The death of motor neurons is one of the main pathological hallmarks of ALS, and the disease often starts at a small muscle and propagates to other muscles. Muscle denervation appears during the early stages of ALS pathogenesis, and it can be observed by electromyography. This denervation is the result of motor neuron degeneration, probably with a series of pathogenetic factors converging to create a toxic microenvironment. Yet some scientists are not so sure motor neurons die, they think they might simply enter a sort of frozen state to mitigate a stressful situation. This article belongs to a tiny circle as it tells that it's possible to partially reverse the disease and it presents a good mechanism of action, whereas most articles are extremely vague about ALS etiology.

Indeed, it is known that plastic events, such as synaptic plasticity, axonal sprouting, and morphological changes, within the spared motor neuron population can be responsible for compensatory adaptation after the loss of function caused by the neurotoxic removal of a spinal motor neuron subset. These spontaneous plastic changes are known to take place also in ALS models, but their ability to sustain motor function is transient and incapable of counteracting disease progression. Therefore, a therapeutic approach to manage the disease (but not cure it) should be capable of both improving plastic changes and supporting neuroprotection to slow down motor neuron degeneration.

In the authors' view, the use of a simplified in vivo model of motor neuron degeneration would help in the step-by-step dissection of ALS pathogenesis.

The authors used a specific toxin, CTB-Sap, to selectively kill certain motor neurons in the spinal cord by injecting a compound into muscles. CTB-Sap is a compound made by combining cholera toxin-B (which binds to neurons) with saporin (a toxin that kills cells). When injected into muscles, this compound is taken up by the synapses of the lower motor neurons that control those muscles. After the motor neurons take up CTB-Sap, it travels backward (retrograde) along the neuron to the cell body in the spinal cord. The saporin then kills the neuron.

It is a valuable tool for studying compensatory plastic changes, including synaptic plasticity, axonal sprouting, and other morphological and functional adaptations. The authors think that in ALS animal models, when motor neuron degeneration occurs progressively, the remaining cells may try to compensate for the motor deficits. It's when the progressive loss of motor neurons exceeds the compensatory capacity of the surviving cells, that the first signs of the disease appear.

Despite intensive research, it remains poorly understood why motor neurons are specifically targeted in ALS. As motor neurons and the skeletal muscle they control consume enormous amounts of energy, mitochondria use aerobic respiration to generate adenosine triphosphate (ATP), which is used throughout the cell as a source of chemical energy. Mitochondria are sort of microbes symbiotes of cells and like other microbes, they can divide or even fusion depending on the needs of the host cell. Several genes encode fission and fusion proteins: MFN1, MFN2, OPA1, DRP1 (Dynamin-Related Protein 1): This protein is essential for mitochondrial fission. MFF (Mitochondrial Fission Factor).

Several publications have associated abnormal mitochondrial dynamics with excessive mitochondrial fission predominantly mediated by the hyperactivation of the dynamin-related protein 1 (DRP1). This cytosolic GTPase, is recruited to the outer mitochondrial membrane, where it assembles into a ring-like structure around the mitochondria, causing constriction and subsequent division. High levels of DRP1 trigger mitochondrial damage which causes insufficient ATP production, indeed fission and fusion events consume a lot of energy.

To prove that an abnormal fission (division) of mitochondria causes a motor neuron disease, it's necessary to show that in such a case inhibiting mitochondria restores some muscle function. Previous studies have proven that spontaneous motor recovery is possible sometimes after toxin administration. Yet these kinds of plastic changes are not enough to counteract the functional effects of the progressive motoneuron degeneration. The authors wanted to use a mitochondrial division inhibitor to prove that it's the mitochondrial division that is a cause of motor neuron disease.

Mdivi-1, a cell-permeable quinazolinone, is an inhibitor of DRP1, so it is capable of inhibiting the fission process by directly decreasing the GTPase enzymatic activity of DRP1. This results in neuroprotection in animal models of Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In an attempt to determine the therapeutic impact of Mdivi-1 after motor neuron loss, the scientists used the already established mouse CTB-Sap model which is characterized by up-regulation of DRP1, together with increased mitochondrial fission. They wanted to investigate if the administration of Mdivi-1 could be neuroprotective on damaged or stressed motor neurons, and whether it may promote spinal cord (SC) plasticity.

The drug was administered to the mouse model, a localized removal of spinal motor neurons was induced by injection of CTB-Sap in the calf muscle and it moved from the muscle to the lower motor neuron retrogradly. This simple model of selective motor neuron depletion allows the scientists to focus on the functional and molecular mechanisms of neuroplastic changes upon motor neuron removal.

