Mrs K is a 72-year-old retired teacher who presents to her GP after becoming lost while driving home from the supermarket she has visited weekly for 20 years.
Her daughter reports that:
- she repeats questions within the same conversation
- she has stopped attending social activities
- she struggles to organise meals she previously prepared routinely
Her neurological examination is normal.
Her blood tests are normal.
Her CT scan is reported as “age-appropriate”.
So what is actually going wrong?
Dementia as a Clinical Syndrome
Dementia refers to a pattern of acquired and progressive cognitive decline that interferes with independence in everyday functioning.
It describes the clinical consequences of a range of underlying brain diseases that disrupt normal cognitive processing over time.
Cognitive functions affected may include:
- memory
- language
- executive function (planning and problem solving)
- attention
- visuospatial ability
- behaviour and social judgement
Dementia develops when structural or functional damage within neural systems impairs one or more of these domains to the point that activities of daily living are affected.
Cognitive Function Depends on Distributed Brain Networks
Cognitive processes emerge from the coordinated activity of multiple brain regions.
Memory formation, for example, involves:
| Structure | Functional Role |
|---|---|
| Hippocampus | Consolidation of short-term into long-term memory |
| Amygdala | Emotional salience of memories |
| Frontal lobes | Attention, working memory, planning |
| Temporal lobes | Declarative memory and language |
The formation of long-term memories requires strengthening of synaptic connections between neurones through long-term potentiation (LTP).
This process involves:
- glutamate release at synapses
- activation of NMDA receptors
- calcium influx into postsynaptic neurones
- activation of intracellular protein kinases
- changes in gene transcription
These cellular changes enhance synaptic efficiency and allow neural networks to encode and store information over time.
Progressive neurodegeneration disrupts these processes, impairing the ability of neural circuits to encode, store, and retrieve information.
Selective Network Degeneration
Different dementias affect different neural systems.
Clinical presentations therefore vary depending on:
- which anatomical structures are involved
- which cognitive networks are disrupted
This relationship between anatomical vulnerability and functional impairment explains why cognitive decline may initially manifest as:
- memory loss
- behavioural change
- language disturbance
- visuospatial difficulty
- impaired attention or executive function
|
Dementia Type |
Primary Pathology |
Brain Regions Commonly
Affected |
Early Cognitive Features |
Other Clinical Features |
Pattern of Progression |
|
Alzheimer Disease |
Amyloid-β plaques and tau neurofibrillary tangles |
Medial temporal lobe (especially hippocampus), parietal cortex |
Episodic memory impairment (difficulty learning new information) |
Word-finding difficulty, visuospatial disorganisation |
Gradual and progressive |
|
Frontotemporal Dementia (FTD) |
Degeneration associated with tau or TDP-43 protein aggregation |
Frontal and anterior temporal cortex |
Behavioural change or language impairment |
Disinhibition, apathy, loss of empathy, compulsive behaviours |
Gradual, often earlier onset |
|
Lewy Body Dementia |
α-synuclein aggregation (Lewy bodies) |
Brainstem nuclei, basal ganglia, limbic system, neocortex |
Impaired attention and executive function |
Visual hallucinations, fluctuating cognition, parkinsonism |
Gradual with fluctuations |
|
Vascular Cognitive Impairment |
Cerebral infarction and chronic small vessel disease |
Subcortical–frontal circuits, white matter |
Slowed processing speed |
Gait disturbance, impaired planning, focal neurological deficits |
Stepwise or gradual |
Alzheimer Disease
Alzheimer disease is the most common cause of dementia.
Pathological features include:
- extracellular accumulation of amyloid-β protein
- intracellular aggregation of hyperphosphorylated tau protein
These changes occur early within:
- the medial temporal lobe
- particularly the hippocampus
As hippocampal function declines, patients experience difficulty forming new episodic memories. Over time, degeneration spreads to:
- parietal association cortices
- frontal networks
| Structure affected | Symptom |
|---|---|
| Hippocampus | Episodic memory loss |
| Dominant hemisphere | Word-finding difficulty |
| Non-dominant hemisphere | Visuospatial disorganisation |
This leads to:
- impaired language
- reduced executive function
- visuospatial disorganisation
Progression is typically gradual and continuous.
