Alzheimer's & other dementias
The brain is rich in lipids (fats), which not only help insulate nerve fibers, but are also a crucial part of the membranes surrounding brain cells. One particular type that is highly enriched in the brain (sphingolipids) produces something called S1P. A mouse study has now found that when their brains were blocked from breaking down S1P, the mice began to show learning and memory problems. Moreover, there was a significant increase in the amount of APP (the precursor of amyloid-beta proteins, characteristic of Alzheimer’s) in their brains.
The problem is that S1P is broken down into simpler products, one of which is vital for autophagy — how cells digest and recycle their own components, when they don’t work properly. This finding suggests a new mechanism for the development of Alzheimer's and other dementias.
A study involving 16 patients at different stages of Alzheimer's disease, who underwent memory tests and PET scans at 17-month intervals, has found a marked difference between individuals in how much tau protein is in the brain and how quickly it spreads. Moreover, there was a strong correlation between the amount of tau and how much episodic memory was impaired.
This may help explain why Alzheimer's progresses at such different rates between people.
It’s generally thought that aging is the result of DNA damage accumulation, because of the breakdown in DNA repair processes. A new mouse study has found that a crucial element in DNA repair is a protein called SIRT6. Mice deficient in SIRT6 showed marked learning impairments, and their brains showed more DNA damage, cell death, and hyperphosphorylated tau (a critical mark in several neurodegenerative diseases, as well as Alzheimer's).
Humans with Alzheimer's disease were also found to have a severe deficiency of the SIRT6 protein.
It’s suggested that SIRT6 loss, leading to DNA damage accumulation, may be the beginning of the chain that ends in Alzheimer’s and other neurodegenerative disease.
We know that high levels of amyloid-beta plaques are characteristic of Alzheimer's, but we also know that people can have high levels of amyloid without displaying symptoms of Alzheimer's. A new study shows that the reason for this apparent discrepancy may lie with another protein, called NPTX2.
It appears that memory loss occurs when high amyloid-beta occurs in combination with low levels of NPTX2.
The gene which expresses the protein NPTX2 belongs to a set of genes known as "immediate early genes," which are activated almost instantly in brain cells when an experience results in a new memory. The protein is used by neurons to strengthen the circuits that encode memories.
A study of 144 archived human brain tissue samples revealed that NPTX2 protein levels were reduced by as much as 90% in brain samples from people with Alzheimer's compared with age-matched brain samples without Alzheimer's. People with amyloid plaques who had never shown signs of Alzheimer's, on the other hand, had normal levels of NPTX2.
A mouse study then confirmed this link, by showing that cell function wasn’t affected by a lack of NPTX2 until a gene that increases amyloid generation was added. With both amyloid and no NPTX2, fast-spiking interneurons could not control brain "rhythms" which synchronize activity between neurons, thus creating circuits / networks that encode memories. Additionally, a glutamate receptor essential for interneuron function was also reduced — as it was in the human Alzheimer's brains.
A study of NPTX2 protein levels in the cerebrospinal fluid (CSF) of 60 living Alzheimer's patients and 72 controls found that
 Mitroi, D. N., Karunakaran I., Gräler M., Saba J. D., Ehninger D., Ledesma M. Dolores, et al.
(2017). SGPL1 (sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production.
Autophagy. 13(5), 885 - 899.
 Chiotis, K.., Saint-Aubert L.., Rodriguez-Vieitez E.., Leuzy A.., Almkvist O.., Savitcheva I.., et al.
(2017). Longitudinal changes of tau PET imaging in relation to hypometabolism in prodromal and Alzheimer’s disease dementia.
 Kaluski, S., Portillo M., Besnard A., Stein D., Einav M., Zhong L., et al.
(2017). Neuroprotective Functions for the Histone Deacetylase SIRT6.
Cell Reports. 18(13), 3052 - 3062.
 Xiao, M-F., Xu D., Craig M. T., Pelkey K. A., Chien C-C., Shi Y., et al.
(2017). NPTX2 and cognitive dysfunction in Alzheimer’s Disease.
eLife. 6, e23798.
A Canadian study involving 40 older adults (59-81), none of whom were aware of any major memory problems, has found that those scoring below 26 on the Montreal Cognitive Assessment (MoCA) dementia screening test also showed shrinking of the anterolateral entorhinal cortex. This brain region is the first affected in the development of Alzheimer's disease. The study found specifically that this area of the brain is involved in configural processing — that is, processing the spatial arrangement of an object's elements. Accordingly, this task provides a very early indicator of developing Alzheimer's.