As expected, a few days after CTB-Sap injection in the right calf muscle, all animals started to display an evident decline in the motor activity of the right back leg that reached a maximum during the first two weeks after the lesion. The observation of limb motion during free exploration of an open field revealed frequent curling of toes, loss of support, and foot-dragging. Motor deficits were accompanied (and caused by) the partial loss of motor neurons innervating the calf muscle and located in the lumbar region of the spinal cord, and the muscle denervation is confirmed by the presence of spontaneous electromyography activity in anesthetized mice.

This functional decline was followed by a spontaneous partial recovery during the experimental period and, as the scientists hypothesized, Mdivi-1 treatment was capable of reducing the early back leg deficit despite the presence of a slightly toxic effect of the drug, as demonstrated by the loss of body weight. The grid walk test confirmed the beneficial effects of treatment in the preservation of motor performance, although a spontaneous recovery (but slower) was seen also in untreated animals.

The beneficial effects of the Mdivi-1 drug were probably limited to some aspects of the motor activity, such as motor coordination, as suggested by clinical scoring and grid walk test results, whereas gait analysis was not able to efficiently reveal the effects of treatment.

However, the observed effects of treatment on motor coordination cannot be explained only by its action on the affected muscle, and a detailed mechanistic study of mitochondrial dynamics should include, for instance, the spinal cord, cerebellum, motor cortex, basal ganglia, and also some general aspects of metabolism.

The phenomena of motor neurons attempting to form new connections and adapt to new conditions in the tissue microenvironment in response to tissue damage or neuronal loss have been well documented in the literature. This process may increase in soma size and dendritic complexity of surviving motor neurons, which might be attributable to their active hunt for new synapses and increased synaptic efficacy. Therefore, the observed increase in motor neurons’ size only in Mdivi-1-treated mice may be proof of neuronal adaptation, promoted by the known activity of the drug onto mitochondrial dynamics, and likely involving motor neuron itself but also the whole sensorimotor spinal cord circuitry and supraspinal pathways.

The results of the present study have confirmed that the CTB-Sap model is a valid tool for research in motor neuron diseases, proving that compensatory plastic changes may take place after the removal of a spinal motor neuron subset. Moreover, it seems likely that treating this animal model with a drug known to inhibit mitochondrial fission may increase this intrinsic plastic capability and protect motor neurons from degeneration.

Some people advocate for Parkinson's patients to consume mannitol. Many individuals affected by the disease began consuming daily oral mannitol. Self-reported outcomes included an improved sense of smell, a reduction in the dose of PD medications, and general improvement in well-being. A clinical trial was done at Hadassah Medical Center in Israel by David Arkadir and colleagues.

The lobby group CliniCrowd was probably instrumental in this decision.

The study lasted 36 weeks and included four dose escalations of oral mannitol (manufacturer Roquette, France) or dextrose as a placebo from 2.5 g to a maximal dose of 18 g per day. The COVID-19 pandemic in 2020 dramatically slowed the recruitment rate in the 3rd year of the clinical trial and led to the decision to earlier trial termination. They did not observe a clear reduction in Parkinson's symptoms. It is possible that a longer exposure would enable clinically to demonstrate disease modification. Anyway, such a high dose of mannitol is not without innuendoes, mannitol is hypertonic, it forces water to be excreted from cells. Yet the mechanism by which mannitol reduces α-synuclein accumulation in PD models was still unknown.

In 2022 another study showed that glycation agents (sugars) can ameliorate α-synuclein folding. Glycation is increased in the brains of hyperglycemic patients. Alpha-synuclein (αSN), a central player in the etiology of Parkinson’s disease, can be glycated so reducing αSN fibril formation. The best glycating agents were unfortunately toxic, but one agent was mildly efficacious while not toxic: Mannose.

Mannitol, while usually derived from fructose, can also be derived from a mannose by reduction. In the human body, mannose residues are used to assemble N-glycans by adding them to a dolichol phosphate (Dol-P) core in the Endoplasmic Reticulum (ER) of cells.

There's a growing body of research suggesting a connection between abnormal N-glycans and neurodegenerative diseases like Alzheimer's and Parkinson's. N-glycans are sugar chains attached to proteins in a specific way, and changes in their structure or abundance seem to play a role in these diseases. This means the sugar chains are either attached differently, have different structures, or are present in abnormal amounts.

