Chapter 2
Causes of Dementia
Introduction
The varied phenotypes of dementia reflect a multitude of causes (see Table 2.1). A better understanding of these aids an accurate diagnosis, which, in turn, should help the person with dementia and their carer(s) access the appropriate support and available pharmacological treatments where indicated. Moreover, a better understanding of the pathology of the different phenotypes will hopefully lead to novel and more successful psychosocial and pharmacological treatments. The main causes of dementia are listed in Table 2.2 and are discussed in detail in this chapter. The less common causes of dementia syndromes are also listed (see Table 2.3).
Table 2.1 Classification of primary neurodegenerative pathologies causing dementias.
| Tauopathies | Progressive Supranuclear Palsy, Corticobasilar Degeneration, PiD and FTDP17 (?AD) |
| α-synucleinopathies | Parkinson’s disease dementia/dementia with Lewy bodies |
| Amyloidopathies | Alzheimer’s disease |
| Prion disease | Creutzfeldt–Jakob disease (CJD) |
| Polyglutamine disease | Huntington’s disease |
Table 2.2 Main causes of dementia (relative proportion in percentage).
| Alzheimer’s disease (62%) |
| Cerebrovascular disease (17%) |
| Mixed Alzheimer and cerebrovascular disease (10%) |
| Dementia with Lewy bodies/Parkinson’s disease (6%) |
| Frontotemporal dementia syndromes (2%) |
| Less common causes of dementia syndromes |
| Alcohol |
| Multiple sclerosis |
| Normal pressure hydrocephalus |
| Paraneoplastic/autoimmune |
| Huntington’s disease |
| Wilson’s disease |
| CJD |
| HIV/AIDS dementia complex |
| Metachromic leucodystrophy |
| Space-occupying lesions |
Table 2.3 Other types of dementia.
| Huntington’s disease Autosomal-dominant degenerative disease characterised by progressive psychiatric and movement disorder followed by dementia. A triplet repeat disorder with a mutation in the Huntington gene on chromosome 4, which causes an enlarged polyglutamine portion to be added to the Huntington protein. Mutated forms aggregate within neurons, causing cell death. |
| Creutzfelt–Jacob disease (CJD)/prion disease Rapidly progressive dementia associated with epilepsy. Pathogenic process involves conversion of a normal cell surface protein termed cellular prion protein into an abnormally folded and protease-resistant isoform. A small minority (15%) are found to be caused by a mutation in the prion protein gene but the majority are sporadic, classically caused by CJD. |
| Multiple sclerosis Chronic disease of the central nervous system (CNS). Involves inflammatory, demyelinating and neurodegenerative processes. Primary, secondary and relapsing/remitting forms. Dementia may form part of the neuropsychiatric presentation of multiple sclerosis (MS), and on rare occasions be the only manifestation of MS. Pattern and severity of cognitive deficits not correlated with either disease duration or physical disability. |
| Limbic encephalitis Encompasses a range of inflammatory conditions selectively affecting the limbic system (amygdala, hippocampus, hypothalamus, insular cortex and cingulate cortex). These can present with a relatively rapid-onset dementia and/or other neuropsychiatric signs and symptoms. Originally thought to only be associated with an autoimmune response to cancer or infection elsewhere in the body, it is now recognised to be related to autoantibodies to voltage-gated potassium channels (VGKCs) and N-methyl d-aspartate (NMDA) receptors. Potentially treatable with plasma exchange. |
| HIV/AIDS dementia complex Feature of advanced HIV 1 disease progression, rare with early antiretroviral use. HIV 1 is neurotropic but necessarily pathogenic in the CNS; nevertheless, it is theorised that in some cases infection leads to an inflammatory cascade, leading in turn to cell death through cytokine. |
| Metachromic leucodystrophy One of a group of genetic lipid storage disorders. Thought to be caused by arylsulfatase A enzyme deficiency. This in turn impairs growth or development of the myelin sheath. Adult form presents with neurological signs as well as dementia. |
| Space-occupying lesions (SOLs) – tumours/subdural haematomas Account for 3% of all cases of dementia. SOLs in certain parts of the brain may increase intracranial pressure, causing dementia. A classic tumour lesion producing signs of dementia is frontal lobe meningioma. |
| Alcohol Alcohol has direct neurotoxic effects on brain cells with chronic excessive exposure. |
Alzheimer’s disease (AD)
There are three main AD phenotypes:
- Typical AD
- Posterior Cortical Atrophy (PCA)
- Logopenic Aphasia (LA)
Clinical features
In each case, the cellular pathology is similar but the distribution of the pathology leads to the characteristic clinical presentations.
Typical AD
Typical AD mostly affects older people, especially those in their late 70s–80s. It presents with insidiously worsening memory, most obviously in new learning but also in recall of previously learnt memories. Attention and concentration are relatively well preserved.
This amnesic presentation relates to the predilection of Alzheimer’s pathology for medial structures of the hippocampus and cingulate gyrus.
Over a number of years, the disease process spreads out across the cortex to affect the temporal, parietal and frontal lobes, with relative sparing of the occipital lobes. Subtle language impairments commonly occur with amnesia, and frontal involvement leads to poor planning and organising skills.
With disease progression, language impairments become more obvious, with anomia and grammatical changes. In severe disease, an individual’s basic understanding and communication becomes severely affected and greater physical disability occurs, with deteriorating mobility, swallowing difficulties and incontinence. The onset of these features makes the individual vulnerable to life-limiting infections and poor nutrition (see Chapter 13).
Posterior cortical atrophy
In PCA, the AD pathology mostly affects occipital areas, leading to early change in visuospatial skills. Visual recognition of objects is affected as is the location of objects in space. The can be thought of as the ‘what’ and the ‘where’ of spatial thinking. It is not just visual skills but the person’s ability to think in three dimensions that changes; this can lead to early loss of practical skills such as dressing.
The triad of Balint’s syndrome of oculomotor apraxia (difficulty fixing the gaze on an object), optic ataxia (difficulty guiding the hand to an object by vision) and simultanagnosia (difficulty perceiving multiple objects in the visual field) is sometimes elicited.
In early stages, other areas of the brain are spared, so memory, language and frontal functions are less affected. Patients often have clear recall of their difficulties and can articulate them clearly. Paradoxically, this means that they may not be taken seriously, a problem compounded by often good performances on simple cognitive assessments. PCA is found in a younger age group than typical AD.
Logopenic aphasia
LA is a primary progressive aphasia, manifesting as prominent early changes in fluent speech production. It resembles progressive non-fluent aphasia (PNFA, a type of frontotemporal dementia) but is usually not a pure language disorder as it is often accompanied with deficits in visual memory and visuospatial skills. The absence of speech apraxia (problems repeating polysyllabic words) helps distinguish it from PNFA. As the condition progresses, it starts to resemble typical AD.
Pathology of Alzheimer’s disease
All three subtypes have the pathological hallmarks of beta amyloid (Aβ)-containing senile plaques and highly phosphorylated tau-protein-containing neurofibrillary tangles (NFTs), which, to some extent, also occur in healthy brains – the ‘amyloid cascade hypothesis’ (see Box 2.1). The pathology leads to disruption in acetylcholine neuronal systems projecting from the nucleus basalis of Meynert, the ‘cholinergic hypothesis’. Serotenergic and noradrenergic projections are also affected to a lesser degree.
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