ALZHEIMER’S DISEASE

CLINICAL ASSESSMENT AND MANAGEMENT

Dr Ravi SoniDM Geriatric Psychiatry

WHAT IS ON PLATE TODAY?

What is Dementia? What is Alzheimer’s Disease? Symptomatology Clinical Assessment Management: Brief

WHAT IS DEMENTIA? Dementia refers to a spectrum of brain disorders all of which involve cognitive impairment but vary widely in terms of cause, course and prognosis. Progressive loss of cognitive/intellectual functions. Without impairment of consciousness. There is disturbance of multiple higher cortical functions, including memory, thinking, orientation, comprehension, calculation, learning capacity, language, and judgment.

DEMENTIA: BACKGROUND Dementia : De = Out from + mens = the mind

Loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning Usually irreversible disorder Egyptians and Greeks of the period 2000-1000 BC were aware of age related memory decline India : Dementia : Smiriti Bhransh : 800 BC : Sathiya Gaye (Turned 60) : Satar- Batar (Turned 70) : “Chinan” in South India

EPIDEMIOLOGY AD is the most common cause of dementia amongst people aged 65 and older Prevalence among people over 60 years–5% to 8 % Starting with 0.5% prevalence at 55 yrs., it goes on doubling every five years (60yrs-1%; 65yrs-2%; 70yrs- 4%; 75yrs- 8% and so on) Risk at the age of 80 years is around 15 to 20% At present nearly 47.5 million people worldwide with dementia. It is expected to be 74.7 million by 2030 and 131.5 million by 2050. About 7.7 million new cases of dementia each year. A new case detected in every 3 seconds somewhere in world. (WHO)

Average prevalence of dementia in India: 3.7%

DEMENTIA OF ALZHEIMER’S TYPE Alzheimer’s disease (AD) is the most common form of dementia, representing approximately 55-60% of all cases. In 1907, Alois Alzheimer first described the condition that later assumed his name. It is a cortical dementia characterized by a slow, progressive loss of cognitive functions. AD is the fourth leading cause of death in USA. No Indian data is available regarding it.

DEMENTIA OF ALZHEIMER’S TYPE Characterized by:Progressive loss of cortical neuronsFormation of amyloid plaques (beta-amyloid is major component) Intra-neuronal neurofibrillary tangles (hyper phosphorylated tau proteins is major constituent)

PATHOGENESIS AND PATHOPHYSIOLGY AD is characterized by generalized cerebral cortical atrophy with widespread cortical neuritic (or senile) plaques (NPs) and neurofibrillary tangles (NFTs). Following mechanisms have been attributed for the development of Alzheimer’s dementia Amyloid cascade theory Neuronal loss Cholinergic hypothesis Excitotoxicity Genetic factors

DIAGNOSIS OF AD (DSM IV TR)A. The development of multiple cognitive deficits manifested by both

1. Memory impairment (impaired ability to learn new information or to recall previously learned information) 2. One (or more) of the following cognitive disturbances:

A. Aphasia (language disturbance) B. Apraxia (impaired ability to carry out motor activities despite intact motor function) C. Agnosia (failure to recognize or identify objects despite intact sensory function) D. Disturbance in executive functioning (i.e., planning, organizing, sequencing, abstracting)

B. The cognitive deficits in Criteria A1 and A2 each cause significant impairment in social or occupational functioning and represent a significant decline from a previous level of functioning.

C. The course is characterized by gradual onset and continuing cognitive decline. D. The cognitive deficits in Criteria A1 and A2 are not due to any of the following: 1. Other central nervous system conditions that cause progressive deficits in memory and cognition

(e.g., cerebrovascular disease, Parkinson's disease, Huntington's disease, subdural hematoma, normal-pressure hydrocephalus, brain tumor)

2. Systemic conditions that are known to cause dementia (e.g., hypothyroidism, vitamin B12 or folic acid deficiency, niacin deficiency, hypercalcemia, neurosyphilis, HIV infection)

3. Substance-induced conditionsE. The deficits do not occur exclusively during the course of a delirium. F. The disturbance is not better accounted for by another Axis I disorder (e.g., major

depressive disorder, schizophrenia).

