# data[].attributes.headline
GO BACK TO TOP FOR CRITICAL ANALYSIS AND FUTURE DIRECTIONS

# data[].attributes.subject
GO BACK TO TOP FOR CRITICAL ANALYSIS AND FUTURE DIRECTIONS

# data[].attributes.body
- 1 in 11 Canadians over the age of 65 currently have dementia. Once you reach 65 years of age, your risk for dementia doubles every 5 years ³⁶

- Currently, roughly just as many individuals are indirectly affected by AD as people directly affected with the disease³⁵

- The Canadian population is aging, and there is still no cure for AD and current pharmacological treatments appear to be effective for a limited time frame within the course of the disease¹⁹

-In 2016, the cost to the Canadian health care system and additional costs to caregivers not covered by health care amounted to 10.4 billion dollars ³⁵.

- As the baby boomers age and as our population ages in general, this number can be expected to increase substantially. This number is expected to increase by over 6 billion annually within the next 15 years³⁵.

-These additional costs to the health care system will have to come from somewhere.  Will the government increase tax rates to offset these added costs? Will there be a reduction in health benefits or a reallocation of benefits?

Additionally, according to a study published by the American Association of Retired Persons, over 40 percent of baby boomers have no intention of retiring yet³. Consequently, will this also affect pension plans/health benefits?

# data[].attributes.headline
Finally we made it to the end of the introduction! 

# data[].attributes.subject
Finally we made it to the end of the introduction! 

# data[].attributes.body
Click and watch the video below

# data[].attributes.attachment_link.description
Uploaded by Rachelle Rodin on 2017-04-28.

# data[].attributes.body
Please see our original presentation for a more detailed overview of the methods

# data[].attributes.headline
Introduction Part 3: The purpose of the de Souza Silva Study 

# data[].attributes.subject
Introduction Part 3: The purpose of the de Souza Silva Study 

# data[].attributes.body
Since NK3-R has been associated with both ACh and memory (see introduction part 3), this group hypothesize that NK3-R stimulation may counteract ACh deficits and thus, based on evidence from the Cholinergic hypothesis (see introduction part 3), improve learning and memory in AD and elderly patients.

In other words: NK3-R stimulation may be beneficial as a target to treat cognitive deficits in AD and elderly patients.

# data[].attributes.body
Cytogenetic Location: 4q24

# data[].attributes.body
- Recall the paper we will review in detail in this padlet is trying to determine if NK3-R can be used to treat cognitive deficits associated with AD and normal aging. So, what is NK3-R?

= a member of family of receptors that specifically bind to neuropeptides called
neurokinins (NKs)¹¹. NK-B is the preferred ligand to NK3-R¹⁴.

= encoded in humans by the TAC3 gene¹⁴

= with the help of G proteins, it will activate a phosphatidylinositol-calcium second
messenger system¹⁴

= Interestingly, it's associated with incomplete sexual maturation but it has also been
1. implicated in learning and memory
- NK3-R disruption = memory deficits⁴⁴
2. connected to the ACh system
- Are localized to cholinergic neurons in the basal forebrain¹¹

- NK3-R agonist stimulate the basal forebrain pathway to
hippocampus³⁰

# data[].attributes.body
- This hypothesis suggests that one significant contributor to cognitive impairments associated with AD and aging is ACh deficits.

# data[].attributes.attachment_link.description
Uploaded by Rachelle Rodin on 2017-04-28.

# data[].attributes.headline
Excerpt from the documentary World's Scariest Drug

# data[].attributes.subject
Excerpt from the documentary World's Scariest Drug

# data[].attributes.attachment_link.description
Uploaded by Rachelle Rodin on 2017-04-28.

# data[].attributes.headline
Support for the Cholinergic Hypothesis - part 3

# data[].attributes.subject
Support for the Cholinergic Hypothesis - part 3

# data[].attributes.body
1. Procholinergic drugs can slow the progression of the cognitive deficits observed with AD¹⁶.
- ChE inhibitors remain the most widely prescribed drugs to treat AD
( ChE = acetylcholinesterase inhibitors, acetylcholinesterase = an enzyme that breaks down ACh)

# data[].attributes.headline
Support for the Cholinergic Hypothesis - part 2

# data[].attributes.subject
Support for the Cholinergic Hypothesis - part 2

# data[].attributes.body
The results above confirm or at least suggest a substantial cholinergic deficit in AD patients and elderly patients. There is also evidence to support a role for ACh in learning and memory in general. For example:

1. If you block cholinergic receptors through antagonists, performance on learning and memory tasks decline²⁷ (see the video on the left below for a list of drugs that alter the ACh synapse).
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
** An interesting Aside/proof of principle:
- one drug that blocks ACh receptors is Scoplamine. It blocks muscarinic ACh receptors².

