuating salience in those living with genetic risk of motor neuron disease: A qualitative interview study.

BACKGROUND: Motor neuron disease (MND) (also known as amyotrophic lateral sclerosis) is a life-limiting neurodegenerative condition. In up to 20% of people with MND, a pathogenic variant associated with autosomal dominant inheritance can be identified. Children of people carrying a pathogenic variant have a 50% chance of inheriting this and a higher, although harder to predict, chance of developing the disease compared to the general adult population. This paper explores the experience of living with the genetic risk of MND. METHODS: We undertook a UK-based interview study with 35 individuals, including: 7 people living with genetically-mediated forms of MND; 24 asymptomatic relatives, the majority of whom had an increased risk of developing the disease; and 4 unrelated partners. RESULTS: We explore how individuals make sense of genetic risk, unpacking the interplay between genetic knowledge, personal perception, experiences of the disease in the family, age and life stage and the implications that living with risk has for different aspects of their lives. We balance an emphasis on the emotional and psychological impact described by participants, with a recognition that the salience of risk fluctuates over time. Furthermore, we highlight the diverse strategies and approaches people employ to live well in the face of uncertainty and the complex ways they engage with the possibility of developing symptoms in the future. Finally, we outline the need for open-ended, tailored support and information provision. CONCLUSIONS: Drawing on wider literature on genetic risk, we foreground how knowledge of MND risk can disrupt individuals' taken-for-granted assumptions on life and perceptions of the future, but also its contextuality, whereby its relevance becomes more prominent at critical junctures. This research has been used in the development of a public-facing resource on the healthtalk.org website. PATIENT OR PUBLIC CONTRIBUTION: People with experience of living with genetic risk were involved throughout the design and conduct of the study and advised on aspects including the topic guide, sampling and recruitment and the developing analysis. Two patient and public involvement contributors joined a formal advisory panel.

Antisense Oligonucleotides (ASOs) in Motor Neuron Diseases: A Road to Cure in Light and Shade.

Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to bind to specific regions of target mRNA. ASOs can modulate pre-mRNA splicing, increase levels of functional proteins, and decrease levels of toxic proteins. ASOs are being developed for the treatment of motor neuron diseases (MNDs), including spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA). The biggest success has been the ASO known as nusinersen, the first effective therapy for SMA, able to improve symptoms and slow disease progression. Another success is tofersen, an ASO designed to treat ALS patients with SOD1 gene mutations. Both ASOs have been approved by the FDA and EMA. On the other hand, ASO treatment in ALS patients with the C9orf72 gene mutation did not show any improvement in disease progression. The aim of this review is to provide an up-to-date overview of ASO research in MNDs, from preclinical studies to clinical trials and, where available, regulatory approval. We highlight the successes and failures, underline the strengths and limitations of the current ASO research, and suggest possible approaches that could lead to more effective treatments.

Importance of lipids for upper motor neuron health and disease.

Building evidence reveals the importance of maintaining lipid homeostasis for the health and function of neurons, and upper motor neurons (UMNs) are no exception. UMNs are critically important for the initiation and modulation of voluntary movement as they are responsible for conveying cerebral cortex' input to spinal cord targets. To maintain their unique cytoarchitecture with a prominent apical dendrite and a very long axon, UMNs require a stable cell membrane, a lipid bilayer. Lipids can act as building blocks for many biomolecules, and they also contribute to the production of energy. Therefore, UMNs require sustained control over the production, utilization and homeostasis of lipids. Perturbations of lipid homeostasis lead to UMN vulnerability and progressive degeneration in diseases such as hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). Here, we discuss the importance of lipids, especially for UMNs.

Increased surface P2X4 receptors by mutant SOD1 proteins contribute to ALS pathogenesis in SOD1-G93A mice.

