You are on page 1of 39

ANATOMICAL &

PHYSIOLOGICAL CHANGES
OF THE CENTRAL NERVOUS
SYSTEM IN ELDERLY
Ginus Partadiredja
The Department of Physiology
Faculty of Medicine UGM
Learning Objectives
1. To understand the anatomical changes of the central
nervous system in elderly
2. To understand the physiological changes of the central
nervous system in elderly
THEORIES OF AGEING

Ageing  What?
 Why?
 How?

Ageing: “The progressive accumulation of changes with


time associated with or responsible for the ever
increasing susceptibility to disease and death which
accompany age” (Harman, 1981).
Hypotheses of Ageing
> 300 hypotheses of ageing (Medvedev, 1990)
1. Evolutionary Hypothesis
a. Mutation Accumulation Hypothesis
b. Disposable Soma Hypothesis
c. Antagonistic Pleiotrophy Hypothesis

2. Gene Regulation Hypothesis


3. Telomere Shortening Hypothesis
4. Oxidative Stress Hypothesis

a. Survival of the Slowest hypothesis


b. Mitochondria-Lysosomal Axis hypothesis

5. Neuroendocrine Hypotheses
6. Neuroendocrine-immuno Hypothesis
FIG. 1. Production of oxygen and nitrogen free radicals and other reactive species in mammalian cells. AA, amino acid; Arg, L-arginine; BH4,
(6R)-5,6,7,8,-tetrahydro-L-biopterin; CH2O, formaldehyde; Cit, L-citrulline; DQ, diquat; ETS, electron transport system; FAD, flavin adenine
dinucleotide (oxidized); FADH2, flavin adenine dinucleotide (reduced); Gly, glycine; H2O2, hydrogen peroxide; HOCl, hypochlorous acid;
H•LOH, hydroxy lipid radical;IR, ionizing radiation; L•, lipid radical; LH, lipid (unsaturated fatty acid); LO•, lipid alkoxyl radical; LOO•, lipid peroxyl
radical; LOOH, lipid hydroperoxide;MPO, myeloperoxidase; NAD, nicotinamide adenine dinucleotide (oxidized); NADH, nicotinamide adenine
dinucleotide (reduced); NADP, nicotinamide adenine dinucleotide phosphate (oxidized); NADPH, nicotinamide adenine dinucleotide phosphate
(reduced); •NO, nitric oxide; O2, superoxide anion radical; •OH, hydroxyl radical; ONOO, peroxynitrite; P-450, cytochrome P-450; PDG,
phosphate-dependent glutaminase; Sar, Sarcosine; SOD, superoxide dismutase; Vit C, vitamin C; Vit E, vitamin E (-tocopherol).
FIG. 2. Removal of oxygen and nitrogen free radicals and other reactive species in mammalian cells. ADP, adenosine diphosphate; Arg, arginine;
BH4, (6R)-5,6,7,8,-tetrahydro-L-biopterin; Carn, carnosine; Cat, catalase; Cit, citrulline; Cyt C, cytochrome C; ETS, electron transport system; Glu,
L-glutamate; Gly, glycine; -Glu-CySH, -glutamyl-cysteine; GS-SG, oxidized glutathione (glutathione disulfide); GSH, glutathione (reduced form);
GSH-Px, glutathione peroxidases; GSH-R, glutathione reductase; GSH-T, glutathione S-transferase; GSNO, nitrosylated glutathione; HbO2,
oxyhemoglobin; Heme-NO, heme-nitric oxide; His, histidine; LOH, lipid alcohol; LOO•, lipid peroxyl radical; LOOH, lipid hydroperoxide; •NO, nitric
oxide; NO3, nitrate; O2, superoxide anion radical; ONOO, peroxynitrite; PC, pentose cycle; R•, radicals; R, non-radicals; R5P, ribulose 5-
phosphate; SOD, superoxide dismutase; Tau, taurine; Vit C, vitamin C (ascorbic acid); Vit C•, vitamin C radical; Vit E, vitamin E (-tocopherol); Vit
E•, vitamin E radical.
MEMORY
Types of Memory
• Explicit  spatial memory (in rats)
• Episodic (events)
• Semantic (words, rules, language)
• Implicit
• Non-associative (single stimulus)
• Habituation
• Sensitization
• Associative (the relation of one stimulus to another)
• Classic conditioning
• Operant conditioning
• Skills & habits
• Priming (facilitation of recognition of objects by prior
exposure; recall word when presented first few letters)
Explicit memory:
- associated with awareness
- easily formed & easily forgotten
- hippocampus & medial temporal lobes (entorhinal cortex,
perirhinal cortex, parahippocampal cortex)
- can be converted into implicit memory (e.g. athlete training)

