00:00 tonight we continue our journey through
00:01 one of the most cutting-edge fields in
00:05 last month we looked at how the brain
00:07 develops during infancy and childhood
00:09 tonight we turn from the developing
00:11 brain to the mature brain our subject
00:14 the aging brain the study of aging is
00:17 more important today than ever over the
00:19 past century life expectancy has
00:22 skyrocketed thanks to a broad range of
00:24 medical advances the average American
00:26 born today is expected to live for
00:28 nearly 80 years but as we extend the
00:31 life of the body we must also extend the
00:33 life of the mind with old age comes
00:36 wisdom and maturity however there's also
00:39 the deterioration of many cognitive
00:41 abilities the aging process affects
00:44 memory in particular Alzheimer's disease
00:47 dementia and age-related memory loss are
00:50 reaching epidemic levels but
00:52 cutting-edge research shows that these
00:56 may one day be preventable like every
00:59 other brain function memory is
01:00 controlled by biological mechanisms that
01:03 can be decoded by science over the past
01:06 century our understanding of memory has
01:08 increased exponentially we now know that
01:12 memory comes in many different forms
01:14 each controlled by different brain
01:16 systems aging degrade certain types of
01:19 memory while leaving others intact
01:21 joining me this evening is a remarkable
01:24 group of scientists who have devoted
01:25 their careers to understanding memory
01:28 and the aging brain they are Brenda
01:31 Milner she is one of the pioneers in
01:33 this field her experiment in the 1950s
01:36 formed the basis for the modern theory
01:38 of memory she is the Dorothy J Killam
01:40 professor of cognitive neuroscience at
01:42 the Montreal Neurological Institute and
01:44 a professor in the department of
01:45 neurology and neurosurgery at McGill
01:49 Larry Squire his work has shown us that
01:51 not all memories are the same in the
01:54 1980's he began categorizing memories
01:56 according to their content their purpose
01:58 and their locations in the brain he is a
02:01 professor at the University of
02:02 California San Diego School of Medicine
02:03 and a scientist at the Veterans Affairs
02:06 Medical College in San Diego John Hardy
02:09 his research into the genetics of
02:11 Alzheimer's disease has given hope to
02:13 Younes in 1992 he discovered a genetic
02:17 mutation responsible for the plaque that
02:20 accumulates in Alzheimer's disease he is
02:22 a professor of Neuroscience at
02:24 University College London Scot small he
02:27 uses brain imaging techniques to study
02:29 how the brain changes in old age he is
02:33 searching for behaviors foods and drugs
02:35 that might prolong our mental acuity he
02:39 is an associate professor at Columbia
02:41 University and once again my co-host is
02:44 dr. Eric Kandel he is a Nobel laureate a
02:47 professor at Columbia University a
02:48 Howard Hughes Medical Investigator and
02:50 the man who is the inspiration the guy
02:53 the spirit of this series and it's
02:56 always good to have him right here in
02:57 this to pleasure to share this with you
02:59 Charlie what's important to understand
03:01 about the aging brain there is good news
03:04 about the aging brain we are living
03:08 longer as you indicated and we're living
03:10 better because of public health measures
03:13 improved diet increased exercise that
03:17 people do increase social involvement
03:19 people live better lives
03:22 the one thing that interferes and a
03:25 number of instances with people living
03:27 productive mature lives as they age is
03:30 an interference with memory memory is
03:33 very susceptible to age and therefore
03:36 one of the issues we want addresses what
03:38 is the nature of memory what is the
03:40 biological basis of memory where is
03:42 memory localized in the brain as we
03:45 discussed in earlier programs we now
03:48 know that most mental functions are
03:50 localized to specific regions or
03:52 combinations of regions in the brain but
03:54 the amazing thing is until 1950 there
03:57 was question whether a memory storage
03:59 could be localized to a particular
04:01 region many people thought it could not
04:03 and then the two major heroes the early
04:08 heroes of the memory story emerged
04:10 while the Penfield and Brenda Milner
04:16 an extraordinary neurosurgeon who
04:20 trained with Harvey Cushing and also
04:24 trained with Sherrington Sherrington was
04:27 the pioneers in brain research and it
04:29 really shows you continuities in
04:31 scientific research great scientists
04:33 don't simply do great science they also
04:35 train other great scientists the
04:39 specialty that Penfield developed was to
04:43 operate on people with epilepsy and he
04:47 developed a particular procedure for
04:49 he developed a piece seizure whereby he
04:51 operated on people who were not
04:53 anesthetized so they could talk to him
04:56 in fact Sherrington wrote him at one
04:58 point that's marvelous that you can
05:00 operate on people's brains while they're
05:02 talking to you you have a preparation
05:04 that speaks back to you working with
05:06 monkeys and cats I never had that what
05:10 he did is he infiltrated the scalp with
05:12 a local anesthetic he exposed the bone
05:15 of the skull and then he exposed the
05:18 brain in order to make sure that he does
05:22 not damage normal parts of the brain he
05:25 stimulated surface of the cortex his
05:27 specialty was epileptic surgery and many
05:31 of these came from scar tissue on
05:33 different parts of the brain so to make
05:35 sure that it didn't damage for example
05:37 areas involved in speech which indicated
05:39 in the orange circles on the right image
05:43 he stimulated different parts of the
05:45 brain to see what the person's response
05:48 was we see her on the left the right
05:50 hemisphere and we see here on the on the
05:53 right the the left hemisphere when he
05:56 stimulated area of the touch area of the
05:59 brain patient felt touch sensation not
06:01 surprising stimulated the motor area
06:03 patients under had movements of their
