Treatment AD MSK March112018

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Diagnosis and management of

Dementia - Recent advances

Dr M Suresh Kumar MD DPM MPH


PsyMed Hospital Chennai
[email protected]
www.drmsureshkumar.com

Pondicherry
March 11 2018
Burden of Dementia
• 47 million people globally are living with dementia today.

• About 10 million new cases being diagnosed every year.

• By 2050, the number of people living with dementia is projected to


nearly triple to more than 130 million.

• Most vulnerable to the predicted rise in prevalence are those in low-


income and middle-income countries.

• Projections for lower-middle-income countries (223%), and low-


income countries (264%) are doubled by comparison to high-income
countries.
Lancet. 2015 Sep 5;386(9997):931
Alois Alzheimer
• Alois Alzheimer, a German psychiatrist, reported at a meeting in
Tübingen, Germany, in 1906 his clinico-pathological study of a
woman who presented with a “peculiar” dementia at age 51 years.

• Alzheimer correlated the woman’s cognitive and behavioral features


with histopathological findings of “miliary foci” and neurofibrillary
change in the cerebral cortex following her death at 55 years.
Types of Dementia and
characteristics
Type of Characteristics
Dementia
Alzheimer’s Difficulty remembering recent conversations, names or events is often an
disease early clinical symptom; apathy and depression.
Impaired communication, disorientation, confusion, poor judgment, behavior
changes, difficulty speaking, swallowing and walking.
Progressive accumulation of the protein fragment beta-amyloid
(plaques) outside neurons in the brain and twisted strands of the protein tau
(tangles) inside neurons
Vascular Impaired judgment or impaired ability to make decisions, plan or organize;
dementia difficulty with motor function, especially slow gait and poor balance
Brain changes of Alzheimer’s and vascular dementia commonly coexist
(Mixed dementia)
Dementia Initial symptoms of sleep disturbances, well-formed visual hallucinations, and
with Lewy slowness, gait imbalance or parkinsonian movement features. These
bodies (DLB) features and early visuospatial impairment, may occur in the absence of
memory impairment.
Types of Dementia and
characteristics
Type of Dementia Characteristics
Frontotemporal Marked changes in personality and behavior and/or difficulty with
lobar degeneration producing or comprehending language. Memory is spared in the early
(FTLD) stages. Most people with FTLD develop symptoms at a younger age.
Parkinson’s Problems with movement (slowness, rigidity, tremor and changes in gait)
disease (PD) are common symptoms of PD.
As PD progresses, it often results in dementia secondary to the
accumulation of Lewy bodies in the cortex (similar to DLB) or the
accumulation of beta-amyloid clumps and tau tangles (similar to
Alzheimer’s).
Creutzfeldt- This very rare and rapidly fatal disorder impairs memory and coordination
Jakob disease and causes behavior changes.
Results from a misfolded protein (prion) that causes other proteins
throughout the brain to misfold and malfunction.
Normal pressure Symptoms include difficulty walking, memory loss and inability to control
hydrocephalus urination.
Onyike, Continuum (Minneap Minn) 2016;22(2):600–614.
Alzheimer’s disease
• Alzheimer’s disease is an important cause of dementia globally

• It is one of the most important health care, social, and economic


challenges of the 21st century

• The time course of AD dementia averages 7-10 years and inevitably


the illness culminates in death

• Available treatments have minimal or no effect on the course of the


disease

http://www.alz.co.uk/research/world-report-2011
Alzheimer’s Disease:
More Than Just Memory Loss
Death
Functional
Cognition Independence
Deterioration

Motor

Mood

Behavior

Baseline 5 yrs 10 yrs


Approximate Time Scale
Copyright © 2006 Neuroscience Education Institute. All rights reserved.
Risk factors for Alzheimer’s
disease
• Genetic mutations (APP, Presenelin 1, 2)

• Age above 65 years

• Family History

• Apolipoprotein E (APOE)-e4 Gene

• Mild Cognitive Impairment (MCI)


Modifiable Risk factors for
Alzheimer’s disease
• Cardiovascular Disease Risk Factors

• Social and Cognitive Engagement

• Education and Cognitive Reserve

• Traumatic Brain Injury (TBI)


Diagnosis
• National Institute on Aging (NIA) and the
Alzheimer’s Association Proposed Guidelines:

• Three stages of Alzheimer’s disease, with the first


occurring before symptoms such as memory loss
develop.

