Re: [GRG] New Study Links White Matter Decay to Micro-Infarcts

Hi Mike,
I found this post to be more interesting and practically oriented
since you described the types of effects that you and others
consider to be due to loss of cognitive ability. However, many of
the graph images did not come through with the post. Is it possible
that you could make another post with these images? The ones that I
cannot see are below are: image1.jpeg, image2.jpeg, image6.jpeg and
–Paul Wakfer
The eventual home for *all* currently accessible, practically usable, scientifically evidential methods for increasing healthy longevity.

On 15-03-06 04:06 AM, Cliff Clue wrote:

is an elegant video showing the impact of micro-infarct
disease on cognitive decline in brain aging:

It is startling in that the time course of multiple infarcts
observed during this study was very short, occurring over the
course of days in otherwise seemingly healthy volunteers who
presented with evidence of age associated white matter

This work
nicely complements previous data indicating that the
degeneration of the white matter is multifactorial in brain
aging. Even in the absence of micro-infarcts, the perforant
pathways in the white matter undergo steady degeneration with
aging. The rate of this degradation is variable, but it’s
progression appears to be universal. It is characterized by
regional gliosis and loss of fiber density. Both the cellular
and micro-infarct mediated forms of white matter degradation
appear to be associated initially with the development of the
“senior moment” syndrome, which then often progresses to word
searching and blocks, or delays in recall, that can last from a
few minutes to a day or more. Because the rate of brain aging
varies greatly between individuals, these problems may start at
different times for different people. Though, usually by age 55,
the majority of people are beginning to have these kinds of
difficulties with recall. 

is almost certainly affected as well, though this is either
less, or not at all noticeable! To the affected individual. We
don’t notice what we don’t notice. One possibly sign of memory
input degradation may be the increasing problem many people in
their 50s and 60s have with misplacing things and having
difficulty remembering things they need to buy or to do.

currently estimated that in normal human aging about 25% of
the perforant pathways are lost by age 70-75, though these
numbers are still both crude and uncertain. They are however,
comparable to those observed in both aging rats and nonhuman
primates.nthe ability to capture this data is only about 6
years old and is largely an artifact of the development of
Diffusion Tensor Imaging and Voxel Based Morphometry data

Group-averaged diffusion tensor
images of anisotropy of white matter in young and normal
elderly. Parallel movement of water molecules through white
matter results in anisotropic diffusion, with greater
anisotropy (and so greater white matter density) indicated
by brighter areas. Older adults tend to show decreased white
matter integrity compared with younger adults, with the
greatest age-related declines occurring in anterior cortex.
(Head, D. et al. Differential vulnerability of anterior
white matter in non-demented aging with minimal acceleration
in dementia of the Alzheimer type: evidence from diffusion
tensor imaging. Cereb. Cortex (in press). This paper offers
a comprehensive DTI study of white matter changes in normal
and demented aging and demonstrates the loss of fiber
tracts, gliosis and scarring that occur in the so called
‘healthy’ aging brain.

VBM-style analysis of WM changes
with age. (A) Colored voxels show regions where WM volume
shows a significant linear (blue) or non-linear (green)
relationship with age (p < 0.05, fully corrected for
multiple comparisons across space). Clusters are overlaid on
the MNI152 template brain. Images are shown in radiological
convention. (B, C) Plots to illustrate relationship between
age and mean WM volume across all voxels showing a
significant linear (B) or nonlinear (C) relationship with
age. The pink triangles represent female subjects. Giorgio
et al. The graph in the green bordered box below shows white
matter volume as evaluated by conventional MRI using T1
weighted imaging. This data shows a steady increase in WM
volume until age ~40, followed by a modest decline in
advanced old age. However, using more sophisticated
directional Voxel Based Morphometric imaging, as shown in
the purple bordered box at the top of this page, WM changes
are revealed to be complex, inhomogeneous between brain
hemispheres, and begin in the early 20’s. As can be seen in
the VBM white matter graph (purple box) there are, in fact,
extensive loses in WM, however they are regional in nature
as opposed to the global losses experienced by gray matter
as a function of ‘normal’ aging. Growth and aging changes in
white matter for 116 living healthy individuals. White
matter volume rapidly increased until 12 to 15 years
of age, and thereafter increased at a slower rate,
plateauing at approximately the fourth decade of life. [From
Courchesne E, Chisum HJ, Townsend J, et al.: Normal brain
development and aging: quantitative analysis at in vivo MR
imaging in healthy volunteers. Radiology. 2000;216:672.]