Amyotrophic lateral sclerosis (ALS) is a fatal motoneuron (MN) disease characterized by protein misfolding and aggregation leading to cellular degeneration. So far neither biomarker, nor effective treatment has been found. ATP signaling and P2X4 receptors (P2X4) are upregulated in various neurodegenerative diseases. Here we show that several ALS-related misfolded proteins including mutants of SOD1 or TDP-43 lead to a significant increase in surface P2X4 receptor density and function in vitro. In addition, we demonstrate in the spinal the cord of SOD1-G93A (SOD1) mice that misfolded SOD1-G93A proteins directly interact with endocytic adaptor protein-2 (AP2); thus, acting as negative competitors for the interaction between AP2 and P2X4, impairing constitutive P2X4 endocytosis. The higher P2X4 surface density was particularly observed in peripheral macrophages of SOD1 mice before the onset and during the progression of ALS symptoms positioning P2X4 as a potential early biomarker for ALS. P2X4 expression was also upregulated in spinal microglia of SOD1 mice during ALS and affect microglial inflammatory responses. Importantly, we report using double transgenic SOD1 mice expressing internalization-defective P2X4mCherryIN knock-in gene or invalidated for the P2X4 gene that P2X4 is instrumental for motor symptoms, ALS progression and survival. This study highlights the role of P2X4 in the pathophysiology of ALS and thus its potential for the development of biomarkers and treatments. We also decipher the molecular mechanism by which misfolded proteins related to ALS impact P2X4 trafficking at early pathological stage in cells expressing-P2X4.

Facial onset sensory and motor neuronopathy (FOSMN syndrome): Cases series and systematic review.

OBJECTIVE: To provide new and comprehensive evidence for diagnosis and management of FOSMN syndrome. METHODS: We reviewed our database to identify patients with FOSMN syndrome. Online database including PubMed, EMBASE, and OVID were also searched for relevant cases. RESULTS: We identified a total of 71 cases, including 4 cases from our database and 67 ones from online searching. A predominance of male was observed [44 (62.0%)] with median onset age of 53 (range: 7-75) years old. The median (range) disease duration was 60 (3-552) months at the time of the visit. The initial symptoms could be sensory deficits in face (80.3%) or oral cavity (4.2%), bulbar paralysis (7.0%), dysosmia (1.4%), dysgeusia (4.2%), weakness or numbness of upper limbs (5.6%), or lower limbs (1.4%). Abnormal blink reflex was presented in 64 (90.1%) patients. CSF tests showed elevated protein level in 5 (7.0%) patients. Six (8.5%) patients had MND-related gene mutation. Five (7.0%) patients showed transient responsiveness to immunosuppressive therapy, then deteriorated relentlessly. Fourteen (19.7%) patients died, with an average survival time of around 4 years. Among them, five patients died of respiratory insufficiency. CONCLUSION: The age of onset, progress of disease course, and prognosis of FOSMN syndrome could be varied significantly. The prerequisites of diagnosis were progressive and asymmetric lower motor neuron dysfunction, with sensory dysfunction which usually showed in face at the onset. Immunosuppressive therapy could be tried in some patients with suspected inflammatory clues. In general, FOSMN syndrome tended to be motor neuron disease with sensory involvement.

Spectrum of SPTLC1-related disorders: a novel case of 'Ser331 syndrome' that expand the phenotype of hereditary sensory and autonomic neuropathy type 1A and motor neuron diseases.

We report a patient with early-onset hereditary sensory and autonomic neuropathy type 1A (HSAN-1A) who developed a distinct phenotype, with tongue fasciculation and atrophy, due to a mutation at serine 331 in the SPTLC1 gene. HSAN-1A manifestation causing tongue fasciculation and atrophy have been rarely found. Our report adds to the growing evidence of the existence of an overlap between hereditary neuropathy and motor neuron disease caused by pathogenic p.S331Y variant in SPTLC1 gene.

Genetic testing in motor neuron disease and frontotemporal dementia: a 5-year multicentre evaluation.

INTRODUCTION: Motor neuron disease (MND) and frontotemporal dementia (FTD) comprise a neurodegenerative disease spectrum. Genetic testing and counselling is complex in MND/FTD owing to incomplete penetrance, variable phenotype and variants of uncertain significance. Affected patients and unaffected relatives are commonly referred to clinical genetics to consider genetic testing. However, no consensus exists regarding how such genetic testing should best be undertaken and on which patients. OBJECTIVE: We sought to ascertain UK clinical genetics testing practice in MND/FTD referrals, with the aim of helping inform guideline development. METHODS: MND/FTD clinical genetics referrals comprising both affected patients and unaffected relatives between 2012 and 2016 were identified and a standardised proforma used to collate data from clinical records. RESULTS: 301 referrals (70 affected, 231 unaffected) were reviewed across 10 genetics centres. Previously identified familial variants were known in 107 cases and 58% subsequently underwent testing (8 of 8 diagnostic and 54 of 99 predictive). The median number of genetic counselling appointments was 2 for diagnostic and 4 for predictive testing. Importantly, application of current UK Genomic Test Directory eligibility criteria would not have resulted in detection of all pathogenic variants observed in this cohort. CONCLUSION: We propose pragmatic MND/FTD genetic testing guidelines based on appropriate genetic counselling.

Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration.

Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer's and Parkinson's diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing PCCA2, result in sphingolipid abnormalities and impaired cell growth that are corrected by treatment with myriocin, a sphingolipid synthesis inhibitor, suggesting that alterations in sphingolipid metabolism contribute to cell dysfunction and death. Here we tested this hypothesis in wobbler mice, a murine model with a homozygous partial loss-of-function mutation in Vps54 (GARP protein) that causes motor neuron disease. Cytotoxic sphingoid long-chain bases accumulated in embryonic fibroblasts and spinal cords from wobbler mice. Remarkably, chronic treatment of wobbler mice with myriocin markedly improved their wellness scores, grip strength, neuropathology, and survival. Proteomic analyses of wobbler fibroblasts revealed extensive missorting of lysosomal proteins, including sphingolipid catabolism enzymes, to the Golgi compartment, which may contribute to the sphingolipid abnormalities. Our findings establish that altered sphingolipid metabolism due to GARP mutations contributes to neurodegeneration and suggest that inhibiting sphingolipid synthesis might provide a useful strategy for treating these disorders.

[Amyotrophic lateral sclerosis-Motor neuron disease with a wide clinical and genetic spectrum]. / Amyotrophe Lateralsklerose ­ Motoneuronerkrankung mit großem klinischem und genetischem Spektrum.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease. Besides a timely diagnosis, precise knowledge of the clinical manifestations and differential diagnoses is essential. While most patients develop the disease at an older age, hereditary causes play a more frequent role in the juvenile forms. OBJECTIVE: What is the current state of ALS diagnostics, which new treatment options exist? MATERIAL AND METHOD: Literature search using Pubmed.gov. RESULTS: The main focus is on an individualized symptomatic treatment as no curative treatment approaches exist. However, new insights into the genetic and pathophysiological principles of the different forms of ALS open the way for future disease-modifying treatment options. CONCLUSION: In cases of a clinical suspicion of ALS molecular genetic diagnostics should be considered, particularly in juvenile and young adult patients, to exclude differential diagnoses and to enable patients access to new treatment approaches.

[Gene Therapies in Motor Neuron Diseases ALS and SMA]. / Gentherapien bei den Motoneuronerkrankungen ALS und SMA.

In the past, the diagnosis of motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and 5q-associated spinal muscular atrophy (SMA) meant powerlessness in the face of seemingly untreatable diseases with severe motor-functional limitations and sometimes fatal courses. Recent advances in an understanding of the genetic causalities of these diseases, combined with success in the development of targeted gene therapy strategies, spell hope for effective, innovative therapeutic approaches, pioneering the ability to treat neurodegenerative diseases. While gene therapies have been approved for SMA since a few years, gene therapy research in ALS is still in clinical trials with encouraging results. This article provides an overview of the genetic background of ALS and SMA known to date and gene therapy approaches to them with a focus on therapy candidates that are in clinical trials or have already gained market approval.

Altered action potential waveform and shorter axonal initial segment in hiPSC-derived motor neurons with mutations in VRK1.

We recently described new pathogenic variants in VRK1, in patients affected with distal Hereditary Motor Neuropathy associated with upper motor neurons signs. Specifically, we provided evidences that hiPSC-derived Motor Neurons (hiPSC-MN) from these patients display Cajal Bodies (CBs) disassembly and defects in neurite outgrowth and branching. We here focused on the Axonal Initial Segment (AIS) and the related firing properties of hiPSC-MNs from these patients. We found that the patient's Action Potential (AP) was smaller in amplitude, larger in duration, and displayed a more depolarized threshold while the firing patterns were not altered. These alterations were accompanied by a decrease in the AIS length measured in patients' hiPSC-MNs. These data indicate that mutations in VRK1 impact the AP waveform and the AIS organization in MNs and may ultimately lead to the related motor neuron disease.

The role of autophagy-lysosomal pathway in motor neuron diseases.

