Alzheimer's Disease: Pathology and Treatment

by Carlo Raj, MD

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    00:02 Gross: what are you going to find in gross examination? Well, I just told you.

    00:05 You’re going to lose your brain.

    00:07 You lose your cortical atrophy.

    00:10 And when you do, what happens to sulci? It gets deeper and deeper and deeper.

    00:14 This is not a good thing.

    00:16 You have compensatory ventricular enlargement.

    00:18 In other words, what do we call this? Hydrocephalus ex-vacuo, all right? Compensatory ventricular enlargement.

    00:24 Why? Due to your cortical atrophy.

    00:27 You put these together, don’t memorize them.

    00:29 It’s the same thing, it’s just a story.

    00:32 Microscopically, what are you going to find? Okay, now, these are interesting.

    00:36 What I haven’t talked to you about yet in great detail is neurofibrillary tangles.

    00:40 But what I have talked to you about, and I’ve shown you, is the beta-amyloid plaques, correct? So, what do the plaques look like? It looks like a plate.

    00:48 The plate is large.

    00:49 So what about neurofibrillary tangle? You know what sperm looks like? You know what sperm looks like? It looks like little tadpoles, don’t they? Whatever you want to use here in terms of description.

    00:59 Yes, I’m being dramatic because I need you to know the difference, and these two are huge points, pathologically, on a microscopic level.

    01:07 So if you find sperm in the brain, well, do you understand how silly that is? Or tadpoles in the brain.

    01:13 That’s your neurofibrillary tangle.

    01:14 What is it? It is hyperphosphorylated tau protein, tau, p-tau.

    01:21 Anyhow, I shouldn’t have say p-tau but tau protein is neurofibrillary tangles.

    01:27 These look like tadpoles or sperm in the brain.

    01:30 Now, let me tell you something.

    01:32 Each one of us as we get older, we’re all going to develop neurofibrillary tangles.

    01:35 So you can’t help it, okay? It’s just kind of like as we get older, there is every possibility developing lipofuscin, right? Why? Because we end up losing the ability to properly manage free radicals and such.

    01:47 So, neurofibrillary tangle is part of normal aging.

    01:49 However, in Alzheimer’s disease, there’s an accelerated accumulation of hyperphosphorylated tau protein in neurofibrillary tangles.

    01:58 So much so, what you must understand is that the degree or the concentration or percentage in neurofibrillary tangle, as it increases, correlates with the severity of the disease.

    02:11 Pretty important stuff, isn’t it? Oh, yeah.

    02:14 Now, do you understand as to why I’ve been so dramatic on this particular point? Next.

    02:19 So, what is it? It’s tau, T-A-U.

    02:23 What happened to that tau? It got hyperphosphorylated.

    02:27 I’ll take you back to biochemistry real quick.

    02:29 Give me the name of the enzyme that causes phosphorylation? I’m sorry, what did you say? I think you said kinase.

    02:36 Right on, exactly right.

    02:38 It’s kinase.

    02:39 So, you’re going to have a type of kinase that is undergoing or accelerating its phosphorylation of your tau.

    02:47 And so therefore, technically speaking, it’s axonal microtubule associated proteins.

    02:52 I would have to say every single word in this particular image or this slide is about most important for you to understand pathologically, every single word.

    03:04 Let’s move on.

    03:06 Microscopically, what else are you going to find? Here’s the plate.

    03:09 These are called senile neuritic plaques.

    03:12 You remember that picture that I just showed you with those green rods? Right? Green rods.

    03:18 That green rods represent -- It is actually quite interesting.

    03:21 It’s amyloid.

    03:23 It’s amyloid.

    03:24 What kind? What do you mean what kind? Is it kappa or lambda? Is it beta-amyloid? Is it -- I don’t know, Portuguese? All I’m saying is it’s amyloid.

    03:38 As far as your concerned, amyloid, Congo red stain, and it then appears being your apple-green birefringence.

    03:44 You know that.

    03:44 So green is a wonderful color to show you that.

    03:47 And so therefore, a bunch of these green rods or beta-amyloid that are now aggregating and they then form a plaque or a plate.

    03:54 Focal, spherical collection of your dilated, tortuous, silver, silver-staining neuritic processes.

    04:03 And so therefore, we call this dystrophic neuritis.

    04:06 Well, that’s around the plaque.

    04:09 Dystrophic neuritis, so the neurons are dying, and that then surrounds a central amyloid core surrounded by a clear halo.

    04:17 All of this is then referred to as being the plaque.

    04:20 This is an important description.

    04:22 So, it’s surrounded by the dead neurons, we called it dystrophic neuritis.

    04:26 And in the middle, you’ll have your beta-amyloid plaque.

