www.thelancet.com/neurology Vol 11 December 2012 1103
Lancet Neurol 2012;
See Comment page 1020
Traumatic Brain Injury
West Orange, NJ, USA
(L Moretti PhD, I Cristofori PhD,
S M Weaver PhD, A Chau MA,
J N Portelli MA,
Prof J Grafman PhD)
Prof Jordan Grafman, Brain Injury
Research, Rehabilitation Institute
of Chicago, Chicago,
IL 60611, USA
Cognitive decline in older adults with a history of traumatic
Laura Moretti, Irene Cristofori, Starla M Weaver, Aileen Chau, Jaclyn N Portelli, Jordan Grafman
Traumatic brain injury (TBI) is an important public health problem with potentially serious long-term neurobehavioural
sequelae. There is evidence to suggest that a history of TBI can increase a person’s risk of developing Alzheimer’s
disease. However, individuals with dementia do not usually have a history of TBI, and survivors of TBI do not invariably
acquire dementia later in life. Instead, a history of traumatic brain injury, combined with brain changes associated with
normal ageing, might lead to exacerbated cognitive decline in older adults. Strategies to increase or maintain cognitive
reserve might help to prevent exacerbated decline after TBI. Systematic clinical assessment could help to diff erentiate
between exacerbated cognitive decline and mild cognitive impairment, a precursor of Alzheimer’s disease, with
important implications for patients and their families.
An increased risk of dementia has been described in
people with a history of traumatic brain injury (TBI);
however, TBI does not invariably lead to the development
of dementia. In this Personal View, we present evidence
suggesting that many patients with TBI might, instead,
be at an increased risk of exacerbated cognitive decline
later in life. We describe the consequences of TBI on
brain structure and function, and we argue that the
initial brain damage resulting from TBI, combined with
the expected pathological changes of normal ageing, can
lead to exacerbated cognitive decline in older adults.
Furthermore, we present potential interventions to slow
cognitive decline in survivors of TBI and suggestions for
the diff erentiation of exacerbated decline from mild
cognitive impairment, which is a precursor of
Alzheimer’s disease and other forms of dementia.
Public health eff ects of traumatic brain injury
TBI is prevalent and disabling; more than 10 million
individuals worldwide are estimated to have a TBI every
year.1 About 1·7 million new injuries happen annually in
the USA, and TBI is the main cause of death and
disability in the USA in people younger than 35 years.2 In
the European Union, a million patients a year are
admitted to hospitals with TBI.1 The incidence (new
cases per year) of TBI ranges from 546 per 100 000 in
Sweden to 50 per 100 000 in Pakistan. In civilians, TBI is
usually the result of traffi c accidents (nearly 60%), falls
(20–30%), contact sports and work-related accidents
(10%), or violence (10%).1 Repetitive brain trauma has
been noted in individuals who play contact sports such as
boxing, American football, hockey, wrestling, rugby, or
soccer.3–5 Similar injury has been noted in military
personnel exposed to blasts from explosive devices.6
In recent years, the incidence of TBI has risen in older
adults. Maas and colleagues7 noted a worldwide increase
in the proportion of adults aged 50 years and older who
had a TBI. For example, in a UK study from 1988, 27% of
people with TBI were older than 50 years, whereas in
2004, fi ndings from Australia showed that 45% of cases
were in this age group. For people age 65 years and older,
falls are the leading cause of TBI (61%), followed by traffi c
accidents (pedestrian, driver, or passenger; 8%).8 Falls can
be attributable to gait impairment, dizziness, previous
stroke, cognitive impairment, or poor visual acuity.9 TBI
in older adults is a particular problem because age can
negatively aff ect the outcome of the injury.10,11
TBI usually results in lifelong disability. Survivors are
faced with enduring motor, cognitive, and social
impairments.12,13 In the cognitive domain, some of the
most common and serious defi cits are in the areas of
attention, memory, and executive functioning. Social and
emotional disorders can manifest as apathy, irritability,
denial and unawareness of defi cit, impulsivity, anxiety,
Unlike physical defi cits, which generally improve with
time, cognitive and psychosocial impairments can
worsen in the years after injury.14,15 Such defi cits can aff ect
several aspects of a patient’s life—eg, psychosocial
defi cits might cause other people, including health-care
workers, to avoid the patient, and diffi culties with social
interaction can hinder an individual’s ability to fi nd and
maintain employment.16 Cognitive and psychosocial
impairments aff ect not only the patient who sustained
the injury but also their social network and environment,
with family and informal caregivers having high levels of
stress and an increased likelihood of health-related
problems. TBI and ensuing disability have high social
and economic costs, which are borne by public and
private health-care systems.17 Additionally, individuals
with TBI might be at increased risk of psychiatric
disorders, suicide, and suicide attempts.18,19
Despite these concerns, the very long-term outcome
for people with TBI and the links, if any, that exist
between the previous occurrence of a TBI and later-life
functional decline remain unknown. This knowledge
could help in elucidating the neural mechanisms that
result in age-related dementias, such as Alzheimer’s
disease or chronic traumatic
Furthermore, research into TBI and cognitive decline
could help in the identifi cation of individuals most likely
to develop dementia later in life, stimulate early use of
interventions to ameliorate some aspects of later decline,
www.thelancet.com/neurology Vol 11 December 2012
and potentially reduce the costs of long-term health-care
management of patients (and caregivers).
