OUR SCIENTIFIC
WEBINAR SERIES

AGING, CALORIE RESTRICTION, AND THE DISEASES OF AGING

The promise of calorie-restriction mimetics.

THE CALORIE RESTRICTION RESPONSE AND PHYSIOLOGY

The synergism of lifestyle change and calorie restriction mimetics

In Part II, we dive into the Alice-in-Wonderland world of cell signals and the (growing) complexity of how cells regulate and organize a bevy of responses to environmental signals – this is clearly part of evolutionary adaptation to shifting environs. We focus specifically on the calorie restriction (CR) response, which is conserved across phylogeny, and on substances that may at least partially mimic CR, termed CR mimetics. To understand these issues better, we need to review the still young and emerging science of mTOR, and the networks around it, and how AMPK, surtuins, other transcription factors and signals create a catabolic cell signaling space counterposed to the fundamental vectors of mTOR, with long term and major health benefits. Harsh blockade of mTOR may be very bad for us, but long term disinhibition – as in obesity, DMII, CAD, CA, and neurodegenerative disorders (most age-related disease) – looks very bad also. Tonic or pulsatile restraint on mTOR with some permission for growth signals (critical to tissue repair/maintenance and decent neuroplasticity) but with concomitant upregulation of autophagy (cellular ‘trash disposal’) and strong dampening of ‘inflammaging’ appears a difficult but highly desirable ‘sweet spot’ – once again the Greeks were prescient in their advocacy for moderation in all things. We look at Adiponectin as an emerging and fairly recently confirmed critical player in this CR catabolic process, with interactions with AMPK and several PPARs, and how Osmotin may offer critical avenues for agonist effects on AdPN receptor families. Many questions remain, and much scientific and technical opportunity lies ahead.

ALZHEIMER'S DISEASE

Challenges to the amyloid hypothesis from a complex disease of aging.

In this introductory review, we will cover the history of misconceptions and corrective revisions about what Alzheimer's disease might be, the substantial changes in how it's diagnosed over the last three decades, and its pathognomonic histopathology and biomarkers, including how various types of functional neuroimaging have significantly expanded our biomarker toolkit but also the critical promise of and need for pathognomonic serum biomarkers which might finally allow widespread screening of elderly cohorts at elevated risk. Diagnosis by biomarkers is slowly but surely taking over the diagnostic process, displacing, or at least complementing, a traditional emphasis on cognitive impairment and its phenotypes. Early diagnosis however is still unusual, with most patients still diagnosed at a mild to moderate dementia stage.

We will discuss those cognitive phenotypes, particularly the classic amnestic phenotype but others as well, including the sequential staging of cognitive impairment and types of impairment through the disease trajectory, and how cognitive impairment indexes synaptic loss and regionally specific tangling and its progression, and while tangling and synaptic loss are not synonymous they are hugely regionally overlapping. The concept of a complex and very long-term (30-40 year) disease trajectory, with much of the disease under the waterline so to speak (meaning preclinical and asymptomatic stages which can be as long as two decades) will set the table for the subsequent discussions of neurodegenerative mechanism(s). We will also explore the possibility of a ‘pre-preclinical stage’, not currently described in the literature, but characterized by virtually invisible intracellular accumulation of amyloid, in the context of failing autophagy. However despite considerable progress with biomarkers and the availability of good screening instruments to establish cognitive phenotypes, widespread elderly cohort screening is largely not recommend or even actively discouraged by opinion leaders. We will examine this troubling Catch-22 and the assumptions behind it in some detail.

Widespread assumptions that “nothing can be done about Alzheimer's disease” encourage both diagnostic and clinical passivity. This is deeply regretful, given evidence that in the context of early diagnosis, we can at least intercept and mitigate several known accelerants, including a number that are classically iatrogenic emerging from clinical ignorance. Unfortunately, widespread ignorance about Alzheimer's disease and the special clinical vulnerabilities of patients in cognitive decline is sadly pervasive within many clinical professions in the healthcare system, including even in psychiatry, neurology and neuropsychology.