    04:30 Now, the dominant component is going to be your amyloid precursor protein which then breaks down into -- this stands for beta-amyloid.

    04:39 Is that clear? Be careful, please.

    04:41 This says beta-amyloid.

    04:43 So, amyloid beta, in other words.

    04:46 A representing amyloid.

    04:48 The operative term is beta.

    04:50 Where is it coming from? APP.

    04:52 What does that stand for? Amyloid precursor protein.

    04:55 Once again, yet another important microscopic feature of Alzheimer’s disease.

    05:02 What else? Well, found in abundance in the hippocampus.

    05:06 What is found in abundance in hippocampus? Don’t just memorize what I’m saying.

    05:10 Ask me.

    05:11 Dr. Raj, what is found in hippocampus and the olfactory bulb? What did we just talk about? What are the tadpoles called? Neurofibrillary tangles.

    05:20 What is it? Hyperphosphorylated tau protein.

    05:23 And then what was the other one? That was the beta-amyloid collection or plaque surrounded by dystrophic neuritis or dead neurons.

    05:29 Good.

    05:29 That was the beta-amyloid.

    05:31 That is what is found in the hippocampus and olfactory bulb.

    05:35 And what happens? Remember that picture that I showed you of the hippocampus? In Alzheimer’s disease, you’re going to tell me, "Dr. Raj, I’m sorry, but I didn’t find the hippocampus in that Alzheimer’s diseased brain.” Very good, exactly right.

    05:48 At some point in time, the hippocampus is gone as are the memories in your patient.

    05:53 Retrograde.

    05:55 Retrograde amnesia.

    05:57 Everything in the past has been completely wiped out.

    06:00 Clear? What about that amyloid? It’s everywhere.

    06:04 It’s everywhere.

    06:05 It’s wreaking havoc.

    06:07 And where else it could accumulate? Around your blood vessels.

    06:10 What do you think you call this? Pathology of your blood vessel in the brain, amyloid angiopathy.

    06:16 Clear? Good stuff.

    06:18 Hope you’re liking it.

    06:19 Know everything about Alzheimer’s disease and make sure that you do medicine all your life is more that you keep your brain active.

    06:29 Research is showing that, perhaps, you’ll be able to prevent Alzheimer’s disease.

    06:33 Just saying.

    06:34 Let’s move on.

    06:36 So, what do we have here? On your left is a neurofibrillary tangle.

    06:40 On your right is the plaque.

    06:42 You knew that already.

    06:43 On your left, which one of these looks more like a tadpole or a sperm in the brain? The left.

    06:50 That’s your neurofibrillary tangle.

    06:52 What is it? Hyperphosphorylated tau protein.

    06:54 What is it on the right? You see that plaque in the middle, you did a silver stain.

    06:57 What did you find? Like an amyloid, beta-amyloid.

    07:01 You’re doing this in your sleep, aren’t you? Just closing your eyes, the information is just coming out of you.

    07:05 You can’t help it.

    07:07 And what it surrounded by? Dead neurons.

    07:08 What do we call this? Dystrophic neuritis.

    07:12 Very good, you all.

    07:12 Let’s move on.

    07:15 Alzheimer’s.

    07:16 So, what’s my prevention? Kind of difficult but may be acetylcholinesterase inhibitors.

    07:22 What does that mean to you? Remember, please.

    07:25 If deficiency of dopamine is Parkinson’s, deficiency of acetylcholine is Alzheimer’s.

    07:32 How about convenience, A and A? What does that mean? Acetylcholine and Alzheimer’s.

    07:39 Close your eyes.

    07:41 Acetylcholinesterase, where are you? Normally, where are you? Okay, you’re at the junction.

    07:47 Good.

    07:48 And normally responsible for breaking down your acetylcholine.

    07:51 And so therefore, in the brain, if you’re able to inhibit acetylcholinesterase, the drugs include donepezil.

    07:58 That’s a big one.

    07:59 Another one called rivastigmine and tacrine.

    08:02 Know these, and therefore, what you’re going to do to your levels of acetylcholine? You’re going to increase it, and maybe perhaps, by doing so, prevent your progression.

    08:11 It is proven to slow the progression.

    08:12 However, it’s not the cure, definitely not the cure, unfortunately.

    08:18 Prophylaxis, maybe anti-inflammatory and antioxidants such as vitamin E, but there is really no data so I’m just going to quickly go through this.

    08:26 Associated symptoms: oh boy, yeah, definitely depression, agitation, sleep disorders, late onset hallucinations, delusions.

    08:34 They have all kinds of issues, don’t they? They walk out the door, maybe they’re naked.

    08:38 They don’t know how to come back.

    08:39 You find them wandering.