Normal brain ageing and cognitive reserve
Normal ageing is accompanied by changes within the
brain.20 Beginning after age 50 years, the size of the brain
diminishes;21 early volume loss is seen within grey
matter, particularly within neurons of the frontal
cortex.22,23 In older adults, increased synaptic pruning and
reduced plasticity of synaptic connections lead to a fall in
synaptic density.24 Masliah and colleagues25 noted a 20%
decrease in synaptic density in people older than 60 years.
Neuronal survival is also threatened by ageing microglia,
which are at increased risk of becoming dystrophic or of
producing toxic substances that can attack neurons.26
Changes in grey matter are typically followed by
alterations in white matter.27 Once these modifi cations
begin, usually when adults reach age 70 years,27 changes
to white matter can be widespread and severe. Marner
and colleagues28 reported a loss of 45% of white matter
volume between the ages of 20 and 80 years. As people
age, more myelin aberrations arise. Dense cytoplasm and
cytoplasmic balloons can cause the myelin sheath to split
or bulge, pushing the axon to one side.29 Segmental
demyelination, redundant myelination, and mal form-
ation of myelin sheaths are also seen.30 Aberrations in
myelination lead to reduced conduction velocity and a
substantial loss of nerve fi bres.31 The functional result is
a decline in cognition that increases with age. In normal
ageing, loss of white matter might underlie the
association between age and cognitive abilities.32
The extent and timing of cognitive decline during
ageing is highly variable and might be determined partly
by cognitive reserve. The theory of cognitive reserve states
that an individual’s experiences aff ect the effi ciency of
their neuronal network, such that people who have had
high levels of cognitive and physical activity during their
life will be less susceptible to cognitive decline associated
with normal ageing—a protective eff ect attributable to
either compensatory or neuroprotective mechanisms.33
Building on studies of environmental enrichment, pro-
ponents of cognitive reserve propose that a high level of
education, an interesting occupation, and higher IQ are
associated with increased synaptic density, neurogenesis,
and synaptic plasticity—a reserve that slows the ageing of
the brain and delays the clinical manifestations of
neurodegenerative diseases.34 There fore, cognitive decline
that is normally associated with ageing can be lessened by
experiences that increase cognitive reserve. However,
factors that reduce cognitive reserve can exacerbate the
cognitive decline that typically accompanies ageing.35
Exacerbated cognitive decline
There is evidence that age-related cognitive decline can
be accelerated. For example, comorbidity of type 2
diabetes and hypertension exacerbates cognitive decline
and increases the risk of developing Alzheimer’s
disease.36 Rafnsson and colleagues37 showed that older
adults with clinically manifest cardiovascular diseases
did worse and declined faster over 4 years on several
cognitive measures than did individuals with no evidence
of major vascular disease.
TBI might also hasten the ageing process. Corkin
and colleagues33 were the fi rst to describe exacerbated
cogn itive decline after TBI. They looked at the eff ects of
focal and penetrating brain injuries on long-term
cognitive stab ility in a group of World War 2 veterans.
