early markers

Alzheimer's produces early brain atrophy

  • A large study finds those who go on to develop Alzheimer's show atrophy of the hippocampus before age 40, and in the amygdala around age 40.

Brain scans from over 4,000 people, across the age range (9 months to 94 years) and including 1,385 Alzheimer's patients, has revealed an early divergence between those who go on to develop Alzheimer’s and those who age normally. This divergence is seen in early atrophy of the hippocampus before age 40, and in the amygdala around age 40.

https://www.eurekalert.org/pub_releases/2019-03/c-ahd030819.php

https://www.nature.com/articles/s41598-019-39809-8

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Navigation difficulties early sign of Alzheimer's

  • A mobile phone game designed to test spatial navigation skills (Sea Hero Quest) has found that performance can distinguish APOE4 carriers from non-carriers.
  • Preliminary findings from a long-term study indicate that middle-aged adults with close relatives with Alzheimer's did worse on a test that measured their ability to visualise their position, and tended to have a smaller hippocampus.
  • A small study found that increasing difficulties with building cognitive maps of new surroundings was linked to Alzheimer's biomarkers. Difficulties in learning a new route appeared later, among those with early Alzheimer's.

Mobile game detects Alzheimer's risk

A specially designed mobile phone game called Sea Hero Quest has found that gaming data can distinguish between those people who are genetically at risk of developing Alzheimer's disease ond those who are not. The game is designed to test spatial navigation skills — one of the first cognitive areas affected in Alzheimer's.

A standard memory and thinking test could not distinguish between the risk and non-risk groups.

Gaming data was taken from 27,108 UK players aged 50-75. This benchmark data was then compared with 60 people who had been genetically tested, of whom about half carried the APOE4 gene. The gene tested individuals were matched for age, gender, education and nationality with the benchmark cohort.

Previous findings from Sea Hero Quest data have shown that people in different countries and populations navigate differently, but this study shows that APOE4 carriers took less efficient (i.e., longer) routes to checkpoint goals. The difference in performance between carriers and non-carriers was particularly pronounced where the space to navigate was large and open.

https://www.eurekalert.org/pub_releases/2019-04/uoea-tmg042419.php

Getting lost may be the first sign of Alzheimer’s

Preliminary findings from a long-term UK study indicate that middle-aged adults (41-59) with close relatives with Alzheimer's did worse on a test that measured their ability to visualise their position. They also tended to have a small hippocampus.

The Four Mountains test involves showing people a picture of a mountain and asking them to identify it in a selection of four other landscapes.

https://www.theguardian.com/society/2017/may/06/getting-lost-may-be-first-sign-of-alzheimers

Building mental maps precedes route navigation problems

A study involving 71 older adults found that increasing difficulties with building cognitive maps of new surroundings was associated with the development of Alzheimer's biomarkers. Difficulties in learning a new route were not evident at this stage, but appeared later, among those with early Alzheimer's.

The computer task involved navigating a virtual maze consisting of a series of interconnected hallways with four wallpaper patterns and 20 landmarks. Participants were tested on two navigation skills: how well they could learn and follow a pre-set route, and how well they could form and use a cognitive map of the environment. Participants were given 20 minutes to either learn a specified route, or to study and explore the maze with a navigation joystick. They were then tested on their ability to recreate the route or find their way to specific landmarks in the environment.

Humans generally find their way using two distinct forms of spatial representation and navigation: egocentric navigation, in which people rely on past knowledge to follow well-worn routes, moving from one landmark to another, and allocentric navigation, in which people become familiar with their big picture surroundings and create a mental map of existing landmarks, allowing them to plot best available routes and find shortcuts to new destinations. Allocentric navigation relies on the hippocampus, while egocentric navigation is more closely associated with a brain region called the caudate.

Those with cerebrospinal markers for Alzheimer’s but no symptoms, had significant difficulties only when they had to form a cognitive map (that is, with hippocampal allocentric navigation processes). However, additional training did enable them to eventually learn the cognitive map.

The researchers suggest that preclinical Alzheimer’s disease is characterized by hippocampal atrophy and associated cognitive mapping difficulties, and then, (if) the disease progresses, cognitive mapping deficits worsen, the caudate becomes involved, leading to route learning deficits.