DIAGNOSTIC TYPES Early onset: < 65 years; familial types; 1, 14 and 21 chromosomes. Late onset: >65 years usually in 70s; sporadic form; Chromosome 19. Mixed: not fitting into above two Unspecified:

STAGES OF ILLNESS DEVELOPMENT Stage 1: Normal Stage 2: Normal aged forgetfulness Stage 3: Mild Neuro-cognitive disorder (MCI) Stage 4: Mild Alzheimer’s Disease Stage 5: Moderate Alzheimer’s Disease Stage 6: Moderately severe Alzheimer’s Disease Stage 7: Severe Alzheimer’s Disease

FAST SCALE (FUNCTIONAL ASSESSMENT STAGING) STAGE 1: No impairment STAGE 2: Complaints of forgetting location of objects. Subjective work difficulties STAGE 3: Decreased job functioning evident to co-workers. Difficulty in traveling to new places. Decreased organizational capacity. STAGE 4: Decreased ability to perform complex tasks, e.g., planning dinner for guests, handling personal finances, difficulty in marketing etc. STAGE 5: Requires assistance in choosing proper clothing to wear for the day, season or occasion, e.g., patient may wear the same clothing repeatedly, unless supervised.

FAST SCALE (FUNCTIONAL ASSESSMENT STAGING) Stage 6:a) Improperly putting on clothes without assistance

or cuing occasionally or more frequently over the past few weeks

b) Unable to bathe properlyc) Inability to handle mechanics of toileting d) Urinary incontinence e) Fecal incontinence

FAST SCALE (FUNCTIONAL ASSESSMENT STAGING) Stage 7:a) Ability to speak limited to approximately a half a dozen

intelligible different words or fewer, in the course of an average day or in the course of an intensive interview.

b) Speech ability limited to the use of single intelligible word in an average day or in the course of an intensive interview (may repeat the word over and over)

c) Ambulatory ability lostd) Cannot sit up without assistancee) Loss of ability to smilef) Loss of ability to hold up head independently

STAGING OF AD IN 3 CATEGORIES: Mild: Although work or social activities are significantly impaired, the capacity for independent living remains, with adequate personal hygiene & relatively intact judgment (~1-3 yrs) Moderate: Independent living is hazardous & some degree of supervision is necessary (~2-8 yrs) Severe: Activities of daily living are so impaired that continuous supervision is required, e.g., unable to maintain minimal personal hygiene; largely incoherent or mute.

EARLY SYMPTOMS: Forgetfulness, especially for recent events Difficulty doing tasks with many steps Feeling lost or disoriented in familiar places Difficulty making quick decisions Problems finding the right words Moodiness, loss of interest in new projects, social activities, anxiety, or depression

TEN WARNING SIGNS OF AD1. Memory loss that affects job skills2. Difficulty performing familiar tasks3. Problems with language4. Disorientation to time and place5. Poor or decreased judgment6. Problems with abstract thinking7. Misplacing things8. Changes in mood or behavior9. Changes in personality10.Loss of initiative (Alzheimer’s Association)

NEURO-PSYCHIATRIC SYMPTOMS IN AD

Neuro-psychiatric domains:

1. Delusions2. Hallucinations3. Agitation/Aggression4. Depression/Dysphoria5. Anxiety6. Elation/Euphoria7. Apathy/Indifference

8. Disinhibition9. Irritability/Lability10.Aberrant motor behavior

Vegetative domains:11.Sleep and Nighttime Behavior

Disorders12.Appetite and Eating Disorders

Neuro-Psychiatry Inventory

OTHERS: Sundowning: Drowsiness, confusion, ataxia, falls Catastrophic reaction Wandering Incontinence Inappropriate Sexual Behaviors

PERSONALITY CHANGES Loss of awareness and normal responsiveness to environment

Individuals may become more anxious or fearful

There is flattening of affect and a withdrawal from challenging situations

Aggressiveness may be exhibited

TYPICAL WORK-UP OF AD PATIENTS: History taking Physical and Neurological examination Mental status Functional assessment Laboratory work-up Neuro-imaging