57 individuals had head injury and another group of
27 had peripheral injuries. Cognitive functioning was
measured 10 years after injury (time 1) and 30 years later
(time 2); the examination was based on the Army
General Classifi cation Test (with vocabulary, arithmetic,
and block counting scales) and the hidden fi gures
test (which measures fi gure–ground discrimination).
Compared with uninjured World War 2 combat veterans
with peripheral injuries, veterans with TBI showed
greater decline in cognitive performance between
times 1 and 2. Commenting on long-term prognosis,
Corkin and colleagues suggested that exacerbated
cognitive decline could result from an interaction
between a previous TBI and normal ageing eff ects.33,38
Subsequently, other study fi ndings showed a link
between mild TBI and accelerated ageing, with even
minor head injuries leading to accelerated cognitive
ageing.39 Similarly, people who had apparently recovered
from a minor TBI who were exposed experimentally to a
stressful situation (induced mild hypoxia) had
signifi cantly impaired vigilance and memory abilities
compared with controls.40
Further evidence suggests that closed-head TBI, such
as repetitive brain injury during contact sports, can aff ect
cognition later in life. In a study by De Beaumont and
colleagues,41 former athletes who had sustained their last
sports concussion more than 30 years previously,
compared with former athletes with no previous history
of sports concussion, showed signifi cant reductions in
neuropsychological and electrophysiological measures of
episodic memory and frontal lobe function.41
Eff ects of traumatic brain injury on brain
structure and function
Local brain structure and function are altered after a TBI,
most prominently in the frontal and temporal lobes.42–44
Changes in neural networks can be interpreted as a
combination of a neuroplastic response and com pen-
satory mechanisms triggered by the injury.45 Structural
damage to neuronal networks might aff ect both short and
long fi bre tracts, as well as tracts within the corpus
callosum. Alterations in white matter, noted as
hyperintense T2 signal on MRI, have been reported after
TBI.46 In mild cases of TBI, damage can be restricted to
axonal injury, mainly aff ecting fi bre tracts. In more severe
instances, axonal injury can be accompanied by diff use
enlargement of the ventricles, focal shearing, contusions,
www.thelancet.com/neurology Vol 11 December 2012 1105
or a combination of these.47 Trivedi and colleagues48
measured changes in global brain volume after TBI and
recorded a mean reduction of 1·43%, with greater loss
associated with longer duration of coma after injury.
One of the most important pathological features after
TBI is diff use axonal injury, which disrupts vital cortical–
subcortical pathways and leads to widespread cognitive
dysfunction.49–51 In particular, after mild injury, acute
abnormalities of the default mode network, which
correlate with subjective symptom scores, have been
described.52 After TBI, functional connectivity patterns
within motor networks might be com promised.53 Also, a
direct relation has been reported between white matter
organisation within the brain’s structural core, functional
connectivity within the default mode network, and
impairment in selected cognitive functions after TBI.54
This association has been attributed to both a
compensatory increase in functional connectivity within
the default mode network and the amount of structural
disconnection that modulates this change in network
function. Moreover, the interaction between brain regions
(ie, functional connectivity) can be disrupted after
both mild and severe TBI. Focal damage and dis rup tion
to neural networks are closely related,55,56 with
changes in functional connectivity refl ecting structural
damage.57 These brain modifi cations are accompanied
by diminished medical, cognitive, and behavioural
Although neuroplasticity and compensatory processes
after TBI can lead to improved functioning, they can also
produce negative eff ects, such as spasticity and early
post-traumatic epilepsy,59,60 which could predispose
patients to unfavourable long-term outcomes. In adults
with TBI, brain volume is altered in the prefrontal,
orbitofrontal, and temporal lobes.61,62 Important long-
term structural brain modifi cations, such as volume
changes in white and grey matter63 and reductions in the
size of the hippocampus and the corpus callosum,64,65 also
take place. Location and severity of injury, network
disruption, and variability in neuroplasticity all contribute
to individual variation in recovery after TBI and
persistence of defi cits. Extensive brain atrophy continues
to progress in the chronic phase of brain injury, but
concurrently with clinical recovery; the clinical relevance
of this late atrophy remains unclear.66 Although
progressive deterioration entails Wallerian degeneration
of white matter tracts disrupted by the traumatic axonal
injury, other mechanisms—such
infl ammation, excitotoxicity, and hypoperfusion—might
also have a role in long-term outcome.67,68
Traumatic brain injury, exacerbated cognitive
decline, and dementia
Epidemiological research over the past 30 years has
focused on the link between TBI and dementia onset.
