Week 1 Flashcards
Where do NFTs accumulate in Braak stages?
Braak stage 0 - NFTs are found in subcortical nuclei (locus coeruleus - involved in anxiety, dorsal raphe nucleus - involved in depression, perifornical nucleus of hypothalamus - sleep disturbances)
Braak stage I/II - NFTs are confined to entorhinal cortex and parts of hippocampus.
Braak stage III/IV - NFTs spread to paralimbic cortices
Braak stage V/VI - NFTs reach higher order association and primary neocortex
What neuropsychiatric symptoms are detected in AD in Braak I/II?
Increased odds for agitation, anxiety, appetite changes, depression and sleep disturbances
What neuropsychiatric symptom continues into Braak III/IV?
Increased odds of agitation
What neuropsychiatric symptom is Braak V/VI associated with?
Higher odds of delusion
What stage of Braak do first signs of cognitive decline occur?
Braak stage III, most cases at Braak stages I/II remain cognitively normal
Amicus Therapeutics - Batten Disease
Phase 1/2 study with Amicus’ one-time gene therapy treatment in CLN6 Batten disease (lysosomal storage disorder) ihad stabilization of motor and language function in 7/8 patients, rather than declined - full study is 12 patients (1000 global cases of CLN6)
Amiculs is also developing gene therapies for 3 more variations of Batten disease: CLN3, CLN8 and CLN1
Batten Disease - Disease, progression, and approved therapies
Typically diagnosed around 4 or 5 years old, fatal by age 10, typical untreated child will see scores drop from 6 to 0 within a few years, averaging about 1-2 points of decline per year.
No therapies approved for all but one of the disease’s more than a dozen subtypes, which are defined by different genetic mutations.
CLN2 Batten Disease has a replacement therapy Brineura (cerliponase alfa) by BioMarin Pharmaceutical which won approval in April 2017
Regenxbio/Pfizer - August 2019 deal
Regenexbio has agreed to grant Pfizer a non-exclusive license to its AAV9 vector technology for use in the pharma’s gene therapy program targeting Friedreich’s ataxia; Regenxbio will get an upfront payment and potential fees, milestone payments and royalties (undisclosed).
High and Low Hemoglobin link to AD
People with high or low serum hemoglobin are at greater risk for dementia. They also have cerebrovascular disease and reduced brain connectivity.
(Out of 1,520 individuals, 1,194 had AD those in the lowest and highest quintiles for hemoglobin levels were more likely to develop dementia with hazard ratio of 1.29 and 1.20 for low and high Hbg)
PSEN mutations and disease onset
Many mutations in PSEN1 cause symptoms by 40’s, the spread across PSEN1 mutations ranges from age 20-80 and even within a given family’s single mutation, onset can differ by a decade
5 Genes that delay Alzheimer’s onset
ApoE2, TMEM106B, phospholipase C, Rab10 and Icelandic APP mutation
Ionis-MAPTRx aka BIIB080
Tau ASO - Phase 1 clinical trial in 44 people with mild AD (Ionis partnered with Biogen) - Aug 2019 (first person dosed in November 2017)
DIAN trial drugs
Solanezumab and gantenerumab - last patient will read out end of this year and then in 2020 will get analyzed.
Ataxin and AD
Ataxin-1 loss of function increases BACE1 transcription and Abeta pathology in cerebrum.
Elevated BACE1 levels impair hippocampal neurogenesis and olfactory axonal targeting.
PolyQ-expanded mutant ataxin-1 causes degeneration of CA2 neurons in hippocampus
Ataxin-1 loss and polyQ-expanded ataxin-1 lead to distinct brain regional vulnerability