- drugs that block ACh receptors have been shown both inside and outside of controlled experimental settings to produce learning and memory deficits

-Scoplamine is derived from the flower of a common shrub found in Colombia. Although its flowers are                      common, it is a very scary drug to most Colombians.  They call it ‘The Devil’s Breath”.  This drug is known to                    produce sleepiness and, more important to our discussion, memory loss, traits ideal for criminal use. Scoplamine, in Colombia, is often added to people’s drunks or blown into an individuals face to facilitate the process of raping or robing an individual leaving the victim with little to no recollection of the incidence and thus unlikely to report the scenario to the police.  Below, on the right, is a clip from a documentary on Scopolamine. It shows a victim sharing his experience².

# data[].attributes.headline
Support for the Cholinergic Hypothesis - part 1

# data[].attributes.subject
Support for the Cholinergic Hypothesis - part 1

# data[].attributes.body
Some prominent evidence is as follows:

1. it is consistently reported that ACh markers in the cerebral cortex are substantially reduced in people who died from AD⁴
- this includes ChAT, the enzyme that synthesizes ACh⁴
- importantly, this deficit is strongly associated with the severity of cognitive deficits in AD patients ⁴

2.  Postmortem AD brain tissue also show:
a) reduce ACh reuptake³⁷
b) reduce ACh release³²

3. In line with the above evidence, there is substantial loss, greater than 75% in some cases, of cholinergic neurons in the basal forebrain in AD patients, specifically in the Nucleus basalis of Meynert¹². The basal forebrain is considered the major output centre for ACh in the CNS (see the video on the left for a more detailed look at ACh pathways in the brain. see the video on the right for a detailed look at the location of the Nucleus basalis of Meynert in the brain or see the image on the far right).

4. Elderly mice synthesize ACh much less than younger mice (up to 75% less) and their cholinergic neurons release less ACh after stimulation⁴⁰

# data[].attributes.headline
Introduction part 2: The Cholinergic Hypothesis 

# data[].attributes.subject
Introduction part 2: The Cholinergic Hypothesis 

# data[].attributes.body
= originally proposed in the 1980s⁴

= it states that: functional disturbances in ACh activity occur both in AD as well as in normal aging and that these disturbances contribute significantly to the observed memory loss and cognitive function of such individuals¹⁶

= this hypothesis was initially proposed after biochemically investigating the brains of AD patients postmortem

# data[].attributes.body
One proposition that resulted from this line of thinking is the Cholinergic Hypothesis.

# data[].attributes.headline
ASIDE: The difference between AD and Dementia 

# data[].attributes.subject
ASIDE: The difference between AD and Dementia 

# data[].attributes.attachment_link.title
What's the Difference Between Alzheimer's Disease and Dementia?

# data[].attributes.headline
This leads to the million-dollar question

# data[].attributes.subject
This leads to the million-dollar question

# data[].attributes.body
What factor(s) are changing in AD or in normal aging that are triggering cognitive deficits?

If we can answer this question, we can target these factors to treat, improve, and potentially reverse or cure the cognitive deficits associated with AD and aging.

# data[].attributes.body
Note: Ignore the error message from youtube. If you click on this image, the video will still play.

# data[].attributes.body
Document: Normal aging vs. dementia

# data[].attributes.attachment_link.readable_text
Alzheimer's disease and other dementias are not a part of normal aging.

Almost 40 per cent of people over the age of 65 experience some form of memory loss. When there is no underlying medical condition causing this memory loss, it is known as "age-associated memory impairment," which is considered a part of the normal aging process.

Brain diseases like Alzheimer's disease and other dementias are different.

Age-associated memory impairment and dementia can be told apart in a number of ways. Below are some examples.
Note: this is not a diagnostic tool.

Not being able to remember details of a conversation or event that took place a year ago

Not being able to recall details of recent events or conversations

Not being able to remember the name of an acquaintance

Not recognizing or knowing the names of family members

Forgetting things and events occasionally

Forgetting things or events more frequently

Occasionally have difficulty finding words

Frequent pauses and substitutions when finding words

You are worried about your memory but your relatives are not

Your relatives are worried about your memory, but you are not aware of any problems

If you are worried about your memory, talk to your family doctor.