Motor neuron diseases (MNDs) include a broad group of diseases in which neurodegeneration mainly affects upper and/or lower motor neurons (MNs). Although the involvement of specific MNs, symptoms, age of onset, and progression differ in MNDs, the main pathogenic mechanism common to most MNDs is represented by proteostasis alteration and proteotoxicity. This pathomechanism may be directly related to mutations in genes encoding proteins involved in the protein quality control system, particularly the autophagy-lysosomal pathway (ALP). Alternatively, proteostasis alteration can be caused by aberrant proteins that tend to misfold and to aggregate, two related processes that, over time, cannot be properly handled by the ALP. Here, we summarize the main ALP features, focusing on different routes utilized to deliver substrates to the lysosome and how the various ALP pathways intersect with the intracellular trafficking of membranes and vesicles. Next, we provide an overview of the mutated genes that have been found associated with MNDs, how these gene products are involved in different steps of ALP and related processes. Finally, we discuss how autophagy can be considered a valid therapeutic target for MNDs treatment focusing on traditional autophagy modulators and on emerging approaches to overcome their limitations.

BiP inactivation due to loss of the deAMPylation function of FICD causes a motor neuron disease.

PURPOSE: The chaperone protein BiP is the master regulator of the unfolded protein response in the endoplasmic reticulum. BiP chaperone activity is regulated by the post-translational modification AMPylation, exclusively provided by FICD. We investigated whether FICD variants identified in patients with motor neuron disease could interfere with BiP activity regulation. METHODS: Exome sequencing was performed to identify causative pathogenic variants associated with motor neuron diseases. Functional studies were conducted on fibroblasts from patients to explore the molecular mechanism of the disease. RESULTS: We identified biallelic variants in FICD causing a neurodegenerative disease of upper and lower motor neurons. Affected individuals harbor a specific missense variant, Arg374His, positioned in the catalytic motif of the enzyme and important for adenosine triphosphate binding. The mutated residue abolishes intramolecular interaction with the regulatory residue Glu234, essential to inhibit AMPylation and to promote de-AMPylation by FICD. Consequently, fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP. CONCLUSION: Loss of BiP chaperone activity in patients likely results in a chronic impairment of the protein quality control system in the endoplasmic reticulum. These findings will guide the development of therapeutic strategies for motoneuron and related diseases linked to proteotoxic stress.

1,2-Dehydropyrrolizidine Alkaloids: Their Potential as a Dietary Cause of Sporadic Motor Neuron Diseases.

Sporadic motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), can be caused by spontaneous genetic mutations. However, many sporadic cases of ALS and other debilitating neurodegenerative diseases (NDDs) are believed to be caused by environmental factors, subject to considerable debate and requiring intensive research. A common pathology associated with MND development involves progressive mitochondrial dysfunction and oxidative stress in motor neurons and glial cells of the central nervous system (CNS), leading to apoptosis. Consequent degeneration of skeletal and respiratory muscle cells can lead to death from respiratory failure. A significant number of MND cases present with cancers and liver and lung pathology. This Perspective explores the possibility that MNDs could be caused by intermittent, low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids (1,2-dehydroPAs) that are increasingly recognized as contaminants of many foods consumed throughout the world. Nontoxic, per se, 1,2-dehydroPAs are metabolized, by particular cytochrome P450 (CYP450) isoforms, to 6,7-dihydropyrrolizines that react with nucleophilic groups (-NH, -SH, -OH) on DNA, proteins, and other vital biochemicals, such as glutathione. Many factors, including aging, gender, smoking, and alcohol consumption, influence CYP450 isoform activity in a range of tissues, including glial cells and neurons of the CNS. Activation of 1,2-dehydroPAs in CNS cells can be expected to cause gene mutations and oxidative stress, potentially leading to the development of MNDs and other NDDs. While relatively high dietary exposure to 1,2-dehydroPAs causes hepatic sinusoidal obstruction syndrome, pulmonary venoocclusive disease, neurotoxicity, and diverse cancers, this Perspective suggests that, at current intermittent, low levels of dietary exposure, neurotoxicity could become the primary pathology that develops over time in susceptible individuals, along with a tendency for some of them to also display liver and lung pathology and diverse cancers co-occurring with some MND/NDD cases. Targeted research is recommended to investigate this proposal.