in gray matter volume proceed approximately linearly with
age in normal aging, and the average gray matter volume
decreases from ~390 mL at age 22, to ~300 ml at age 82. Total
loss in brain mass between age 20 and age 80 is, on average,
~450 g, or roughly 1/3rd of our youthful
brain volume. If you are not on the metric system, all you
need to know is that an average human brain weighs ~3 pounds
when you are age 20, and by the time you are 80, your brain
will weigh a pound less. And that is absent disease – if you
have Alzheimer’s, hypertension, or atherosclerosis
(cardiovascular disease) your losses will be greater – a lot

in gray matter mass are actually much larger per unit of time,
though they also progress linearly with age in the absence of
any discrete neuropathology, such as AD, multi-infarct
dementia, and the like.


Top: Voxel Based Morphometry
(VBM) analysis of gray matter changes in aging. (A) Colored
voxels show regions demonstrating significant negative
correlations between gray matter volume and age (p <
0.05, fully corrected for multiple comparisons across
space). Clusters are overlaid on the MNI152 template brain.
Images are shown in radiological convention. (B) Plot to illustrate
relationship between age and mean gray matter volume across
all significant voxels. The pink triangles represent female
subjects. [From: Giorgio, A,
Santelli, L, Tomassini, V, Bosnell, R, Smith, S, De Stefano,
N, Johansen-Berg, H. Age-related changes in grey and white
matter structure throughout adulthood. Neuroimage.
2010;51(3):943-51.Epub 2010 Mar 6.]

unclear whether losses in gray matter volume represent true
neuron/glial cell loss, loss of neuronal arborization and
connectivity, loss of brain cell volume, or a combination of
these things. Some recent research indicates that neuronal
cell is not occurring and that the decrease in gray matter
volume is due neuronal atrophy and loss of neuronal
arborization and connectivity. What is not under debate is the
profound loss of cognitive function in normal, "healthy",
aging which accompanies these changes in brain morphology. 

The prefrontal cortex and
underlying white matter are the last areas of the brain to
complete myelination and to reach their maximum volume and,
presumably, cell density. They are also the first white
matter areas of the cerebral cortex to begin to undergo
neurodegeneration. Myelination of the frontal cortex
typically isn’t completed until the early to mid 20s, and
its relentless degeneration begins essentially upon the
completion of its development. This more or less linear
degradation of the prefrontal and medial temporal lobe white
matter correlates with slowed processing speed initially
and, later in life, with declines in all areas of cognition.

The impact of this structural
degeneration on cognitive performance in most areas of
intellectual processing is not usually apparent until the
mid 50s; many abilities such as verbal fluency continue to
increase until the mid 50s or even the early 60s. While
there is linear brain matter loss with increasing age,
specific anatomical areas of the brain degenerate at
different rates, with some areas exhibiting volume increases
into the mid 50s, after which virtually all areas of the
neocortex undergo relentless degeneration (including
lesioning, as well as volume loss) until death occurs. There
is also considerable variation amongst individuals which
appears to occur independent of any discrete pathological

Paradoxically, the fact that this
neurodegeneration is occurring is masked to a large degree
by several compensatory mechanisms that preserve overall
function, as we shall soon see. This leads to a nearly
universal attitude of denial in most aging people who
continue to insist, often into their 60s and 70s that they
(presumably unlike all the others of their species) are
being spared meaningful cognitive decline – and in fact may
be intellectually ‘sharper’ as they age, as opposed to
actually losing neurocognitive ability. There is a good
reason for this omnipresent delusion and that is that even
though cognitive performance starts to seriously decline, on
average, in the mid 50s, a few cognitive domains increase
between age 25 and age 55; thus, the declines in late life
often merely bring cognitive performance back down to where
it was in the mid 20s. Of course, processing speed in late
life is vastly slower than it was when it peaked in the 20s,
but verbal memory and abilities, reasoning, and spatial
abilities are generally well preserved into late life.