WHAT IS DRIVING ALZHEIMER'S DISEASE?

Neurodegeneration - the amyloid hypotheses. a primary failure of proteostasis.

In part II, we will dive headlong into the molecular and cellular complexities of neurodegeneration, examining first the traditional villain of the story, beta amyloid, in terms of its canonical processing pathways, and the evidence for physiological roles for beta-amyloid, as well as products from the competing pro-plasticity alpha pathway.

We will examine the problem of autophagy in considerable detail, as the neglected underbelly of the amyloidosis storyline. Both familial AD mutations (presenilin 1/2) and APOE4 disrupt autophagy. Amyloid itself may also present intrinsically difficult challenges for the autophagy systems, suggesting its unique status as ‘agent provocateur’ in the complex loops and sequences driving neurodegeneration. Amyloid oligomers also interact pathogenically with a host of cell receptor systems including those for classic neuromodulators, which may have significant consequences in terms of a basic neuroplasticity challenge, and may lead or at least contribute potently to processes driving tangling and the hyper phosphorylation of tau proteins. As cells fill up with proteinaceous trash, several compensatory mechanisms are recruited, and as neurons discharge this trash or undergo programmed cell death, the extracellular space is progressively littered with proteinaceous trash, ushering in the next player in the neurodegenerative process, glial activation. Glial systems largely fail to clear up the debris for uncertain reasons as there is no lack of glial system ‘attention’ to plaque in most individuals – perhaps an example again of failing compensation, and indeed just like neurons, glial cells may even undergo ‘autophagy fatigue’, and transition from a resting and homeostatic/neuroprotective phenotype to neuro-predatory/inflammatory phenotypes, as well as becoming dystrophic (echoing the ultrastructural and morphological changes in neurons earlier in the disease) and even become senescent, at which point they contribute significantly to the problems rather than relieving them. Both increasing inflammation and the regional network spreading of tangling, which may in part be fostered by a prion like synaptic mechanism involving tau oligomers, characterize the clinical stages of the disease. Evidence is compelling that removal of amyloid, particularly extracellular plaque and fibrils, may offer little to nothing once clinical stages of the disease have been initiated, suggesting that although amyloid may initiate some aspects of the neurodegenerative process, that other players sustain and even deepen the destruction of the brain's networks.

EMERGING NEURO-INFLAMMATORY VIEW

Inflammation vs neuroplasticity

In part II, we took our first dive into the complexities of the early stages of neurodegeneration by examining failing autophagy and amyloidosis, which involved some degree of synaptic loss from amyloid oligomers. This brings us to the more downstream and clinical stages of neurodegeneration where synaptic loss accelerates to the point of first subjective or minimal cognitive impairment, then MCI (mild cognitive impairment typically amnestic) and then the stages of dementia proper, with these clinical stages characterized by the emergence of tauopathy and destructive forms of inflammation. Once clinical stages are engaged, removing amyloid appears to offer little if any value (raising questions about the application of popular amyloid antibodies to anyone in a clinical stage and the recent approval of Aducanumab for such patients). Both tauopathy and inflammation contribute to an emerging and spreading cellular senescence, which further exacerbates both neuroplasticity challenges and more destructive forms of inflammation, perhaps particularly the progressive engagement of the complement system. Although amyloidosis initiates a neuroplasticity challenge for the brain (and where CNS infection may be an initiating or potentiating event), synaptic loss accelerates in clinical stages and appears proportional to tauopathy and not amyloidosis. Once again, as with amyloid, tau oligomers appear more destructive of synaptic function than large-scale aggregations of phosphorylated tau (neurofibrillary tangles), and tau oligomers appear to spread synaptically, possibly explaining the progressive nature of tangling as we saw in Part I. Relationships between amyloid in different assembly states, hyper-phosphorylation of tau, various forms of inflammation, and how all of the above contribute to and drive synaptic loss remain to be fully clarified. In any case, tauopathy constitutes an additional challenge for autophagy systems in the CNS, and evidence argues that they also fail to clear this problematic protein. In any case, synaptic loss appears to accelerate during clinical stages, and while MCI might last five years, stages of dementia proper (mild, moderate, etc.) almost never do. This suggests a tipping point process in which positive feedback between these various destructive processes and subsequent erosion of neuroplasticity accelerate at the initiation of clinical stages. Approved treatment options for clinical stage patients are at best modestly effective, underscoring the importance of prevention, which is systematically neglected in our healthcare system, and further research into synaptic loss and its several drivers. Will CR mimetics help fill these sizeable treatment gaps?