N-glycans can influence how proteins fold, interact with other molecules, and get transported within cells. In a recent publication, scientists analyzed neurons in iPSC midbrain cultures derived from patients with Parkinson's disease and they discovered the disruption of a metabolic pathway, the hexosamine pathway. The hexosamine pathway is important for protein synthesis, transport, and folding in the neuron's endoplasmic reticulum. The hexosamine pathway produces N-linked glycans, essential molecules that support protein folding in the endoplasmic reticulum.

The hexosamine pathway (a biological pathway is the way a molecule is created from components) uses glucose and uridine-5’-triphosphate to generate N-linked glycans for protein folding in the endoplasmic reticulum. In Parkinson's midbrain cultures, however, this N-glycosylation process was interrupted, causing protein misfolding and accumulation of α-synuclein.

Accelerating glucose flux through the hexosamine pathway rescued hydrolase function and reduced pathological α-synuclein.

So as a non-scientist, I can conclude this post by saying that there is some rationality in using mannitol in Parkinson's disease, while it might not be the silver bullet people are waiting for.

This post is about a new article about the means to rejuvenate organisms, which indeed has important implications for neurodegenerative diseases.

Telomerase restores short bits of DNA known as telomeres, which are otherwise shortened after repeated division of a cell via mitosis. In normal circumstances, where telomerase is absent, a cell can't divide in daughters indefinitely. When it reaches the Hayflick limit the cells become senescent and cell division stops. Telomerase allows each daughter cell to replace the lost bit of DNA, allowing the cell line to divide without ever reaching the limit. This same unbounded growth is a feature of cancerous growth. Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a subunit of the enzyme telomerase. TERT inhibition has been linked directly or indirectly to all hallmarks of aging, but TERT expression is linked to the development of many cancers. Unfortunately, TERT gene is epigenetically repressed with the onset of aging markers in all tissues.

Researchers at the University of Texas MD Anderson Cancer Center have shown they can therapeutically restore "youthful" levels of TERT and this can significantly reduce the signs and symptoms of aging in preclinical models (primary human cells and naturally aged mice).

Maintenance of TERT levels in aged lab models reduced cellular senescence and tissue inflammation, spurred new neuron formation with improved memory, and enhanced neuromuscular function, which increased strength and coordination.

In the brain, scientists report that a new therapy (TAC) alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. This is probably too beautiful to be entirely true. Enhancing TERT expression notoriously promotes cancer and some cancer drugs downregulate TERT transcription, inhibiting telomerase activity and TERT expression.

To find a suitable compound, the authors used a high-throughput screen of over 650,000 compounds. TAC restores TERT levels to promote telomere maintenance and reprogram gene expression.

The usual suspects enhance TERT levels: Physical activity, good diet, and resveratrol.

It can also be done with a genetic therapy: Scientists insert a specific DNA sequence into a safe and predictable location on the genome to insert new genes. The new DNA fragment includes, for example, a "loxP-flanked stop cassette." This cassette acts like a switch that can be turned on or off. Under the control of an enzyme, for example, the "Cre recombinase" the "loxP" sites in the inserted DNA remove the stop cassette, allowing the TERT gene to be expressed in the targeted cells.

If these findings are confirmed in clinical studies, there may be major therapeutic implications for age-related diseases such as Alzheimer's, Parkinson's, heart disease and cancer.

In 2019 I wrote a book about ALS research that was subtitled "From stopping the disease to restoring the motor function". Several chapters were dedicated to future techniques to repair neurons or even replace them. Few research has been published on the later topic since 2019. Scientific publications of that time are now more or less considered as dubious if not fraudulent. Anyway there is the problem of replacement in vivo which is entirely unsolved. More practical is the notion of repairing neurons. It is based on the remark that motor neurons may not die in ALS, but somehow becomes non-functional. There are case studies of people with ALS having gain strength and functionnality as we recently reported, obviously for those people at least motor neurons didn't die. A possibility is that the cellular stress response is one cause of ALS, neurons under cellular stress response become non-functional, they stop protein production. Cellular stress response normally do not last very long or the cell die. The stressing events might be of diverse origin.

An obvious way to help a cell to get out of cellular stress response is to provide it with energy and growth factors. Several drugs based on growth factors had been proposed and tested (Brian Kaspar 2003, Hwang, Kim 2009), yet this does not fit well with the current scientific mindset which is oriented molecular biology, and BrainStorm's Nurown clinical trial failed which does not bode well for this line of research.

