Download Neuroprotection in Dementia

Neuroprotection:
Strategies for Dementia
Sesath Hewapathirane
PGY3 Resident in Psychiatry (UBC)
May 25, 2017
Dementia: clinical definition
• decline in cognition involving one or more of the
following cognitive domains:
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learning and memory: short and long-term memory
language: expressive and receptive
executive function: complex tasks, overall insight + judgement
complex attention: sustained/divided/selective attention, processing speed
perceptual-motor: apraxia, agnosia, perceptual distortions, visuospatial orientation
social cognition: personality changes
• decline from previous level of function
• interfere with daily function and independence
• progressive illness, eventually unable to care for themselves
Dementia: prevalence and burden
• 47.5 million affected worldwide
• mainly seen in people over age 65 (early onset variants also exist)
• prevalence increases steeply with age
• starting age 65, risk doubles every 5 years
• by age 85, 25-50% will exhibit signs of dementia
• 3rd leading cause of death in developed world (after cadiovasc. and cancer)
• significant illness burden (US$604 billion/yr)
• hospitalizations, specialized medical facilities + staff + treatments
• home supports, care facilities
• societal burden (caregivers’ mental health and income potential)
• prevalence on the rise (longer life expectancy +/- exposures)
Dementia: subtypes
• over 50 different causes
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Alzheimer’s disease: 50%-70%
Vascular dementia: 20%-30%
Lewy body dementia: 10-15%
Fronto-temporal dementia
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Traumatic brain injury
Inherited e.g. Huntington’s
Infectious e.g. HIV, prion
Substance-related e.g. alcohol
Other neurological/medical
conditions e.g. Parkinson’s disease
• mixed etiologies also observed
• clinical characteristics vary based on brain areas affected, may also
demonstrate different time-courses
Alzheimer’s dementia
• cause is poorly understood
• genetic (multiple genes, est 100-1000s)
• environmental (e.g. head injuries, depression, hypertension)
• toxic plaques and tangles in the brain, temporal lobes often affected
Alzheimer’s dementia
• Neuritic plaques and neurofibrillary
tangles  neuron death
• Amyloid hypothesis – abnormal cleavage of
APP to β-amyloid peptide (Aβ)/N-APP/other
extracellular amyloid plaques
• Tau hypothesis – hyperphosphorylation of
Tau protein leading to microtubule
disintegration and cytoskeletal collapse
intracellular NFTs
Amyloid hypothesis
• Positive feedback  prionic loops
• APP as a mediator of synaptic plasticity
signaling
• Endogenous molecular switch
• Anti-tropic peptides shown to mediate
neurite retraction, loss of synapses,
caspase activation, apoptosis
• AD a result of imbalance of APP
singaling
• anti-trophic>>tropic
Vascular dementia
• complex interplay genes—
environmental exposures
• multiple small infarcts (strokes) +/reduced blood flow due to vascular
narrowing, vascular remodeling,
changes in BP regulation
Lewy body dementia
• Lewy bodies  intracellular
aggregations of misfolded proteins
in combination with α-synuclein
• Concomitant AD/vascular
pathology may also be present
Dementia: treatment
• few available medications aim to treat cognitive symptoms but have
no effect on the underlying disease process
• cholinesterase inhibitors: donepezil, rivastigmine*, galantamine (mildmoderate AD and *PDD)
• NMDAR antagonists: memantine (moderate – severe AD)
• clinical benefits often minimal
• benefits are transient (6-24 months)
Disease modifying treatments for AD
Aβ therapeutics
• Immunization with Aβ
• trial halted in phase II due to meningoencephalitis (6%), presumed T-cell hyperresponse
• post-mortem, fewer plaques but did not prevent clinical progression to severe dementia
• ongoing trials with truncated Aβ (aimed at circumventing T-cell hyperresponse)
completed phase II without reports of encephalitis
• Passive immunization with pre-formed antibodies against Aβ
• Several large scale phase III studies, primarily negative results
• Bapineuzumab observed to reduce amyloid levels (PET) and CSF phos-Tau however failed
to show improvement in clinical outcomes
• Solanezumab showed mixed results with one meta-analysis of 2 studies indicate very mild
benefit in cognition in people with mild AD
• Was therapy initiated too late in the disease process?
• Crenezumab, solanezumab, gantenerumab in “prodromal” AD & familial AD
APP cleavage
• Gamma-secretase inhibitors, (e.g.
avagacestat, semagacestat)
• no improvement in cognitive function
reported in Phase II trials
• trend towards a dose-dependent
decrease in cognition
• more APP-specific inhibitors in pipeline?