UNDERSTANDING PARKINSON'S DISEASE

Update on our second most common neurodegenerative disease

Differential diagnosis, common phenotypes, symptoms and prodromes.

In this review we will cover the basic epidemiology, genetics, environmental risk factors and neurobiology associated with PD, with an eye towards examining alpha synuclein, its promoting interactions with both inflammation and mitochondrial decline, and why substantia nigra DA neurons might be particularly vulnerable in PD – a core aspect of the PD phenotype still not fully explained. Recent work suggests a heightened vulnerability in those nigral DA systems to age-related changes and to the effects of alpha synuclein, associated with their enormously long axons, huge dendritic trees, and special forms of calcium processing and mitochondrial vulnerability.

Like we saw with AD, we will see evidence that declining and eventually failing autophagy proceeds clinical stages, (but unlike AD?), the disease may start outside the CNS proper, in the enteric nervous system, as well as in olfactory systems. Like AD, and explaining its pattern of spread, there is evidence for a prion-like seeding mechanism for aggregates of alpha synuclein and again like AD, oligomers may have unique toxicities compared to other assembly states. Also like AD, the pathognomonic and pathogenic protein alpha synuclein may be upregulated in aging while also intrinsically blocking autophagy systems and thus may be intrinsically difficult to clear (just like amyloid).

All this suggests a deep shared vulnerability in aging to neurodegenerative disorders around the upregulation of proteins which help compensate for age-related change in neural networks that just happen to be autophagy-inhibiting. In other words, slim margins around these proteins, in terms of the system's ability to clear them in the first place, may be all too easily exceeded in the context of numerous environmental and genetic risk factors. This shared preclinical mechanism of autophagy failure sets the stage for what takes place in the clinical stages of PD where Lewy bodies and progressive dopaminergic loss impacting systems beyond the putamen (such as the caudate which has almost entirely cognitive functions) characterize the shifts from preclinical to early clinical to late clinical phenotypes. We will also discuss the difficult differential diagnosis between PD and so-called Parkinsonian Plus Disorders such as progressive supranuclear palsy, striatal-nigral degeneration, and multiple system atrophy, which can also show synucleinopathy. Once again emerging work on biomarkers may help along with careful attention to symptoms “at the margins”. Remaining questions include what might differentiate classic PD from more diffuse Lewy body disease. Is this a clear bifurcation or a rough continuum?

Implications for both prevention and treatment will be explored, and once again, we currently lack well validated strategies for both more highly effective prevention and for better neuroprotection in clinical stage patients, once progressive degeneration of nigral DA systems is underway. Treatment for early clinical stage patients is ameliorative but modestly to reasonably effective, at least in relationship to classic motor issues, and L-dopa may even have modest neuroprotective effects, although this is still debated. Cognitive, affective, and other nonmotor symptoms are often times neglected in the clinical treatment equation, under the paradigm that PD is a movement disorder, a meme that obscures and obfuscates PD's considerable depressogenic and cognition-eroding impact. This neglect is regrettable, but it points to the need for more concerted focus both in research and clinical care on nonmotor issues, which is slowly happening, and better education for all the relevant clinical disciplines. Do CR mimetics (which may be antidepressant), deep brain stimulators or other innovative treatments offer promise (treatment issues in PART 2)?