A new work shows that both in C57BL mouse and human bone marrow neutrophils, when polarized with a combination of recombinant interleukin-4 (IL-4) and granulocyte colony-stimulating factor (G-CSF), upregulate alternative activation markers and produce an array of growth factors, thereby gaining the capacity to promote neurite outgrowth. The most interesting effect was that it triggered substantial axon regeneration within the optic nerve and spinal cord after eight weeks.

The experiments in the retina involve intraocular injection of the neutrophils while experiments on the Dorsal root ganglion involve injections into the sciatic nerve. While the retinal experiments suggest that the neutrophils act on neuronal cell bodies (or their associated glia), the Dorsal root ganglion experiments indicate that they act on axons (or their associated glia).

Yet no functional recovery was verified as it would take many months, so we don't know it this work is useful for (mice) patients.

The possible therapeutic use of these neutrophils would be administering them in response to specific neural damage. The authors have speculated that administering neutrophil cell therapy directly at sites of CNS injury (using surgical approaches) could be a viable option.

Yet Brainstorm's Nurown failure is still in all minds.

In February, a proposal was made to diagnose Parkinson's disease based on the presence of α-synuclein accumulation, even in the absence of specific clinical symptoms. This proposal follows a similar trend observed in other neurodegenerative diseases. Clinically, this approach is somewhat controversial as it would label asymptomatic individuals as diseased. Furthermore, it raises questions about why individuals in good health would seek medical consultation.

This follows a similar trend in other neurodegenerative diseases. This initiative may be driven by the pharmaceutical industry's frustration over unsuccessful clinical trials. By using molecular criteria, clinical trials could achieve higher success rates, despite the persistence of clinical symptoms. This strategy is already evident in the Alzheimer's field, where several drugs have been approved without significantly alleviating symptoms.

This reflects a situation with disease animal models which are successfully cured by many proposed therapies but when those therapies are applied to humans they fail.

The proposal has not been universally welcomed but is likely to gain approval from regulatory bodies due to pressure from patient associations and the pharmaceutical industry to demonstrate progress.

Here is a small list of readers' reactions and answers by authors:

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00211-4/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00212-6/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00213-8/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00214-X/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00215-1/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00217-5/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00222-9/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00225-4/fulltext

https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00233-3/fulltext

From a political and economic perspective, this approach is problematic. It would lead to the treatment of healthy individuals in an already overburdened healthcare system. Additionally, these treatments are expected to be very costly while being ineffective on clinical symptoms.

We went too far into a mechanical and technological vision of medicine led by molecular biology.

Progranulin haploinsufficiency (PGRN) is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Haploinsufficiency means that the produced protein is in a form that is unable to fill its biological roles. We are discussing a new article on this subject because potentially this therapy could also be applied to ALS. Several therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of therapeutic approaches aimed at alleviating pathologies associated with FTLD could be their ineffective diffusion across the blood-brain barrier.

A fairly common strategy is to develop an adeno-associated virus (AAV) targeting the liver to achieve sustained peripheral expression capable of entering the brain. This was experimented in two mouse models of FTLD-GRN, namely Grn knockout and GrnxTmem106b double knockout mice.

This is what a drug (DNL593) from the company Denali Therapeutics does. It is administered intravenously, the viruses attach to the liver, the cells of which they exploit to generate the PGRN protein fused to a segment of antibodies that binds to the transferrin receptor, thereby facilitating transcytosis of transfer across the BBB.

Potential issues include short half-life, potential association with autoimmunity], risk of PGRN overexpression in the periphery and potential off-target effects, BBB permeability, and the possibility that the fusion protein may affect PGRN processing in the lysosome.

This therapeutic strategy, however, avoids the potential safety and biodistribution issues of AAV administered directly into the CNS while maintaining a level of PGRN in the brain after a single dose.

PGRN treatment reduced several pathologies commonly associated with FTLD-GRN in mice models of frontotemporal lobar degeneration, including severe deficits in motor function, aberrant TDP43 protein solubility and phosphorylation, and dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain.

Although AAV-type gene treatments are often associated with disastrous side effects such as hepatotoxicity, here a priori the mice did not suffer from side effects detectable by scientists.

The translatability of these results was confirmed in human induced pluripotent stem cells (hiPSCs). As was the case in mice, aberrant TDP43 levels, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with an exogenous TfR-binding protein transport vehicle fused to PGRN (necessarily different from the therapy administered to mice).