HISTORY TAKING History taking: Collateral history is very important From patient Informant: one who lives with the patient throughout the day, taking care of patient, helping in daily activities

Another informant: to confirm findings, suspected cases of abuse and neglect

Attention should be paid to Mode of onset, Course of progression, Pattern of cognitive impairment Presence of non-cognitive symptoms such as behavioral disturbance, hallucinations and delusions

HISTORY TAKING:

History taking as per ABC: A: Activities of daily living (ADL) B: Behavioral and Psychological symptoms of dementia C: Cognition

SYMPTOMS FROM DECREASED FUNCTIONING OF DIFFERENT COGNITIVE DOMAINS:

HISTORY TAKING:o Activities of daily living: (ADL) Basic activities:•Bathing, dressing, toileting, transferring, continence, Feeding etc.

Instrumental activities: • Ability to use telephone• Shopping• Food preparation• Laundry• House keeping• Ability handle finances, responsibility of own medications, mode of transportation

HISTORY TAKING:o Behavioral and Psychological symptoms of dementia: Types of delusions encountered in AD: patient believe that he/she is in danger ‐ that others are planning to hurt him/her? others are stealing from him/her? his/her spouse is having an affair? unwelcome guests are living in his/her house? his/her spouse or others are not who they claim to be? his/her house is not his/her home? family members plan to abandon him/her? television or magazine figures are actually present in the home? (Does he/she try to talk or interact with them?)

HISTORY TAKING: Past history: Family history: Medication history: Medical history: Family assessment: Examination: General Physical Examination Systemic examination: Neurological Mental status examination:

COGNITIVE ASSESSMENT: Can be done by: MMSE: Mini Mental Status Examination HMSE: Hindi Mental Status Examination HCST: Hindi Cognitive Screening Test Detailed assessment can be done by separate tests for each cognitive domains Based on the basic assessment the patient can be categorized into: Mild: 20-24 Moderate: 10-19 Severe: <10

• CDT (clock drawing test): if the patient has MMSE more than 24 than try CDT

• If CDT is abnormal than dementia is confirmed

• CDT + Delayed recall: MINI Cog

RECOMMENDATIONS FOR DIAGNOSTIC CRITERIA

o DSM-IV or NINCDS-ADRDA criteria should be used for the diagnosis of Alzheimer’s diseaseo The Hachinski Ischemic Scale or NINDS-AIRENS criteria may be used to assist in the diagnosis of vascular dementia.o Diagnostic criteria for dementia with Lewy bodies and fronto-temporal dementia should be considered in clinical assessment. o Clinical criteria for dementia with Lewy bodies (Consortium for DLB criteria) fronto-temporal dementia (Lund-Manchester criteria) are not closely associated with neuropathological diagnoses but can still provide useful differentiating clinical features

NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders AssociationNINDS-AIREN: National Institute of Neurological Disorders and Stroke- Association Internationale pour la Recherche et l'Enseignement en Neurosciences

DIAGNOSIS: Initial Cognitive Testing: MMSE is used widely for screening purpose It provides superficial assessment of memory, language, visuoperceptual function. Processing speed and executive function are not tested. Evidence from a systematic review has shown that the MMSE is suitable for the detection of dementia in individuals with suspected cognitive impairment

Recommendations: In individuals with suspected cognitive impairment, the MMSE should be used in the diagnosis of dementia. Initial cognitive testing can be improved by the use of Addenbrooke’s Cognitive Examination, Montreal Cognitive Assessment (MoCA) A questionnaire, such as the IQCODE, completed by a relative or friend may be used in the diagnosis of dementia (The Informant Questionnaire on Cognitive Decline in the Elderly)

MoCA assesses executive functions, it is particularly useful for patients with vascularimpairment, including vascular dementia.