GENES, PROTEINS AND NEUROBIOLOGICAL AND NEUROPATHIC MECHANISMS

An update on a challenging disease of aging.

In part I, we summarized basic epidemiology, diagnostic criteria, and the differential diagnosis of classic PD versus diffuse Lewy body disease versus Parkinsonian plus disorders, along with a basic circuit topography in terms of what happens to the neo-striatal basal ganglia circuits when progressively deprived of dopamine. We will circle back briefly to one confusing section in that first talk, just to clear up a couple of issues and then begin a systematic exploration of a host of remaining issues – and those include the most troubling questions about PD around mechanism and pathogenesis.

First, we will talk briefly about the genetics of PD, and how there are both more deterministic and merely higher risk gene endowments, much as we saw with Alzheimer's disease. We will review – in at least a cursory fashion – current treatment paradigms including classic L-dopa, dopamine agonists, and DBS. We will also briefly summarize major animal models, and the troubling parallels with much of AD research, where numerous interventions effective in several of those animal models have not proven effective in clinical PD. This raises a bunch of questions which we will explore in greater detail.

Fundamental questions include: 1) is it more sensible to continue to approach Parkinson's disease from a “lumper's” or a “splitter's” point of view? Is the obvious clinical diversity of PD better integrated under one umbrella, or should we aim for more consistent molecular and genetic subtyping to allow more precisely targeted and rational treatments? Does an overly ‘lumping’ diagnostic paradigm explain the numerous treatment failures of putative disease modifying agents when in fact a single agent is being used to treat what may be mechanistically “different enough” diseases? Or do the failures simply suggest that we have not penetrated into the true drivers of neurodegeneration? These remain unanswered questions.

Additionally, there is evidence that – just like with Alzheimer's disease – basic proteinopathy concepts (that the entire neurodegenerative process can be conceptualized as downstream effects of ‘toxic’ proteins) may leave out critical aspects of pathogenesis, including how proteinopathy may activate several secondary/compensatory processes that are not simply ‘reeled back’ by removal of toxic protein. Just as with AD in relationship to amyloid moieties, recent monoclonal antibodies directed at alpha synuclein have failed their primary endpoints. What does this say about our proteinopathy concepts and their core assumptions? We will look at how proteinopathy might interact with other cellular phenotypes of aging, namely destructive inflammation/dysregulation of the innate immune system, and mitochondrial dysfunction, and what might explain the unique vulnerability of nigral dopaminergic neurons. Indeed there is decent evidence that mitochondrial dysfunction and failure may be more central in PD than in some other neurodegenerative disorders, given that several of the genes mutated in familial PD are critical to mitochondrial function. This recognition may however also support cautious optimism about exercise and CR mimetics as therapies given their offering a kind of ‘primary mitochondrial support,’ along with attenuation of inflammation, promotion of sleep, promotion of autophagy and mitigation of many other classic aging cellular phenotypes.

We will summarize interesting novel treatments including a recent report just earlier this year of a novel tyrosine kinase inhibitor that appears neuroprotective (again with parallels to recent findings in AD), along with initial animal model work showing neuroprotective effects of cinnamon in a synucleinopathy. There appears to have been virtually no work on CR mimetics in PD other than glucagon like peptide agonists where animal model work has been promising, and where opinion is leading towards regular exercise as a recommended intervention. Once again, treatment in clinical PD may need to be staged, and we may need to move away from our assumption that a single treatment should suffice if it's a really good one. Standard treatment emphasizing compensatory dopaminergic therapies appears to have virtually no substantive or long-term neuroprotective, disease-modifying value, suggesting that disease modification will need to think outside the box of conventional dopaminergic pharmacology. Clinicians working in PD must also expand their traditional monocular focus on motor issues to encompass cognitive, affective, and other troubling challenges in this complex disease of aging.