Tips for coping with normal age-related memory difficulties:

Keep a routine

Organize information (keep details in a calendar or day planner)

Put items in the same spot (always put your keys in the same place by the door)

Repeat information (repeat names when you meet people)

Run through the alphabet in your head to help you remember a word

Make associations (relate new information to things you already know)

Involve your senses (if you are a visual learner, visualize an item)

Teach others or tell them stories

Get a full night's sleep

Learn more about what you can do to maintain your brain health and strengthen your memory

It's important to know when to see your doctor about memory concerns but it's equally important to know that forgetting someone's name doesn't necessarily mean that you are getting dementia. Watch the video I have trouble remembering things - am I getting dementia?

The material was created by TCD, through the NEIL Programme at the Institute of Neuroscience with support from GENIO.
© 2014 The Provost, Fellows, Foundations Scholars, and the Other Members of Board, of the College of the Holy and Undivided Trinity Of Queen Elizabeth, near Dublin. Permission to use this material was granted by TCD which reserves all rights in the material.

Related Content

Last Updated: 11/08/2017

# data[].attributes.attachment_link.description
Alzheimer's disease and other dementias are not a part of normal aging. Almost 40 per cent of people over the age of 65 experience some form of memory loss. When there is no underlying medical condition causing this memory loss, it is known as "age-associated memory impairment," which is considered a part of the normal aging process.

# data[].attributes.body
Memory loss is also a prominent symptom of Alzheimer's disease. There are however some key differences in the types and extent of age-associated memory impairments compared to AD-associated memory impairments.  For a list of differences, click on the document below. For a very brief explanation of the some memory loss differences between normal aging and AD, given by Peter V. Rabins, MD, MPH from The Johns Hopkins Hospital, click the video clip below.

# data[].attributes.body
This is also true of long-term episodic memory: the memory that encodes the what, when, and where of our everyday lives²⁸.  This is not typically true, however, of semantic memory or procedural memory²⁵. With age other cognitive functions such as multi-tasking, shifting focus, and information processes can also be negatively impacted²⁵.

# data[].attributes.body
Here we have the results of three different spatial memory experiments, performed in different mammals, including humans¹⁴.  The higher the percent correct, the better the animals performed on that task, implying that they have better memory. It is pretty evident that, at least with spatial memory, it declines with age¹⁸.

# data[].attributes.body
This has been supported by scientific literature. Below is just one example.

# data[].attributes.headline
Click the image below to read the original paper

# data[].attributes.subject
Click the image below to read the original paper

# data[].attributes.body
Hello inquisitive minds!

Welcome to our interactive Padlet! Through this online interactive board, you have the chance to explore the 2013 scientific endeavour of de Souza Silva and her colleagues.  This Padlet explores and expands on the following paper.

The authors of this paper are interested in finding a
treatment for memory decline associated with normal
aging as well as with Alzheimer's disease.

The researchers focus on the receptor Neurokinin3
(NK3-R).

The authors are trying to determine if this Neurokinin3
receptor can be used as a target to treat memory decline
associated with normal aging as well as Alzheimer's disease¹⁴.

# data[].attributes.body
If you read the cartoon to the right, you probably chuckled. Why? - Because we all know there is some truth to it.  We all know, at least anecdotally, as we age our memory starts to decline.

# data[].attributes.body
Using NK3-R Stimulation to Improve Memory in the Elderly & AD Patients

# data[].attributes.headline
References (for Methods, Conclusions, Discussion, Critical Analysis, & Future Directions sections)

# data[].attributes.subject
References (for Methods, Conclusions, Discussion, Critical Analysis, & Future Directions sections)

# data[].attributes.body
(Rachelle will update this with her references once she is finished)

# data[].attributes.headline
Critical Analysis & Future Directions: Translation of findings in rats to clinical settings

# data[].attributes.subject
Critical Analysis & Future Directions: Translation of findings in rats to clinical settings

# data[].attributes.body
(Expand to full screen for best view?)

# data[].attributes.attachment_link.title
Translation of findings in rats to clinical settings

# data[].attributes.attachment_link.description
HMB360 Final Project - Critical Analysis & Future Directions - Video 1

# data[].attributes.headline
Critical Analysis & Future Directions: Functional relationship between TACR3 and learning/memory

# data[].attributes.subject
Critical Analysis & Future Directions: Functional relationship between TACR3 and learning/memory