Findings indicate that people with a previous history of
TBI have a higher risk of developing dementia later in life
compared with those without such a history.69–78 Reports of
a link between TBI and a later diagnosis of dementia have
been based mainly on reviews of case records. For example,
the fi rst suggestion of a contribution of TBI to Alzheimer’s
disease came from a case report documenting early-onset
Alzheimer’s disease pathology in a 38-year-old man who
had suff ered severe head trauma 16 years earlier.79
Epidemiological studies with a case-control or cohort
design were undertaken to investigate this potential
association.80 In a meta-analysis of seven case-control
studies,81 a strong association was reported between TBI
and Alzheimer’s disease. Rasmusson and colleagues82
concluded that even mild head injury is a predisposing
factor for some cases of Alzheimer’s disease. A pathological
link between TBI and Alzheimer’s disease has been
suggested by the observation of amyloid-β plaques83 in up
to 30% of patients who died after severe TBI.84 The plaques
seen are strikingly similar to those noted in the early stages
of Alzheimer’s disease.85 The APOE ε4 genotype might
aff ect amyloid pathology and outcome after TBI, and this
allele is implicated as a risk factor for later development of
Alzheimer’s disease after TBI.86–90
Despite these studies, consensus has not been reached
on the link between TBI and dementia.91 In a meta-analysis
of seven studies,92 no signifi cant association was seen
between brain injury and Alzheimer’s disease. Further
studies found no association between carriers of the
APOE ε4 allele and outcome.93,94 TBI is neither necessary
nor suffi cient for the development of dementia. Patients
with a dementia usually do not have a history of TBI, and
people who have survived a TBI do not invariably acquire
dementia later in life. Therefore, uncertainty surrounds
the question of whether dementia is caused by TBI or if it
is associated with another factor (such as presence of an
APOE allele). Another possibility is that brain damage
after a TBI lowers cognitive reserve and, thus, causes an
earlier manifestation of Alzheimer’s disease.
Brain injury and normal ageing both lead to structural
and functional brain alterations. What might be the
result if these two types of alteration occur in the same
individual? The neural loss that accompanies normal
ageing might combine or interact with the neuronal
damage caused by a TBI and lead to a worsening of
patients’ cognitive and social abilities as they age,
compared with healthy people (fi gure 1). This exacerbated
decline in functional performance might be unrelated to
the onset of a dementia such as Alzheimer’s disease.
Although exacerbated cognitive decline and the
development of dementia could coincide in some
individuals, the lesion caused by TBI (or any chronic
brain lesion) and neuronal changes associated with
normal ageing will always co-occur. The degree to which
exacerbated decline is seen would depend partly on a
patient’s cognitive reserve; thus, if two people have
diff erent cognitive reserves, in terms of cortical size or
synaptic density, they will be aff ected diff erently by brain
damage.95,96 One theory for the association between TBI
www.thelancet.com/neurology Vol 11 December 2012
and exacerbated cognitive decline is that normal ageing
might be more likely to result in functional cognitive
defi cits in an individual with previous TBI, because less
age-related neuronal loss would be needed to exceed a
threshold suffi cient to produce a defi cit. This idea is not
dissimilar to the notion that, for symptoms of Parkinson’s
disease to be detected, a specifi c proportion of neurons in
key brain structures such as the substantia nigra need to
The risk of developing dementia might increase with
severity of a TBI.81,98–100 Plassman and colleagues99
investigated the risk of dementia in 548 veterans who
had received a brain injury about 50 years earlier, and
they reported that moderate and severe head injuries in
young men were associated with an increased risk of
Alzheimer’s disease in late life. Findings for mild head
injuries were inconclusive. Other researchers speculate
that TBI might lead to an earlier onset of dementia,
rather than increasing the lifetime risk of developing
An exacerbated decline in functioning could be
associated with other pathological changes induced by
TBI, which might also increase the likelihood of
dementia. For example, cyclophilin A is a cofactor in an
induced cell-death process that happens after TBI, as
shown in a knockout mouse model.102 Cyclophilin A
contributes to apoptosis and might have a role in
weakening blood–brain barrier permeability after TBI.