You can do a preliminary assessment of your memory using Baycrest's scientifically-validated, online brain health assessment tool, Cogniciti at http://www.cogniciti.com.
 Olsen, R.. K., Yeung L.. - K., Noly-Gandon A.., D’Angelo M.. C., Kacollja A.., Smith V.. M., et al.
(Submitted). Human anterolateral entorhinal cortex volumes are associated with cognitive decline in aging prior to clinical diagnosis.
Neurobiology of Aging.
A study involving 35 adults with MCI found that those who exercised four times a week over a six-month period increased their volume of gray matter. But those who participated in aerobic exercise experienced significantly greater gains than those who just stretched, who also showed signs of white matter loss.
Aerobic activity included treadmill, stationary bike or elliptical training.
The study was presented at the annual meeting of the Radiological Society of North America (RSNA) in November, 2016.
In Australia, it has beens estimated that 9% of people aged over 65, and 30% of those aged over 85 have dementia. However, these estimates are largely based on older data from other countries, or small local samples.
A new technique based on an ecological method for estimating species population size has been used to estimate dementia rates in the Australian population. The study used 16 years of data from 12,432 Australian women born between 1921 and 1926 who participated in the Women's Health Australia study. Survey data was linked to aged care assessments, the National Death Index, the Pharmaceutical Benefits Scheme, and hospital admissions data to find any instance where the women participating in the study were diagnosed with dementia. This additional data helped overcome the problem of such studies, where participants often just drop out, and the cause isn’t known.
Applying the ecological technique to all this data led to the conclusion that an additional 728 women with dementia had not been identified, increasing the 16 year prevalence from 20.4 to 26.0%. Breaking this down by age, we have:
 Waller, M., Mishra G. D., & Dobson A. J.
(2017). Estimating the prevalence of dementia using multiple linked administrative health records and capture–recapture methodology.
Emerging Themes in Epidemiology. 14, 3.
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).
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.
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:
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.
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.
 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.
 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.
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:
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.
Janet Sherman presented the findings at the annual meeting of the American Association for the Advancement of Science in Boston, in February 2017.
Following on from a previous study showing that such a virtual supermarket game administered by a trained professional can detect MCI, a small study used a modified Virtual SuperMarket Remote Assessment Routine (VSM-RAR) that was self-administered by the patient at home on their own, for a period of one month.
Using the average score over 20 assessments, the game correctly diagnosed MCI 91.8% of the time, a level of diagnostic accuracy similar to the most accurate standardized neuropsychological tests.
The study involved six patients with MCI and six healthy older adults.The level of diagnostic accuracy was better using the average score than in the previous study in which only a single score was used.
A tablet PC was provided to the participants, on which to play the game.
 Zygouris, S., Ntovas K., Giakoumis D., Votis K., Doumpoulakis S., Segkouli S., et al.
(2017). A Preliminary Study on the Feasibility of Using a Virtual Reality Cognitive Training Application for Remote Detection of Mild Cognitive Impairment.
Journal of Alzheimer's Disease. 56(2), 619 - 627.
Data from the Women's Health Initiative Memory Study, involving 6,467 postmenopausal women (65+) who reported some level of caffeine consumption, has found that those who consumed above average amounts of coffee had a lower risk of developing dementia.
Caffeine intake was estimated from a questionnaire. The median intake was 172 mg per day (an 8-ounce cup of brewed coffee contains 95mg of caffeine, 8-ounces of brewed black tea contains 47mg, so slightly less than 2 cups of coffee or less than 4 cups of tea). The women were cognitively assessed annually.
Over ten years, 388 were diagnosed with probable dementia (209) or MCI (179). Those who consumed above the median amount of caffeine had a 36% reduction in risk. The average intake in this group was 261 mg (3 cups of coffee), while the average intake for those below the median was 64 mg per day (less than one cup).
Risk factors such as hormone therapy, age, race, education, body mass index, sleep quality, depression, hypertension, prior cardiovascular disease, diabetes, smoking, and alcohol consumption, were taken into account.
The findings are consistent with other research finding a benefit for older women. It should not be assumed that the findings apply to men. It also appears that there may be a difference depending on education level. This sample had a high proportion of college-educated women.
It should also be noted that there was no clear dose-response effect — we could put more weight on the results if there was a clear relationship between amount of caffeine and benefit. Part of the problem here, however, is that it’s difficult to accurately assess the amount of caffeine, given that it’s based on self-report intake of coffee and tea, and the amount of caffeine in different beverages varies significantly.
Moreover, we do have a couple of mechanisms for caffeine to help fight age-related cognitive decline.