DETAILED ASSESSMENT:o Alzheimer’s Disease Assessment Scale- Cognitive and Non-Cognitive Sections (ADAS-Cog, ADAS Non-Cog)o Cambridge Assessment of Memory and Cognition (CAM Cog)o PGI Battery of Brain Dysfunction (PGIBBD)o NIMHANS neuropsychological battery for elderlyo AIIMS comprehensive neuropsychological battery in Hindi: assessment of Lobar functions

RECOMMENDATIONS FOR NEUROPSYCHOLOGICAL TESTING

Assessment of cognition is useful in both the initial and differential diagnosis of dementia It is possible to detect even very early Alzheimer’s disease using neuropsychological testing. Neuropsychology is superior to imaging in discriminating people with AD from controls. Neuropsychological testing also aids in the differential diagnosis of dementia:• FTD is characterized by deficits of semantic memory and attention/executive function rather than the episodic memory deficit seen in AD

• Dementia with Lewy bodies has more pronounced visuoperceptual and frontal impairment compared to AD

• Vascular dementia exhibits executive dysfunction • Depression shows a subcortical pattern of cognitive impairment

RECOMMENDATIONS FOR NEUROPSYCHOLOGICAL TESTING

o Recommendation: Neuropsychological testing should be used in the diagnosis of dementia, especially in patients where dementia is not clinically obvious.

o It may be useful to repeat neuropsychological testing after six to 12 months in patients where: The diagnosis is unclear Measurement of the progression of deficits in a typical pattern supports a diagnosis of dementia and helps in differential diagnosis.

LABORATORY WORK UP: Routine Blood Examination:o CBCo RFTo LFTo RBSo Lipid profileo Vit. B12 and folate (based on affordability)o Vit. D3 (Based on affordability)o Serum Homocysteine level (if Vascular risk factors present)o Urine Routine and microscopic examination

• ECG and CXR: When needed• HB1AC: Diabetes, when RBS is

increased• Screening for syphilis: only in high risk

individual• HIV screening: only in high risk

individual Screening for Genetic markers: Not recommended

THE ROLE OF CEREBROSPINAL FLUID AND

ELECTROENCEPHALOGRAPHY: There is insufficient evidence to support routine use of CSF markers in the diagnosis of dementia.

Recommendations: CSF and EEG examinations are not recommended as routine investigations for dementia.

CSF and EEG examinations may be useful where CJD is suspected.

IMAGING: The use of Imaging: The ability of clinical examination (for example, history-taking and physical examination) to predict a structural lesion has been reported as having sensitivity and specificity of 90%.

Imaging can be used to detect reversible causes of dementia and to aid in the differential diagnosis of dementia. The choice of imaging technique varies widely, and includes CT scan, MRI, SPECT and PET.

Assessment of delayed recall is at least as good as volumetric MRI in distinguishing people with probable AD from controls.

Recommendation: Structural imaging should ideally form part of the diagnostic workup of patients with suspected dementia.

Recommendation: CT may be used in combination with CT to aid the differential diagnosis of dementia when the diagnosis is in doubt.

PHARMACOLOGICAL INTERVENTIONS: Core symptoms: Cognitive decline: all cholinesterase inhibitors Functional decline: all cholinesterase inhibitors Social decline: no evidence

Associated symptoms: Agitation: Trazodone and ? SSRI Aggression: Antipsychotics Depression: Antidepressants Psychosis: Donepezil, Rivastigmine, Antipsychotics Repetitive vocalization: no evidence ? SSRI Sleep disturbance: no evidence Non-specific behavior disturbance: all cholinesterase inhibitors and antidepressants

PHARMACOLOGICAL INTERVENTIONS: DONEPEZIL

Recommendations for Donepezil:o Donepezil, at daily doses of 5 mg and above, can be used to treat cognitive decline in people with Alzheimer’s disease.o Age and severity of Alzheimer’s disease should not be contraindications to the use of donepezil.o A systematic review of the use of donepezil in people with vascular dementia demonstrated some benefit to patients with mild to moderate cognitive impairment examined over a six month period.o Donepezil, at daily doses of 5 mg and above, can be used for the management of associated symptoms in people with Alzheimer’s disease.

