Dementia

Introduction

Dementia is a more prevalent syndrome nowadays. It is characterised by deterioration in cognition that results in impairment in the activities of daily living. It is of chronic/progressive nature and involves multiple higher cortical functions such as:

Memory

Thinking

Orientation

Comprehension

Language.

There are multiple causes of dementia:

It affects both semantic and implicit memory:

Semantic memory - explicit memory such as recalling words, names, facts and events.
Implicit memory - nondeclarative memory (does not require conscious recollection) such as learned skills and tasks.

Almost all causes are degenerative or vascular in origin. More than one cause may contribute to the dementia.

Other causes are:

Psychiatric - delirium, depression.
Neoplastic
Endocrinological - Cushing’s, vitamin B12 deficiency, thyroid diseases.
Trauma - haemorrhage and haematomas.
Infection - Lyme disease, neurosyphilis, tuberculosis meningitis, HIV.
Drugs - barbiturates, alcohol.

ALZHEIMER’S DISEASE (AD)

Alzheimer’s is a chronic, progressive neurodegenerative disorder characterised by brain lesions of neurofibrillary tangles, amyloid plaques, neuronal loss, ACh synthesis dysfunction.

It is the leading cause of dementia and has a deteriorating course of about 8-10 years.

Pathophysiology

The initiating event for development of AD is improper cleavage of APP. Normally a-secretase and y-secretase sequentially cleave APP to produce a harmless, soluble peptide. However, if we have sequential B-secretase and y-secretase cleavage, we produce an AB monomer, which is insoluble. The AB42 isoform specifically is hydrophobic and is prone to aggregation.

As these AB42 monomers aggregate and oligomerize, they cause kinase activation (→ tau hyperphosphorylation, tau is a protein that stabilises microtubules thus we get microtubule disassembly), cell death and synaptic dysfunction. All these factors cause neuronal damage. The hyperphosphorylated tau proteins also aggregate to form neurofibrillary tangles. The AB42 oligomers also then form fibrils and then amyloid plaques.

Both these tangles and plaques persist extracellulary after cell death and cause further neuronal dysfunction

😷 Presentation

It can be difficult to identify as it has such a gradual onset with non-specific signs and symptoms.

The major

The 4 A’s of Alzheimer’s is useful to remember the clinical features:

Amnesia - recent memories are lost first. Difficulty learning new information.
Aphasia - difficulty finding the correct words, muddled speech, disjointed conversations.
Agnosia - problems with recognition using the senses of hearing, smell, taste, touch, vision. For example, an inability to recognise the smell of a food or the feeling of a full bladder.
Apraxia - the inability to carry out skilled tasks despite normal motor function.

Let’s discuss some of the pathological changes that we may see microscopically, microscopically and biochemically:

Macroscopic

Cerebral atrophy involving cortex and hippocampus.

Microscopic

Cortical plaques due to AB amyloid protein as well as neurofibrillary tangles.
Tau hyperphosphorylation

Biochemical

Acetylcholine deficiency

⚠️ Risk factors

Increasing age
Caucasian ethnicity
Down’s syndrome
Family history

Genetics

APP - codes amyloid precursor protein.
PSEN1 (presinilin 1) - codes for presinilin 1.
PSEN2 - codes for presinilin 2. Together with presinilin 1 they form subunits of the y-secretase enzyme.
ApoE - encodes apolipoprotein E which is a cholesterol transport protein.

🔍 Investigations

Assessment and investigations:

An initial history from the person and someone who knows the person very well should be taken in which we ask about the timescale (gradual onset is consistent with AD). We should enquire on the impact on their activities of daily life (ADL).
After the initial history we can do a physical examination which includes a neurological examination looking for:

Focal neurological signs such as coordination and gait abnormalities, peripheral neuropathy, tremor, bradykinesia, rigidity.
Visual/auditory deficits
CVS signs such as hypertension, arrhythmias, PVD.

Bloods - this includes:

FBC, ESR, CRP, U&Es
LFTs
TFTs
B12 and folate levels
HbA1c

Cognitive assessment

10-point cognitive screener (10-CS) - 3 temporal orientation questions (year, month, date), 3-word recall, 4 point scaled animal naming task,
6-item cognitive impairment test (6-CIT) - 6 questions including temporal orientation, remembering an address, counting backwards from 20, months in reverse etc.
There are many more cognitive assessment tools that we can use.