• Beta-secretase inhibitor (MK-8931)
• Phase III ongoing, animal studies shown
sig. side effects…
Anti-Tau therapies
• Target tau-tau binding  methylene blue-based compounds
• Rember (Phase II) reduced cognitive decline over 24 weeks
• TRx0237 (Phase III) ongoing
• Target tau-phosphorylation  Glycogen synthase-kinase 3β
• sodium valproate showed no benefit in Phase III trials
• Li showed stabilization of cognitive function with low dose Tx, delayed d/t
adverse Tx effects
• tideglusib failed Phase II trials
Other directions in early stages
• α-secretase upregulators (etazolate, bryostatin-1, exebryl-1)
• Microtubule stabilizers
• Repression of AD-related transcription factors
AD Tx: Drug repurposing
• Pro: existing safety data and established mechanisms of action in
order to bring to clinical trial rapidly
• Type 2 diabetes mellitus Tx:
• 65% increased risk of developing AD in T2DM
• Hypothesized that disrupted insulin signalling contributes to AD
• Phase II trial with intranasal insulin reported positive impacts on key AD
markers, now progressed to Phase III
• A number of Phase II and III trials are currently examining GLP-1 analogues
AD Tx: Drug repurposing
• Calcium channel blockers:
• preclinical studies: reduction of Aβ production, aggregation and neurotoxicity
and improved neuronal function
• underlying mechanism is independent of the anti-hypertensive action due to
the differential effects seen with the different CCBs
• evidence from epidemiological studies support the efficacy of
dihydropyridine CCBs in reducing or delaying the development of AD,
supported by recent SYST-EUR RCT, which reported a 55% reduction in
incident dementia with nitrendipine Tx over a 5-yr follow-up
• Large scale RCT investigating nivaldipine is ongoing
AD Tx: Drug repurposing
• Trials ongoing:
• ARBs
• centrally acting angiotensin II has role in release of inflammatory mediators and
inhibition of acetylcholine release
• epidemiological evidence, mixed data from large scale RCTs ONTARGET & TRANSEND
• RCTs of peridopril and losartan ongoing
• Anti-inflammatories
• inhibitor of mast cell activation (masitinib) shown some promise in slowing cog. decline
• NSAIDs and COX-2 inhibitors have not performed well
• RAGE-receptor blockers (multi-ligand receptor binding Aβ promoting influx to CNS)
• Minocycline
• Retinoids
Dementia: the problem
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>47.5 million affected (~1 in 4-5 over age 85)
3rd leading cause of death in wealthy countries
>US$640 billion yearly costs
immeasurable effects on family/caregivers
immense burden on health care system
AND:
• available therapeutic interventions offer a marginal, unsustained
symptomatic effect, with little or no effect on disease progression
• hundreds of clinical trials, billions of dollars, minimal success
• companies are teaming up – unprecedented in history of drug development
Background
• Hypothesized model in which AD results from an imbalance in endogenous
plasticity signaling
• synapse loss >> synaptogenesis & maintenance of existing connections
• dysfunctional circuitry  loss of brain function
• preclinical studies have identified multiple pathogenic targets for potential
intervention
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amyloid-β (Aβ) oligomers and tau
inflammatory mediators
apolipoproteins and lipid metabolism factors
hormonal mediators
trophic factors and their receptors
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calcium regulatory pathways
axoplasmic transport machinery
neurotransmitters and their receptors
prion protein
and a host of other potential targets
Background
• preclinical studies show large effects of targeting one pathway,
whereas in human studies, such approaches have not borne out
• successes with other chronic illnesses such as cardiovascular disease,
neoplasia, and HIV support the efficacy of multi-component systems
• Present study (n=10; 2.5 yr follow-up):
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novel programmatic approach involving metabolic enhancement
aimed at altering balance of synapse loss & synaptogenesis/maintenance
individualized, combination therapies based on research evidence
iterative—continued optimization over time
Multimodal approach
Case
• 69-year-old male, entrepreneur, with an 11 year Hx of slowly
progressive memory loss with prosopagnosia, which had accelerated
over the past 1-2 years.
• Unable to work due to memory impairment.
• FDG-PET showed a pattern typical for early Alzheimer’s disease, with
reduced glucose utilization in the parietotemporal cortices bilaterally.
• Neuropsychological testing showed a reduction in California Verbal
Learning Test) from 84%ile to 1%ile, a Stroop color test at 16%ile, and
auditory delayed memory at 13%ile.