PHARMACOLOGICAL INTERVENTIONS: GALANTAMINE

Galantamine is effective for the maintenance of cognition in people with mild to moderate Alzheimer’s disease. There is evidence of some cognitive benefit to patients with mixed Alzheimer’s disease and cerebrovascular disease. Recommendations for Galantamine: Galantamine, at daily doses of 16 mg and above, can be used to treat cognitive decline in people with Alzheimer’s disease and people with mixed dementias. Galantamine should be used with slow escalation to doses of up to 24 mg. Galantamine, at daily doses of 16 mg and above, can be used for the management of associated symptoms in people with Alzheimer’s disease. Evaluation of the efficacy of Galantamine in people with moderate to severe dementia needs further research.

PHARMACOLOGICAL INTERVENTIONS: RIVASTIGMINE

Recommendations for Rivastigmine: Rivastigmine, at daily doses of 6 mg and above, can be used to treat cognitive decline in people with Alzheimer’s disease. Rivastigmine, at daily doses of 6 mg and above, can be used to treat cognitive decline in people with dementia with Lewy bodies and dementia associated with Parkinson’s Disease. Rivastigmine, at daily doses of 6 mg and above, can be used for the management of associated symptoms in people with Alzheimer’s disease and dementia with Lewy bodies.

PHARMACOLOGICAL INTERVENTIONS: Memantine: The efficacy of memantine has been examined in people with moderate to severe Alzheimer’s disease and mild to moderate vascular dementia.

Recommendations: Memantine can be used in the dose of 20 mg per day in a patient with moderate to severe Alzheimer’s disease.

Antidepressants:The use of antidepressants for patients with dementia accompanied by depressive symptoms is widespread, but their effect on depression and cognitive function is uncertain.

Antidepressants can be used for the treatment of comorbid depression in dementia providing their use is evaluated carefully for each patient.

PHARMACOLOGICAL INTERVENTIONS: ANTIPSYCHOTICS

Recommendation: If necessary, conventional antipsychotics may be used with caution, given their side effect profile, to treat the associated symptoms of dementia. The atypical antipsychotics, olanzapine and risperidone are useful in the management of psychotic symptoms, aggression and other behavioral problems associated with dementia. Atypical antipsychotics with reduced sedation and extrapyramidal side effects may be useful in practice, although the risk of serious adverse events such as stroke must be carefully evaluated. In patients on stable antipsychotic regimens, who are free from behavioral disturbances, withdrawal of antipsychotic treatment may not be associated with relapse.An individualized approach to managing agitation in people with dementia is required.Where antipsychotics are inappropriate cholinesterase inhibitors may be considered. In patients who are stable antipsychotic withdrawal should be considered.

PHARMACOLOGICAL INTERVENTIONS: Trazodone: One small RCT of trazodone showed reduction in agitation when accompanied by depressive symptoms in patients with dementia.

Trazodone may be considered for patients with depressive symptoms and dementia associated agitation.

Clinically Ineffective Interventions: Anti-inflammatories Melatonin Estrogen Physostigmine Selegiline

PHARMACOLOGICAL INTERVENTIONS: Intervention lacking evidence of clinical effectiveness Anticonvulsants: Anticonvulsants may be considered for the symptomatic treatment of seizures or myoclonus associated with dementia but are not recommended for other symptoms of dementia.

Aspirin: Aspirin is only recommended in people with vascular dementia who have a history of vascular disease.

Benzodiazepines: No systematic reviews or RCTs examining the usefulness of benzodiazepines in the management of associated symptoms of dementia, including anxiety, were identified.

Lithium In the absence of concurrent evidence of bipolar affective disorder lithium is not recommended for the reduction of behavioral problems in dementia.

TREATMENT FOR SLEEP DISTURBANCES:o Interventions include maintaining daytime activities and giving careful attention to sleep hygiene.Pharmacological intervention could be considered when other approaches have failed.

o If a patient also requires medication for another psychiatric condition, an agent with sedating properties, given at bedtime, could be selected.o Primarily for the treatment of sleep disturbance, medications with possible effectiveness include trazodone, zolpidem, or zaleplonBenzodiazepines are not recommended for other than brief use because of risks of daytime sedation, tolerance, rebound insomnia, worsening cognition, falls, disinhibition, and delirium.