Implicit memory:
- does not involve awareness
- requires repetitive practice, longer time to form & store, but
not easily forgotten
-  hippocampus; striatum (basal ganglia), cerebellum
- Skills (riding a bicycle, tying shoes, playing piano), habits,
conditioned reflexes
AGEING IN THE CENTRAL NERVOUS SYSTEM
• Effects of ageing on memory related to hippocampus
and medial temporal lobe structure  variable among
individuals
• On average, explicit memory declines with age, but
marked variability occurs
• Spatial memory (explicit memory) in rats declines with
age (as measured in Morris water maze test), but variable
• Recognition memory declines with age in monkeys, but
variable
Morris water maze test
Neurobiology of Age-Related Memory Decline
Hippocampal Physiology
• Hippocampal physiology is affected selectively:
• Not affected:
• Resting potential, input resistance, amplitude &
duration of evoked potentials
• Percentage of neurons for location-specific firing &
spatial selectivity of place fields
• Affected:
• Intensity & frequency of stimulation required for LTP
(long-term potentiation) increase with age
• LTP decays more rapidly in aged subjects (rapid
forgetting)
• Long-term depression (LTD) changes
• Informational content of place (confuse familiar
environments sharing certain stimulus elements)
• Hippocampal encoding increasingly rigid (more
prevalent in the CA3 field than CA1)
Figure 2. A three-dimensional
organisation of the septo-
hippocampal system in the rat
brain. The hippocampus is the C-
shaped structure. Abbreviations: fx
= fornix; fi = fimbria; HC =
hippocampus; MS = medial septum
(modified from Amaral and Witter
1995).
CA1
CA2 S

ML

CA3 H GL

Figure 3. A micrograph of a 3 μm-thick horizontal section of hippocampal


formation stained with toluidine blue. This shows the dentate gyrus with the
granule cells and molecular layer, the hilus, the hippocampus proper (CA1,
CA2, and CA3 regions), and subiculum. GL, granule cell layer; ML, molecular
layer; H, hilus; S, subiculum
Hippocampal Anatomy
• Old views: Substantial number of neurons of many
neocortical areas (including primary sensory and
association areas) die with ageing
• Previous methods of quantifying cell number  based on
cell density (number of neurons in an area or volume of
tissue)
• Problems: Density varies in the absence of difference in
cell number (depending on reference area or volume) 
larger brain could have lower density
• Problems with density  reference trap

Treatment A Volume = 1 unit


Nv = 10/1
= 10

Treatment B

Volume = 2 units
Nv = 10/2
=5 Volume = 0,5 units
Nv = 10/ 0,5
= 20
The advent of Unbiased Stereology
• Methods in unbiased stereology:
• Physical disector  hippocampus
• Physical fractionator
• Optical disector
• Optical fractionator  hippocampus
• Single disector or ‘cheating disector’
• Double disector
• ‘Molecular’ or ‘golden’ disector  average number of
molecules per cell in biological sections
A bv

Figure 1. An illustration of the


x
physical disector method.
p
Micrographs A and B represent two
x consecutive 3 μm-thick horizontal
x
sections of CA2 – CA3 region of the
hippocampus. Micrograph A
represent “reference” section and
micrograph B represent “look-up”
section. The rectangular frame
B bv represents the counting frame. X
represents the nuclear profile which
x
appears in one section, but not in
the other section. The procedure of
p the counting is described in the text.
bv, blood vessels; p, pyramidal cells.
x
x
Hippocampal Anatomy
• Findings in stereological study  total number of granule
cells, pyramidal neurons in the CA3 & CA1,
parahippocampal regions  generally preserved (in rats,
monkeys, humans)
• Age-related impairment not necessarily = loss of cells
• Hippocampal neuron numbers remains stable in elderly
with marked learning and memory disturbance
Hippocampal Connectivity
• Significant loss of different subset of synapses in outer
molecular layer of dentate gyrus
• Alterations of synaptic structures ( decreased post-
synaptic density length)
• Age-related changes in other targets of perforant path
projection
• Conclusion: Entorhinal cortex inputs are affected
Fig. 2. The trisynaptic loop of the hippocampus. The filled triangles represent the
pyramidal cell layer (CA1 and CA3) and the filled circles represent the granular
cell layer of the dentate gyrus. Abbreviations: EC = entorhinal cortex; DG =
dentate gyrus; pp = perforant pathway; mf = mossy fibers; sc = Schaffer
collaterals; ff = fimbria fornix.
Prefrontal Cortex & Executive Functions
• Ageing of CNS: Generalized process of nonspecific
deterioration in which the functions of many neural systems
decline gradually  not the case/ little evidence
• Current view: Ageing is selective (such as in the
hippocampal circuitry)
• E.g: Age-related behavioural deficits of prefrontal cortex
tend to emerge earlier than that of medial temporal lobe
structures (declarative memory)  independent to each other
Dysfunction of prefrontal cortex (“executive functions”):
• Does not produce amnesia
• Affect strategic use & manipulation of remembered
information, ability to identify the source of information & order
presented (“source memory”)
• Affect spatial and temporal components of memory
• Short-term spatial memory (dorsolateral prefrontal cortex) is
affected >< longer-term memory (hippocampal system)
• Marked preservation & behavioural rigidity (slower to make
behavioural adjustment)
• Shift of balance (increased prefrontal & blunted medial
temporal activation)  adaptive reorganization
Prefrontal Cortex