These studies suggest that peripherally administered brain-penetrating PGRN replacement strategies can ameliorate relevant FTD GRN phenotypes (there are other FTDs phenotypes that it can't ameliorate), including TDP-43 pathology, neurodegeneration, and behavioral deficits.

It should be noted that most of the authors are employees of the Denali company, so this fact must be taken into account when assessing the results. Another aspect is that several clinical trials are launched for the use of progranulin during FTD, we could perhaps see progress within a few years.

It's well known that reduced exposure to sunlight, during winter months, is associated with depression. The skin, upon UV exposure, produces various cytokines and other signaling molecules that can affect brain function. For instance, it can increase the production of serotonin, a neurotransmitter that regulates mood, appetite, and sleep. In a recent article UV exposure is associated (in mice) with deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Ironically, previous studies show that moderate UV exposure can increase blood urocanic acid levels and enhance learning and memory in the mouse brain via the glutamate biosynthetic pathway. So as usual in biology, there is no single, linear effect of UV exposure.

Dopamine is instrumental in various brain functions and is commonly linked to feelings of pleasure, reward, motivation, and memory. Sustaining a balanced and regulated level of dopamine signaling in the brain is essential since excessive or dysregulated dopamine signaling can harm mental and physical health. Lack of dopamine production in substancia nigra is believed to be causative of Parkinson's disease.

The article discussed today is a small (tiny?) study on 17 mice (9 control and 8 intervention's arm) in Korea. These naked mice allow easy experiments on the skin, application of topical agents, and exposure to UV. To investigate the effects of UV irradiation on hippocampal memory and neurogenesis, mouse skin was irradiated with UV for 6 weeks. After 6 weeks of UV irradiation, the mice underwent behavioral tests. Photoaged mice exhibit impaired cognitive function and neurogenesis.

The scientists analyzed 28 neuropeptides in mouse serum to elucidate the neurotransmitter-mediated mechanisms underlying these skin–brain interactions. Among these neuropeptides, dopamine was the most significantly upregulated. The dopamine level was ~130–145% greater in the serum of UV-irradiated mice than in that of sham-irradiated mice.

The authors measured dopamine levels in the skin and adrenal glands as serum dopamine levels are influenced by the sympathetic nervous system. Dopamine levels in the skin and adrenal glands were significantly greater in UV-irradiated mice than in control mice. In response to UV exposure, no significant changes in dopamine levels were detected in the ventral tegmental area (VTA), substantia nigra (SN), or hippocampus (HPC). However, dopamine levels in the prefrontal cortex (PFC) and hypothalamus (HT) significantly increased.

So unfortunately, it seems UV irradiation would not be useful for patients with Parkinson's disease, as no significant changes in dopamine levels were detected in the ventral tegmental area (VTA), substantia nigra. Yet these mice were exposed to high levels of UV, maybe with moderate levels the effect could be beneficial?

Dopamine levels and cognitive function exhibit an inverted U-shaped relationship, suggesting that cognitive performance can be reduced with either deficient or excessive dopamine. In contrast, peak cognitive function is associated with an optimal dopamine level. Insufficient dopamine can lead to difficulty maintaining attention, reduced motivation, and impaired working memory.

Conversely, excessive dopamine can impair cognitive function, inducing challenges in maintaining a stable focus, as noted in conditions such as schizophrenia, where dopamine pathways are hyperactive.

In conclusion, this is a well-done tiny study that may or may not tell something about the human response to high doses of UV. It might be worth investigating if UV exposure might be beneficial in Parkinson's disease.

Adult-onset diabetes is a known risk factor for cognitive impairment and dementia, yet the study of diabetes in young people has been neglected until now.

The average age of onset of diabetes in adults is ~46 years, and roughly thirty years later neurodegenerative diseases may appear. People with early-onset diabetes when they reach the age of 46 years, have lived with their disease for at least 30 years. It is therefore possible that early-onset diabetes leads to early-onset dementia.

A recent prospective population-based cohort in the United Kingdom did find that a younger age at the onset of diabetes corresponded to a younger age at the onset of dementia, but this study did not specifically look at people with early diabetes. A new study on this subject indicates that people with early-onset diabetes are at significant risk of prematurely developing cognitive impairment and dementia with possible neuropathology. This study aimed to explore neurodegenerative disease biomarkers in cohort-derived biomarker banks as changes in key plasma biomarkers between the time of diabetes diagnosis and early adulthood have been correlated with worsening cognitive function in young adults with early-onset diabetes.