Frontotemporal Dementia (FTD)
Frontotemporal dementia involves degeneration of:
- the frontal cortex
- anterior temporal lobes
Networks responsible for:
- behavioural regulation
- social cognition
- language processing
are particularly affected.
| Region | Presentation |
|---|---|
| Frontal lobe | Disinhibition, apathy |
| Temporal pole | Language loss |
| Limbic connections | Loss of empathy |
Clinical features may include:
- disinhibition
- apathy
- loss of empathy
- compulsive behaviours
- progressive language impairment
Episodic memory may remain relatively preserved in early disease.
Lewy Body Dementia
Lewy body dementias are characterised by intracellular accumulation of:
-
α-synuclein protein
Pathology affects:
- brainstem nuclei
- basal ganglia
- limbic structures
- neocortex
Disruption of attentional and visuospatial networks contributes to:
- fluctuating cognition
- visual hallucinations
- impaired executive function
Motor features resembling Parkinson disease may also occur.
Vascular Cognitive Impairment
Vascular contributions to cognitive decline arise from:
- large cortical infarcts
- lacunar infarctions
- chronic small vessel disease
- white matter lesions
Damage to subcortical–frontal circuits leads to:
- slowed processing speed
- impaired planning and organisation
- gait disturbance
Progression may occur in a stepwise pattern following cerebrovascular events.
Mixed Pathology
In older individuals, multiple pathological processes often coexist.
Neurodegenerative changes may occur alongside:
- vascular disease
- protein aggregation disorders
This overlap contributes to variability in clinical presentation and progression.
Functional Consequences
As neural networks deteriorate, patients may experience:
- impaired activities of daily living
- medication mismanagement
- increased falls risk
- hospitalisation
- episodes of delirium
Cognitive impairment therefore has:
- neurological
- functional
- and social implications
requiring long-term support and multidisciplinary care.
Risk Factors for Dementia
The strongest risk factor for dementia is increasing age.
However, a number of additional biological and environmental factors influence the likelihood of developing cognitive impairment over time.
Non-modifiable risk factors
- Increasing age
- Family history
- Genetic susceptibility (e.g. APOE ε4 allele)
- Developmental factors affecting cognitive reserve
These factors influence baseline vulnerability of neural networks to degeneration.
Modifiable risk factors
Many recognised risk factors are vascular or metabolic in nature:
- hypertension
- diabetes mellitus
- hyperlipidaemia
- smoking
- obesity
- physical inactivity
- chronic kidney disease
- excessive alcohol use
- depression
- low levels of cognitive or social engagement
These contribute to:
- cerebrovascular disease
- neuroinflammation
- oxidative stress
- disruption of blood–brain barrier integrity
Over time, these processes accelerate neuronal injury and synaptic dysfunction.
The concept of cognitive reserve is also important. Individuals with higher baseline cognitive engagement may tolerate greater neuropathological burden before clinical symptoms become apparent.
Pathophysiology of Dementia
Although different diseases produce dementia through distinct mechanisms, several shared pathological processes are observed across neurodegenerative and vascular conditions.
These include:
Protein Misfolding and Aggregation
Abnormal folding of neuronal proteins can result in accumulation of:
- amyloid-β
- tau
- α-synuclein
- TDP-43
These proteins form intracellular or extracellular aggregates that interfere with:
- synaptic transmission
- axonal transport
- mitochondrial function
Protein accumulation may also trigger:
- microglial activation
- chronic neuroinflammation
- oxidative injury
leading to progressive neuronal loss.
Synaptic Dysfunction
Before widespread neuronal death occurs, many dementias involve early disruption of synaptic function.
Impairment of long-term potentiation interferes with:
- memory encoding
- information storage
- retrieval processes
Loss of synaptic connectivity reduces the efficiency of neural networks responsible for cognitive processing.
Neurotransmitter Deficiency
Degeneration of cholinergic pathways, particularly within:
- the basal forebrain
- hippocampal projections
leads to reduced acetylcholine availability.
This contributes to:
- impaired attention
- reduced memory formation
- executive dysfunction
Other neurotransmitter systems (dopaminergic, serotonergic, noradrenergic) may also be affected depending on disease type.
Vascular Injury
Cerebral hypoperfusion resulting from:
- small vessel disease
- microinfarction
- chronic white matter ischaemia
can disrupt subcortical–frontal circuits.
This contributes to:
- impaired processing speed
- executive dysfunction
- gait disturbance
Vascular pathology frequently coexists with neurodegenerative disease in older patients.
Mild Cognitive Impairment and Progression to Dementia
Cognitive decline often develops gradually.
Some individuals experience measurable impairment in one or more cognitive domains while remaining functionally independent in daily activities. This stage is referred to as mild cognitive impairment (MCI).