DEPRESSION: AN EVOLUTIONARILY CONSERVED MECHANISM

Implications for the current crisis of depression in western societies

In the conventional view, depression is just an illness caused by a chemical imbalance, commonly treated with SSRIs or SNRIs that are both safe and effective. All four of these popular notions may be more wrong than right, and they all contribute to a basic obfuscation of depression’s core biological mechanisms widespread in our medical industrial complex. These popular misconceptions also hide a fundamental failure of truly effective treatment: depression is now the single most expensive condition in Western societies, and it has a worrisome and long list of comorbid companions, also with ferocious price tags both in dollars and in human suffering. In other words, depression has substantial clinical and hidden mechanistic overlap with many other chronic diseases that are overwhelming Western healthcare systems, including on the more medical side DMII, CVD, neurodegenerative disorders, and on the psychiatric side, anxiety disorders, addictions, personality disorders, and PTSD.

Depression also isn't simply an illness, as the core depressive mechanism may contain an adaptation aimed at the termination of intolerable and protracted forms of separation distress (an emotional state shared across all mammals), explaining why depression is ubiquitous not just in human but in all mammalian species studied so far. It may reflect a fundamental vulnerability of the social brain, deprived of social connection and social comfort and safety. The disinhibition of this conserved behavioral shutdown mechanism may create depressive illness, which often is not successfully treated simply with antidepressants, as this class of drugs has a low rate of achieving remission, helping to explain why the incidence of depression in Western societies has steadily increased, despite an enormous rise in the prescription of popular antidepressants. Depression shares a deep evolutionary relationship with other evolutionarily conserved behavioral shutdown mechanisms, most especially sickness behavior, but also hibernation, relationships consistent with growing evidence for a primary role of pro-inflammatory cytokines in depression. Depression is prototypically triggered by social losses and other forms of painful social defeat, and the risk for depression may also be potentiated by many common pro-inflammatory lifestyle conditions and by the widespread social isolation in Western societies, where social media function as addictive substitutes for real intimacies, and where common social media conflicts serve to potentially deepen experiences of shame and rejection, both classically depressogenic. Social isolation, loss of various work and social rewards and exposure to pro-inflammatory states all have been significantly exacerbated during the COVID 19 pandemic, helping to explain why COVID has seen an upsurge in depression across most societies.

What does a more ‘social brain-centric’ view of depression do to our treatment algorithms and emphases? It fundamentally, if not profoundly, changes them, but change is long overdue in view of the evidence that antidepressants have neither been proven safe in chronic administration nor are they terribly effective, particularly in mild to moderate depression – its most common manifestation – where they simply do not separate from placebo. Additionally, in moderate to severe depressions where antidepressants do separate from placebo, ketamine and psilocybin, ECT and rTMS may be more effective than most mainline antidepressants, suggesting that antidepressants may actually have few good indications, contrasting painfully with their status as among the most prescribed drugs (21 million scripts in the last three months of 2020 up from 19 million during the same 3 month time period in 2019). Most disturbing is the possibility that conventional SSRIs, SNRIs, TCAs, etc. may increase the vulnerability to depressive relapse upon discontinuation through uncharted mechanisms, creating ‘lifers’, as biopharma has been aversive to exploring this question adequately.

We must change a losing game in relationship to this very common human vulnerability, reduce the shaming and stigmatizing associated with the diagnosis (both of which are ironically depressogenic), help depressed patients get out of traumatizing situations and social isolation that maintains the chronicity of depression, reduce pro-inflammatory lifestyle factors that also might be pouring gas on the depressive process, and help depressed patients to reconnect, repair their relationships when possible, or rebuild attachments from the ground up when necessary. Instead of seeing depression as a sign of a mystified ‘chemical imbalance’, we should see it as a sign that individuals have been exposed to intolerable levels of psychic pain (compounded sometimes by concurrent physical pain), lack adequate social support, are suffering at the grinding intersection of severe stress and inflammation, and have lost basic hope.