• Incorporate biomarker tests


Diagnosis
• Preclinical Alzheimer’s Disease
– biomarkers that indicate the earliest signs of disease, but no
noticeable symptoms

• MCI Due to Alzheimer’s Disease


– Mild but measurable changes in thinking abilities that are
noticeable to the person affected and to family members and
friends
– Do not affect the individual’s ability to carry out everyday
functioning
– Biomarkers
Diagnosis
• Dementia Due to Alzheimer’s Disease

– Noticeable memory, thinking and behavioral symptoms.


– Unlike MCI, impair a person’s ability to function in daily
life.
Biomarkers

• Biomarkers showing the level of beta-amyloid


accumulation in the brain.

• Biomarkers showing that neurons in the brain are


injured or actually degenerating.
Biomarkers
• Biomarkers of fibrillary Ab deposition:
– Low CSF Ab42 or High ligand retention on amyloid PET

• Biomarkers of tau pathology (neurofibrillary tangles):


– Elevated CSF phosphorylated tau (p-tau) and tau PET

• Biomarkers of AD-like neurodegeneration or neuronal


injury:
– CSF total tau (t-tau)
– [18F]- fluorodeoxyglucose (FDG)-PET hypometabolism,
– atrophy on structural MRI in regions characteristic of AD
Imaging Biomarkers

FDG-PET
Hypometabolism
in medial parietal and lateral
temporal-parietal isocortex

MRI
Atrophy in the medial temporal
allocortex and basal-lateral temporal isocortex

Amyloid PET
Ligand
Uptake in Jack et al,
isocortex Neurology® 2016;87:539–547
Longitudinal Changes of
Alzheimer Disease Biomarkers

Babic et al, Croat Med J. 2014 Aug; 55(4): 347–365.


Treatment of AD

• Current treatments
– Acetylcholinesterase inhibitors
• Donepezil
• Rivastigmine
• Galantamine

– NMDA antagonist
• Mementine
Treatment of AD

• Experimental treatments
– Disease modifying approaches
• Modulation of amyloid deposition
• Modulation of tau deposition
• Additional approaches (eg., cholesterol and vascular related
risk factors)

– Preventive approaches
• Antioxidant therapy
• Anti inflammatory therapy
Timeline of the emergence of various
experimental and clinical therapies for AD

Stone JG et al, Ther Adv Chronic Dis (2011) 2(1) 923


Pharmacological Treatment of AD
Cholinesterase Inhibitors
Cholinesterase Inhibitors
• Tacrine, first drug CI drug used discontinued due to hepatotoxicity

• Three CIs galantamine, donapezil, rivastigmine show benefit on


cognitive functions, ADL for patients with mild and moderate AD

• CIs delay decline in cognition as measured by ADAS-cog, ADL and


behaviour over 6-12 months

• Initiation of CI treatment in the early stages of AD is preferred

Konstantina G, Ther Adv Neurol Disord (2013) 6(1) 19–33


N-methyl-D-aspartate (NDMA)
antagonist
• Option in moderate to severe AD

• Protect neurons from excitotoxicity

• Improvement in cognition, ADL and behaviours in people with


moderate to severe AD after 6 months of use

• May reduce behavioural and psychological symptoms of dementia


(BPSD)

Konstantina G, Ther Adv Neurol Disord (2013) 6(1) 19–33


Treatment of AD

www.progressnp.com
Donapezil 23 mg/d
• Compared with patients who continued taking donepezil 10 mg/d,
those whose dose was increased to donepezil 23 mg/d demonstrated
a significantly greater cognitive benefit on the Severe Impairment
Battery after 6 months of treatment

• The 23 mg/d dose of donepezil was associated with typical


cholinergic AEs, particularly gastrointestinal-related AEs, similar to
those observed in studies with a dose increase from 5 to 10 mg/d

Farlow MR et al, Clin Ther 2010, 32(7):1234-1251


Farlow MR et al, BMC Neurology 2011, 11:57
Rivastigmine patch: access to higher
doses via improved tolerability
• Provides smooth and continuous drug delivery 1
• Reduces incidence of cholinergic AEs; 2 improves treatment adherence3
• The 9.5 mg/24 h (10 cm2) patch provides comparable efficacy to
12 mg/day rivastigmine capsule, but with improved tolerability 2

