Transcript AChE inhibitor

Aging of the Nervous
System:
Functional Changes
P.S. Timiras
Acetylcholinesterase Inhibition
Presynaptic
nerve terminal
Muscarinic
receptor
Postsynaptic
nerve
terminal
Nordberg A, Svensson A-L. Drug Safety. 1998;19:465-480.
Again, in the normal aging brain the changes are
relatively few. However impaired function and
increased pathology do occur.
Major functional deficits/ pathologies involve:
Motility (e.g. Parkinson’s Disease)
Senses and communication
Cognition (e.g. dementias)
Affect and mood (e.g. depression)
Blood circulation (stroke, multi-infarct dementia)
Parkinson’s Disease: Chapter 8, pp. 110-113
Dementias: Chapter 8, pp. 130-136
Control of Posture, Balance
and Mobility
Central Nervous
System
– Cerebral Cortex
– Basal Ganglia
– Cerebellum
– Vestibular-ocular &
proprioceptive
pathways
– Limbic System
– Spinal Cord
Skeletal Muscles
Bones and Joints
Hormones
Blood Circulation
With aging, normal adult gait changes to:
•Hesitant
•broad based
•small stepped
•Stooped posture
•Diminished arm swings
•Turns performed en bloc
With Parkinson’s, there is also:
•Rigidity
•Tremors (at rest)
•Akinesia (loss of power of movement)
•Bradykinesia (slowed movement)
Pathology of Parkinson’s entails:
•Presence of Lewy bodies
•Loss of dopaminergic neurons in the
substantia nigra
Definition of Dementia
Dementia (from the Latin de-mens, without
mind) is a clinical syndrome that refers to a
global deterioration of intellectual and
cognitive functions characterized by a defect
of all five major mental functions:
• Orientation
• Memory
• Intellect
• Judgment
• Affect
But with persistence of a
clear consciousness.
Dementia (cont.)
• There are two types of dementia:
– Reversible
– Irreversible
T ABLE 8 - 8 Type s of Co gnitive Impa irment in t he Elderly
to be Differentiated
from Alzheime r’ s Disea se
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Delirium: an acute or subacute alte ration of men t al status
characterized by clouding of con sciousness, fluctuation of
symptoms and improvement of
men t al function after remova l of
cause (reversible dementi a).
Depression : a speci f ic psychiatric entity t hat can preced e
or be associated with dementia, and t hat can be dif f erenti ally
diagnosed and trea t ed.
Benign Senescent Forgetfulness : not pr ogressive and not of
sufficient severity to
interfer e with ever yday functions.
Paranoid States and Psychoses: psychiatric diseases
Amnesic Syndrome : short -term memory
dement ia.
losses without delirium or
T ABLE 8 - 7 Underlyin g and Rever sible
Cau se s of Dementia
D
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Drugs
Emotional disorders
Met abolic or endocrine disorde rs
Eye and ear dysfunctions
Nutritional d eficienc ies
T umor and trauma
Infections
Arteriosclerotic complications
i.e., myocard ial inf arction,
stroke or heart f ailure
From Table
8.10
Anatomo-Histology
Brain atrophy,
flattening of gyri,
widening of sulci,
& cerebral ventricles
Loss of cholinergic neurons, in nucleus of Meynert,
hippocampus
& association cortices
Loss of adrenergic neurons, in locus ceruleus
Denudation of neurons, stripping of dendrites,
damage to axons
Increased microglia
Pathology
Accumulation of cell inclusions: lipofuscin, Hirano
and Lewy bodies,
altered cytoskeletal
Tau proteins,
ubiquitin
Neurofibrillary tangles, neuritic plaques with
amyloid,
Perivascular amyloid, distributed throughout the
brain, but especially in frontal,
prefrontal lobes,
Hippocampus, 
association cortices
Metabolism
Decreased oxidative metabolism, slower enzyme activity (Ch. 7)
Free-radical
accumulation (Ch. 5)
Impaired iron
homeostasis (Ch. 7)
Other minerals, zinc, aluminum
Reduced level/metabolism/ activity of neurotransmitters
Increased amyloid  peptide with accumulation of amyloid
proteins
Increased prion protein
Altered immune response
TABLE 8 - 9 Chara cteri stic s of Multi - Infarct Deme ntia
Hist ory of abrupt onset or stepwise deter ioration
Hist ory of transient ische mic at t ack or st roke
Presence of hy pertension or arrhythmia
Presence of any neurologic focal symptoms or signs
Learning at all Ages Induces
Successful Aging
T ABLE 8 - 6 Mechani sms of Effect s of
In crea sed Educat ion on Succe ssful Ag in g
Adequate income
Better access to medica l care
Better access to recreational activity
Good nu t rition
Responsible he alth behaviors
Moderate alcohol intake
Abstinence from smoking
Possibility of increased br ain reserve capacity
More dendritic branching, more synapse s
Better cerebra l blood flow
Better neura l cel l ef f iciency, adap t ability,
redundancy, su rvival and growth
T ABLE 8 - 12 Ba sic Goal s of Alzheimer’ s Disea se Man agement
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to optimiz e the pat ient’s function by tre ating underlying
medica l conditions and avoiding the use of drugs with side
ef fects on the nervo us syst em;
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to prevent stressful situations that may
exacerbat e ca t astrophic reactions;
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to identif y and ma nage complica t ions that may arise from
agitation, depression and incontinence;
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to pr ovide medica l and social information to the pat ient's
f amily in addition to any needed counseli ng.
to main t ain th e pat ient's saf et y whi le all owing as much
independence and dignity as possible;
cause or
For further information on brain plasticity in old age and factors
which may enhance this plasticity, see the below papers (full
texts are available on the course website under “Relevant
Articles”):
• Merabet LB et al. What blindness can tell us about seeing
again: merging neuroplasticity and neuroprostheses. Nat Rev
Neurosci 2005, 6(1) 71-77.
• Adlard PA et al. Voluntary exercise decreases amyloid load in a
transgenic model of Alzheimer's disease. J. Neuroscience 2005,
25(17), 4217-4221.
• Colcombe S, Kramer AF. Fitness effects on the cognitive
function of older adults: a meta-analytic study. Psychol Sci
2003, 14(2), 125-130.
• van Praag H et al. Exercise enhances learning and
hippocampal neurogenesis in aged mice. J Neuroscience 2005,
25(38), 8680-8685.
END
Amyloidal
Connection