Diphenhydramine is not recommended because of its anticholinergic properties.

Antipsychotic medications should not be used solely for the purpose of treating sleep disturbances.

NON-PHARMACOLOGICAL INTERVENTIONS: BRIEF Non-pharmacological interventions are used to ensure that underlying causes of behavioral disturbance are explored and to provide personalized approaches to presenting problems.

CORE SYMPTOMS: Cognitive decline Functional decline Social decline

ASSOCIATED SYMPTOMS: Agitation Aggression Depression Psychosis Repetitive Vocalization Sleep disturbance Non-specific behavior Disturbance

NON-PHARMACOLOGICAL INTERVENTIONS: BRIEF COGNITIVE DECLINE: Cognitive stimulation: may occur informally through recreational activities, or formally through specific activities Recommendation: Cognitive stimulation should be offered to individuals with dementia. Reality Orientation Therapy: [ROT] The purpose of ROT is to reorientate the person by means of continuous stimulation and repetitive orientation to the environment. Recommendation: Reality orientation therapy should be used by a skilled practitioner, on an individualized basis, with people who are disorientated in time, place and person.

NON-PHARMACOLOGICAL INTERVENTIONS: BRIEF Functional Decline: Caregiver intervention programs: Caregiver intervention ranges from the simplest reassurance to the most complex multi-faceted interaction with the person with dementia, including in one case, a caregiver residential program. Improvement in associated symptoms of dementia Improvement in basic daily activities and other functional activitiesDelay in nursing home placement

Recommendation: Caregivers should receive comprehensive training on interventions that are effective for people with dementia. Reality orientation therapy has been also found to be effective

Social Decline: No robust evidence identified

NON-PHARMACOLOGICAL INTERVENTIONS: BRIEF

Agitation: Aromatherapy and recreational activities are beneficial

Aggression: no robust evidence identifiedDepression: Behavior management is beneficialPsychosis: no robust evidence identifiedRepetitive vocalization: no robust evidence identifiedSleep disturbance: no robust evidence identified, sleep hygiene

Non-specific behavior disturbance: Care giver intervention and training, multisensory stimulation and recreational activities have shown benefits

NON-PHARMACOLOGICAL INTERVENTIONS: BRIEF

Interventions showing short term benefit but the benefits are not sustained once intervention stopped:Aroma therapyLight therapyMusic therapyMulti sensory stimulationPhysical activities Recreational activitiesSimulated presenceValidation therapy

INFORMATION FOR DISCUSSION WITH PATIENTS AND CARERS Supportive information for patients and carers:Patients and carers should be offered information tailored to the patient’s perceived needs.

Good communication between healthcare professionals, patients and carers is essential.

Disclosure of the diagnosis: Healthcare professionals should be aware that many people with dementia can understand their diagnosis, receive information and be involved in decision making. Healthcare professionals should be aware that some people with dementia may not wish to know their diagnosis. Healthcare professionals should be aware that in some situations disclosure of a diagnosis of dementia may be inappropriate. The wishes of the person with dementia should be upheld at all times. The diagnosis of dementia should be given by a healthcare professional skilled in communication or

counselling. Where diagnosis is not disclosed there should be a clear record of the reasons.

INFORMATION FOR DISCUSSION WITH PATIENTS AND CARERS Information at other stages of the patient journey: Information provision at other stages of the patient’s journey of care is generally more focused on carer needs than

that of the patient. In decision making, people with mild dementia are more involved, largely in a collaborative role. Beyond that carers

generally make final decisions. Patients and carers should be provided with information about the services and interventions available to them at all stages of the patient’s journey of care.

Information should be offered to patients and carers in advance of the next stage of the illness. Methods of disseminating information which may be appropriate for people with dementia and their carers include: Written information Individual education programs Group education programs Counselling Telemedicine service Communication workshops Cognitive behavior therapy (CBT) Stress management Combinations of the above.

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