Memory Systems in Dementia Andrew E. Budson, M.D. Cognitive & Behavioral Neurology, VA Boston Boston University Alzheimer’s Disease Center Memory Disorders Unit, Brigham & Women’s Hospital Harvard Medical School Today I’m going to tell you about a clinical problem that I came across when I was a fellow in behavioral neurology, and share with you my research in this area. I’m going to show you many experiments--not so that you’ll understand the details of all of them--but so you’ll get a sense as to some of the different experimental techniques which can be used to explore this issue. I hope that my research will ultimately lead to an improved understanding of memory in general, the cognitive deficits of Alzheimer’s disease in particular, and therapies which can improve the lives of these patients and their caregivers.

Disclosures Royalties from Publishing for Memory Loss, Alzheimer’s Disease, and Dementia: A Practical Guide for Clinicians, 2016 (Elsevier) Seven Steps to Managing Your Memory: What’s Normal, What’s Not, and What to Do About It (Oxford University Press)

Long Term Memory Episodic Memory Semantic Memory Procedural Memory

Episodic Memory Personal, conscious, explicit recollection of experienced events framed in your own context Where you parked your car What you had for dinner last night Anatomy: Medial temporal lobe limbic system frontal lobes

Patient 1 Alzheimer’s disease 81 M with memory difficulties. 8 years ago got lost, began asking questions repetitively. Gradual worsening, last 6-12 mos unable to learn new information Remembers everything about his days during WWII Alzheimer’s disease

From Budson & Solomon, 2016

Other diseases which can disrupt Episodic Memory Tumors Strokes Hypoxic/Ischemic Head Trauma

Ribot’s Law

The Papez Circuit

Episodic memory system

Hippocampal anatomy

Entorhinal cortex Dentate gyrus unique index assigned CA3 Hilus binding

Entorhinal cortex Subiculum Dentate gyrus CA3 CA1 Hilus

Consolidation Sleep Dreams

Entorhinal cortex Subiculum Dentate gyrus CA3 CA1 Hilus

1 2 happy sad Day 1 Day 2 Day 3 ½ way down, on left Red Blue 1 2 happy sad ½ way down, on left ½ way down, on right All way down, on left Day 1 Day 2 Day 3

1 2 happy sad Days 2 & 3 Day 1 ½ way down, on left Red Blue 1 2 happy sad Days 2 & 3 ½ way down, on left ½ way down, right OR All way down, left Day 1

Recently, an procedure has been developed which allows us to measure one type of memory distortion experimentally. To illustrate this point, I would like to give you all a memory test: Are you ready? I would like you to remember the following words: candy, sour, sugar, bitter, good, taste, tooth, nice, honey, soda, chocolate, heart, cake, eat, pie. OK, raise your hand if you remember that the word sugar was on the list. flag; sweet. Sweet was not on the list. This is one type of memory distortion--an example of a false alarm or false memory or false recognition.

Gist

1 2 happy sad Days 2 & 3 Day 1 ½ way down, on left Red Blue 1 2 happy sad Days 2 & 3 ½ way down, on left ½ way down, right OR All way down, left Day 1

Failure of source monitoring Externally heard: sugar Internally generated: sweet

B.G.

Frontal lobes in Episodic Memory Memory for the temporal order of events Memory for contextual information Encoding information Frontal and medial temporal lobes work together Left brain for words, right for images

Left MTL & frontal lobes activated for words Wagner, Schacter, et al., Science 1998 281 1188-1191

Bilateral MTL & right frontal lobe for scenes

good idea Other cortical regions Frontal Lobes Medial Temporal lobes

Frontal lobes damaged  more work to get information in and out of storage. Hippocampus/parahippocampal cortex damaged  impossible to get information in and out of storage. Hippocampus/parahippocampal cortex damaged  Remote information that has been consolidated is available from other cortical areas.

Patient 2 Vascular Dementia Misattributes statements 74M 6 yr history of “Small TIAs.” Misattributes statements Confuses order and context of events Variable performance on memory testing: from above average to extremely poor recall with preservation of recognition. Vascular Dementia

Frontotemporal Dementia Patient 3 78M with memory & behavior problems. Frontal memory problems. Extreme memory distortions: Confused events on television with his own life Frontotemporal Dementia

Normal Pressure Hydrocephalus Patient 4 76F with poor cognition impaired attention Very poor recall but preserved recognition magnetic gait disorder incontinence Normal Pressure Hydrocephalus

Patient 5 Alzheimer’s disease 79 F with memory problems, delusions and possible hallucinations. Believed that she has recently spoken with her parents, long since deceased. Believes that people are breaking into her apartment, stealing her money, and moving around her stuff. Alzheimer’s disease

Red Blue 1 2 happy sad Days 1, 2 & 3 ½ way down, on left OR ½ way down, right OR All way down, left

“In NYC, the 53 bus will take you uptown: FALSE” “It takes 32 coffee beans to make a cup of espresso: TRUE” Neuropsychology 2006 20 185-192

Illusory Truth Older Controls: Patients with AD Remembered 77% of the true statements true Remembered 39% of the false statements true Patients with AD Remembered 69% of the true statements true Remembered 59% of the false statements true!! Thus, if one tells a patient with AD, “The 53 bus will not take you to your sister’s house; take the 67 bus instead,” the patient will be likely to remember that the 53 bus is the one to take! Neuropsychology 2006 20 185-192

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Picture superiority effect

Semantic Memory Our general store of conceptual and factual knowledge not related to any specific memory. George Washington Anatomy Broad definition: Many cortical association areas Words and their meanings: Lateral temporal lobes

Naming Damasio et al., Nature 1996 380 499-505

Patient 1 Alzheimer’s disease 81 M with memory difficulties Word finding difficulties Speech empty of content Sentences do not make sense. Difficulty with comprehension Alzheimer’s disease

Patient 6 Semantic Dementia 63 F with language problems Difficulty naming Impaired comprehension of language Impaired knowledge about the world Easily found 10 hidden objects 20 min later Directed daughter from NH to Boston easily Semantic Dementia

Semantic Dementia Temporal variant of Frontotemporal dementia Progressive atrophy of left > right temporal lobe

(all modalities of input and output) Semantic Dementia Impaired Preserved Semantic Memory (all modalities of input and output) Phonology, syntax Problem solving Visuospatial Perception

Picture Naming

Word to Picture Matching Ball Pear Motor-cycle

Pyramid and Palmtrees Test

Drawing Object to Name Sheep Lamp

Knowledge of Correct Color JL FM

Traumatic Brain Injury Autobiographical memory?

Procedural Memory Learning of behavioral & cognitive skills & algorithms that operate on an automatic, unconscious level Riding a bike Driving with a stick shift Anatomy Basal ganglia Cerebellum

Parkinson’s disease

Patient Controls

Rehabilitation Potential

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