06:07 hands but when he stimulated a temporal
06:09 lobe which indicated here in these green
06:13 he found an amazing phenomenon but he
06:16 called experiencial as responses the
06:19 patient but all of the suddens say you
06:21 know I something is coming back to me as
06:24 if it's a memory I hear sounds songs
06:30 parts of symphonies one person said I
06:32 hear the lullaby my mother used to sing
06:35 amazing another person said the segment
06:38 of the symphony that I loved when I was
06:40 young is coming back to me so he
06:42 realized he was getting close to
06:44 something related to memory storage and
06:46 he called in Brenda Milner an
06:48 extraordinarily gifted young
06:50 psychologist and she worked with
06:52 Penfield and they showed that the
06:54 temporal lobe particularly its medial
06:56 surface is involved in memory and they
06:59 made several absolutely striking
07:01 discoveries they found that if you
07:04 resected the temporal lobe on one side
07:07 for surgery you could stop the epilepsy
07:11 but you didn't interfere with memory at
07:14 all but if for example you remove one
07:17 side but the other side was damaged so
07:19 the person had an interference with both
07:21 temporal lobes person actually had a
07:24 significant memory loss they could no
07:27 longer convert short-term memory into
07:29 long-term memory and they'd been to
07:33 Penfield got a telephone call from a
07:36 neurosurgeon in New Haven called William
07:39 Scoville who had operated on both sides
07:42 of the temporal lobe and he in fact had
07:44 left the patient without any seizures
07:46 this is HM a very famous patient that
07:49 Brenda studied extensively but the
07:51 person had enormous difficulty Brenda
07:53 found in converting new short-term
07:56 memory to new long-term memory so he
07:59 would meet Brenda repeatedly but each
08:01 time she walked into the room is it is
08:03 if he met her for the first time for the
08:07 longest time she thought this applied to
08:09 all areas of knowledge that the medial
08:12 temporal lobes are required to convert
08:13 short-term to long-term memory and then
08:15 she made another fantastic discovery she
08:18 found that in terms of certain a certain
08:20 motor skill HM could do it as well as
08:23 you and me so he retained certain memory
08:26 capabilities perfectly well Larry Squire
08:29 entered the scene and began to explore
08:32 this and found it wasn't just limited to
08:35 motor skills there were whole family of
08:37 perceptual and motor skills that people
08:40 with medial temporal lobe lesions
08:42 bilateral could perform perfectly well
08:44 and that made him realize there are two
08:47 major memory systems in the brain
08:49 those that involve the medial temporal
08:51 lobe he called this declarative memory
08:53 memory for people places and objects and
08:57 there were family of skills called
09:00 non-declarative memory modern perceptual
09:03 skills hitting a tennis ball golf swing
09:06 wooden does automatically you and I are
09:08 talking to each other we're using the
09:10 English language it is presumably
09:12 grammatically correct but neither you or
09:14 I paying attention to my grandma
09:17 this is implicit it's a remarkable
09:20 insight once we knew about these two
09:22 memory systems the question arose how do
09:25 they age how do they handle the aging
09:28 process turns out the implicit memory
09:30 system the non-declarative system
09:32 handles aging quite well but the
09:35 declarative memory system which involves
09:38 the medial temporal lobe is quite
09:40 sensitive to the aging process and it's
09:43 susceptible to two kinds of disturbances
09:45 a gradual progression called age-related
09:48 memory loss and a very serious rapid
09:51 progression called Alzheimer's disease
09:54 we're going to discuss the differences
09:56 between them and we have here John Hardy
10:00 who discovered the first gene absolutely
10:02 critical for Alzheimer's disease and he
10:05 showed exactly how it works this is
10:07 responsible the beta amyloid gene for
10:09 terrible plaque deposits that is
10:12 responsible first for killing synapses
10:14 and then nerve cells now over now that
10:18 we understand something about memory
10:20 loss we want to understand how do we
10:21 keep it how do we keep intellectual
10:24 engage and we realize that several
10:27 things are very helpful intellectual
10:30 involvement social involvement and
10:32 physical fitness so we really want to
10:34 understand is what allows Brenda Milner
10:36 at age 91 to be the most intellectually
10:39 capable person at this table alright
10:41 we're gonna meet in just a second and
10:43 pick up the conversation with Brenda
10:44 Miller remarkable woman of 91 and and
10:47 who's as someone might say as sharp as a
10:49 tack sharp as a tack so I have three
10:52 questions one here's a book that you
10:55 bring me every week you every month you
10:57 bring me a book and this one is by the
11:00 pen field in which it's called the
11:02 Texan conscious man a series of lectures
11:05 I guess that he gave what's amazing to
11:07 me is that we have in every instance or
11:11 in many instances found out that these
11:13 people on the frontier were amazingly
11:16 prescient and that later evidence with
11:20 all kinds of new techniques and new
11:21 studies and imaging showed how good they
11:25 were even though they were working
11:27 number of decades ago it's amazing this
11:31 is why they call the Giants of science
11:34 they not only have insight into what the
11:38 immediate findings mean but they can
11:40 extrapolate them for their implications
11:42 and Sherrington was extraordinary for
11:44 this and he trained Penfield who made a
11:46 similar impact we're still living in the
11:49 Penfield Milne era all right this is
11:51 really really interesting stuff here we
11:54 begin with the remarkable Brenda Miller
11:56 at our table for a conversation about
11:59 these themes that we just were
12:01 introduced to here is Brendan my task
12:04 was to explore the functions of the
12:07 human temporal lobe about which really
12:09 very little was known and so there we