Patients with MCI may:
- forget appointments
- misplace objects
- have difficulty recalling recent conversations
but are still able to:
- manage finances
- prepare meals
- travel independently
- perform occupational tasks
At this stage, neural network dysfunction may already be present, but compensatory mechanisms allow preservation of overall function.
Progression to dementia occurs when:
- neuronal loss
- synaptic disruption
- network connectivity failure
reach a threshold beyond which functional independence can no longer be maintained.
Not all patients with MCI develop dementia. However, the presence of:
- underlying neurodegenerative disease
- vascular injury
- or ongoing metabolic stress
increases the likelihood of progression.
Management Principles
Management of dementia is directed toward:
- symptom control
- preservation of function
- prevention of complications
- support for patients and carers
There is currently no curative therapy for most forms of dementia.
Non-Pharmacological Management
Multidisciplinary approaches are central to care and may include:
- cognitive stimulation
- occupational therapy
- physiotherapy
- environmental modification
- behavioural support strategies
Interventions may aim to:
- maintain independence
- reduce falls risk
- support medication adherence
- manage behavioural symptoms
Management of vascular risk factors is also important in slowing further decline.
Pharmacological Management: Mechanism and Rationale
Pharmacological therapies currently used in dementia are symptomatic.
They do not reverse the underlying pathological processes such as:
- protein aggregation
- neuroinflammation
- or neuronal loss
Instead, they aim to improve the efficiency of remaining neural networks.
Cholinesterase Inhibitors
Examples include:
- donepezil
- rivastigmine
- galantamine
Many forms of dementia — particularly Alzheimer disease — involve degeneration of cholinergic neurones originating in the basal forebrain.
These neurones normally release acetylcholine, which plays a key role in:
- attention
- memory encoding
- executive function
Loss of cholinergic input contributes to impaired communication between cortical regions.
Acetylcholine is normally broken down in the synaptic cleft by the enzyme:
-
acetylcholinesterase
Cholinesterase inhibitors block this enzyme, resulting in:
- increased availability of acetylcholine at synapses
- enhanced neurotransmission between surviving neurones
This may improve:
- memory
- attention
- cognitive processing speed
in some patients by supporting residual network function.
NMDA Receptor Antagonists
Memantine acts on the:
-
N-methyl-D-aspartate (NMDA) receptor
Glutamate is the primary excitatory neurotransmitter in the brain and is essential for learning and memory.
However, chronic neuronal injury may lead to:
- excessive glutamate release
- sustained NMDA receptor activation
This causes prolonged calcium influx into neurones, contributing to:
- excitotoxicity
- mitochondrial dysfunction
- neuronal death
Memantine partially blocks NMDA receptors, reducing pathological overactivation while allowing normal physiological signalling.
This may:
- protect remaining neurones from further injury
- stabilise cognitive function
particularly in moderate to advanced disease.
Behavioural and Psychological Symptoms
Behavioural disturbances such as:
- agitation
- hallucinations
- sleep disturbance
may arise from disruption of:
- dopaminergic
- serotonergic
- noradrenergic pathways
Pharmacological agents may be used cautiously to manage these symptoms where non-pharmacological strategies are insufficient.
Potential adverse effects must be considered, particularly in older patients with:
- frailty
- polypharmacy
- or increased falls risk
Pharmacological therapy therefore aims to:
- optimise neurotransmitter availability
- reduce excitotoxic injury
- support communication between surviving neural networks
rather than halt the underlying neurodegenerative process.
Ongoing Care
Dementia is a progressive condition requiring:
- longitudinal monitoring
- advance care planning
- carer support
Functional decline often leads to increasing dependence and risk of:
- delirium
- hospitalisation
- institutionalisation
Early recognition of changing care needs is therefore essential.
Clinical Reasoning
When assessing a patient with cognitive decline, it is useful to consider:
- which cognitive domains are affected
- which neural systems subserve those functions
- which disease processes preferentially involve those systems
For example:
- hippocampal degeneration often presents with memory loss
- frontal lobe dysfunction may manifest as behavioural change
- subcortical pathology may produce slowed cognition
- attentional network disruption may cause fluctuating awareness
Patterns of impairment can therefore provide insight into the underlying disease process.
Dementia reflects the progressive disruption of neural systems that support memory, behaviour, planning, and social interaction.
Understanding how different pathologies affect specific cognitive networks helps explain the clinical features observed and informs ongoing assessment and care.
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