Dementia (Kaminski)

What are the signature lesions in Alzheimer’s?

Which neurons and NTs are affected?

• Amyloid plaques and neurofibrillary tangles

• Reduction in number of cholinergic neurons and loss of nicotinic receptors

  • Basically ACh

How is AD diagnosed

Diagnosis of exclusion

• Only way to confirm diagnosis is with autopsy or biopsy

• Should evaluate blood cell counts, electrolytes, liver function tests, thyroid, and B12 to rule out other causes

• Imaging (MRI, CT) recommended by guidelines

What are the stages of dementia

What is the MMSE score of each

• Mild Cognitive impairment

• Mild dementia (26-21)

• Moderate dementia (20-10)

• Severe dementia (9-0)

Patient characteristics of Mild Cognitive Impairment (MCI)

• Precedes dementia

• Cognitive complaints that do not impact patient functioning

Patient characteristics of Mild dementia

• Difficulty remembering recent events

• Ability to manage finances, prepare food, and carry out other household activities declines

• May get lost when driving

• Begins to withdraw from difficult tasks and give up hobbies

Patient characteristics of Moderate dementia

• Requires assistance with activities of daily living (ADLs)

• Frequently disoriented to time (date, year, season)

• Severe impairment to recall of recent events

• Begins to lose long term memory (life events, names of family members)

• Functioning may fluctuate

• Unable to drive safely

• May become suspicious or tearful; agitation, paranoia, delusions common

Patient characteristics of Severe dementia

• Loses ability to speak, walk and feed self

• Incontinent of urine and feces

• Requires around the clock care

What are the treatment goals for a patient diagnosed with AD

Primary Goals

• Symptomatically treat cognitive difficulties

• Preserve patient function for as long as possible

Secondary Goals

• Managing psychiatric and behavioral sequelae

Do current treatments prolong life?

Current treatments do NOT prolong life, cure AD, or halt or reverse pathophysiology

What type of treatment should be done first

Nonpharm treatment

What are some general principles for interacting with someone with AD

• Consider vision, hearing, or other sensory impairment

• Find optimal level of patient autonomy and adjust expectations over time

• Avoid confrontation – remain calm, firm, and supportive; validate feelings

• Maintain a consistent, structured environment with appropriate level of stimulation

• Provide frequent reminders and orientation cues

• Reduce choices, keep requests simple, avoid complex tasks

• Redirect to an enjoyable activity
  
  “Meet the patient where they are at”

How should we address symptoms of AD like sleep disturbances and incontinence

Use behavioral interventions rather than meds whenever possible for symptom management

1. Sleep hygiene for sleep disturbances

2. Redirection for wandering

3. Identifying triggers for agitation and aggression

4. Bladder training/habit training for incontinence

Who needs to be educated aside from the patient

Caregiver

Which meds are associated with cognitive impairment

• Benzodiazepines and sedative hypnotics

• Anticholinergics

• Antipsychotics

Which meds can cause delirium or acute cognitive changes

• H2 receptor antagonists

• Corticosteroids

• Merperidine

What would we want to do with the meds that cause delirium and cognitive impairment

Deprescribe where possible/clinically appropriate

How do you treat MCI due to AD

Anti-amyloid mAb

How do you treat mild-moderate AD

Cholinesterase inhibitor (or anti-amyloid mAb)

How do you treat moderate-severe AD

• Memantine

• Memantine + cholinesterase inhibitor

  • or Donepezil or Rivastigmine patch alone

List the Cholinesterase inhibitors

• Donepezil (Aricept)

• Rivastigmine (Exelon)

• Galantamine (Razadyne, Razadyne ER)

• Benzgalantamine (Zunveyl) (new)

What is the MOA of Cholinesterase inhibitors

Inhibit hydrolysis of ACh by AChE → enhance cholinergic activity

What are the Adverse Effects with Cholinesterase Inhibitors

• Dizziness, syncope

• Bradycardia*, atrial arrhythmias, SI and AV block, MI

• N/V/D, anorexia, weight loss

• Peptic ulcer disease, GI bleed

• Insomnia, vivid dreams, nightmares
  

*C/I if HR <50 BPM

What is monitored with Cholinesterase Inhibitors

• Reports of dizziness or falls

• Pulse at baseline, monthly during dose titration and every 6 months

• Periodic BP and postural BP changes

• Weight and GI complaints

• Signs/Symptoms of GI bleed

• Complaints of sleep disturbances, daytime drowsiness

Which Cholinesterase Inhibitors are available as a patch?