Participants included 42 who were cognitively healthy and had no cerebrospinal fluid markers for Alzheimer’s, 13 cognitively normal individuals who had the biomarkers, and 16 with early Alzheimer’s.

http://www.futurity.org/alzheimers-maps-nativation-1143342-2/

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[4415] Coughlan, G., Coutrot A., Khondoker M., Minihane A-M., Spiers H., & Hornberger M.
(2019).  Toward personalized cognitive diagnostics of at-genetic-risk Alzheimer’s disease.
Proceedings of the National Academy of Sciences. 116(19), 9285 - 9292.

[4446] Ritchie, K., Carrière I., Su L., O'Brien J. T., Lovestone S., Wells K., et al.
(2017).  The midlife cognitive profiles of adults at high risk of late-onset Alzheimer's disease: The PREVENT study.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 13(10), 1089 - 1097.

[4445] Allison, S. L., Fagan A. M., Morris J. C., & Head D.
(2016).  Spatial Navigation in Preclinical Alzheimer’s Disease.
Journal of Alzheimer's Disease. 52(1), 77 - 90.

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Anxiety linked to rising amyloid-beta levels

  • A study found an association in healthy older adults between higher amyloid beta levels and worsening anxiety.

Data from the Harvard Aging Brain Study found that higher amyloid beta levels were associated with increasing anxiety symptoms in cognitively normal older adults. The results suggest that worsening anxious-depressive symptoms may be an early predictor of elevated amyloid beta levels.

The study involved 270 cognitively healthy older adults (62-90). For five years, participants were annually assessed for depression, apathy-anhedonia, dysphoria, and anxiety.

https://www.eurekalert.org/pub_releases/2018-01/bawh-aa011118.php

Reference: 

Donovan et al. 2017. Longitudinal Association of Amyloid Beta and Anxious-Depressive Symptoms in Cognitively Normal Older Adults. The American Journal of Psychiatry DOI: 10.1176/appi.ajp.2017.17040442

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New retinal test for early Alzheimer's disease

  • A new test can quickly detect reduced blood capillaries in the back of the eye that are an early indication of Alzheimer's, and shows that it can help distinguish Alzheimer's from MCI.

A study has shown new technology can quickly and non-invasively detect reduced blood capillaries in the back of the eye that are an early indication of Alzheimer's. It also shows that these signs can help distinguish between Alzheimer's and MCI.

The study compared the retinas of 39 Alzheimer's patients, 37 people with MCI, and 133 cognitively healthy people. The Alzheimer's group had loss of small retinal blood vessels at the back of the eye and a specific layer of the retina was thinner when compared to people with MCI and healthy people. The differences in density were statistically significant after researchers controlled for factors including age and sex.

It's been known that patients with Alzheimer's had decreased retinal blood flow and vessel density but it had not been known if these changes were also present in individuals with early Alzheimer's or aMCI.

Larger datasets are required to validate the marker.

https://www.eurekalert.org/pub_releases/2019-04/nu-ere040519.php

https://www.eurekalert.org/pub_releases/2019-03/aaoo-nss030719.php

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Brain changes linked with Alzheimer's years before symptoms appear

  • A long-running study found subtle cognitive deficits evident 11-15 years before clear impairment, as were changes in tau protein.

A very long-running study involving 290 people at risk of Alzheimer's has found that, in those 81 people who developed MCI or dementia, subtle changes in cognitive test scores were evident 11 to 15 years before the onset of clear cognitive impairment. They also showed increases in the rate of change of tau protein in cerebrospinal fluid an average of 34.4 years (for t-tau, or total Tau) and 13 years (for a modified version called p-tau) before the beginning of cognitive impairment.

https://www.eurekalert.org/pub_releases/2019-05/jhm-bcl051419.php

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Difficulties identifying odors early sign of dementia

  • A large study found that most of those who were very poor at identifying common odors developed dementia within 5 years.
  • A study of older adults with a parent who had Alzheimer's found that those who were poorest at identifying odors showed the most Alzheimer's biomarkers.
  • A largish study found that poorer odor identification in older adults (average age 80) )was associated with a transition to dementia and with cognitive decline.
  • An animal study found olfactory dysfunction precedes cognitive problems, and relates amyloid-beta protein in the olfactory epithelium.
  • A large 13-year study found that a poor sense of smell was linked to a greater risk of death within 10 years, and of death from dementia and Parkinson’s disease in particular.

A long-term study of nearly 3,000 older adults (57-85) has found that those who couldn’t identify at least four out of five common odors were more than twice as likely as those with a normal sense of smell to develop dementia within five years.