A recent study using rats modified to have impaired receptors for the adenosine A2A produced rats showing typical characteristics of an aging brain. In humans, too, age-related cognitive decline has been associated with over-activation of these receptors and dysfunction in glucocorticoid receptors.
The rat study shows that over-activation of the adenosine A2A receptors reduces the levels of glucocorticoid receptors in the hippocampus, which in turn impairs synaptic plasticity and cognition. In other words, it is the over-activation of the adenosine receptors that triggers a process that ends with cognitive impairment.
The point of all this is that caffeine inhibits the adenosine A2A receptors, and when the rats were given a caffeine analogue, their memory deficits returned to normal.
Another more recent study has found that caffeine increases the production of an enzyme that helps prevent tau tangles.
Building on previous research finding that an enzyme called NMNAT2 not only protects neurons from stress, but also helps prevent misfolded tau proteins (linked to Alzheimer’s, and other neurodegenerative disorders), the study identified 24 compounds (out of 1,280 tested) as having potential to increase the production of NMNAT2. One of the most effective of these was caffeine.
When caffeine was given to mice modified to produce lower levels of NMNAT2, the mice began to produce the same levels of the enzyme as normal mice.
 Driscoll, I., Shumaker S. A., Snively B. M., Margolis K. L., Manson JA. E., Vitolins M. Z., et al.
(2016). Relationships Between Caffeine Intake and Risk for Probable Dementia or Global Cognitive Impairment: The Women’s Health Initiative Memory Study.
The Journals of Gerontology: Series A. 71(12), 1596 - 1602.
 Batalha, V. L., Ferreira D. G., Coelho J. E., Valadas J. S., Gomes R., Temido-Ferreira M., et al.
(2016). The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.
Scientific Reports. 6, 31493.
 Ali, Y. O., Bradley G., & Lu H-C.
(2017). Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons.
Scientific Reports. 7, 43846.
Our bodies’ ability to regulate its temperature gets worse with age, along with a slowing metabolism. We also become more vulnerable to Alzheimer's as we age. A study compared mice genetically engineered to manifest Alzheimer's symptoms as they age with normal mice. They found that these transgenic mice were worse at maintaining their body temperature as they aged, with the difference reaching almost 1° Celsius by the age of 12 months.
Moreover, there was an increase in Alzheimer’s symptoms (such as a greater increase in abnormal tau proteins and loss of synaptic proteins) in transgenic mice when they were exposed to low temperatures.
But — and this is the exciting bit — when the mice were given one week in a 28°C environment, and their body temperature increased by 1°C, beta-amyloid production dropped substantially, and memory test results were comparable to those of normal mice.
While obviously these results need to be replicated in humans, the findings do suggest that improving body temperature might be helpful for those in early stages of Alzheimer’s. Body temperature can be increased through physical activity, diet, drugs, or simply by turning the heat up.
 Vandal, M., White P. J., Tournissac M., Tremblay C., St-Amour I., Drouin-Ouellet J., et al.
(Submitted). Impaired thermoregulation and beneficial effects of thermoneutrality in the 3×Tg-AD model of Alzheimer's disease.
Neurobiology of Aging. 43, 47 - 57.
People with Alzheimer's disease develop problems in recognizing familiar faces. It has been thought that this is just part of their general impairment, but a new study indicates that a specific, face-related impairment develops early in the disease. This impairment has to do with the recognition of a face as a whole.
Face recognition has two aspects to it: holistic (seeing the face as a whole) and featural (processing individual features of the face). While both are useful in object recognition, expert recognition (and face recognition is usually something humans are expert in) is built on a shift from featural to holistic processing.
The study compared the ability of people with mild Alzheimer's and healthy age- and education-matched seniors to recognize faces and cars in photos that were either upright or upside down. It found that those with Alzheimer's performed comparably to the control group in processing the upside-down faces and cars. This type of processing requires an analysis of the various features. Those with Alzheimer’s also performed normally in recognizing upright cars (car experts are likely to use holistic processing, but those with less expertise will depend more on featural processing). However, they were much slower and less accurate in recognizing faces.
Realizing that impaired facial recognition is based on a holistic perception problem, rather than being simply another failure of memory, suggests that strategies such as focusing on particular facial features or on voice recognition may help patients recognize their loved ones for longer.
 Lavallée, M. Maxime, Gandini D., Rouleau I., Vallet G. T., Joannette M., Kergoat M-J., et al.
(2016). A Qualitative Impairment in Face Perception in Alzheimer’s Disease: Evidence from a Reduced Face Inversion Effect.
Journal of Alzheimer's Disease. 51(4), 1225 - 1236.
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