Aging of the Nervous System:

Functional Changes

P.S. Timiras

Acetylcholinesterase Inhibition

Nordberg A, Svensson A-L. Drug Safety. 1998;19:465-480.

Postsynaptic nerve

terminal

Nicotinic receptor

Presynaptic nerve terminal

Muscarinic receptor

Acetylcholine(ACh)

Acetic acid Choline

Acetylcholinesterase(AChE)

AChE inhibitor

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. 110-113Dementias: 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 MusclesBones and JointsHormonesBlood 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• AffectBut with persistence of a clear consciousness.

Dementia (cont.)

• There are two types of dementia:– Reversible– Irreversible

TABLE 8-8 Type s of Cognitive Impairment in the Elderly to be Differentiated from Alzheimer’s Disease

• Delirium: an acute or subacute alter ation of mental status

characterizedby clouding of conscious ,ness fluctuation of symptoms and improvement of ment al function after removal of

( cause reversibledementia).

• Depression: a specific psychiatric entity that can precede or be associated withdem , entia and th at can be differentiall y

diagnosed and treat .ed

• Benign Senescent Forgetfulness: not progressive and not of sufficient severity to interfere with every .day functions

• Paranoid States and Psychoses: psychiatric diseases

• Amnesic Syndrome: short- term memorylosses without delirium or

dementi .a

TABLE 8-7 Underlying and Reversible Causes of Dementia

D Drugs E Emotional disorders M Metabolic or endocrine disorders E Eye and ear dysfunctions N Nutritional deficiencies T Tumor and trauma I Infections A Arteriosclerotic complications

i.e., myocardial infarction, stroke or heart failure

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

From Table8.10

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

MetabolismDecreased 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 8-11 Genes Known to be Linked to Alzheimer’s Disease*

Chromosomal Location

Gene Type Age of Onset % Cases Familial

% Cases All

1

Presenilin 2

AD 40-70 yrs. 20 2-3

10

Risk factor > 60 yrs. ------ ------

14

Presenilin 1

AD 30-60 yrs. 40-60 5-10

19

Apolipoprotein E4

Risk factor > 60 yrs. ------ 40-50

21

APP Mutation ( APP) Down’s Syndrome

Trisomy

AD 45-60 yrs. 2-3 < 1

* Given the rapid progress in genetics, additional genes may be related to AD.

TABLE 8-9 Characteristics of Multi-Infarct Dementia

History of abrupt onset or stepwise deterioration History of transient ischemic attack or stroke Presence of hypertension or arrhythmia Presence of any neurologic focal symptoms or signs

Learning at all Ages Induces Successful

Aging

TABLE 8-6 Mechanisms of Effect s of Increased Education on Successful Aging Adequate income

Better access to medical care Better access to recreational activity Good nutrition Responsible health behaviors Moderate alcohol intake

Abstinence from smoking Possibility of increased brain reserve capacity More dendritic branching, more synapses Better cerebral blood flow Better neural cell efficiency, adaptability,

redundancy, survival and growth

TABLE 8-12 Basic Goals of Alzheimer’s Disease Management

• to maintain the patient's safety whil e allowing as much independence and dignity as ;possible

• to optimize the pati ’ent s function by treating underlying medical conditions and avoiding the use of drugs with side effects on the nervous syst ;em

• to prevent stressful situations that maycause or exacerbate catastrophic ;reactions

• to identify and manage complications that ma y arise from , ;agitation depression and incontinence

• to provide medica l and social in formation to the patient's family in addition to any needed counselin .g

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