Of the participants, some 14% could name just three out of five, 5% could identify only two scents, 2% just one, and 1% couldn’t identify a single smell.

Five years after the smell test, almost all of the study subjects who were unable to name a single scent had been diagnosed with dementia, and nearly 80% of those who provided only one or two correct answers.

The test involved a well-validated tool known as "Sniffin'Sticks." The five odors, in order of increasing difficulty, are peppermint, fish, orange, rose and leather.

https://www.eurekalert.org/pub_releases/2017-09/uocm-ewh092617.php

A study involving nearly 300 older adults (average age 63) who had a parent with Alzheimer’s has found that those with the most difficulty in identifying odors were those in whom Alzheimer's biomarkers were most evident.

Sense of smell was assessed using multiple choice scratch-and-sniff tests to identify scents as varied as bubble gum, gasoline or the smell of a lemon. A hundred of the participants had regular lumbar punctures to measure the Alzheimer's biomarkers in the cerebrospinal fluid.

https://www.eurekalert.org/pub_releases/2017-08/mu-col081617.php

A seven-year study involving a multi-ethnic (34% White, 30% African-American, 36% Hispanic) sample of 757 healthy older adults (average age 80.7) found that lower odor identification scores on UPSIT were significantly associated with both the transition to dementia and cognitive decline.

For each point lower that a person scored on the UPSIT, the risk of Alzheimer's increased by about 10%.

The report was reported at the Alzheimer's Association International Conference® 2014 in Copenhagen

http://www.eurekalert.org/pub_releases/2014-07/aa-sae071114.php

Loss of smell sense linked to amyloid-beta protein

An animal study has shown that olfactory dysfunction occurs much earlier than cognitive dysfunction, and that this is related to the amyloid-beta protein. Although it’s been thought that this protein is expressed only in the central nervous system, the study detected direct expression of the protein in the olfactory epithelium, part of the peripheral nervous system. Moreover, the amyloid-beta protein had a fatal effect on olfactory nerve cells in the olfactory epithelium and directly induced the failure of olfactory function.

A less alarming explanation for why our sense of smell tends to decline in old age comes from a mouse study that found that fewer stem cells become olfactory cells in old age as they tend to remain in the stem cell pool and become less active.

https://www.eurekalert.org/pub_releases/2017-09/dgi-oun092517.php

https://www.eurekalert.org/pub_releases/2018-12/hzm--bc-121918.php

Poor sense of smell linked to greater mortality risk

Following on from a previous study in which more than 2,200 older adults (71-82) undertook smell identification tests, investigation 13 years later found that a poor sense of smell was linked to a 46% greater risk of dying within 10 years compared with those ranked as having a good sense of smell. Poor sense of smell was particularly linked to death from dementia and Parkinson’s disease, with some signs that poor smell might also be linked to death from cardiovascular disease. There was no link between poor sense of smell and death from cancer or respiratory diseases. 22% of the overall increased risk of death among those with a poorer sense of smell was down to neurodegenerative diseases.

The link was only present among those who were in very good health at the start of the study.

https://www.theguardian.com/science/2019/apr/29/routine-sense-of-smell-tests-could-be-used-to-spot-signs-of-dementia

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Reduced face memorization ability in those with MCI

  • A small study suggests that the ability to remember faces specifically is impaired in those with amnestic mild cognitive impairment.

A small Japanese study has found evidence that those with amnestic mild cognitive impairment (aMCI) show a specific decline in their ability to recognize faces, and this is accompanied by changes in the way they scan faces.

The study involved 18 patients with aMCI and 18 age-matched healthy controls. Participants were tested on their ability to perceive and remember images of faces and houses.

Those with aMCI showed poorer memory for faces compared to their memory for houses, while control participants showed no difference between the two. Moreover, compared with controls, those with aMCI spent less time looking at the eyes in the image, while increasing the time they spent looking at the mouths of faces.

In general, people have an excellent memory for faces compared to other visual stimuli, and the eyes are particularly useful in helping us remember the face. The researchers suggest that damage to the brain region known as the fusiform face area (FFA) is responsible for the abnormal processing of faces. It is worth noting that a case study of a patient with acquired prosopagnosia revealed the same pattern of fixating on the mouth rather than the eyes.

The finding is consistent with several other studies showing impaired face processing in those with aMCI, but there is some controversy about that conclusion.

https://www.eurekalert.org/pub_releases/2017-11/ku-pso112117.php

Full text available at https://www.nature.com/articles/s41598-017-14585-5

 

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Personality changes during transition to MCI

  • Behavioral and personality changes seen in those with Alzheimer's appear to be reflected in very early increases in neuroticism and declines in openness.