APOE regulates blood–brain barrier integrity via
cyclophilin A, and APOE ε4-mediated neurovascular
degeneration is at least partly attributable to the actions
of cyclophilin A.103 Neuro degeneration immediately after
TBI—acting via the molecular pathway that cyclophilin A
is a member of—might permanently, albeit modestly,
dysregulate the blood–brain barrier, and this eff ect could
become magnifi ed by the deleterious eff ects of ageing on
inhibitory mechanisms that regulate and inhibit
cyclophilin A. These two eff ects, in combination, could
lead to a pathologically porous blood–brain barrier,
thereby increasing the possibility that blood-borne toxic
agents will enter the CNS and facilitating the onset of
various neurodegenerative disorders in older adults,
made worse by the initial severity of the TBI. In this case,
exacerbated decline in cognitive or social functioning
would refl ect the combination of initial brain damage
and neuronal ageing eff ects, along with the eff ects of a
breakdown in the blood–brain barrier, leading to the
onset of neurodegenerative disease. If this were the case,
inhibition of cyclophilin A could be regarded as
neuroprotective early after TBI, even delaying the eff ects
of the APOE ε4 allele on the development of Alzheimer’s
disease. Another cause of exacerbated cognitive decline
could be attributable to the original eff ects of a TBI on
neuroplasticity resources. As suggested by Mesulam,104
a TBI could induce a “heightened state of neuroplasticity
to accommodate the brain damage and there is evidence
that this abnormal neuroplastic response induces an
earlier-in-life upregulation of the processes that lead to
neurofi brillary tangles and plaques”. Furthermore,
Mesulam speculated that the abnormal drain on
neuroplastic resources as a result of the TBI reduces the
later neuroplastic response to the onset of Alzheimer’s
disease. However, not every TBI patient eventually
develops Alzheimer’s disease, so other risk factors must
be present that contribute, such as genetic predisposition.
The general neuroplasticity resource allocation failure
following a TBI proposed by Mesulam could also help
account for an exacerbated decline in function without
the development of Alzheimer’s disease.
Clinical considerations, diff erential diagnosis,
TBI has the potential to combine with normal ageing to
worsen the decline in cognitive and social functioning.
Nevertheless, the level of exacerbated decline that an
individual with TBI will have probably depends on
several factors, including medical disorders, education,
intelligence, and genetic predisposition (panel 1).
Grafman and colleagues105,106 studied several factors with
the potential to modulate outcome. Loss of brain volume
Neuronal loss due to ageing Before normal ageing
Network damaged by brain injury
Figure 1: Hypothetical changes in neural networks in normal ageing and after brain injury
Initial brain damage resulting from traumatic brain injury combined with the expected pathological changes of
normal ageing can result in an increased risk of exacerbated cognitive decline. (A) A healthy neural network.
(B) Some connections in the healthy network are lost with normal ageing. (C) After traumatic brain injury, several
nodes (small-scale neuronal networks within a brain region) are missing. (D) Whereas the healthy network is
virtually unaff ected by the loss of connections associated with normal ageing, the network damaged by traumatic
brain injury can be severely impaired during normal ageing.