IMPLICATIONS FOR TREATMENT AND PUBLIC HEALTH

Neuroendocrine alterations in depression

In Part I, we looked at the criteria for major depression, the worrisome penetration of depressive illness into Western societies, and how the meme of ‘chemical imbalance’ hides depression's deep connections to separation distress, as the core mechanisms in depression may be evolutionarily conserved and aimed at terminating protracted separation distress and/or withdrawing from dominance conflicts that are going badly. These two major adaptive benefits may explain why all mammals appear capable of some form of depression. Depression may also have close mechanistic relationships with other conserved forms of behavioral shutdown – sickness behavior and hibernation.

In Part II, we will zoom in on this evolutionarily close relationship between inflammation and depression and how inflammatory signals and stress axis activation are conjoined. We examine evidence that psychiatry's monocular focus on neurochemical and genetic factors and its ignoring of what might constitute a ‘depressive environment’ obscures evidence of depression's connection to larger interpersonal and societal problems, to a deepening social isolation particularly in the United States, and to the growing evidence that declining social connection is actually a public health problem of the first rank. As with the chronic diseases of aging, depression’s enormous footprint in modern societies indexes a significant gene-environment mismatch – an ‘evolutionary discordance, ’ in which our prosocial genome is being asked to function in isolation, or worse, in chronic social defeat (aka poverty). We will look at the evidence that as our society has slid into deepening income inequality and declining social support, depression and what have been called ‘deaths of despair’ (deaths not normally attributed to depression but to OD, suicide and violence) have steadily increased, along with deaths from depression’s massive list of comorbidities.

This general neglect of the environment and lifestyle within mainstream psychiatry has implications for improving our treatment paradigms, which have been dominated by SSRIs/SNRIs (80% of which are prescribed by PCPs), despite the evidence that they minimally separate from placebo in mild to moderate depression while the placebo mechanism declines in moderate to severe depression, allowing a clear impression of efficacy, yet with underappreciated and minimized toxicities. Psychotherapy on the other hand is systematically shorted in the current treatment environment, despite evidence that psychotherapy protects against relapse whereas SSRIs etc. may actually predispose to relapse through poorly charted opponent process effects. While cognitive behavioral therapy is widely regarded as some kind of gold standard, evidence supports no clear separation of efficacy between putative ‘types’ of psychotherapy – with acknowledgment that this technical/ theoretical orientation distinction may be ultimately specious, as therapist empathy, trustworthiness and insightfulness may be largest share of psychotherapy effect variance. Focused work on precipitating stressors, especially classic depressogenic forms of separation distress, alleviation of concomitant social isolation/protection from any ongoing abuse or physical threat, exercise therapies, meditation and yoga disciplines, improvement in pro-inflammatory dietary patterns/dysbiosis, normalization of circadian dysfunction with improved sleep, and in more severe depressions, consideration to ketamine/psilocybin, rTMS, and ECT should all be part of the considered treatment space, not a reflexive and largely exclusive reliance on SSRIs and similar drugs. For the most severely refractory depressions that fail multiple therapies including ECT, DBS may offer hope. Once again, much better education of front-line clinicians within multiple disciplines, and education of the public such that patients can become more sophisticated consumers, may offer long-term correctives.