Mild cognitive impairment (MCI) is a precursor of Alzheimer's disease, although having MCI does not mean you are definitely going to progress to Alzheimer's. A new study suggests that one sign of MCI development might be personality changes.

The study involved 277 cognitively healthy residents of a U.S. County, who had the apolipoprotein E (APOE) ɛ4 gene (otherwise known as the ‘Alzheimer’s gene’). Over the study period (around 7 years), 25 developed MCI. Their performance on the Neuroticism, Extraversion, and Openness Personality Inventory—Revised (delivered at the beginning of the study, as well as at other times during the study) was compared with that of the other 252 participants.

Neuroticism increased significantly more in those developing MCI, and openness decreased more. Those developing MCI also showed significantly greater depression, somatization, irritability, anxiety, and aggressive attitude. (Somatization refers to the tendency to generate physical manifestations in response to psychological distress.)

While such personality changes may be barely noticeable at this stage, it may be that diagnosing such early personality changes could help experts develop earlier, safer, and more effective treatments — or even prevention options — for the more severe types of behavior challenges that affect people with Alzheimer's disease.

https://www.eurekalert.org/pub_releases/2018-01/ags-pcd012318.php

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Smell tests provide early evidence of dementia

  • It seems clear now that a substantial decline in sense of smell is a very early sign of developing MCI and Alzheimer's.
  • Several tests have been developed to assess this.
  • It should always be remembered that there is substantial difference between individuals in their 'natural' sense of smell, and this needs to be taken into account in any test.

In the past few months, several studies have come out showing the value of three different tests of people's sense of smell for improving the accuracy of MCI and Alzheimer's diagnosis, or pointing to increased risk. The studies also add to growing evidence that a decline in sense of smell is an early marker for mild cognitive impairment and Alzheimer’s. Indeed, it appears that this sensory loss is a very early symptom, preceding even the shrinking of the entorhinal cortex (the first brain region to show signs of atrophy).

Smell test improves accuracy of MCI & Alzheimer's diagnosis

A simple, commercially available test known as the Sniffin' Sticks Odor Identification Test, in which subjects must try to identify 16 different odors, was given to 728 older adults, as well as a standard cognitive test (the Montreal Cognitive Assessment).

The participants had already been evaluated by doctors and classified as being healthy (292 subjects), having MCI (174: 150 aMCI, 24 naMCI), or having Alzheimer's (262).

It was found that, while the cognitive test alone correctly classified 75% of people with MCI, the number rose to 87% when the sniff test results were added. Diagnosis of Alzheimer's, and of subtypes within MCI, was also improved.

The smell test normally takes 5 to 8 minutes to administer; the researchers are trying to get it down to 3 minutes, to encourage greater use.

A new smell test

Another recent study validates a new smell test which is rather more complicated. The test was developed because the standard University of Pennsylvania Smell Identification Test doesn’t take into account the great variation in olfactory ability among healthy individuals. The ability of normal individuals to recognize and discriminate between odors can vary by as much as 40 times!

The new test is actually four tests:

  • In the OPID (Odor Percept IDentification)-10 test, participants are presented with 10 odors (menthol, clove, leather, strawberry, lilac, pineapple, smoke, soap, grape, lemon) for two seconds each. They are then asked whether the scent is familiar and given a choice of four of the 10 words from which are asked to pick the best one that describes the odor.
  • The Odor Awareness Scale (OAS) assesses their overall attention to environmental odors and how they are affected emotionally and behaviorally by scents.
  • The OPID-20 test includes an additional 10 odors (banana, garlic, cherry, baby powder, grass, fruit punch, peach, chocolate, dirt, orange). Participants are first asked whether a presented odor was included in the OPID-10 test and then asked which word best describes the odor. Their ability to remember odors from the first test determines their POEM (Percepts of Odor Episodic Memory) score.
  • In the Odor Discrimination (OD) test, participants are presented with two consecutive odors and asked whether they were different or the same, a process that is repeated 12 times with different paired scents.

The study involved 183 older adults, of whom 70 were cognitively normal, 74 tested normal but were concerned about their cognitive abilities, 29 had MCI and 10 had been diagnosed with possible or probable Alzheimer's disease.

