Neuropsychology of Aging Tilburg University A.E.M. van Wordragen
Jagust (2013)
o Distinguishing age and disease has led to the concept of ‘normal
aging’, which may be defined as what is left when disease is
excluded.
Are such individuals ‘normal’ in the sense of being free of
disease, or do age-related deficits simply reflect undetected
neurodegeneration?
o A frequent shortcoming of studies, is the use of cross-sectional data
instead of longitudinal data.
o Changes in older individuals can be described using two approaches
Defined in terms of cognitive processes
Defined in terms of neural systems
o Semantic memory or knowledge is relatively preserved with age.
o The cognitive abilities that most consistently decline with age are
processing speed, working memory, and episodic memory.
o Declining processing speed and executive functioning are
responsible for decline in multiple cognitive areas.
o Differential decline of cognitive processes reflects varying degrees of
involvement of the medial temporal lobe memory system and a
prefrontal cortex/striatal executive system.
Alzheimer’s Disease (AD)
o At the age of 65, at least 1% of the people have AD. At the age of
80, this prevalence is increased to 30%.
o AD usually begins with anterograde amnesia, although other
cognitive disturbances can occur in the initial stage.
o AD evolves from more subtle syndromes, often referred to as Mild
Cognitive Impairment (MCI).
o AD is defined by the association of cognitive symptoms with the
neuropathological finding of neuritic or senile plaques and
neurofibrillary tangles (NFTs).
Plaques are composed of β-amyloid (Aβ) protein surrounded
by dystrophic and degenerating neurites.
NFTs are composed of the microtubule-associated protein tau,
which is hyperphosphorylated and aggregated as paired
helical filaments.
Soluble forms of Aβ initiate the disease leading to
alternations in synaptic structure and function, followed
by Aβ aggregation into plaques.
,Neuropsychology of Aging Tilburg University A.E.M. van Wordragen
There is limited association between plaque Aβ and dementia
severity, but strong associations between cognition and NFTs
and synaptic number and size.
o This amyloid cascade hypothesis holds that early soluble Aβ
unleashes a chain of events causing alternation in synapses and tau,
and a host of downstream structural and functional neural changes
that are closely related to cognitive decline.
o Recent neuropathological criteria recognize that AD pathological
change can exist in the absence of symptoms.
This indicates that some patients may be resistant to the
pathology of AD.
o NFTs, without Aβ-plaques, are seen in many cognitively normal
people, usually in medial temporal lobe structures, and they
increase exponentially with advancing age.
These NFTs particularly affect entorhinal cortical neurons that
project to dentate gyrus as the perforant pathway, functionally
disconnecting the hippocampus.
Cerebrovascular Disease (CVD)
o Stroke, or cerebral infarction, is also associated with both advancing
age and cognitive decline.
o The most fulminant effect of stroke on cognition appears as ‘multi-
infarct dementia’.
o CVD include alternations in subcortical white matter involving
demyelination, rarefaction, and high signal intensity on magnetic
resonance images, thinning of cerebral cortex and cerebral atrophy,
and subclinical, silent infarction related to small vessel occlusion.
Parkinson’s Disease (PD)
o Parkinson’s disease is a disorder of the motor system with cardinal
manifestations of slowing of motion (Bradykinesia), tremor, rigidity,
and gait and postural instability.
o The characteristic neuropathology involves loss of dopaminergic
neurons in the pars compacta of the Substantia Nigra (SN).
o Both dementia, and MCI are common in PD patients.
o This type of major cognitive dysfunction is associated with
widespread limbic and neocortical Lewy Body pathology as well as
associated AD pathology.
o PD is also associated with a range of more subtle cognitive
manifestations that may reflect dopamine deficiency.
,Neuropsychology of Aging Tilburg University A.E.M. van Wordragen
Effects of AD Pathology in Normal Aging
o About 20-40% of cognitively normal individuals in their 8 th or 9th
decades, have at least intermediate levels of Aβ and NFT-tau
pathology on autopsy examination.
Such individuals were in a stage of preclinical AD that would
have progressed to dementia if they had lived longer.
o These individuals remain normal because of neural compensation or
reserve.
A static or passive form of reserve, often referred to as ‘brain
reserve’.
A more dynamic form of reserve, described as ‘cognitive
reserve’.
o The dynamic concept of reserve implies a more active compensatory
process that could represent functional reorganization that recruits
additional neural resources to maintain task performance.
o Individuals with AD pathology who maintain normal cognition are the
focus of intense investigation because they may represent the
earliest phase of AD, and thus are the types of individuals most
amenable to therapy.
o Aβ can be obtained in cerebrospinal fluid (CSF).
Lower levels of CSF Aβ reflect increased deposition in insoluble
forms in the amyloid plaque.
o Declines in episodic memory and longitudinal memory appear to be
greater in those with evidence of Aβ.
o Brain atrophy is associated with Aβ deposition in normal and
hippocampal atrophy may mediate effects of Aβ on cognition so that
individuals with Aβ who have not yet developed these downstream
changes could be spared symptoms.
o Older people with evidence of Aβ may remain normal because they
have not expressed the full phenotype of AD.
They have amyloid pathology without clear evidence of
neurodegeneration and will look like other older individuals on
every measure expect Aβ.
Evidence suggest that very subtle alternation in brain function
may also be present in such individuals.
o Aβ disposition is associated with disruption of large-scale neural
networks.
These networks may be task-positive, which are activated by
externally-directed cognitive tasks or task-negative, which are
deactivated during externally driven cognition.
, Neuropsychology of Aging Tilburg University A.E.M. van Wordragen
The primary task negative network is the Default Mode
Network (DMN).
The major nodes of the DMN include the
praecuneus/posterior cingulate, and lateral parietal, and
medial prefrontal cortices.
The pattern of Aβ deposition in the brain overlaps
spatially with the topography of the DMN.
Older individuals deactivate the DMN less than younger
individuals and the degree of deactivation is inversely
proportional to the amount of Aβ deposition.
o Increased fMRI activation in task positive networks during the
performance of cognitive tasks has also been reported in patient
with AD and those with a genetic risk of AD.
However, reduced activation has also been reported and
studies may vary considerably by disease stage of
participants, the cognitive task and its difficulty, and the
particular brain regions examined.
o Differentiating older people by Aβ deposition shows that older
people who deposit Aβ activate more than young.
Normal healthy young vs. healthy old = young more activated.
Aβ-old vs. healthy young = Aβ-old more activated.
o Many features seen with Aβ deposition (decline in episodic memory,
brain atrophy, altered resting state functional connectivity, and
changes in brain activity) are commonly described to normal aging.
o Epidemiologic cohort studies who that subtle cognitive decline is
seen in some normal individuals up to 12 years before the diagnosis
of dementia.
o Cognitive and neural effects ascribed to normal aging could be
related to presymptomatic AD.
o Older individuals with no evidence of fibrillar brain Aβ show decline
in visual memory and executive function compared to young people.
o Whole brain volume loss in normal individuals that include grey and
white matter and begins in middle age, are doubled in AD patients.
o People who develop AD show atrophy in cortical thinning in specific
regions including the entorhinal cortex, hippocampus, and
praecuneus, angular and supramarginal gyri.
These regions overlap with the brain regions that are atrophic
in cognitively normal people with evidence of Aβ.
Prominent volume loss in both prefrontal cortex and striatum
are neither associated with Aβ or development of AD.
This fronto-striatal atrophy (frontal hypothesis of
cognitive aging) must have other explanation than AD
or Aβ.