12:13 see the left hemisphere of typical brain
12:16 and we see that red areas of the speech
12:19 areas on the left hemisphere which
12:20 you've already seen from that candle the
12:25 typical temporal lobectomy and this is
12:27 the first important point that you do
12:30 for the treatment of epilepsy and is
12:31 still a very successful way of treating
12:33 epilepsy to this day of this kind that
12:36 has its origin in one temporal lobe is
12:38 unilateral that's to say the surgeon
12:41 operates only on one half of the brain
12:43 and and the other half it is assumed to
12:46 be functioning normally we were able to
12:48 compare the effects of removals in the
12:50 left hemisphere that speaking hemisphere
12:52 with those and removal on the other side
12:54 and there we got a gain an instance of
12:57 localization of function within the
12:59 domain memory there were small memory
13:03 changes and if it was from the left side
13:05 it was to do with memory for words to
13:07 language if it was from the right side
13:09 it was affecting a little one's memory
13:11 for faces and places and and tunes
13:16 linguistic but these changes were very
13:19 mild effects it was not anything of
13:23 which the patient's particularly
13:24 complained and often was present anyway
13:28 before the surgery and in exchange for
13:30 that the control of the epilepsy when it
13:32 was successful as it usually was was
13:35 really changing their quality of life
13:37 and was also often showing improvement
13:39 on general tests of intelligence and all
13:42 this was going very smoothly and I was
13:43 collecting all my results my group data
13:46 when suddenly we had a really great
13:50 surprise and certainly for dr. pantry oh
13:52 degrade unpleasant shock was when one
13:55 patient an engineer 46 year old engineer
14:01 whom we call PBS from New Jersey came to
14:04 have a left temporal removal PB came
14:07 back and had his operation in two stages
14:09 because the first superficial one had
14:12 not cured him and after the second
14:14 operation this highly intelligent man
14:16 whom I had tested preoperatively
14:18 extensively said rather angrily a little
14:22 bit early what have you people done to
14:24 my memory and he had from then on a what
14:28 we call a continuous and to regret
14:31 amnesia a forgetting of the events of
14:33 his life as he moved forward so that he
14:36 couldn't remember if his wife had been
14:37 to see him that day he couldn't remember
14:39 what he had had for breakfast he said as
14:42 he woke up in the morning it was buzzing
14:44 booming confusion but then in his case
14:47 gradually he would say that right now
14:50 everything is clear and all these
14:52 patients those few patients actually
14:54 that I have seen with this kind of
14:56 amnesia this kind of forgetfulness say
14:58 this right now everything is clear so we
15:02 have short-term memory preserved but we
15:04 have this inability to to transfer
15:06 information into a long-term storage now
15:10 we had this patient and wondered why we
15:13 lost his memory and were very worried
15:15 and a month later we had a similar case
15:17 and at that point dr. pantry was very
15:19 worried but also very excited and
15:22 interested as we both were and so we
15:24 reported these two findings and in a
15:26 meeting in Chicago but we also had to
15:29 with some explanation and the
15:31 explanation that we offered was that
15:33 perhaps because we couldn't see into the
15:36 brain beforehand and because we never
15:38 saw the other side we only saw the left
15:40 side perhaps in these two patients there
15:43 was some atrophy there was some scarring
15:44 there was some damage in the medial
15:47 temporal region in the hippocampal
15:49 region of the opposite hemisphere on the
15:51 right hemisphere which was not operated
15:53 on by dr. panttiere
15:54 this is the first demonstration that one
15:56 could localize a memory function to a
15:58 specific region of the brain yes yes and
16:01 so so we reported these cases with this
16:04 hypothesis it was just conjecture for us
16:07 in those days and then we dr. Penfield
16:10 got a telephone call from a neurosurgeon
16:14 in Hartford Connecticut dr. William
16:16 Scoville who called and said I've just
16:19 read the abstract with interest because
16:21 I think that the memory loss that you
16:23 are describing your to patients is
16:25 similar to the memory loss that I have
16:28 seen in a patient and whom I carried out
16:31 my operation dart discovers operations
16:34 differed first of all he was operating
16:36 on both sides of the brain our
16:38 operations in Montreal were on one side
16:40 with the hypothesis that was damaged on
16:43 the other here we're operating just on
16:45 both sides it differed also in not
16:47 involving the lateral cortex the lateral
16:50 surface and so here you can see a
16:52 comparison between a brain of a control
16:55 subject of normal healthy brain and the
16:57 patient HM this is a section through and
17:00 you're looking in the two hemispheres
17:02 and you can see that the medial
17:05 structures the deep midline structures
17:07 in HM which have been removed for a
17:10 certain distance of about five
17:11 centimeters going back and now what
17:14 about to the patient because dr.
17:16 Scoville invited me to go down to
17:19 Hartford Connecticut and study this
17:21 patient and others let's HM when he was
17:24 young and when I met him here he was
17:26 young I used to go around talking about
17:27 this young man but but he died recently
17:29 the age of 82 so but he was at 29 when I
17:36 now hm also had a seizures epileptic
17:42 at the age of 16 he began having major
17:45 really major convulsions really very
17:48 very serious epilepsy and it was treated
17:51 with the maximum doses of the
17:53 medications available the day and it
17:55 didn't make any difference he had great
17:57 difficulty although he was bright
17:59 finishing high school because of this he
18:01 had great difficulty keeping a job he
18:03 worked as a motor winder because he was
18:05 having these big attacks and falling and
18:09 so on and during this period dr.