Patch Capsules Placebo


AE, n (%) (n = 291) (n = 294) (n = 302)
Any AE 147 (51) 186 (63)*** 139 (46)
Nausea 21 (7) 68 (23)*** 15 (5)
Vomiting 18 (6) 50 (17)*** 10 (3)
Diarrhoea 18 (6) 16 (5) 10 (3)
Weight decrease 8 (3) 16 (5)** 4 (1)
Dizziness 7 (2) 22 (8)** 7 (2)
Decreased appetite 2 (1) 12 (4)* 3 (1)
Headache 10 (3) 18 (6)** 5 (2)
Asthenia 5 (2) 17 (6)*** 3 (1)
AEs occurring in  5% of patients in either group are reported 1
Lefèvre, G et al. Clin Pharmacol Ther 2008;83:106–14
*p < 0.05; **p < 0.01; ***p < 0.001 versus placebo
2
Winblad, B et al. Int J Geriatr Psychiatry 2007;22:456–7
3
Molinuevo, J and Arranz F. Expert Rev Neurother 2012;12:31–7
Treatment of BPSD
• BPSD include hyperactivity, affective symptoms, psychotic symptoms
and apathy

• SSRIs to treat depression in AD dementia?

• Anti-psychotics for psychotic symptoms, agitation/aggression


– Risperidone, olanzapine, quetiapine, aripiprazole

• Benzodiazepines used to reduce agitation- caution in view of rapid


cognitive decline
Treatment of BPSD
• Sensory stimulation interventions (acupressure, aromatherapy, massage/touch therapy, light
therapy)

• Cognitive/emotion-oriented interventions (cognitive stimulation, music/dance therapy, dance


therapy, reminiscence therapy, validation therapy, simulated presence therapy)

• Behaviour management techniques

• Other therapies (exercise therapy, animal-assisted therapy, special care unit and dining room
environment-based interventions)

• Music therapy was effective in reducing agitation

• Home-based behavioural management techniques, caregiver-based interventions or staff


training in communication skills, person-centred are effective for symptomatic and severe
agitation

Abraha et al, BMJ Open 2017;7


Onyike, Continuum (Minneap Minn) 2016;22(2):600–614.
Indications for discontinuation of therapy in AD

1.The patient and (or) their proxy decision maker decide to stop

2. Refusal to take the medication

3. Nonadherence to the medication

4. No response to therapy after a reasonable trial

5. Intolerable side effects

6. Comorbidities making continued use of the agent risky or futile

7. Progression to a stage of the disease where there is no significant benefit from continued
therapy
Hogan DB et al, Alzheimers Dement. 2007;3:355–384
Amyloid cascade hypothesis of AD

Massoud F. Can J Psychiatry. 2011;56(10):579–588


Disease modifying approaches to AD

• Aß and tau are prime targets


– Decrease the production of Aß and tau
– Prevent aggregation of misfolding of these proteins
– Neutralizing or removing the toxic forms of these proteins
– Combination

• Additional approaches
– Oxidative damage
– Inflammation
– Iron dysregulation
– Cholesterol metabolism
Konstantina G, Ther Adv Neurol Disord (2013) 6(1) 19–33
Sites of action of
future drug treatments

www.progressnp.com
Subgroups of AD

• There are at least five subgroups of AD based on cerebrospinal fluid


levels of Aβ1–42, a marker of Aβ plaques, and tau and ubiquitin, two
markers of neurofibrillary tangles

• These five subgroups, called AELO, ATEO, LEBALO, HARO, and


ATURO, and each present a different clinical profile

• These different AD subgroups may respond differently to a given


disease modifying drug

Iqbal K & Iqbal IG. Alzheimers Dement. 2010 September ; 6(5): 420–424
Amyloid-β immunotherapy
• Preclinical studies support the idea that AD can be prevented by amyloid-β (Aβ)
immunotherapies

• Adverse events, but some efficacy, were observed in clinical trials of the AN1792 Aβ vaccine
and the passive Aβ immunotherapy bapineuzumab

• At least 13 Aβ immunotherapies are in clinical trials in patients with mild to moderate AD

• Second-generation Aβ vaccines that avoid the adverse events observed with AN1792 and
improve antibody generation might improve Aβ immunotherapy efficacy

• Aβ immunization might be considerably more efficacious in AD if administered before Aβ


aggregation, protecting the brain from downstream neurodegenerative effects

Lemere CA & Masliah E. Nat Rev Neurol. 2010 February ; 6(2): 108–119
Active immunotherapy for AD
• Development of an immunotherapy that can delay AD onset by 5
years would reduce the prevalence of the disease by half