    08:40 You do, you do find these such cases, don’t you? Introduce yourself every single day because they forget as to who you are.

    08:47 And depression, obviously.

    08:50 So, a lot of associated symptoms.

    08:51 Spend a little bit of time with Alzheimer’s disease, please.

    08:54 Summary: Risk factors: female, genetic predisposition.

    08:58 I talked to you about PS1 and PS2.

    09:00 Specifically, I talked to you about APOE e4.

    09:02 That’s your focus should be on.

    09:04 There was Down’s syndrome and you have trisomy 21.

    09:07 Things we’ve talked about in great detail.

    09:08 Preventive medicine: antioxidants, but really, no data out there.

    09:12 Continued mental activity.

    09:13 I told you about that, huh? Hence, my addiction to medicine.

    09:16 Medicine meaning mental medicine, huh? I don’t take anything here.

    09:20 Move on.

    09:21 Signs and symptoms: short-term memory loss, getting lost in familiar places.

    09:26 Differentials: we’ll get into these.

    09:29 Fronto-temporal dementia, formally known as Pick’s disease.

    09:34 What else do we have? Wernicke-Korsakoff.

    09:36 What do you know about Wernicke-Korsakoff? Probably drinker, alcohol.

    09:40 What may then happen over a period of time? You’ll lose your thiamine, maybe damage your hippocampus, so on and so forth.

    09:46 Normal pressure hydrocephalus, we talked about this, and we’ll talk about this further.

    09:51 Neurosyphilis.

    09:53 Diagnostic workup.

    09:55 This is an important paragraph.

    09:58 You want to rule things out, okay? So, you’re doing a neurologic examination and you found papilledema and what are you thinking possibly? Maybe normal pressure hydrocephalus.

    10:08 Argyll Robertson pupil, that to you should indicate neurosyphilis.

    10:12 Ophthalmoplegia.

    10:14 Here, maybe Wernicke’s or progressive supranuclear palsy.

    10:19 And always check for TSH and B12.

    10:21 Diagnostic workup: All for B12 so you can rule things in, rule things out so that you’re on the right track of management.

    10:28 Extremely important in terms of management.

    10:30 Let’s then move on to the next column.

    10:32 Here, we have cholinesterase inhibitors, and here, where are you? You’re trying to save the brain.

    10:38 So, this is not so much about myasthenia gravis.

    10:40 Please don’t do that right now.

    10:41 I want you to know about donepezil, and we talked about rivastigmine, and tacrine.

    10:46 And side effects are mainly bradycardia and vivid, vivid dreams due to such drugs.

    10:52 Keep these in mind.

    About the Lecture

    The lecture Alzheimer's Disease: Pathology and Treatment by Carlo Raj, MD is from the course Dementia. It contains the following chapters:

    • Alzheimer's Disease: Pathology
    • Alzheimer's Disease: Treatment

    Included Quiz Questions

    1. Paired helical filaments
    2. Amyloid precursor protein
    3. Beta amyloid
    4. Hypophosphorylated tau proteins
    5. Neuritic process
    1. Neuritic process
    2. Amyloid precursor protein
    3. Beta amyloid
    4. Hypophosphorylated tau protein
    5. Paired helical filaments
    1. Axonal microtubules
    2. Schwann cells
    3. Dendritic process
    4. Nissl substance
    5. Nodes of Ranvier
    1. Silver staining
    2. Congo red staining
    3. Prussian blue staining
    4. Sudan black
    5. Oil red O staining
    1. Central amyloid core structure surrounded by focal spherical dilated tortuous neuritic process.
    2. Central spherical dilated neuritic process surrounded by beta amyloid.
    3. Central amyloid core surrounded by diffuse spherical dilated tortuous neuritic process.
    4. Central amyloid core surrounded by a spherical straight neuritic process.
    5. Central triangular dilated neuritic process surrounded by beta amyloid.
    1. Hypophosphorylated tau
    2. Neuritic plaques
    3. Dystrophic neuritis
    4. Amyloid angiopathy
    5. Neurofibrillary tangles
    1. Neostigmine
    2. Galantamine
    3. Donepezil
    4. Rivastigmine
    5. Tacrine
    1. Cognitive impairment
    2. Argyle Robertson pupil
    3. Papilledema
    4. Intranuclear ophthalmoplegia
    5. Asterixis

    Author of lecture Alzheimer's Disease: Pathology and Treatment

     Carlo Raj, MD

    Carlo Raj, MD

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    Very clear explaination
    By Andre Ho Yan W. on 08. July 2018 for Alzheimer's Disease: Pathology and Treatment

    Excellent explanation in every perceptive ! I would like to have a bit more pictures in the PPT !