www.thelancet.com/neurology Vol 11 December 2012 1107
correlated signifi cantly with exacerbated decline in
intelligence, from before TBI to 35 years after injury, in
the presence of other factors. Genetic variables also
aff ected cognitive decline.105,106 Furthermore, an assoc ia-
tion was noted between the level of cognitive decline after
penetrating head injury and the possession of specifi c
genetic markers linked with brain injury and
neurodegeneration. For instance, two glutamic acid
decarboxylase markers—GAD1 rs11682957 and GAD1
rs2241165—predicted change in the Armed Forces
Qualifi cation Test (AFQT) score (which is highly corre-
lated with intelligence test scores)107 from before injury to
15 years after injury. Catechol-O-methyl transferase
(COMT) rs9332330 also predicted recovery of the AFQT
score, with the analysis suggesting that people
homozygous for the marker had better recovery of
function (based on AFQT score) than those who were
Findings of a meta-analysis support the hypothesis that
the APOE ε4 allele increases the risk of poor long-term
outcome after TBI.108 Several groups have noted a genetic
association between APOE ε4 and poor outcome after
moderate-to-severe head injury.109–113 Inheritance of APOE
ε4 might aff ect cognitive dysfunction many years after
TBI.114 Also, genetic variations in brain-derived
neurotrophic factor (BDNF) have an important role in
recovery after focal penetrating TBI.115 Two single-
nucleotide polymorphisms, rs7124442 and rs1519480,
were associated signifi cantly with negative post-injury
recovery of general intelligence, with more pronounced
eff ects taking place during the early period after injury.116
The strongest and most consistent predictor of
cognitive outcome across all phases of potential recovery
and decline is cognitive reserve. Individuals with higher
cognitive reserve are less susceptible to cognitive117–119 and
emotional120 defi cits after TBI. Additionally, occupations
that are cognitively stimulating can help to maintain
higher cognitive functioning by increasing reserve.121
Schwab and colleagues16 reported that the greatest
predictor of employment after TBI was the patient’s
intelligence level before injury. Higher pre-injury
intelligence scores apparently act as a surrogate for
protective factors related to genetic predisposition,
environmentally induced opportunities for learning, and
development of adaptive strategies—all compatible with
a neural explanation of protection after TBI, attributable
to increased cognitive reserve.105,106
If TBI accelerates the eff ects of ageing by reducing
cognitive reserve, activities that increase reserve could
help to protect against exacerbated decline. For older
adults, participation in cognitive training exercises might
help to minimise the eff ects of low levels of reserve on a
decline in cognitive function. Randomised controlled
trials and long-term follow-up studies are needed to
address the eff ectiveness of cognitive rehabilitation.122–124
Findings of randomised trials in people with TBI suggest
that interventions can improve cognitive abilities and
protect against the risk of dementia.125–127
Cognitive training programmes can facilitate brain
plasticity in regions of the brain known to be crucial for
the trained cognitive function.128–130 The ability to aff ect
neuroplasticity via behavioural strategies in combination
with other methods, such as non-invasive brain
stimulation, could prove to be of benefi t in the amelioration
of exacerbated decline in many patients with TBI.131 It is
noteworthy, however, that although non-invasive brain
stimulation can facilitate rehabilitation in patients with
focal brain injury,132,133 few studies have been undertaken
in those with non-focal TBI. Therefore, whether this
method will be as eff ective in individuals with diff use
injuries is unclear.
Another strategy to prevent exacerbated decline would
be to minimise factors known to reduce cognitive reserve.
Alcoholism, drug abuse, psychiatric history, and other
neurological insults, all factors thought to reduce
cognitive reserve, can make individuals with TBI more
susceptible to cognitive decline, even when controlling
for the initial severity of brain injury and pre-injury IQ.134
Therefore, treatment of post-injury medical disorders,
alcohol use, social alienation, and depression could help
to prevent exacerbated decline.
The presence of post-traumatic epilepsy modulates
intelligence and cognitive decline in later life. Patients
who developed epilepsy after TBI showed a greater level
of cognitive decline 35 years later.135 The frequency and
type of last-reported seizure had an important role. Those
with simple partial seizures or less frequent episodes had
the highest AFQT scores 35 years after injury and the
lowest level of decline in intelligence.
