Memory changes across the spectrum of brain aging.

Douglas Galasko, MDProfessor, Department of Neurosciences, UCSD

Disclosures

Dr Galasko receives research grant funding from NIH, Michael J Fox Foundation and the California Institute for Regenerative Medicine

Editor of Alzheimer’s Research and Therapy

DSMB for clinical trials: Eli Lilly, Astra-Zeneca, Prothena

Consultation: VTV Therapeutics, Axovant Therapeutics

MCI

Normal brain aging

Tangles

Cognition and function

Brain Pathology

Vascular disease

Preclinical AD Dementia

1. How does memory change with ‘normal aging?’

2. How can we preserve brain health in aging?

3. How do we diagnose Mild Cognitive Impairment (MCI) and

Alzheimer’s disease?

60% or more of older people complain about their memory … why?

• Aging• Depression• Anxiety• Medications with CNS side effects• Neurological illness e.g. stroke• Medical illness e.g. heart, lungs, kidney• Sleep disturbance• MCI• Dementia

Memory Complaints in Healthy Aging

Recalling names/words 83%

Recalling where you put things 60%

Knowing you told someone something 49%

Forgetting a task after starting it 41%

Losing the thread of conversation 40%

Bolla et al., Archives of Neurology, 1991

Cognitive changes and “normal” aging

Worse•Memory: can learn new information well, but slower and less efficient•Decreased recall (retrieval) ability:

e.g. remembering people’s names, occasional word-finding … tip of tongue•Slowing of cognition and motor function•Difficulty multi-tasking, easier attention lapses

Preserved: verbal IQ, vocabulary, remote memoryBetter: wisdom

Different types of memory

Working (short-term) memory vs remote (long-term) memory

LONG-TERM MEMORYExplicit (declarative) …. hippocampus and cortex• Semantic – facts = what ?• Episodic – events = when and where ?Implicit• Procedural memory

– Motor skills– Simple conditioning

• PerceptualEmotional memory

Age effects on components of Learning and Memory

• Learn information across repeated presentations

• Retain information over a delay

• Effectively retrieve stored information

Encoding can be affected by aging

Storage not affected by aging

Retrieval affected by aging

Evaluating memory and cognition

• Who to screen:– Everyone aged 65 and over

• Medicare Annual Wellness Evaluation• Can help to direct people’s attention to brain

health• Unproven if there are beneficial outcomes

– People with complaints• Noted by self, informant or MD/provider

Testing memory and cognition• Cutoffs are influenced by age and education• Performance is influenced by motivation, anxiety,

depression, attention, concentration• List learning: e.g. word list (CVLT = 16 words) is one

of the most sensitive tests:– Immediate recall: 5 trials– Delayed recall– Savings (immediate/delayed x 100)

• Story recall is also sensitive But these need more time and expertise than most physicians can provide

Brief screening tests for dementia• Mini-Mental State Exam (MMSE):

– 75-80% sensitive and specific for Dementia– Only 20 - 50% sensitive for MCI– Takes about 10 minutes

• MiniCog– Three Word Recall – Each recalled word = 1 pt– Clock Drawing Test – Normal Clock = 2 pts– Repeat Three Word Recall – Each recalled word = 1 pt– 3 recalled words OR 1-2 words + normal CDT suggests

LACK of impairment

MMSEsensitivity = 18 – 50%Costs $1 (stealth

patent!)

MOCA 90%sensitive for MCI at a cutoff of < 26/30Has alternate versionsTranslated into many

languages

Office testing for MCI

Informant-based screening

• People with memory problems on the path to Alzheimer’s often deny problems

• An informant’s report can be more accurate

• Some screening tools are:– 10 warning signs (Alzheimer Association)– AD8

The AD8

Scores >1 suggest cognitive impairment

Brief cognitive and informant screening can detect abnormal cognition

To detect subtle changes in working memory, processing speed and memory, more detailed profiling is needed, e.g., through formal neuropsychological testing.

On-line tests, e.g., Lumosity, provide some measures of working memory and processing speed

Lumosity data - Sternberg et al, 2013

Cognitive aging• A process that occurs across the lifespan• May lead to problems in tasks such as medications, paying

bills and driving in the elderly.

• Good Cognitive Aging: Institute of Medicine report, 2015 Physical activity Cardiovascular risk management (HTN, Diabetes,

smoking) Avoid medications with cognitive side effects

• Cognitive and social stimulation• Adequate sleep• Avoid delirium

? Computerized training? Nutritional supplements and vitamins

Cognitive training and memory – the ACTIVE study

Advanced Cognitive Training for Independent and Vital Elderly2802 participants, aged 60 – 94 (mean 73.4), randomized to

– 10 weeks of structured training in one of:• Memory• Reasoning• Speed of processing (visual search)

– Or no intervention

Cognitive testing, interviews at:– Baseline, 10 weeks– 12 months, 24 months– 5 years (67% of group participated)

Results over 24 months (Ball et al, JAMA 2002)

- Each training module led to improvements on test performance regarding that ability/domain.- Training in one ability did not carry over to other abilities- Effect sizes are small.- No differences in complex activities of daily living

5 year follow-up

No clear benefits on complex daily activities

Cognitive training and brain games

• Can improve the task trained• ? may improve the domain e.g., reaction speed,

working memory• No clear evidence for improvement of other domains,

improvement of general cognitive abilities, or of improved daily function

• Newer studies are using more complex training materials, e.g. video games, and also looking at interventions such as meditation and transcranial electrical stimulation

Exercise to preserve memory

• ? exercise may decrease the risk of age-associated cognitive decline and possibly of AD

