9th Dimension Biotech, Inc.
  • WELCOME
  • THE TEAM
    • CHIEF EXECUTIVE OFFICER
    • COMPANY PRESIDENT
    • CHIEF PHYSICIAN ADVISOR
    • CLINICAL NEUROSCIENCE
    • BIOTECHNOLOGY ADVISOR
    • CHIEF FINANCIAL OFFICER
  • ABOUT FORZA
  • THE REVIEWS
  • THE STORY
  • INDEPENDENT R&D
  • THE SOURCE
  • THE PLAN
  • THE PRODUCTION
  • ABOUT US
  • WEBINARS
    • WEBINAR GALLERY
    • THE BIOLOGY OF AGING
    • ALZHEIMER'S DISEASE
    • PARKINSON'S DISEASE
    • DEPRESSION
    • FRONTOTEMPORAL DEMENTIAS
  • SHOP
  • CONTACT US
  • NEWS
9th Dimension Biotech, Inc.
  • WELCOME
  • THE TEAM
    • CHIEF EXECUTIVE OFFICER
    • COMPANY PRESIDENT
    • CHIEF PHYSICIAN ADVISOR
    • CLINICAL NEUROSCIENCE
    • BIOTECHNOLOGY ADVISOR
    • CHIEF FINANCIAL OFFICER
  • ABOUT FORZA
  • THE REVIEWS
  • THE STORY
  • INDEPENDENT R&D
  • THE SOURCE
  • THE PLAN
  • THE PRODUCTION
  • ABOUT US
  • WEBINARS
    • WEBINAR GALLERY
    • THE BIOLOGY OF AGING
    • ALZHEIMER'S DISEASE
    • PARKINSON'S DISEASE
    • DEPRESSION
    • FRONTOTEMPORAL DEMENTIAS
  • SHOP
  • CONTACT US
  • NEWS

FRONTOTEMPORAL DEMENTIAS


BY DR. DOUGLAS WATT, PH.D.

FRONTOTEMPORAL DEMENTIAS

FRONTOTEMPORAL DEMENTIAS

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

THE FRONTOTEMPORAL LOBAR DEGENERATION / ALS NEURODEGENERATIVE DISORDERS GROUP

 

By Douglas F. Watt, Ph.D.

Adjunct Professor, Graduate Department of Psychology Lesley University

Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc.

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.

FTOD SLIDESHOW

COMING SOON

WEBINAR GALLERY

These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.

  • WELCOME
  • ABOUT FORZA
  • THE REVIEWS
  • THE STORY
  • THE PLAN
  • THE PRODUCTION
  • ABOUT US
  • SHOP
  • CONTACT US
  • NEWS

Copyright © 2022

9th Dimension Biotech, Inc.

All Rights Reserved.

This site uses cookies to offer you a better browsing experience

We use cookies to analyze website traffic and optimize user experience.
By accepting, you agree that your data will be aggregated with the data of all other users.

Accept