Comorbid histories of TBI and drug or alcohol misuse
have been described.18,136 This comorbidity contributes to
negative outcomes after TBI137 and worsens neurological
sequelae.138,139 If we can clarify the mechanisms by which
these outcomes of TBI arise, we might then be able to
improve the implementation of eff ective treatments for
each of these conditions.137
Panel 1: Factors that can modulate exacerbated
• Genetic predisposition (APOE, COMT, BDNF)
• Pre-injury intelligence (acts as protecting factor)
• Medical factors (presence of post-traumatic epilepsy,
• Lesion location
• Amount of brain-volume loss
• Psychosocial factors (eg, social isolation, reduced
• Other post-injury related considerations (eg, drug or
www.thelancet.com/neurology Vol 11 December 2012
Depression after TBI is also associated with a poorer
global outcome.140,141 Major depression is associated with
impaired performance across an array of cognitive
domains.142 Treatment of post-injury psychiatric disorders
such as depression is, therefore, crucial for the alleviation
of cognitive impairment.143,144
Similarly, social isolation, a common experience for
patients with TBI,145,146 is a risk factor that leads to poor
overall cognitive performance and faster rates of cognitive
decline.147–149 The creation of social rehabilitation training
programmes to improve participation in community
activities and general aspects of everyday social
functioning could help to maintain or even improve the
cognitive status of patients and help to diminish age-
related cognitive decline.150
Diff erential diagnosis
Exacerbated cognitive decline is an important possibility
to consider when diagnosing suspected early Alzheimer’s
disease or a related dementia. For example, a man aged
in his mid 60s arrives at a clinic, and both he and his
family are complaining about his cognitive decline over
the past few years; he reports that he had a TBI when he
served in the military as a teenager. Is his cognitive
decline consistent with normal ageing? Perhaps he is
depressed or has an, as yet undetected, acute neurological
disorder. Could his exacerbated cognitive decline be
caused by the long-term sequelae of his TBI plus normal
ageing? Another possibility is that his cognitive decline is
due to mild cognitive impairment, which is often a
precursor of Alzheimer’s disease.151 Assessment might
reveal symptoms similar to mild cognitive impairment,
refl ecting his recent memory complaints, but that do not
meet criteria for a diagnosis of Alzheimer’s disease.
Similar diff erences in eff ect size can be expected on
many neuropsychological and behavioural tests that are
used to diff erentiate between either mild cognitive
impairment and normal ageing or exacerbated decline
and normal ageing; therefore, selected tasks or other
variables would be needed to contribute to a diff erential
diagnosis. For example, according to Collie and
colleagues,152 standardised eff ect sizes (Cohen’s d) for
the diff erence in memory function between controls
and patients with mild cognitive impairment are small
(≤0·3). Similarly, we calculated the diff erence in AFQT
scores between patients with TBI and controls, using
data from the study by Raymont and colleagues,106 and
noted that standardised eff ect sizes are also small
(≤0·2). Such small eff ect sizes point not only to potential
overlap between controls and patients but also to the
importance of comparing the profi le of performance
change along with other variables, rather than the
absolute value of a small set of scores. Findings of a
study undertaken by Himanen and colleagues100 showed
that, many years after TBI, patients had greater
deterioration on visuospatial and visual memory tests
but semantic memory was preserved. Therefore, the
profi le of long-term cognitive decline after TBI seems to
be qualitatively diff erent from the early signs of
Alzheimer’s disease, which typically include defi cits of
Exacerbated decline should be included in the
diff erential diagnosis of patients presenting with late-life
cognitive decline who have a history of TBI. By combining
neuropsychological measures, structural brain imaging,
biomarker variables, and reports from patients and their
caregivers, a short assessment to discriminate between
exacerbated decline and mild cognitive impairment
could be produced and tested for usefulness (fi gure 2). A
versatile and objective support system has been
developed to reduce diagnostic errors and highlight early
predictors of Alzheimer’s disease.153,154 This statistical
method (namely, the disease state fi ngerprint) provides a
quick interpretable visual overview of a patient’s state,
obtained from evidence-based statistical analysis of
pertinent data (eg, key neuropsychological measures,
MRI-derived volumes, amyloid and total tau from CSF
samples, and APOE status).
The presence and strength of a relation between TBI
and onset of later-life dementia remains controversial.
When assessing a patient with evidence of functional
decline and a history of TBI, clinicians currently are most
likely to consider a diagnosis of mild cognitive
impairment or Alzheimer’s disease. Such a diagnosis
would have diff erent implications for the patient and
their family than a diagnosis of exacerbated decline.