The devastating impact of the loss
of raw processing power is best seen in the absolute decline
in mathematical abilities, which decrease relentlessly over
the course of a human life span. The graphs below show
cognitive performance, as measured by the Seattle
Longitudinal Study, a 35-year long longitudinal study
(actually a sequential research design – both
cross-sectional and longitudinal). As can be seen in Graph
A, cross-sectional analysis of data from the study
demonstrate that cuts are evident in all cognitive domains
in aging, with the exception of preserved verbal and numeric
ability. Graph B shows the longitudinal data which
demonstrate that declines occur in all cognitive domains
after age 55.

and longitudinal estimates of age-related change in
cognition. A) Cross-sectional data from the Seattle
Longitudinal Study. Declines are evident in all domains,
with the exception of preserved verbal and numeric
ability. B) Seven year longitudinal data from the same
study. Declines are evident in all domains after age 55,
with only processing speed displaying declines before
55. These graphs graph shows
cognitive performance as measured by a 35-year
longitudinal study (actually a sequential research
design – both cross-sectional and longitudinal) [Schaie,
K. W. Intellectual Development in Adulthood: The Seattle
Longitudinal Study.
Cambridge Univ. Press, Cambridge, 1996.]

for neurodegeneration as a result of life-experiences and
learning, as well as physiological compensation within the
aging brain itself, as illustrated by the increase in word
knowledge over the course of the life span.

At least
one reason why these enormous functional cuts are not more
apparent, or more devastating to individual functioning,
is shown in The graph above. If word knowledge is used as
a marker for life experience and the general accumulation
of knowledge, then it becomes apparent that knowing more
and having more ‘wisdom’ act to offset some of the losses
in processing power. Wisdom, as opposed to knowledge or
skill, is likely of particular importance, since wisdom is
a complex integration of knowledge with emotional learning
and divergent life experiences. The difference between
knowledge and wisdom can perhaps best be appreciated by an
adult telling a child not to play in traffic, or engage in
hazardous behavior, at which point the child has the
knowledge, but very likely lacks the wisdom (based on
repeated, robust, and emotionally charged experiences) to
refrain from such behavior.

There are
also compensatory changes in the brain itself in terms of
how it utilizes its increasingly diminishing processing
resources. For instance, it is well established that there
is a generalized, age-related reduction of activity in the
occipital cortex as a result of the deterioration of
sensory processing. Concurrently, there is also an
age-related increase in pre-frontal cortex activity, in an
attempt to compensate for these deficits. This
relationship between declining occipital function and
sensory deficits is consistent with abundant evidence that
perceptual processing declines as a function of
aging. These declines in occipital cortical function have
been documented across many different kinds of
visual-spatial tasks and support the view that sensory
decline is a major factor in cognitive aging.

Those with
a ‘glass half full’ approach to brain aging will point to
the data that show the compensation for these losses and
cheerfully exclaim “Brain aging isn’t all that bad – life
has its compensations, and whilst your brain is
deteriorating with age, you are also becoming wiser, and
that offsets some of the losses.†This attitude begs the
unasked (and unanswered) question, namely, “What would the cognitive
performance of the aging or aged human be if there were
no accompanying age-associated neurodegeneration?â€
That graph has not yet been prepared, but the answer
should be obvious: people would be vastly smarter and more
capable as they aged, as opposed to barely holding their
own in just a few domains of cognitive performance, while
continuing to deteriorate in most others.

outstanding and highly accessible paper documenting and
integrating the structural and functional deterioration of
cognition in aging is, Hedden T, Gabrieli JD. Nat Rev Neurosci. 2004
Feb;5(2):87-96. Insights into the aging mind: a view from
cognitive neuroscience. PMID 14735112, which is
available as full text from this link:
I cannot recommend this paper highly enough. Additionally,
the Salthouse Cognitive Aging Laboratory, which oversees
the Virginia Cognitive Aging Project (VCAP) at the
University of Virginia, is the premier facility in the US
(and arguably the world) undertaking active, longitudinal
studies of aging. The VCAP study has done comprehensive
cognitive assessments in adults ranging from 18 to 98
years of age. Approximately 3,800 adults have participated
in their three-session (6-8 hour) assessment at least
once, with about 1,600 participating at least twice, and
about 450 of them participating three or more times. The
data from this project have served as the basis for a
veritable cornucopia of scientific publications which are
available in the Resources Section of their website
Nearly 200 papers on the cognitive impact of aging are
available free of charge on their website. It is necessary
to register with your name and email address to access the
papers, but it is well worth it. This reservoir of data
would take countless hours of on-line research to gather,
and many thousands of dollars to download from the web
sites of the respective publishers of these papers.

Mike Darwin


About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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