18:12 Scoville suggested that perhaps this
18:16 operation might help his epilepsy he
18:19 suggested that because he was impressed
18:21 by the work that was coming out of
18:23 Montreal from dr. Penfield doctor
18:25 Penzias work was real pioneering and and
18:27 Scoville was impressed that that perhaps
18:30 even though this didn't look like
18:31 temporal lobe epilepsy perhaps these
18:34 structures in the deep to the brain in
18:36 the temporal lobes had an effect of at
18:39 least encouraging or fostering epileptic
18:41 seizures so he proposed this and he
18:44 carried out this operation bilaterally
18:46 on HM and after that it was immediately
18:49 evident that he had this same inability
18:54 to remember it was described it was in
18:56 the hospital that he could not learn the
18:58 way to the bathroom though he preserved
19:00 all the amenities of a ward life that's
19:03 to quote dr. Scoville that he was very
19:05 remain the polite gentle calm Pleasant a
19:08 young man that he was but he could and
19:11 he knew dr. Scoville because he'd known
19:12 dr. Scoville for many years but that he
19:14 did not remember the residents or the
19:17 people that had been with him just
19:18 around the time you work with him Brenda
19:20 well I started I met him in 1955 which
19:24 was a year and a half after the surgery
19:26 and I used to go down to Hartford and
19:29 test him and we had him in Montreal for
19:32 a week if you remember you at any time
19:35 he never even when I was would go down
19:38 to Hartford and typically we'd spend
19:40 three days and during those three days
19:42 he that I could I could spend a session
19:45 with him as I we're talking across this
19:47 table I could be talking and working
19:49 with him and then I could go back he
19:51 would be it after lunch early I could
19:55 you just looked blankly I want to
19:56 emphasize that he was such an extremely
19:58 polite person did you discovered that
20:00 there was any memory capability
20:02 well the challenge for me was whether he
20:06 could learn learn something you know
20:08 this was obviously a challenge you can't
20:10 just say you can't just say somebody
20:12 can't learn until you've tried and so I
20:15 would go to the over to the psychology
20:18 department at McGill I was in Montreal
20:20 and pick up the three tests I would
20:23 choose to a street test take the night
20:24 train to Hartford spend three days
20:26 working with a chair and I'd be putting
20:28 him through his paces going through all
20:30 sorts of tests various learning tests
20:32 wouldn't you find among those tests I
20:35 chose a I chose a motor learning task
20:39 which among them and also something that
20:43 always intrigued me about this is if
20:45 somebody is practicing a lot or having
20:47 lessons and in tennis or golf or
20:50 whatever if you say to them well what
20:52 did you learn today or this week of
20:55 course they can't tell you I'm what Mora
20:57 was the attempt to tell you it impairs
21:00 the performance so this is something
21:01 that's going on in it so there were
21:03 reasons why I chose included a motor
21:05 task before they drove down there though
21:07 I was you know I didn't know what I was
21:10 going to find and here you see a young
21:12 man on hm practising this task that I
21:15 took which is essentially that you have
21:18 to do given a a star shape of a star a
21:21 piece of paper with a double contour and
21:23 you are asked to start at the point of
21:25 the star and trace align it keeping
21:28 within the narrow confines of the
21:29 startle you come around to the top that
21:31 sounds easy until you realize that you
21:33 have to do this we're only seeing your
21:36 hand and the star as reflected in a
21:39 and so it's just we all do terribly
21:43 because you get to the points of the
21:45 star and you do this kind of thing but
21:47 with practice we gradually learn and the
21:51 amazing thing was that HM learnt now we
21:54 see HMS performance on the first day and
21:57 what I am scoring here is the errors a
22:00 number of times he went out of the
22:01 pathway and had to come back that's an
22:03 error and you can see over the those 10
22:06 trials that we did of
22:07 his performance is getting better now
22:10 what would I expect I probably expected
22:12 the next day he might be back this is
22:19 carried over and and he's continuing
22:23 knowing you know that she's done this
22:25 but continuing and then on day three
22:28 perfect performance is just amazing
22:32 Charlie Rose impressed me at the end was
22:37 he is penny Tomac so this is one of my
22:40 vivid memories personal memories
22:42 he stood up like that like listened and
22:45 looked at what he'd done and he said he
22:47 speaks rather slowly he said well this
22:50 is a little strange he said I thought
22:53 that that would be difficult but I seems
22:57 as though I've done it quite well so
23:00 this was an amazing dissociation between
23:03 you know he's a total unawareness of all
23:05 this experience he lived through these
23:07 three days and and the beautiful
23:10 performance and from this you know he
23:12 speculated that maybe motor learning was
23:16 was mediated by some other systems in
23:18 the brain it was certainly not affected
23:21 by the by the hippocampal medial
23:24 temporal lobe lesion this must have
23:26 inspired you Larry well it was
23:29 fascinating because for a long long time
23:31 we thought that motor skills were
23:33 special and that everything else was
23:35 memory and everything else with what HM
23:37 couldn't do but eventually it was it was
23:40 discovered that there's a whole family
23:41 of abilities which are preserved in
23:44 patients with damage in the medial
23:47 temporal lobe so it's not just motor
23:48 skills but also perceptual skills like
23:51 learning to read upside down patients
23:52 come in to do that and habits things
23:54 that you learn over a long period of
23:56 time by trial and error like learning to
23:58 say please and thank you or learning to
23:59 wash your hands before dinner Pavlovian
24:02 conditioning other simple forms of
24:03 learning so there ended up being a major
24:06 distinction to be made between what we
24:09 now call declarative memory on the one
24:11 hand and non-declarative memory on the
24:12 other hand the declarative memory is
24:14 what we mean when we use the term memory
24:16 in everyday language that's what's
24:17 impaired in HM that's what is dependent
24:19 on the medial temporal lobe
24:20 and that refers to our conscious ability
24:22 to remember the facts and events of
24:24 passing days but in contrast to that we
24:27 have non-declarative memory which is a
24:28 whole class of things that depend on
24:30 different brain systems of the caudate
24:33 nucleus the amygdala the cerebellum so
24:35 in the case of non declarative memory
24:37 and the reason that was so mysterious is
24:38 that as Brenda said it is unconscious
24:40 it's like it's a it's a case where
24:42 performance changes as a result of
24:44 experience and so in that sense it does
24:45 deserve the term memory yeah but in the
24:47 case of non declarative memory we don't