# data[].attributes.body
(Expand to full screen for best view!)

# data[].attributes.attachment_link.title
Functional relationship between TACR3 and learning/memory

# data[].attributes.attachment_link.description
HMB360 Final Project - Critical Analysis & Future Directions - Video 2

# data[].attributes.headline
Critical Analysis & Future Directions: Lack of healthy controls in the genetic association study

# data[].attributes.subject
Critical Analysis & Future Directions: Lack of healthy controls in the genetic association study

# data[].attributes.body
(Expand to full screen for best view!)

# data[].attributes.attachment_link.title
Lack of healthy controls in the genetic association study

# data[].attributes.attachment_link.description
HMB360 Final Project - Critical Analysis & Future Directions - Video 3

# data[].attributes.headline
Discussion: NK3-R agonists as clinical treatments

# data[].attributes.subject
Discussion: NK3-R agonists as clinical treatments

# data[].attributes.body
Acetylcholinesterase (AChE) inhibitors are the most common treatment for cholinergic degeneration and learning/memory deficits in aging/dementia. However, AChE inhibitors have wide-ranging side effects due to the role of AChE in the PNS (for a review see Buckley et al., 2015). Conversely, NK3-R is found primarily in the CNS (Griebel et al., 2012), so NK3-R agonists may be a safer alternative treatment. Chao et al. (2015) found that senktide alleviates temporal order memory deficits in a rat model of Parkinson's disease (PD); since PD can involve cholinergic degeneration and memory loss similar to AD, this supports the potential use of NK3-R agonists to treat learning and memory deficits in neurodegenerative disorders.

# data[].attributes.body
There are only 2 studies of TACR3 knockout (KO) mice, with conflicting results. Siuciak et al. (2007) found that KO mice had deficits on the MWM task compared to WT mice, supporting the results of our paper; while Nordquist et al. (2008) found that KO mice did not show any deficits on this task. This may be due to differences in the strains used to create the KO mice, and/or differences in MWM protocol. Notably, the authors of our paper only cited the paper which supported their results.
TACR3 polymorphism (and specifically, the rs2765 SNP) was later examined in one other study. Teipel et al. (2015) found that rs2765 was associated with the volume of the anterior basal forebrain (and the decrease in volume with age) but not with hippocampal volume. rs2765 was also associated with MMSE scores. However, Teipel et al. do not specify the genotypes of the participants in this study, so it is unclear whether the association is with the same allele as in our paper.

# data[].attributes.headline
Discussion:  Neurokinin receptor function in aging

# data[].attributes.subject
Discussion:  Neurokinin receptor function in aging

# data[].attributes.body
While neurokinins are known to be involved in memory generally,  there is relatively little research on the involvement of neurokinins in learning/memory in aging. Substance P, a neuropeptide that targets both NK1-R and NK3-R, can improve learning & memory in aged rats (Hasenohrl et al., 1994). Mileusnic et al. (1999) found that NK3-R expressing neurons decrease with age in the human frontal and temporal cortex, but found no differences in NK3-R expression with age in rats.

# data[].attributes.headline
Discussion: Effects of senktide/NK3-R agonism on learning, memory, and ACh

# data[].attributes.subject
Discussion: Effects of senktide/NK3-R agonism on learning, memory, and ACh

# data[].attributes.body
This study is the first to show improvements in spatial learning in aged animals after NK3-R agonism. Previously,  Schable et al. (2011) demonstrated improvements in episodic-like memory and increase ACh levels in aged rats treated with senktide. Subsequent publications have shown that senktide treatment leads to improved learning & memory in adult animals, rather than in aging specifically (Chao et al., 2014;  2016).  Several studies have found that senktide improves scopolamine-induced memory deficits (Ukai et al., 1998; Schable et al., 2012); since scopolamine is a muscarinic ACh receptor blocker, this supports the finding that senktide improves learning and memory by increasing ACh levels.

# data[].attributes.body
(Click on picture to expand and read!)

# data[].attributes.body
From Folkersma et al. (2011)

# data[].attributes.attachment_link.title
3D Hippocampus and Hippocampal Subfields of a Human Brain

# data[].attributes.attachment_link.description
Segmentation of hippocampal subfields. The segmentation was performed on a T1-weighted structural volume (MPRAGE, resolution: 0.6 mm isotropic) as part of a 7 Tesla ultra high-resolution fMRI study at the DZNE/ IKND. DZNE = Deutsches Zentrum für Neurodegenerative Erkrankungen (http://www.dzne.de/en/ ); IKND = Institut für Kognitive Neurologie und Demenzforschung (http://www.iknd.ovgu.de ).