• Heterozygous for ApoE4 (3/4).
Case
• Underwent baseline investigations and initiated on a personalized
therapeutic program:
• optimize metabolic parameters
• optimize lifestyle factors (exercise, sleep, stress reduction, healthy balanced
diet)
Case
• (1) fasted for a minimum of three hours between meals, and for a minimum of 12
hours between dinner and breakfast; (2) eliminated simple carbohydrates and
processed foods from his diet; (3) increased consumption of vegetables and
fruits, and limited consumption of fish to non-farmed, and meat to occasional
grass-fed beef or organic chicken; (4) probiotics; (5) coconut oil i tsp bid; (6)
exercised strenuously, swimming 3-4 times per week, cycling twice per week, and
running once per week; (7) melatonin 0.5mg po qhs, and tried to sleep as close to
8 hours per night as his schedule would allow; (8) herbs Bacopa monniera 250mg,
Ashwagandha 500mg, and turmeric 400mg each day; (9) methylcobalamin 1mg,
methyltetrahydrofolate 0.8mg, and pyridoxine-5-phosphate 50mg each day; (10)
citicoline 500mg po bid; (11) vitamin C 1g per day, vitamin D3 5000IU per day,
vitamin E 400IU per day,CoQ10 200mg per day, Zn picolinate 50mg per day, and
α-lipoic acid 100mg per day; (12) he took DHA (docosahexaenoic acid) 320mg and
EPA (eicosapentaenoic acid) 180mg per day.
Case
• Six months later, Pt and wife noted improvement. Returned to work.
• At work, unlike before, able to recognize faces, remember his daily
schedule, and functioned without difficulty.
• Noted to be quicker with his responses. His life-long ability to add
columns of numbers rapidly in his head, which he had lost during his
progressive cognitive decline, returned.
• Had been accelerating in his decline over the prior 1-2 years, decline
appeared to have halted
Author’s conclusions
• memory loss in patients with subjective cognitive impairment, mild
cognitive impairment, and at least the early phase of AD may be reversed
• subjective improvement sustained for 2.5 years
• 6 of the 10 patients had discontinued working; all were able to return to work
• major side effect – improved health and optimal BMI; stark contrast to
medications
• may be useful as a platform on which drugs that would fail as
monotherapeutics may succeed as key components of a multimodal
therapeutic system
• program is not easy; none of the patients followed the entire protocol
• the current, anecdotal results require a larger trial
Design
• n=10, on MEND protocol for 5-24 months, up to 4 years follow-up
• quantitative MRI and neuropsychological testing pre/post
• heterogeneous measures  not amenable for statistical analysis
Examples of outcomes
• well documented MCI, positive amyloid-PET and FDG-PET scans, abnormal
neuropsychological testing, hippocampal volume reduced to 17th percentile;
after 10 months on the MEND protocol, hippocampal volume increased to 75th
percentile, in association with a reversal of cognitive decline.
• well documented early Alzheimer’s disease, positive FDG-PET scan and markedly
abnormal neuropsychological testing. After 22 months on the MEND protocol,
CVLT-IIB had increased from 3rd percentile to 84th percentile, total recognized
hits from <1st percentile to 50th percentile, CVLT-II from 54th percentile to 96th
percentile, auditory delayed memory from 13th percentile to 79th percentile,
reverse digit span from 24th percentile to 74th percentile, and processing speed
from 93rd percentile to 98th percentile. His business, which had been in the
process of termination, was reinvigorated, and a new site was added to the
previous sites of operation.
Limitations + Future directions
• pilot/anecdotal
• cannot rule out reversible non-AD etiologies in the subject group
(?psychiatric, ?improved perfusion)
• most SCI/MCI or early AD; how late in the course of cognitive decline can
reversal be effected?
• MCI does not necessarily progress to dementia
• how long can improvement be sustained?
• compliance, cost
• larger study size, +/- existing medications
• curative therapies in pipeline
Paradigm shift in Tx of MCI/Dementia
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>47.5 million affected (~1 in 4-5 over age 85)
no current disease modifying treatments
immense personal/family/societal burden
unsustainably growing costs to healthcare system
(very) early clinical data exists showing potential to reverse cognitive
decline in MCI/early AD
• Utilization of personalized, assertive, iterative programs to optimize
potential risk factors; multimodal approach targeting several pathways
promoting neuroprotection
• Consider as primary focus of treatment plan, versus “supportive”