• Delaying onset for 10 years would almost eradicate symptomatic AD

• The new second-generation vaccine comes as a welcome and


promising addition to available evidence on what will probably be a
long road to the ultimate successful immunotherapy

Wisniewski T, Lancet Neurol. 2012 July ; 11(7): 571–572


Other drugs
• Human studies of statins show highly variable outcomes, making it
difficult to draw firm conclusions

• Estrogens and androgens exert a wide range of protective actions


that improve multiple aspects of neural health, suggesting that
hormone therapies have the potential to combat AD pathogenesis

• LH ablating therapies
Preventive therapies
• Antioxidant therapy
– Oxidative stress
– Reactive oxygen species (ROS)
– MitoQ
– ALCAR and LA

• Anti-inflammatory therapy
– NSAID and low risk for AD
– Naproxen

Stone JG et al, Ther Adv Chronic Dis (2011) 2(1) 923


Antioxidant Therapies for AD
• Metabolic antioxidants, mitochondria-directed antioxidants, and SS peptides have
proved to be effective in AD mouse models and small clinical studies

• It has also been shown that treatment with antioxidants vitamin E, vitamin C,
selegiline, estrogen, Ginkgo biloba, and so forth may exert certain positive effects
on the development of AD

• But the efficacy of those antioxidants in clinical patients is still controversial and not
so conclusive

• Clinical trials for AD prevention and treatment by antioxidants are still in their
infancy

Feng Y & Wang X. Oxidative Medicine and Cellular Longevity Volume 2012 Article ID 472932
Nutrition
• Mediterranean diet (plant-based foods in abundance, fresh fruit as
the typical daily dessert, olive oil as the principal source of fat, dairy
products - principally cheese and yogurt, fish and poultry consumed
in low to moderate amounts, zero to four eggs consumed weekly, red
meat consumed in low amounts and wine consumed in low to
moderate amounts)

• A meta-analysis of eight prospective studies related to Mediterranean


diet indicate significant reduction in incidence of Parkinson’s disease
and AD (13%)

Thaipisuttikul P & Galvin JE, Clin Pract (Lond). 2012 March ; 9(2): 199–209
Nonpharmacological Treatment of AD

• Various nonpharmacological interventions confer cognitive benefits to


people with AD

• The nonpharmacological interventions include:


– Cognitive training
– Cognitive rehabilitation and Implicit learning
– Cognitive stimulation therapy (CST)
– Reality Orientation

• There may be additive benefits by combining nonpharmacological


interventions and cholinesterase inhibitor therapy
Ballard C et al. Can J Psychiatry. 2011;56(10):589–595
Noninvasive brain stimulation in AD
• TMS holds promise as a physiologic biomarker in AD to identify therapeutic
targets and monitor pharmacologic effects

• Short-latency afferent inhibition and resting motor threshold are reduced in AD

• Motor cortical plasticity and connectivity are impaired in AD

• TMS/tDCS may have therapeutic utility in AD, but evidence is still very
preliminary

• TMS/tDCS appear safe in AD, but longer-term risks have been insufficiently
considered
Freitas C et al, Exp Gerontol. 2011 August ; 46(8): 611–627
Deep brain stimulation for AD
• The evidence of functional alterations in memory networks is commonly seen in AD
patients

• Patients with AD have defects in heteromodal interconnected cortical areas known


collectively as the “default mode network”

• It is possible that AD be considered a circuit disorder as well as a degenerative


disease

• It may be possible to improve or sustain cognitive function in early AD, particularly


memory within the integrated cognitive networks involving the hippocampus and
cortex, by stimulation at the level of the fornix

Lyketsos CG et al, Innov Clin Neurosci. 2012;9(11–12):10–17


Conclusions
• Currently available treatments for AD are donepezil,
rivastigmine, galantamine and memantine

• These are symptomatic and do not decelerate or prevent


the progression of the disease.

• These therapies demonstrate modest, but particularly


consistent, benefit for cognition, global status and functional
ability
Conclusions
• The development of disease-modifying drugs for AD is recognized as a worldwide
necessity

• The search for disease-modifying interventions has focused largely on compounds


targeting
– the Aβ pathway
– tau deposition and hyperphosphorylation
– neuroinflammation
– oxidative stress
– stabilizing mitochondrial function,
– ablate LH production

• The role of non-pharmacological interventions should be considered for the


treatment of AD

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