• No substantial loss of neurons during ageing of dorsolateral

prefrontal lobe

• Marked decline in density of synapses

• Changes in dendritic architecture prefrontal circuitry

• Abnormalities in myelination of axons


Neurochemical Subcortical Systems
• Neurochemically specific classes of ascending cells
projecting to widespread areas of brain are affected
• Cholinergic neurons of basal forebrain projecting to
hippocampus, amygdala, neocortex  consistent with
behavioural impairment
• Dopaminergic neurons of midbrain
anterior brain
• Noradrenergic neurons of locus coeruleus

deficits of cognitive & motor functions


Dementia
• Dementia: Debilitating deterioration in more than one
domain of cognitive function (not like aphasia or amnesia)
• Dementing disorders: varies in age of onset, rate of
progression of symptoms
• Insiduous onset & develop slowly: Alzheimer’s disease,
Huntington’s disease, frontotemporal dementia, dementia
in Parkinson’s disease
• Insiduous onset & rapid progression: Creutzfeldt-Jakob
disease
• Develop acutely & step wise fashion: Vascular dementia/
multi-infarct dementia
Alzheimer’s Disease
• Most common form of dementia
• Tightly coupled to age; increases after 4th decade of life
• Impairment in establishing & maintaining memories of
recent events
• Early stage: Remote memory & other memory NOT
related to hippocampus/ medial temporal lobe structures
are preserved (>< Huntington’s disease  declarative
memory is preserved; procedural memory is impaired
(cortico-striatal circuitry)
• Progression  decline of multiple cognitive capacities
• Generally alert & responsive in early & middle phases
Alzheimer’s Disease
• Difficulty in identifying the meaning of simple words, uses
of common household objects, the meaning of numbers
• General confusion, agitation, delusions, social disinhibition,
paranoia.
• Language deterioration
• End stage: Mute, densely amnesic (recent & remote
memory)
Pathological Hallmarks of Alzheimer’s Disease
• Late stage: Extensive neuropathology  limbic system,
association cortices, basal forebrain cholinergic system,
striatum, thalamus, cerebellum
• Diagnostic hallmarks: Amyloid-containing plaques &
neurofibrillary tangles
• Plaques: Extracellular deposits of amyloid -protein (A)
surrounded by dystrophic neurites (abnormal dendrites &
axons)
• Neurofibrillary tangles: Intracellular abnormal fibres
occupying cytoplasm & proximal neuronal processes
Pathological Hallmarks of Alzheimer’s Disease
• Paired helical filaments (PHF)  pairs of twisted filaments
composed of cytoskeletal protein (microtubule-associated
protein tau)  disrupt intracellular trafficking of materials
• Early phase  declarative memory impairment  plaques
& tangles in entorhinal cortex & hippocampus
• Progress  more widespread to cortical & subcortical
systems of language, semantic knowledge, abstract
reasoning.
Genetics of Alzheimer’s Disease (AD)
• Early onset Alzheimer’s Disease (< 65 yrs old):
• Chromosome 21
• Presenilin 1 gene on chromosome 14
• Presenilin 2 gene on chromosome 1
• Late onset Alzheimer’s Disease:
• Apolipoprotein E gene on chromosome 19
• Apolipoprotein E gene  codes for a glycoprotein
involved in cholesterol transport and metabolism
• ApoE gene  3 alleles (ApoE2, ApoE3, ApoE4)
• AD patients carry more ApoE4 allele than non-AD
subjects
Prospects of Treatment of AD
• Up to present  incurable
• All drugs target acetylcholine (tacrine & donepezil)
• AD is accompanied with loss of cholinergic neurons in
basal forebrain that project to hippocampal formation
• Vaccination with Aβ
Reference
• Rapp PR & Bachevalier J. 2008. Chapter 45: Cognitive Development
and Aging. In: Squire LR et al (ed.). Fundamental Neuroscience, 3rd
edition, Academic Press, pp. 1048-1055; 1062-1066.
Further Readings
• Fang YZ, Yang S, & Wu G. 2002. Free Radicals, Antioxidants, and
Nutrition. Nutrition 18, 872-879.
• Weindruch R. 1996. Caloric Restriction and Aging. Scientific American
274, 46-52.
• Weinert BT & Timiras PS. 2003. Invited Review: Theories of Aging.
Journal of Applied Physiology 95, 1706-1716.

You might also like