How frequently is each patch applied?

• Donepezil (Adlarity) applied once weekly

• Rivastigmine (Exelon Patch) applied daily

Which needs dose adjustments for renal or hepatic impairment

Rivastigmine

Which can cause serious skin reactions, like SJS

Galantamine

Goal dose is reached by titration over several weeks.

What would cause titration to restart and what would happen then?

Titration for a treatment interruption due to potential for GI upset will have to restart

Memantine (Namenda) MOA

NMDA receptor antagonist

• Blocking NMDA receptors mitigates excitatory neurotoxicity and potentially provides neuroprotection

Memantine (Namenda) adverse effects

• Generally well tolerated

• HA, confusion, dizziness, hallucinations

• Constipation

Memantine (Namenda) Counseling

• Interruptions require re-titration of dose

• Taken w/ or w/o food

• Capsules can be open and sprinkled on applesauce

Does Memantine require dose adjustments for renal or hepatic impairment

Yes

• Not recommended w/ severe renal or hepatic impairment

Memantine goal dose

Titrated up to goal dose over several weeks and interruptions require re-starting the titration

What is the name of the product that combines Memantine and Donepezil

Namzaric

Should any of these agents be stopped abruptly?

No

What are the Monoclonal Antibodies

• Aducanumab - withdrawn

• Lecanumab (Leqembi)

• Donanemab (Kisunla)

• Gantenerumab (in trial)

Which stage(s) of disease are these approved for

FDA approved for MCI due to AD or mild AD

Monoclonal Antibodies MOA

Is there any evidence that this mechanism has a significant effect on symptoms?

• Anti-amyloid antibodies bind to and remove amyloid in the brain

• Currently approved agents show modest slowing of cognitive decline, not reversal

Monoclonal Antibodies adverse effects

• Infusion related reactions

• Amyloid-related imaging abnormalities (ARIA)

  • Cerebral edema (ARIA-E)

  • Microhemorrhage (ARIA-H)

What monitoring is needed because of these AE

• Test for ApoE ε4 allele (not used in homozygotes)

• Consider patients on anticoagulation

• All mAbs require baseline and routine MRIs to monitor for ARIA - specific recs for each

• Monitor for HA, confusion, dizziness, visual disturbances, nausea, gait difficulty, seizures

What is the dosage form of mAbs

What else should be known

• Lecanemab (IV and SubQ)

• Donanemab (IV)

• require a provider to administer

• Require significant (and expensive!) monitoring

What are some examples of neuropsychiatric symptoms

• Psychotic

• Hyperactive - inappropriate or disruptive behavior

• Affective - depression

• Apathy - lack of emotion
  
  Often reason for nursing home placement

How should neuropsych symptoms first be addressed

Nonpharm therapy

• Identify and eliminate potential causes – medications, illnesses, environment

• Identify triggers – noise, glare, background distractions, personal discomfort (pain, hunger, thirst, skin irritation, temperature, fear)

• Redirect patient rather than confront

When are meds warranted for neuropsych symptoms

• Are severe enough to cause significant distress to patient or caregivers

• Interfere with function/cause disability

• Impede delivery of necessary care

• Pose a danger to self or others

• Have not responded to nonpharmacologic measures

What are general best practices for pharm treatment?

• General principles:

  • Reserve for situations where nonpharmacologic therapies have failed

  • Used reduced doses

  • Monitor closely

  • Titrate doses slowly

  • Minimize duration of therapy

  • Attempt tapers/discontinuation – behaviors fluctuate over time

  • Document carefully

• Treatment should be considered temporary

• Manage caregiver expectations

Which antidepressants are generally preferred?

Which class should be avoided

• SSRIs generally preferred based on AE, risk of interactions, and efficacy

  • Best evidence for Sertraline and Citalopram

• Avoid tricyclic antidepressants

Which antipsych has an FDA-approved indication for management of agitation associated with AD

Brexpiprazole (Rexulti)

What is the BBW for all antipsychs?

What other AEs of antipsychs may be concerning in AD patients

• BBW

  • increased risk of mortality in older adults with dementia related psychosis

  • Suicidal thoughts and behaviors

• Risk of sedation

• Extrapyramidal symptoms

• Anticholinergic effects

• Hypotension