Results of the OPID-20 test significantly differentiated among the four groups of participants, and those results correlated with the thinning of the hippocampus and the entorhinal cortex. Participants' ability to remember a previously presented aroma, as reflected in the POEM score, was also significant, with participants with Alzheimer's disease performing at no better than chance.

POEM scores of the two cognitively normal groups were compared with what would have been predicted based on their ability to identify and differentiate between odors, as reflected in the OAS and OD tests. Poor POEM performers were more likely to have the ‘Alzheimer's gene’ (APOEe4), showed thinning of the entorhinal cortex, and poorer cognitive performance over time.

Validation of UPSIT

However, two 2016 studies support the use of the University of Pennsylvania Smell Identification Test (UPSIT), and suggest it may offer a practical, low-cost alternative to other tests.

In one study, UPSIT was administered to 397 older adults (average age 80) without dementia, who were also given an MRI scan to measure the thickness of the entorhinal cortex (the first brain region to be affected by Alzheimer's disease). After four years, 50 participants (12.6%) had developed dementia, and nearly 20% had signs of cognitive decline.

Low UPSIT scores, but not entorhinal cortical thickness, were significantly associated with dementia and Alzheimer's disease, and with cognitive impairment. Entorhinal cortical thickness was significantly associated with UPSIT score in those who transitioned from MCI to dementia.

In other words, it looks like impairment in odor identification precedes thinning in the entorhinal cortex.

In another study, UPSITwas administered to 84 older adults, of whom 58 had MCI, as well as either beta amyloid PET scanning or analysis of cerebrospinal fluid. After six months, 67% had signs of memory decline, and this was predicted by amyloid-beta levels (assessed by either method), but not UPSIT score. However, participants with a score of less than 35 were more than three times as likely to have memory decline as those with higher UPSIT scores.

The researchers suggest the association wasn’t as strong in this study because of the younger age of participants (median age 71), their higher education, and the short follow-up.

https://www.eurekalert.org/pub_releases/2016-12/uops-psc122016.php

https://www.eurekalert.org/pub_releases/2016-11/mgh-atr111416.php

http://www.eurekalert.org/pub_releases/2016-07/cumc-stm072516.php

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[4209] Quarmley, M., Moberg P. J., Mechanic-Hamilton D., Kabadi S., Arnold S. E., Wolk D. A., et al.
(2017).  Odor Identification Screening Improves Diagnostic Classification in Incipient Alzheimer’s Disease.
Journal of Alzheimer's Disease. 55(4), 1497 - 1507.

[4210] Dhilla, A. Alefiya, Asafu-Adjei J., Delaney M. K., Kelly K. E., Gomez-Isla T., Blacker D., et al.
(2016).  Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly.
Annals of Neurology. 80(6), 846 - 857.

Lee, Seonjoo et al. 2016. Predictive Utility of Entorhinal Cortex Thinning and Odor Identification Test for Transition to Dementia and Cognitive Decline in an Urban Community Population. Presented at the Alzheimer's Association's International Conference in Toronto.

Kreisl, William et al. 2016. Both Odor Identification and Amyloid Status Predict Memory Decline in Older Adults. Presented at the Alzheimer's Association's International Conference in Toronto.

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Long-winded speech could be early sign of Alzheimer's

  • Rambling and long-winded explanations may be an early sign of mild cognitive impairment. The problem is not the increase in verbosity, however, but a growing inability to be precise.

A study comparing the language abilities of 22 healthy young individuals, 24 healthy older individuals and 22 people with MCI, has found that those with MCI:

  • were much less concise in conveying information
  • produced much longer sentences
  • had a hard time staying on point
  • were much more roundabout in getting their point across.

So, for example, when given an exercise in which they had to join up three words (e.g., “pen”, “ink” and “paper”), the healthy volunteers typically joined the three in a simple sentence, while the MCI group gave circuitous accounts such as going to the shop and buying a pen.

Additionally, when asked to repeat phrases read out by the interviewer, those with MCI had trouble when given phrases involving ambiguous pronouns (e.g., “Fred visited Bob after his graduation”), although they had no trouble with more complex sentences.

A caveat: if you're just one of those people who has always talked like this, don't panic! It's a matter of change and deterioration, not a stable personality trait.

https://www.theguardian.com/society/2017/feb/21/long-winded-speech-could-be-early-sign-of-alzheimers-says-study

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Janet Sherman presented the findings at the annual meeting of the American Association for the Advancement of Science in Boston, in February 2017.

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