🧰 Management

🧠

Non-medical management:

Well-being activities and group cognitive stimulation are to be offered, according to NICE.
Group reminiscence therapy and cognitive rehabilitation are to be considered.

💊

Medical management:

🥇 Acetylcholinesterase inhibitors - increase neuronal excitation by increasing nAChR activity. These are neuronal AChE specific. They are recommended for mild-moderate Alzheimer’s.

Donepezil - contraindicated in bradycardic patients. May cause insomnia.
Galantamine
Rivastigmine

Memantine - a weak-NMDA antagonist that is extremely weak. It may seem counterintuitive as NMDA is excitatory, but chronic weak NMDA activity is pathological. So by inhibiting weak activity, we boost strong activity and thus cognitive function.

It is reserved for patients who are contraindicated to acetylcholinesterase inhibitors.
It can be used as an add-on for severe Alzheimer’s or even monotherapy in severe Alzheimer’s.

DEMENTIA WITH LEWY BODIES (DLB)

DLB is another progressive neurodegenerative disorder accounting for approximately 10-15% of all dementia cases. It is another proteinopathy where we see Lewy body deposition inside the brain cells.

Lewy bodies are cytoplasmic inclusions of alpha-synuclein. Alpha-synuclein is a lipid-binding protein within synaptic terminals that regulate synaptic vesicle trafficking and recycling. When we have impairments in mitochondrial function and also an increase in oxidative stress, we get misfolding and aggregation of alpha-synuclein → Lewy body inclusions.

It occurs especially in the substantia nigra, paralimbic and neocortical areas

There is a relationship with Parkinson’s and DLB as there is a lot of overlap in the features.

😷 Presentation

3 main features:

Fluctuating cognition - the difference is mainly that attention and executive function is lost early on as opposed to memory loss as seen in Alzheimer’s disease. However, we can say that with DLB, cognition may fluctuate as opposed to solely declining as in other forms of dementia. It is however, progressively declining.
Parkinsonism - this develops after cognitive impairment. Parkinsonism is a motor syndrome that is characterised by bradykinesia, pill-rolling tremor, lead pipe rigidity and instability.
Visual hallucinations

🔍 Investigations

Clinical diagnosis usually.

Single-photon emission CT (SPECT) may also be used. It is known as a DaTscan, and what it measures is the uptake of dopaminergic iodine with about 90% sensitivity and 100% specificity.

🧰 Management

💊

Medical management

Once again, acetylcholinesterase inhibitors may be used (donepezil, rivastigmine, galantamine) as well as memantine.
🚨 Neuroleptics (antipsychotics) are to be avoided as they may cause irreversible Parkinsonism in patients with DLB as they are highly sensitive.

VASCULAR DEMENTIA

Vascular dementia is the second most common form dementia after Alzheimer’s. It comprises a group of syndromes of cognitive impairment caused by ischaemia or haemorrhage secondary to cerebrovascular disease.

Vascular cognitive impairment is a spectrum of disease caused by impaired blood flow to the brain, and vascular dementia is the most severe form of VCI.

⚠️ Risk factors

Vascular disease
Male gender - thought to be due to increased risk of vascular disease.
Stroke - 9x higher than general population.
AF
Hypertension

Diabetes mellitus
Smoking
Obesity
CHD
Hyperlipidaemia

🔢 Classification

Stroke-related vascular dementia - multiple-infarct or single-infarct dementia
Subcortical vascular dementia - due to small vessel disease.
Mixed dementia - VD and Alzheimer’s together.
Inherited vascular dementia - cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare genetic condition causing stroke due to small vessel disease.

😷 Presentation

⭐️ It has a typical stepwise deterioration in which we have a period of stability followed by an acute decline progression, followed by another period of stability. This may occur over several months or even several years. This is due to progressive infarcts over time.

⭐️ Mood disturbances are common.
⭐️ Focal neurological abnormalities - motor, sensory, or visual symptoms for example.
⭐️ Impaired concentration
Seizures
Memory disturbances
Gait disturbance
Speech disturbance
Psychosis, hallucinations, delusions can be seen, especially in later stages of the disease.

🔍 Investigations

NICE guidelines:

🏆 NICE recommends the NINDS-AIREN criteria for vascular dementia diagnosis. This includes:

Presence of cognitive decline interfering with ADL

This is established with clinical examination and cognitive assessment.

Presence of cerebrovascular disease

MRI and/or neurological signs (such as dysarthria, aphasia, motor weakness, visual field defect, ataxia, facial paralysis etc.)