24:49 necessarily have any conscious memory
24:50 content nor do we even have the the
24:53 sense that we're using memory so a nice
24:55 example of this might be say the
24:57 development of a phobia yeah so a person
24:59 at the age of 7 gets knocked down by a
25:00 large dog and then later on you could
25:03 say well at least two different things
25:04 have happened on the one hand the person
25:06 may remember the incident and that's
25:08 declarative memory it's a memory that
25:09 can be brought to mind it's conscious
25:11 they remember the fact in the event of
25:13 the of the incident but in the other
25:15 hand the person may be afraid of dogs
25:16 well that's a learned experience a
25:19 learned behavior and emotion not even
25:21 experienced as a memory its experience
25:23 as an attitude or as a part of your
25:25 personality and but it is a kind of
25:27 memory and it depends on the amygdala
25:29 and how both of these affected by age
25:31 well they're rather differently affected
25:33 by aging yeah what the clarity of memory
25:36 does weaken inexorably early by by aging
25:39 this is a situation where 400 different
25:43 people were tested at different decades
25:45 on a simple list of 15 words and has to
25:48 recognize them later and one can see a
25:51 weakening across time although one has
25:53 to make the point that it's not ignore
25:56 mas' and mount of memory loss it's
25:58 actually rather modest and second of all
26:00 there's an enormous amount of
26:01 variability in this process we often
26:04 like to say that as we age we become
26:06 more different from each other because
26:07 we aged in different levels of success
26:09 and it's even true in this case that 20%
26:13 of the 70 year olds are performing as
26:15 well as the average 30 year old so there
26:17 was an enormous amount of difference the
26:19 declarative memory declines like that
26:21 due to changes that we understand take
26:23 place in the hippocampus and the other
26:25 structures in the medial temporal lobe
26:26 but implicit memory non-declarative
26:28 memory tends to be more preserved tends
26:30 to be more stable as father's
26:32 genetically early you some
26:34 important habits are important but they
26:38 don't they don't change as much across
26:39 time one thing that's been very
26:42 important in coming to all this is the
26:44 importance of the of work with
26:45 experimental animals in order to
26:48 delineate all these systems indeed even
26:50 to figure out in the first place exactly
26:52 what structures mean hm were the ones
26:54 that were important for understanding is
26:55 memory deficit that couldn't really be
26:57 addressed until we had an animal model
26:59 of the human condition in the non-human
27:02 primate initially in the monkey this
27:04 finding that came out of the work of
27:05 these two people really indicated that
27:09 memory is not a unitary function of mine
27:11 that there are different kinds of
27:13 memories they have processed in
27:15 different ways and they're stored in
27:16 different regions a major major advance
27:19 and that's the essence of a summary of
27:21 what we just heard that's right she'll
27:24 well what I've been focusing on is
27:25 trying to understand the causes of this
27:27 change in medial temporal lobe function
27:29 as Larry has already described and and
27:31 as Eric already mentioned there really
27:33 are two major things one needs to
27:35 consider as causes one is normal aging
27:38 itself just like aging affects every
27:41 organ system it also affects the brain
27:43 within the brain it's not a diffuse
27:45 process it seems to target select areas
27:47 of the brain aging does and the medial
27:49 temporal lobe is one of these areas the
27:51 other thing to consider as Eric
27:52 mentioned is Alzheimer's itself
27:54 Alzheimer's disease we know that
27:56 Alzheimer's disease begins in the
27:58 hippocampus and the medial temporal lobe
27:59 presenting with mild forgetfulness
28:01 before it sweeps throughout other areas
28:04 of the brain other cortical areas
28:06 causing a more profound cognitive
28:08 impairment something we would call
28:10 dementia and so it's sort of interesting
28:12 here you have two two processes Aging in
28:14 Alzheimer's disease or early stages of
28:16 Alzheimer's targeting the same general
28:18 vicinity the same general area in the
28:20 brain and so an important question is
28:22 can we try to dissociate those two and
28:25 one way one might imagine doing that is
28:30 based on the observation that the
28:33 neurons in the medial temporal lobe the
28:35 brain cells are not homogeneous and are
28:37 not all equivalent you have different
28:38 types of neurons that are organized into
28:41 different parts of the medial temporal
28:43 lobe and it's because of that because we
28:45 assume that aging and Alzheimer's are
28:47 Stickley distinct that they might target
28:49 different parts of the medial temporal
28:51 lobe and so let me let me illustrate
28:53 that this is an MRI scan magnetic
28:55 resonance imaging and as Brenda
28:58 mentioned the circle really is the
29:00 medial temporal lobe these are zoomed in
29:04 images of the medial temporal lobe and
29:06 these are fMRI or functional magnetic
29:09 resonance imaging scans and they give
29:10 you not only anatomical information but
29:12 also functional information and so I've
29:15 color-coded these images such that
29:17 cooler colors reflect less function
29:19 whereas warmer colors the Reds reflect
29:21 more function and I've also labeled two
29:24 main areas in the medial temporal lobe
29:26 that are most relevant you have the
29:28 n-terminal cortex which is the main
29:30 gateway into the hippocampus and then
29:32 you have the hippocampus itself so on
29:35 the left you see the control subject
29:37 this is a healthy subject on the right
29:40 panel this is a patient who has
29:42 alzheimers disease and you might
29:44 appreciate that there's the most amount
29:45 of blue or dysfunction in the n-terminal
29:48 cortex more so than other areas of the
29:51 hippocampus although over time
29:52 alzheimer's does spread to include all
29:55 of the hippocampus now if you look at
29:57 the middle panel that's a subject who we
29:59 think has normal age-related memory
30:01 decline and as you can appreciate the
30:03 n-terminal cortex is relatively
30:05 preserved there that's affected by
30:07 Alzheimer's and instead we see the most
30:09 dysfunction within the hippocampus
30:11 itself talk a bit more about age-related
30:14 in terms of how that works and and what
30:17 are what are we learning about that well
30:19 I mean I think perhaps the the important
30:22 thing to emphasize is that what used to
30:25 be thought historically senility right
30:28 was the old term used for Alzheimers
30:30 dementia and there was this assumption
30:32 that senility it happened inevitably if
30:35 all of us live long enough but I think
30:37 there's now a growing awareness but
30:39 Alzheimer's disease is a disease and by
30:41 definition disease doesn't target
30:42 everyone within a population and so now
30:44 you have these two processes or things
