Dementia

Pathology and aetiology

There is cerebral atrophy, usually starting in the temporal lobes with characteristic neurofibrillary tangles and senile plaques. An important constituent of the senile plaques is amyloid-β-protein, which is derived from amyloid-β-precursor protein (APP) and apolipoprotein E4. Studies support the importance of genetic abnormalities of both of these proteins in the aetiology of AD. The pathophysiology includes neurotransmitter defects, especially of cholinergic projection to the basal forebrain.

Clinical features

AD usually presents in three stages: (i) memory disturbance; (ii) global cognitive decline with relatively intact personality; and (iii) severe global decline with disorders of social behaviour, failure of self-care, incontinence and dependence.

The first symptom is commonly forgetfulness, which may be reported by family members or may cause failure at work. On formal testing, there is evidence of more global impairment of cognitive function. As the disease evolves, depression (30%) and personality change (75%) commonly develop, especially apathy. Behavioural changes such as verbal and physical aggression, inappropriate sexual behaviour and eating disorders occur later in 30–85% of cases. Hallucinations and psychotic disturbance are less common. Seizures occur in 10–20% of cases.

An examination may reveal a gegenhalten pattern of increased tone (p. 22), release of primitive reflexes (pout, palmo-mental and grasp) but any major physical neurological deficits suggest a different or additional disease. The hippocampus may show extreme atrophy in AD on MRI but there is no diagnostic test.

Diffuse Lewy body disease

A characteristic dementia is associated with the development of the Lewy body, the pathological hallmark of Parkinson’s disease (PD), in the cerebral cortex. There are marked fluctuations in cognition, mimicking reversible acute confusional states, visual hallucinations, usually faces or animals, and behavioural disturbances and agitation are prominent. There are usually some signs of Parkinsonism, which can be subtle or severe. The disease progresses more rapidly than AD but the hallucinations respond particularly well to cholinesterase inhibitors, for example rivastigmine.

Familial dementia

About 5% of AD is familial (autosomal dominant). The age at presentation is usually in the 40s or 50s and the disease is more rapidly progressive than the sporadic form. Seizures are also more common. Huntington’s disease is the other common autosomal dominant dementia, presenting with associated movement disorder (p. 93). Other inherited dementias are rare; they usually present at a younger age than AD and are usually associated with physical neurological deficits. Wilson’s disease is an important treatable cause (p. 92).

Infections

In younger patients, infections may cause dementia that is usually rapidly progressive. Examples include AIDS dementia, syphilis, subacute sclerosing panencephalitis (SSPE) and Creutzfeldt–Jakob disease (CJD; p. 99). Syphilis is very rare nowadays, though as it is treatable, syphilis serology should be checked.

Other dementias

Structural brain disease, for example frontal tumours or hydrocephalus, can produce a dementia. Normal pressure hydrocephalus (NPH) is a syndrome where there is a loss of higher function, a gait apraxia (p. 62) and urinary incontinence. This is associated with an enlargement of the lateral ventricles, but not the cerebral sulci, without obstruction. Some patients improve after shunting. Diagnosis is difficult.

Occasionally dementia can be caused by metabolic or nutritional disturbance, for example hypothyroidism, vitamin B12/folic acid or thiamine deficiency. Thiamine deficiency is common (up to 7% of dementia) and is seen in alcoholics, the malnourished and occasionally in hyperemesis of pregnancy. It causes a characteristic picture of memory disturbance (Korsakoff’s syndrome) with an inability to retain new information and variable retrograde amnesia associated with confabulation. In acute deficiency, there may be Wernicke’s encephalopathy with confusion and eye movement disorders, mixed with acute alcohol withdrawal.

Vascular disease, usually recurrent infarction (arteriosclerosis or rarely vasculitis) or occasionally recurrent haemorrhage (amyloid angiopathy, arteriovenous malformations) may cause a stepwise decline over months or years. There are usually other focal signs such as hemianopia. Cerebrovascular disease may coexist with Alzheimer’s disease.

Epilepsy may present with recurrent subtle seizures that mimic cognitive decline. Usually there is a history of more obvious seizures and of more clear-cut fluctuations in the patient’s condition, with episodes of confusion early in the illness.

Focal cognitive decline

A progressive focal deficit suggests a focal lesion, for example a tumour. However, if no other structural abnormality is found then the likely diagnosis is a focal dementia. These are usually described by clinical pattern, for example progressive aphasia, semantic dementia or fronto-temporal dementia. They have focal, usually lobar, atrophy and their pathology includes abnormalities of Tau protein.

Depressive pseudodementia

Depression may present with a ‘pseudodementia’ without the obvious mood changes usually associated with depression. Patients are usually more concerned about their memory problems than are their relatives. The reverse is true in dementia. Usually patients are able to give a clearer account of their illness. If there is any suggestion of depression, there is little to be lost by a trial of antidepressant therapy. Patients with early dementia may also be depressed.