Normal ageing Exacerbated
impairment* or mild
Report from patients
functional MRI data
Traumatic brain injury (closed or
Current difficulties (family reports and
Figure 2: Guidelines for clinical diff erentiation after traumatic brain injury
A diagnostic evaluation based on systematic assessment of all relevant clinical variables should be encouraged to
discriminate between exacerbated cognitive decline, mild cognitive impairment, and other possible outcomes in
patients presenting with late-life cognitive decline after TBI. *Mild cognitive impairment includes several
diagnostic possibilities beyond mild Alzheimer’s disease, including other forms of dementia, such as
www.thelancet.com/neurology Vol 11 December 2012 1109
Future research should incorporate longitudinal studies,
not only to record long-term cognitive impairment after
TBI but also to note the interaction of injury with normal
ageing, dementia, and other diseases (panel 2). For
example, researchers might investigate whether TBI can
damage the blood–brain barrier slightly, but not to a
degree that leads to relevant porosity at the time of the
injury. With ageing and deterioration of the blood–brain
barrier, the previous TBI could leave an individual
vulnerable to CNS disorders that depend on blood–brain
barrier protection. Also, using currently available PET
ligands, such as fl orbetapir (¹⁸F), investigators should be
able to ascertain whether a relation exists between a
previous TBI and the development of plaques.155
Development of PET ligands that can detect tau
abnormalities would be helpful.
The eff ects of newly recognised causes of brain injury,
such as the blast force from the detonation of an explosive
device, need to be compared with data for the eff ects of
closed and penetrating brain injuries on late-life cognitive
decline and dementia. In most previous studies in which
an increased risk of Alzheimer’s disease was noted in
patients with previous TBI, closed head injuries were
looked at, whereas in most studies of exacerbated decline,
individuals with penetrating brain injuries were
included. Mechanism of injury could be an important
factor in both cases.
The identifi cation of key structural and functional
variables that contribute to brain and cognitive reserve
would be useful to ascertain individual diff erences in
neurobehavioural presentation by patients in later life who
had an earlier TBI. From a molecular biology point of view,
understanding genetic and epigenetic pre dispositional
factors that aff ect brain damage response and post-injury
neuroplasticity could help to triage patients with TBI
before rehabilitation and target future treatments that
could potentially prevent exacerbated decline.
Another line of investigation could address the question
of whether exacerbated cognitive decline attributable to a
disproportionate loss of neurons in ageing is another risk
factor for the development of a dementia. In this case,
neural and molecular mechanisms might become
increasingly susceptible to the pathological processes (eg,
abnormal tau deposits) that are a precursor to dementia
because of an overall depletion of the neural resources
responsible for maintaining normal neural network
molecular homoeostasis. The identifi cation of any link
between TBI and late-life exacerbated decline or dementia
would be important, because this knowledge could enable
decades of possible interventions, which might eventually
change the course of events for patients and their families.
JG had the idea for the report and suggested search strategies for the
literature review. He also revised drafts of the paper and had fi nal say on
its submission. LM and IC wrote the fi rst draft of the paper. LM also
assisted in revision of the manuscript. SMW contributed to the writing
of the fi rst draft of the paper and the fi rst revision of the manuscript.
AC and JNP helped with the outline of the paper, completed the
reference search, and abstracted fi ndings from the selected references.
Confl icts of interest
We declare that we have no confl icts of interest.
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Panel 2: Possible future directions
• Further longitudinal studies to investigate long-term
cognitive impairment after traumatic brain injury and
its interaction with normal ageing, dementias, and
• Understanding genetic and epigenetic predispositional
factors that aff ect brain damage response and
• Use of currently available PET ligands as biomarkers to
ascertain whether a relation exists between a previous
traumatic brain injury and development of plaques
• Comparison of newly recognised causes of brain injury
with data on the eff ects of closed and penetrating brain
injuries on late-life cognitive decline
• Identifi cation of key structural and functional variables
that contribute to brain and cognitive reserve
• Discovery of neuroprotective agents and rehabilitation
strategies to help modify the slope of exacerbated
decline or onset of dementia
Search strategy and selection criteria
We searched PubMed with the terms “exacerbated decline”,
“normal aging”, “TBI and cognitive decline” “TBI and
dementia”, “structural and functional changes after TBI”, and
“cognitive reserve”. We selected only articles published in
English between 1980 and 2012. Further references were
selected from the bibliographies of cited papers. The fi nal
reference list was generated on the basis of relevance to the
broad scope of this Personal View.
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