Participants with youth-onset diabetes (age of onset less than 20 years) were found in the SEARCH for Diabetes in Youth study, a multicenter population-based registry and cohort. A randomly selected subset of 50 SEARCH participants (n=25 type 1 diabetics, n=25 type 2 diabetics) was identified for inclusion in the plasma biomarker analysis.

Among SEARCH participants eligible for plasma biomarker analyses, the authors recruited and enrolled a subset of the Colorado SEARCH clinic site to complete positron emission tomography (PET) imaging to measure plasma accumulation amyloid and tau density in brain regions susceptible to Alzheimer's disease.

For their study of plasma biomarkers of neurodegeneration, scientists identified age-matched controls without diabetes from two cohorts with plasma samples stored to include adolescent controls from the Exploring Perinatal Study Outcomes in Children (EPOCH) (n = 25) and young adult controls from the CROCODILE (Control of Renal Oxygen Consumption, Mitochondrial Dysfunction and Insulin Resistance) study (n = 21).

The authors also recruited and enrolled a group of young adult controls from the University of Colorado Anschutz Medical Campus to complete PET imaging for amyloid density and tau in brain regions susceptible to Alzheimer's disease.

By studying these two types of biomarkers (plasma and molecular imaging), scientists found evidence of potentially greater neuropathology of neurodegenerative diseases in young adults with early-onset diabetes, where plasma pTau181 was significantly higher and Aβ40 and Aβ42 were significantly lower, compared to controls, and over time from diabetes diagnosis from adolescence to young adulthood.

Furthermore, changes in key plasma biomarkers of neurodegeneration from diabetes diagnosis to early adulthood have been correlated with worsening cognitive function in young adults with early-onset diabetes. These preliminary data suggest the possibility of an early risk trajectory for Alzheimer's disease among individuals diagnosed with diabetes during childhood or adolescence.

It is important to emphasize that the participants with youth-onset diabetes had lower plasma Aβ42 and Aβ40 concentrations than age-matched controls both in adolescence and early adulthood, suggesting amyloid dysregulation potentially early and sustained in diabetes beginning in young people. Lower levels of Aβ40, Aβ42 and their ratio, especially in plasma and cerebrospinal fluid, correspond to monomer sequestration and amyloid plaque formation. Overall, the lower plasma concentrations of Aβ42 and Aβ40 in their sample suggest the development of Alzheimer's disease neuropathology, but could also indicate disrupted neurodevelopment in those with early-onset diabetes.

NfL was not different from controls in adolescence, but was higher on average in the group of young adults with youth-onset diabetes, compared to young adult controls. These results are consistent with other larger studies in adults with diabetes. However, the scientists are cautious in interpreting their NfL results, given that NfL is a non-specific marker of neuronal damage and could also indicate involvement of peripheral neuropathy in people with diabetes. diabetes

The moral integrity of the authors of this study is reflected in the number of limitations highlighted by the authors. Too often, scientists (and their university's public relations department) make overblown, ridiculous, and deliberately misleading claims.

• The young age of their sample limits confounding by age, such that changes in plasma biomarkers are more likely to be attributed to diabetes pathophysiology and not typical aging-related processes.

• Their age-matched control groups were sampled from different cohorts. Thus, scientists cannot interpret biomarker differences between adolescent controls and young adult controls as a typical developmental change in these biomarkers. It should be noted that the shelf life of plasma samples from each group differed, which imposed yet another limitation on their study, with diabetes samples appearing in young people having on average a longer shelf life than control samples. .

Longer storage duration could impact the observed protein concentrations of the measured plasma biomarkers. However, if protein levels were differentially impacted between groups given variability in storage duration, we might expect to see lower concentrations in the youth diabetes group compared to control groups for all proteins measured. This was not the case in their study.

• The scientists did not have APOE4 status among the subjects of their study.

• The SEARCH study did not measure cognitive function at the initial visit so scientists could not study cognitive changes over time in relation to changing plasma biomarker levels.

• Scientists do not have corresponding biomarkers measured in the CSF.

• The sample of young adults with early-onset diabetes who participated in the PET imaging study was small.

In conclusion, although neurodegenerative diseases are conceptualized as a disease of the elderly, increasing evidence suggests that factors linked to early life may have an impact on risk trajectories.

Such life-span course disease models will contribute to a better understanding of how currently used neurodegeneartion biomarkers evolve during critical periods of development across the lifespan, and how they can be used to predict the risk of neurodegenerative diseases early onset and cognitive impairment in high-risk clinical populations such as early-onset diabetes.