30:47 that seem to be targeting the
30:48 hippocampus contributing to why if we
30:51 just sample a group of healthy seven
30:53 year olds many of them will have
30:54 forgetfulness some of them have the
30:56 earliest stages of Alzheimer's and some
30:59 normal age an interesting point that
31:01 emerges from from scotts discussion is
31:04 that until 50 years ago this was a
31:07 little bit of an academic issue because
31:09 not that many people live to be 70 80
31:11 Alzheimer's is now a disease were much
31:15 more aware of because many more people
31:17 suffer from it because they live to be
31:18 old enough to be susceptible to it yeah
31:21 I mean I think there are two parts of
31:22 that I think Alzheimers clearly now is
31:24 emerging as an epidemic but so is
31:26 normally yes it's it's it's relatively
31:30 subtle but as more more of us are living
31:32 longer and we all want to stay
31:33 cognitively engaged in cognitively rich
31:36 environments even subtle forgetfulness
31:38 is a bothersome and I have many patients
31:41 now who really aren't patients at all
31:43 they're just people who just noticed a
31:44 subtle changes there they're very
31:46 healthy and vibrant they're not patients
31:48 at all they're healthy vibrant 7080
31:50 rodas total changes in their ability
31:52 memory now now I think a really
31:54 important point here is the limitations
31:57 of studies and humans and that if I can
32:00 illustrate is one of the great utilities
32:02 of turning to animal models and what
32:04 I've done here I've oriented on the
32:06 upper row is again the panel you the
32:10 series of human brains you just saw and
32:13 on the lower row I'm showing you the
32:15 mouse hippocampus and as Larry already
32:18 mentioned there's a lot of an a
32:19 remarkable amount of of similarities
32:22 between the structures and the
32:24 organization of the medial temporal
32:25 lobes in a mouse and in a human and
32:29 again I'm showing you now functional MRI
32:31 or fMRI scans of mice down below on the
32:34 lower left panel you can see a control
32:36 mouse and again I'm highlighting the
32:38 internal cortex the main gateway into
32:40 the hippocampus and if you look now on
32:43 the panel on the right lower right
32:45 that's a mouse and where we introduce a
32:48 gene that causes alzheimers disease and
32:50 john will talk about this in a second so
32:51 these mice have been shown to develop
32:54 Al's and relied changes at a relatively
32:56 young age and that's an advantage
32:58 because we know with certainty who has
33:00 the gene who doesn't because we've
33:01 introduced it and we're not confounded
33:03 by aging we're not confused by the aging
33:05 process because these mice are
33:06 relatively young and if you look at the
33:08 panel on the on the right I think you
33:10 can appreciate that the dominant side of
33:13 mouse models is found again in the
33:15 internal cortex very similar to what's
33:18 found in out and inpatients themselves
33:20 although over time it spreads to involve
33:22 other areas and now if you look at the
33:25 middle panel the middle lower panel
33:27 that's the mouse who we know with
33:28 certainty has normal age-related memory
33:31 decline this is a wild-type Mouse as we
33:33 call it we don't introduce any genes we
33:35 just follow it across this lifespan
33:37 which is around two years and we can
33:39 image their hippocampus and medial
33:42 temporal lobes and again as you can see
33:43 in the middle lower panel the internal
33:45 cortex is relatively preserved and the
33:48 sites that are targeted are within the
33:49 hippocampus itself so together we're
33:52 starting to see this nice dissociation
33:54 between Alzheimers and aging and perhaps
33:57 to get to your question we can use that
34:00 information to get an underlying
34:01 mechanism in other words in the mouse
34:03 that has Alzheimer's that gene is
34:05 expressed in every part of the medial
34:07 terminal of in fact in every part of the
34:09 brain if there's one part of the brain
34:11 than terminal cortex that seems to be
34:12 differentially vulnerable or
34:14 particularly vulnerable why is that what
34:16 is it about the internal cortex that
34:18 makes it vulnerable if we can understand
34:20 that question we can perhaps get it
34:21 mechanism which brings us to
34:22 understanding genes and what impact they
34:24 have on these disorders actually my
34:27 story and listening to Brenda it my
34:30 story has a lot of similarities in
34:31 Brenda you you just you just hear and
34:34 you hear it's exceptional patience and
34:36 exceptional you know people who give of
34:38 themselves really in their families who
34:41 make this research happen
34:43 I mean it's and that's when I when I
34:45 heard HM story so the first phone for me
34:48 the story started with a family which
34:51 I'll show in the first image a woman who
34:54 came who wrote to me about her family
34:58 and she's called Carol Jennings she's
35:00 still a friend of mine she wrote to me
35:03 about her family and in her family there
35:06 was really an exceptional type of
35:08 Alzheimer's disease now you know what we
35:10 think of as Alzheimer's disease is is
35:13 late onset Alzheimer's disease people in
35:15 their 70s and 80s but there are rare
35:17 cases of Alzheimer's disease where it's
35:20 very early onset in Carol's family the
35:24 age of onset was about
35:25 fifty-five years old so multiple
35:28 generations is where the where the
35:30 family had got Alzheimer's disease and
35:32 they're in their 50s and I actually I
35:34 know of other families subsequent to her
35:37 family where people get sick in their
35:39 their mid-30s with Alzheimer's disease
35:42 the record is someone in their late 20s
35:45 with a familial Alzheimer's disease and
35:48 you know these families are really of
35:50 course it's terrible to be in these
35:52 families in many ways but they really
35:54 offer us the opportunity to try and
35:57 understand what causes the disease in
35:59 those families in Carol's family what we
36:02 can see is the is that three generations
36:07 affected by disease we see that her
36:11 great-grandfather had the disease and
36:14 grabbed her grandfather and great-uncle
36:17 both had the disease the read images
36:20 show the disease and the yellow ones
36:22 squares a man circles of women and for
36:26 obvious reasons sort of thing Brad is
36:29 affected yellow is unaffected and what
36:32 you can see here is three generations
36:34 Carol is one generation below that these
36:37 three generations so you see the
36:39 great-grandfather had the disease the
36:42 great-grandmother was fine they had two
36:44 sons both of whom had Alzheimer's
36:47 disease like I've said in the fifties
36:48 and then in the main branch of the
36:51 family you can see five out of ten
36:54 children had Alzheimer's disease all at
36:56 the same time so all the five siblings
36:59 had the disease at the same at the same
37:02 time and in the smaller branch of the
37:05 family the cousins one cousin was sick
37:08 out of three so we had six affected
37:11 individuals and seven unaffected
37:13 individuals in that generation and what