Lautenschlager et al, 2008: • RCT in 170 people with memory complaints, mean age =

68, in Perth, Australia• Exercise x 150 min/ week vs general health education

24 weeks of controlled intervention, 18 month follow-up• Exercise group showed slightly better performance on:

– ADAS-cog: 1.3 point difference at 24 weeks; 0.7 point difference at 18 months

– Word List recall test

World 200 m record for centenarians

Philip RabinowitzAge 100Time: 77.59 seconds

The LIFE study Sink et al, JAMA 2015

• Clinical trial of exercise in sedentary 70-89 year olds• Walking, resistance training and flexibility exercise vs

health education and stretching, x 24 months• Benefits: cardiovascular health, mobility• No overall benefit on cognition

Subgroup: • Age > 80 or poor baseline physical performance

showed improvement on executive function• No reduction of incident MCI or dementia

Medical Foods, supplements and diet

• No proof for any diet or supplement in a randomized clinical trial

• Epidemiological studies support a Mediterranean type diet, and there is weak evidence for omega-3 fatty acids.

• Increased homocysteine is typically not a problem in the USA

• No rigorous evidence for combinations that have been marketed for boosting memory

Cognition and the aging brain

Brain healthDevelopmentEducationExerciseCognitive activitySocial activity? dietGenetics

Age-related damageAlzheimer’s diseaseVascular diseaseMedical illnessThe aging process

MCI

Normal brain aging

Tangles

Cognition and function

Brain Pathology

Vascular disease

Preclinical AD Dementia

Mild Cognitive Impairment (MCI)

• Memory: decline reported by patient +/or family

impaired on testing ( > 1.5 SDs below normal)• General cognition normal e.g. MMSE > 23/30• Minimally impaired functional abilities• No major depression

Patients with MCI progress to dementia at about 8-15% per year

(Peterson 2000)

MCI and progression to dementia

Mayo Clinic Study of Aging

Early diagnosis of MCI and Dementia - why?

• Plan social issues:– finances, driving– durable power of attorney, support groups– assistance at home and in ADL

• Medical treatment:– maintain level of function as long as possible– AChE inhibitors when appropriate– treatment aimed at slowing progression while

brain structure is relatively intact

Dementia• Intellectual decline “of sufficient severity to interfere with occupational or social performance, or both”.

• Impaired cognitive abilities: memory, reasoning, language, visuospatial skills, calculation.

• Normal state of awareness (i.e. not delirium)

• Can have behavioral symptoms such as depression, delusions and hallucinations

Causes of Dementia• Alzheimer’s Disease (AD)• Vascular dementia – stroke(s)• AD + vascular dementia• Dementia with Lewy bodies• Fronto-temporal dementia• Other degenerative disorders e.g. PSP,

Huntington’s disease, Parkinson’s disease• Infections (e.g. HIV, syphilis), • Metabolic (e.g. B12, thyroid)• “surgical” e.g. subdural hematoma, hydrocephalus• Trauma, anoxia

Over 90%

1907: What Dr. Alzheimer foundAn ‘unusual disease of the cerebral cortex’:- a 51 year old woman with progressive memory loss and delusions

A new research tool: silver staining -> identified senile plaques and neurofibrillary tangles

Neurofibrillary tangle

Amyloid in plaques

Cerebrovascular amyloid

Brain atrophy and neuron loss

Risk Factors for ADMajor Risks Age Family history Genes – APOE e4

Interacting factors stroke hypertension

Lesser Risks Head trauma Low education Female sex Diabetes Poor sleep

Protective factorsPhysical activityCognitive activitySocial activity

MCI and Dementia evaluation

History, exam, hearing, visionMental status testingNeurological examSpecial tests:

Blood: B12, TSHBrain imaging - CT, MRI = rule outPsychometric testing

LP if indicated EEGVolumetric MRI and Amyloid biomarkers

Biomarkers and early diagnosis of AD

Biological markers related to the brain:

Structure: volumetric measures: MRI or CTwhole brainhippocampus

Function: glucose metabolism: PET, SPECT MRI spectroscopy functional MRI

Biochemistry: CSF: A42 , tau , P-tau amyloid imaging (PET)

Vascular factors and cognitive decline

Hallmarks of vascular cognitive impairment

•White matter changes•Lacunar infarcts•Stroke•Microhemorrhage

•Contribute to cognitive loss, especially executive function

MRI: computerized brain measurement

AD hallmarks: Volume loss in the hippocampus and temporal lobe; decreased cortical thickness, especially the parietal lobe; enlargement of ventricles

Hippocampal atrophy may support an AD diagnosis

Alzheimer’s Disease

Cognitively intact Aging (Amyloid Positive)

Amyloid PET imaging

~30% of normal older people show fibrilar A deposition with PET

Trends in Alzheimer’s research

• Biomarkers for early diagnosis and to stage AD• Therapy aimed at pathogenic proteins

– Amyloid in plaques– Tau in tangles

• Starting therapy as early as possible– Prevention trials in people at risk– Autosomal dominant inherited AD– APOE e4/e4– Older people with positive amyloid scans

A Dutch woman donated her body to science at age 82. She called the research center at age 113 to find out if they were still interested.They tested her cognitive abilities for 2 years.She died of cancer at 115.

Is successful brain aging possible?

EvaluationCognitive performance at age 113 age 114 MMSE 27 26 Memory and learning Normal Category fluency (animals) Normal Normal Calculation Normal Mild ↓ Executive function Normal Sl ↓

Neuropathology: Mild tangles in entorhinal cortex (Braak 2) No amyloid plaques 1 Lewy body in substantia nigra, which was well-pigmented

Live long and prosper!

Thank you !