FRONTOTEMPORAL DEMENTIAS

A complex multi-syndrome family of neurodegenerative disorders: many questions, few answers

The frontotemporal lobar degeneration / ALS neurodegenerative disorders group

In this review we will explore the confusing and complex umbrella concepts surrounding the frontotemporal dementia family, which has recently been united with the ALS group. This super category thus includes an enormous spectrum of clinical phenotypes, including progressive supranuclear palsy, corticobasal degeneration, two forms of primary progressive aphasia, the classic behavioral variant frontotemporal dementia (the most common of all of these), something called LATE (‘limbic age-related tar DNA binding protein encephalopathy’), ALS, and admixtures of these various clinical syndromes with ALS or some lesser form of motor neuron disease. This overarching superordinate concept of the FTLD/ALS family was created in part due to the discovery that 95% of ALS patients show deposition of the most common proteinopathy in FTD, along with the frequent clinical finding that patients can start out with motor neuron disease and over time progress to one of the FTLD syndromes, or conversely, start with one of the frontotemporal syndromes and then segue towards motor neuron failure. This creates clinical courses sometimes characterized by “phenotypic dedifferentiation.”

This umbrella concept of FTLD/ALS thus forms the largest, most confusing, and most diverse family of neurodegenerative disorders, and this phenotypic diversity and histopathological and genetic diversity remains to be fully explained in terms of how such diverse genetic and sporadic causes can yield a family of shared syndromes and proteinopathies. This family of disorders is characterized by three forms of proteinopathy: ubiquitinated tar-DNA binding protein, tauopathy including Picks's bodies, and a more rarely found ubiquitinated ‘fused-in-sarcoma’ proteinopathy.

Some of the multivariate clinical phenotypes tend to more commonly load on one particular proteinopathy versus another, but in general, most clinical phenotypes can present with any of these three proteinopathies, particularly the common behavioral variant FTD. There are also a handful of mutations that appear to be responsible for almost all of the autosomal dominant forms of these frontotemporal/ALS syndromes: mutations in progranulin, in tau, and in a chromosome 9 ‘open reading frame’ gene characterized by pathogenic repeats in ‘intron’ areas. FTLD/ALS shows a higher percentage of disease associated with a clear pathogenic mutation than any other neurodegenerative family, but still, most of the disease is sporadic. All of these concepts are challenging and even esoteric notions, particularly for newcomers to the field, that we will have to unpack and demystify, making the FTLD/ALS family one of the most challenging for clinicians, students, and patients and their families to understand.

In any case, from mechanistic standpoint, this diverse family of disorders may show failure in RNA processing and derailment of the critical RNA lifecycle as a/the principal neurodegenerative stressor. Both fused in sarcoma protein and TAR DNA binding protein are critical RNA binding proteins that operate throughout the RNA lifecycle and support both maturation, inhibition, and other forms of modulation of transcription and translation – a failure that strikes at the core of the cell and its biologic work. Although they shuttle back and forth typically between the nucleus and cytoplasm, they are found pathologically aggregated in the cytoplasm, suggesting failure of the nuclear shuttle process, which is still somewhat mysterious. As in other neurodegenerative disorders, we have once again an incomplete understanding of precisely what is driving neurodegeneration in this family of disorders, including an unclear, but probably nontrivial burden from disinhibited inflammatory process/gliosis. Additionally, the appearance of TAR DNA binding protein in other neurodegenerative disorders challenges our popular boxology models and forces us to consider a bigger picture or more global ‘field theory’ of neurodegeneration. Therapeutic opportunities remain virtuallY completely undefined, beyond the modestly to minimally successful symptomatic psychopharmacologic approaches, including promotion of progranulin (unclear how to do this but is AdpN a promotor?), exploration of multiple CR mimetics (which may take a ‘load’ off the RNA transcript process via mTOR inhibition while upregulating autophagy and modulating inflammation). Many more questions than answers, but yet despite this, there has been enormous progress in the last 10 years.

MULTIPLE SYSTEM ATROPHY

Update on a tripartite disease

A puzzling outlier in NDD? A strange first cousin to PD?