37:16 we did was of actually of conceptually
37:18 very simple experiment what we did was
37:21 we looked at the inheritance of the
37:24 genome in those individuals and asked
37:28 what part of the genome was inherited by
37:32 all the affected family members which
37:34 they're unaffected brothers and sisters
37:36 did not it's incredibly simple it's not
37:39 not rocket science it's really very
37:41 straightforward and what we were able to
37:43 see is that the the um part part of the
37:48 smallest chromosome chromosome 21 which
37:51 is the diagram at the bottom you can see
37:53 that the five affected individuals and
37:56 the affected cousin share a whole
37:58 section of that chromosome but you can
38:01 also see that two of the unaffected
38:04 individuals the woman the ninth woman on
38:08 the left hand of branch of the family
38:09 and the middle man on the right hand
38:12 branch of the family have little parts
38:15 of the chromosome but they're not sick
38:17 so that tells us the disease gene is not
38:20 in the bits that those unaffected
38:23 siblings and cousins have and he tells
38:26 us the gene must be between those two
38:29 bits and when we look carefully we saw
38:31 that the amyloid gene was in that bit
38:34 the bit that was only inherited by the
38:36 affected individuals now in fact the
38:39 amyloid gene have been identified about
38:42 four years before and it had been
38:45 identified because the the people are
38:50 interested in the pathology of the
38:51 disease have been keen to find out what
38:54 goes wrong in the brain of people with
38:56 Alzheimer's disease what proteins are
38:59 deposited and they had shown that the
39:02 amyloid protein was deposited in the
39:05 plaques and those horrible brown lumps
39:08 there they're about a tenth of a
39:09 millimeter meter across and they're full
39:12 of this amyloid peptide so what our
39:14 finding really showed was the in that
39:17 and that family in Carol's family the
39:20 disease started with that amyloid
39:22 peptide we found a mutation in the
39:26 amyloid peptide gene which caused that
39:28 protein to be deposited so it was a very
39:31 simple observation it just tells us that
39:34 disease starts with that peptide
39:36 fantastic observation gene identified
39:41 that dramatically defeated with memory
39:43 loss the first gene identified
39:45 Alzheimer's disease and open up the
39:47 whole study of the disease and they so
39:52 and others have found lots of other
39:54 mutations but we so that was a stat was
39:57 certainly a start and there's some great
39:59 work from Peter his lops group in
40:02 Toronto he found that the families that
40:05 we had not sorted out with amyloid
40:07 mutations in fact had mutations in a
40:11 different gene called the priests and L
40:13 in gene and we now know that the role of
40:15 the priests inulin gene is to digest the
40:18 amyloid Peten protein together so
40:23 beautifully and showed that all of these
40:25 rare families have mutations in the same
40:28 process and this process was a process
40:31 which led that peptide that protein to
40:34 be deposited in the brain so it was it
40:37 was a it was a great thing and I
40:38 captured from Brenda to be excitement
40:41 you you get we all share this is
40:47 something for the first time what is so
40:49 interesting about this also is that it's
40:52 only hippocampal medial temporal lobe
40:54 memory that is lost
40:56 implicit memory storage is for the
40:58 longest time intact in people like that
41:00 and you can get people like the cooling
41:03 the great artists with Alzheimer's
41:06 disease could continue to paint rather
41:08 interesting paintings because that to
41:09 him had become an automatic task like
41:12 playing tennis is to you tell me about
41:15 Layton what onset Alzheimer's disease
41:17 you know that's a that's a difficult
41:19 that as you know you know that's a
41:22 difficult why I asked you yeah so we've
41:26 been trying to work out what are the
41:28 risk factors there was some great work
41:30 from Duke in the 90s that found the
41:34 first risk factor for Alzheimer's
41:35 disease it's a gene for late onset
41:39 typical late onset disease which is a
41:41 gene called a Poe a great work really a
41:44 breakthrough this is a gene involved in
41:46 cholesterol metabolism it was entirely
41:48 unexpected so that was great work we
41:51 actually don't really understand the
41:53 connection between cholesterol
41:56 metabolism and Alzheimer's disease but
41:58 that gene a po e points to that
42:00 connection then we've had ten years of
42:04 no not really making much progress but
42:07 just this last two years I'm proud to
42:11 say back in England in particular
42:12 there's been breakthroughs using the new
42:15 genetic technologies to try and find
42:18 other genes and what we're finding in
42:20 these other genes is other genes
42:22 involved in cholesterol metabolism
42:23 actually also I think it fits in the
42:26 general pattern that one of the
42:28 predictors for good memory function is
42:32 good health physical fitness and good
42:34 health reasonable levels of cholesterol
42:37 and things like that do you want to
42:39 discuss this so there are a number of
42:40 genes that are risk factor genes and
42:42 when we think about ways of modifying a
42:44 risk obviously currently we can't affect
42:47 we can't modify our genes so the
42:49 question is are there other things that
42:50 occur as we age perhaps that we can
42:53 modify and that perhaps gets to your
42:55 question and and one there been a lot of
42:58 interesting research into this area but
43:00 one story that's really emerging is
43:02 quite elegant has to do with the way our
43:04 body handles glucose as we age so
43:07 glucose of course is the main sugar the
43:09 main energy source as we eat a large
43:11 meal and the way the body handles
43:13 glucose is it releases insulin from the
43:15 pancreas and that allows essentially the
43:17 muscles to absorb the glucose now it
43:20 turns out as we age all of us become a
43:22 little bit insulin resistant that's the
43:24 term used meaning the muscles are a
43:26 little bit less sensitive to the insulin
43:27 and what that effectively means is that
43:29 the pancreas tries to crank out a little
43:31 bit more insulin and glucose regulation
43:34 is less stable if that becomes profound
43:37 enough that becomes type 2 diabetes that
43:39 as a definition of type 2 diabetes but
43:41 even without that that that that
43:44 diagnosis that's an age-related process
43:47 now it turns out that insulin and
43:50 glucose are our two pronged problem that
43:53 are very relevant to what we're talking
43:55 about so a number of studies have shown
43:57 that increases in insulin are a risk
43:59 factor for Alzheimer's whereas the
44:02 changes in glucose regulation seem to
44:04 target the areas of the hippocampus that
44:06 are related more to normal aging and
44:08 therefore more linked to normal
44:10 cognitive aging so insulin and glucose
44:13 both part of the same metabolic pathway
44:16 seem to be players here
44:18 perhaps the most important thing to