Relationship between cognitive decline and cerebrovascular disease

Onset of dementia <3 months after stroke
Abrupt deterioration in cognitive function
Stepwise progression of cognitive decline

🧰 Management

Approach for management:

🏆 Treating the underlying vascular risk factors to slow progression.

🏆 Symptomatic treatment is also provided to provide support to the patient and carers.

We have non-pharmacological treatments:

Cognitive stimulation, multi-sensory stimulation, music and art therapy, animal assisted therapy.

Pharmacological treatments are not considered unless they are suspected to have Alzheimer’s, Parkinson’s or DLB as comorbidities. Aspirins and statins have not proven to be effective for VD.

FRONTOTEMPORAL DEMENTIA + PICK’S DISEASE

Frontotemporal dementia (FTD) is caused by atrophy of the frontal and temporal lobes. It is the 3rd most common type of cortical dementia (after Alzheimer’s and DLB).

It’s aetiology is unknown in most cases. Family history is considered a risk factor as well as certain genes. Ultimately we get frontal and temporal lobe neuronal death due to protein deposition. It is often tau proteins once again that are involved.

There are a couple types of FTD:

Pick’s disease
Progressive non-fluent aphasia/chronic progressive aphasia
Semantic dementia

😷 Presentation

The common features of FTDs are:

⭐️ Onset before 65
⭐️ Personality changes and social conduct issues early on
Gradual onset
Preserved memory and visuospatial skills

Pick’s disease

This is caused by tau aggregation in neurones, however, it is only diagnosed post-mortem. These tau proteins differ from Alzheimer’s tau protieins as they stain differently (silver stain identifies these ones).

It is characterised by behavioural changes mainly:

Personality changes
Impaired social conduct
Hyperorality - compulsive need to place objects in one’s mouth.
Disinhibition
Increased appetite
Perseveration behaviours - uncontrolled repetition of action, word, thought, activity, or emotion.

Microscopic changes may show:

Pick bodies - these are tau aggregates that stain with silver-staining.

Chronic progressive aphasia

This presents with speech changes mainly:

Progressive breakdown in language output
Effortful and non-fluent speech
Speech apraxia - poor articulation of speech.
Comprehension is preserved relatively.

🧰 Management

Semantic dementia

This presents with semantic changes (changes to meaning in language or logic):

Decline in understanding in meaning of words
Fluent speech but is empty and conveys little meaning.
Inability to retrieve names
Inability to recognise objects and familiar faces (prosopagnosia)

In this instance, NICE does not recommend any of the pharmacological treatment used for other dementias.

NORMAL PRESSURE HYDROCEPHALUS

Pathophysiology

This is a reversible cause of dementia. It is seen in elderly patients and is thought to be due to impaired absorption of CSF by the arachnoid villi. It may occur secondary to head trauma, subarachnoid haemorrhage, or meningitis.

😷 Presentation

⭐️ It presents with a classic triad of wet, wobbly, weird that develops over a few months.

Wet - urinary incontinence.
Wobbly - gait abnormality (similar to Parkinson’s disease).
Weird - dementia or bradyphrenia (slowed thinking and processing of information).

🔍 Investigations

🏆 MRI is best to visualise the anatomical differences. We may see hydrocephalus with ventriculomegaly without a widened sulcus between the ventricles.

🧰 Management

🏆 Ventriculoperitoneal shunt helps drain fluid from the brain into the peritoneal cavity.

CREUTZFELDT-JAKOB DISEASE

This is a rapidly progressive neurological condition that occurs as a result of prion proteins. These proteins occur as a result of misfolding, in which we have beta-pleated sheets that are resistant to proteases.

It is very rare with only in 1 in 1 million affected annually.

😷 Presentation

⭐️ Rapid onset dementia
⭐️ Myoclonus - brief, involuntary twitching of muscle groups.

DEMENTIA VS. DELIRIUM

Delirium usually has some factors in favour, such as:

Impaired consciousness
Fluctuating symptoms - worsening at night usually, with periods of normality.
Abnormal perception
Agitation and fear
Delusions

Patients may seem out of this world and tend to wander around.

DEMENTIA VS. DEPRESSION

Things that favour depression over dementia are:

Rapid onset with short history
Biological symptoms such as weight loss, low mood, sleep disturbances.
Patient is aware of their memory loss
Global memory loss (pseudodementia) - this is when you lose all memory. Dementia presents with recent memory loss typically.