Multiple system atrophy is a tripartite disease, a similar ‘meta-category’ to the more recent integration of the frontotemporal dementias with ALS, but achieved some 40 years earlier, in which seemingly unrelated clinical phenotypes are shown to share identical cellular neuropathology. MSA is the diagnostic umbrella label, a ‘super-category’ emerging from Graham & Oppenheimer’s (1969) unification of three previously distinct syndromes: olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome. This phenotypic integration was supported by pathological demonstration of pathognomonic glial (oligodendrocyte) cytoplasmic inclusions (GCIs) in all MSA by Papp in 1989. GCIs are composed of a unique strain of alpha synuclein aggregates, similar but not identical to strains in neurons in Parkinson's disease (‘Lewy bodies’), with seeding/templating of protein aggregation in a prion-like fashion. What makes multiple system atrophy something of an outlier in the already confusing pantheon of neurodegenerative disorders are: 1) GCIs are non-neuronal – MSA is an ‘oligodendropathy’ in which the cells supporting the brain's white matter degenerate, with neuronal degeneration apparently secondary to this; 2) there is no known genetic version of the disease (virtually all sporadic), in stark contrast to every other known neurodegenerative disorder, and where its closest relative PD has several genetically determined as well as genetically predisposed phenotypes, although copy number variations on SYNC have been found; 3) despite its close similarity to the PD family, with both a parkinsonian version that is roughly as commonplace as the cerebellar variant, and with a synucleinopathy somewhat similar to PD, it does not respond very well to levodopa, probably because the target system (putamen initially, then caudate) is degenerating more than in PD, while both show degeneration in SNc. In that sense, MSA is a more complex/diffuse disorder of neural networks, while PD (at least early-stage) may be viably (if incompletely) modeled as DA deafferentation. MSA is also more significantly aggressive than PD.

DA therapies may be modestly effective about 35-40% of the time, and may be worth trying with the parkinsonian variant, but often times autonomic dysfunction, and progressive cerebellar dysfunction pose greater challenges for patient quality of life, with cerebellar ataxia currently untreatable, other than removing risk for falls by walker or wheelchair support. Major questions remain about how degeneration initiates and apparently centers in the oligodendrocytes, and how to readily identify and then modify this neurodegenerative trajectory. Unfortunately, the lack of biomarkers makes identification of prodromal and preclinical stage patients difficult, particularly given lack of knowledge about risk genes, which significantly hampers research. OM-αSynD (detection of alpha synuclein in olfactory mucosa) may serve as a novel non-invasive biomarker for clinical diagnoses of PD, MSA-P, and MSA-C, but cannot yet discriminate these three, but skin biopsy may do better. Clinical stage patients can be neuroimaged, which has characteristic findings in both parkinsonian and cerebellar versions, about the only cost-effective biomarker and technical assist in differential diagnosis, beyond delineating symptom clusters and identifying classic ‘red flags’ that separate MSA & other Parkinsonian Plus disorders from PD. An experimental PET ligand has shown promise separating MSA from PD, but with no current clinical availability. DTI can separate PD & MSA, due to greater white matter degeneration in MSA.

Classic disease modification targets in MSA (targeted in other NDD) have included: 1) antibodies aimed at alpha synuclein (all phase I), 2) inhibition of protein aggregation, 3) modulating central inflammation, and 4) augmenting growth factor/neuroprotection signals. So far, although no major disease modifying therapy has emerged, high-dose CoQ10 shows modest slowing of progression, suggesting that MITO dysfunction is part of the neurodegenerative causal loops (primacy of MITO dysfunction thought central to PD). Mesenchymal stem cell treatment also modestly slows progression. Only rapamycin has had any kind of probing in terms of clinical trials using CR mimetics (not successful in its one trial); this suggests a wide-open field of clinical opportunity for other CRMs, such as AMP kinase modulators, or perhaps combination approaches using a CRM and other classic targets from the above list. Virtually nothing is known in a systematic way about prevention and the relationship of MSA risk to classic disease-of-aging-relevant lifestyle risk factors of sleep, diet, exercise, or social support/stress, but attention to these classic risk factors may take gas off the neurodegenerative fire.