44:19 emphasize is that there are ways in
44:21 which we can modify those age-related
44:23 changes so a good example is physical
44:25 exercise aerobic exercise and what about
44:29 social engagement what about cognitive
44:31 training is equally important it's
44:34 extremely important to be intellectually
44:36 active and continue your career as long
44:41 as you can possibly carry it on other
44:43 things that give you intellectual
44:45 Olinda feed who is the Dean of the
44:48 School of Public Health at Columbia is
44:49 interested in cognitive function in
44:51 aging and she's found that if you take
44:53 people in their 70s and put them into
44:56 elementary schools as assistants a
44:58 volunteer corps their intellectual
45:01 function tends to persist on fairly high
45:04 level compared to controls that don't do
45:06 this so cognitive involvement
45:08 particularly in social situations is
45:09 very very helpful and certainly social
45:13 involvement is extremely important tell
45:15 me how you explain your remarkable yes
45:17 Brenda had a harder life than I did
45:32 lived to be 95 and she worked her she
45:34 was in music different career altogether
45:36 and she worked at teaching and till the
45:38 age of 88 she taught music and sing and
45:41 yes till the age of 88 and she had to
45:44 stop because she was getting death which
45:46 fortunately I have escaped so far and so
45:49 otherwise she would have continued genes
45:53 genes office well I think engagement
46:04 I believe engagement in comes of
46:07 activities but not solitary ones for me
46:09 I it's very important to me to be
46:11 engaged with young people and I as I say
46:14 when I was young I'd like to be engaged
46:16 with older people across the spectrum of
46:19 Ages and some problem that excites one's
46:22 curiosity I think my real secret is the
46:25 time so curious I'm extremely nosy about
46:27 everything oh my god
46:28 best news I don't take formal exercise
46:39 of anything I walk I don't drive a car
46:41 never driven a car I live near my place
46:44 of work I've been 50 60 years of the
46:47 neurological institute Montreal is a
46:49 hilly city more they are not royal and
46:51 so I walk up the hill to work and I walk
46:54 back and I walk all over that city and I
46:57 think I do that because I enjoy walking
47:03 where is the good news in all this in
47:05 terms of memory so there are two parts
47:07 to the good news perhaps one is that not
47:09 everything exactly right we haven't
47:16 really explored that that something
47:17 important happens that matches some of
47:20 the loss of memory which is a certain
47:22 advantage system perspective that
47:24 certainty matures anxiety levels tend to
47:27 decrease so many aspects of cognitive
47:32 function that don't require memory
47:34 actually mature quite well memory is
47:38 built so that we even as a young person
47:40 the way our memory system works is that
47:42 we are always going for the gist I don't
47:44 care so much about the details I mean
47:46 thankfully we don't remember everybody
47:48 that makes it possible you're actually
47:50 just in over people then you know that's
47:53 that's something they can do things I
47:55 mean in terms of the good news right
47:57 because there is some bad news let's be
47:59 a school particularly in dealing with
48:01 Alzheimer's disease so the first thing
48:04 is that the earliest stages of
48:07 Alzheimer's is not does not immediately
48:11 cause cell death and rapid cell loss
48:13 it's really characterized by loss of
48:15 synapses and I think in this program you
48:17 discussed different derivatives between
48:19 yeah right and and I think that's a very
48:22 important point because as Eric and
48:24 others have shown there is plasticity in
48:26 other words you can regrow synapses but
48:28 you can't regrow neurons and I think
48:30 that that it hidden in that observation
48:32 is good news because if we can detect
48:34 Alzheimer's at the very earliest stage
48:36 before their cell death I think it's
48:39 obvious to say that it's easier to to
48:41 or to fix a sick cell in a dead cell and
48:44 so that there's some good news in that
48:46 and I think the other for a long time
48:48 the notion was and then I'm allowed to
48:50 be the sort of layman here for a long
48:52 time the notion was that nerve cells
48:54 died and now we're looking at it and
48:57 saying synapses between neurons that's
48:59 right that's where the functional
49:04 imaging and various techniques to try to
49:05 capture as easy as possible that's gonna
49:08 be the window that's going to be most
49:09 therapeutically efficacious it's not
49:11 hidden away in the closet anymore - good
49:14 point it's not hidden away in the closet
49:15 there's there's openness about it and
49:17 that of itself was bought brought it's
49:19 much better to be an outsider patient
49:22 today than it was 25 years ago when I
49:25 used to go around and see Alzheimer
49:27 patients 25 years ago they were in much
49:29 they were hidden away in in the back
49:33 rooms of of long-stay institutions that
49:36 has certainly been enormous progress and
49:39 now vegan exactly much better caring and
49:48 Ronald Reagan deserves credit that we've
49:55 learned so much about the cell biology
49:56 and molecular biology of the pathways
49:58 that lead to the deposition of amyloid
50:00 at every every detail that's added to
50:03 give us another potential drug target
50:05 gives us another potential way of
50:06 intervention a lot better points out
50:09 which many people don't appreciate how
50:11 difficult it is to get a really good
50:13 drug for any disease even once it's
50:15 identified Huntington's disease we've
50:17 known the gene for a long time this is a
50:19 very it's an essential beginning but it
50:22 doesn't guarantee immediate therapeutic
50:25 efficacy you takes a long time to
50:27 develop a really useful drug this man
50:29 has made some real contributions he's
50:31 too modest to talk about it in this
50:33 whole area of understanding memory and
50:35 my rights not her absolutely
50:41 that'd be would be defined well I mean
50:44 if we said that understanding the basic
50:47 mechanism of an abnormality Alzheimers
50:49 you have to get to the basic cellular
50:50 and molecular understanding that's what
50:53 the Candela in' project really began in
50:55 the late sixties or Kent Eric began he
50:57 really started dissecting out this
50:59 complexity of memory down to the level
51:02 of the molecules and the cells and
51:04 that's really been transformative so
51:07 what's up next time next time we're
51:09 going to consider the emotional brain
51:12 emotions are the instinctive forces that
51:16 drivers to seek pleasure and to avoid
51:18 pain and this is such an important topic
51:20 we're gonna have two consecutive
51:22 programs on it in the second program
51:25 we're going to consider misery
51:26 unhappiness anxiety in the coming
51:30 program the first program we're going to
51:32 consider how we seek pleasure and how
51:35 addictive drugs co-opt the pleasure
51:38 system for their own purposes it's gonna
51:40 be a wonderful program I look forward to
