Dementia is a common, chronic and progressive condition of several different types. It is a complex spectrum of disease states with no single cause. Dementia is characterised by the long-term decline in memory, neuropsychiatric and behavioural disorders. It is common in the elderly, but can occur at any age. Dementia affects 5-8 % of all people between ages 65 and 74, and rises with increasing age to 25 %. More than 24.3 million people are estimated to have dementia globally, with 4.6 million new cases being diagnosed each year.
At the molecular level, dementias have been recently classified according to the presence of abnormal proteins such as tau and synuclein.
Alzheimer’s disease (AD) is the most common age-related cause of neuro-degenerative disease and is defined by the presence of the protein tau. The progressive death of nerve cells in the brain is associated with twisted strands (neurofibrillary tangles) of the tau protein (Fig. 1) and deposits of the protein fragment beta-amyloid in amyloid plaques (Fig. 2).
Parkinson’s disease is a progressive, neuro-degenerative condition characterised by the loss of dopaminergic neurons in the midbrain substantia nigra. The abnormal presence of the protein alpha-synuclein has been demonstrated in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Lewy bodies are protein aggregates of alpha-synuclein together with others such as ubiquitin, neurofiliament protein and alpha-B crystallin (Fig. 3).
There is considerable overlap between these disease states where concomitant DLB and AD pathology is present, the so-called Lewy body variant of Alzheimer’s disease. Other proteins, such as amyloid precursor protein (APP) (Fig. 4) and tyrosine hydroxylase (TH) (Fig. 5), may also be useful in the detection of pathogenesis in Alzheimer’s disease.
Muscular dystrophy is characterised by the progressive weakness and degeneration of skeletal muscles. Some patients may only experience mild symptoms within a lifetime whereas others will have severe symptoms and die at a young age. The muscular dystrophies share common muscle histology demonstrating a characteristic variation in muscle fibre size, fibre death, infiltration by inflammatory cells and ultimately, replacement of the muscle fibres by fat and connective tissue. In combination with routine microscopic examination of a muscle biopsy, immunohistochemistry can be used to make a definitive diagnosis in some muscular dystrophies by identifying deficiencies of key proteins.
Of the nine types of muscular dystrophy, the most common and severe form is Duchenne muscular dystrophy (DMD) which affects young boys. It occurs in around 1 in 3,500 male births and is inherited on the X chromosome. Although females may be carriers of the defective gene, they usually show no symptoms. In severe DMD, the dystrophin protein that stabilizes the muscle membrane during contraction is absent resulting in impaired function of the muscle cells and deterioration of the muscle fibres (Fig 6).
In Becker muscular dystrophy (BMD), the second most common form of muscular dystrophy, the dystrophin molecule is also affected but patients show a less pronounced reduction in protein expression. BMD is also linked to the X chromosome, occurring in around 1 in 30,000 male births.
The other types of muscular dystrophy are rare with proteins such as emerin, sarcoglycans and calpain affected and not all are linked to the X chromosome. A differential diagnosis may be achieved by labelling muscle biopsies with antibodies to these proteins.