Neurodegenerative Disease Dementia

in whom chromosome 21 is present in triplicate, are at an increased risk of Alzheimer’s disease. The clinical presentation is similar to that of sporadic AD, apart from age at onset, but some mutations can present with characteristic clinical features such as early behavioural change,18

speech production deficit19 white-matter changes.20 or spastic paraparesis with In addition, the apolipoprotein E (ApoE)

polymorphism on chromosome 19 has been identified as a risk factor. There are three alleles of ApoE (2, 3 and 4), and about two-thirds of the general population has the ApoE3 form of the gene. However, ApoE4 is known to be a relative and gene-dosage-dependent risk factor for AD.

Lewy Body Dementia

In contrast to other neurodegenerative dementias, pre-senile onset of LBD is very rare, comprising only 4% of early-onset dementias. LBD is characterised by deposits of so-called Lewy bodies, which are eosinophilic cytoplasmatic inclusion bodies consisting of ubiquitin, neurofilament, α-synuclein and other proteins in cortical and subcortical structures. The clinical picture of LBD consists of dementia in combination with Parkinson’s disease-like symptoms (extrapyramidal motor disorders). Clinical criteria in support of the diagnosis are visual hallucinations, recurrent falls and pronounced fluctuations in symptoms.21

Magnetic resonance imaging (MRI) scans

showed only non-specific atrophy, but single-photon-emission computed tomography (SPECT) with 123I-ioflupane (DaTSCAN®) improved LBD diagnostics, with high sensitivity for differentiation from Alzheimer’s disease. Immune therapies for LBD are being developed that aim at eliminating or preventing synuclein deposits. Recently, some antibodies have been reported.22

Correct diagnosis is

important as neuroleptics are obsolete in LBD, causing marked reduction of vigilance.

Vascular Dementias

There is agreement in the literature that dementia can be caused by cerebrovascular diseases. However, the most common concepts and classifications are heterogeneous. In general, a distinction is made between macroangiopathy and microangiopathy, cortical and subcortical multi-infarct dementia and dementia due to strategic infarcts. One common classification distinguishes between dementia after stroke (post-stroke dementia), subcortical vascular dementia (cerebral microangiopathy has to be present here) and dementia associated with vascular pathology and Alzheimer’s disease-specific changes. The known cardiovascular risk factors such as increased blood pressure, diabetes, abuse of nicotine, disorders of fat metabolism and cardiac arrhythmia are believed to be causes of vascular dementia. The clinical symptoms are as heterogeneous as the underlying causes. Multiple infarcts result in extensive neuronal cell loss, eventually leading to multi-infarct dementia. This form is primarily associated with word-finding deficits, impaired object recognition and loss of attention and judgement, in addition to the infarct-typical, position-dependent symptoms such as hemiplegia. By contrast, strategic infarcts affect important brain structures such as the thalamus, striatum or head of the caudate nucleus, and may result in dementia after only one infarct. This form of dementia is mainly characterised by deficits in memory, orientation and naming. Microangiopathic vascular dementia (Binswanger’s disease) is associated with marked apathy, cognitive slowing and attention and memory deficits. Recurrent ischaemic events lead to a gradual worsening of symptoms, and in the case of Binswanger’s disease also to a continuous progression of symptoms.

24

Diagnostic criteria (National Institute of Neurological Disorders and Stroke and Association Internationale pour la Récherche et l’Enseignement en Neurosciences [NINDS-AIREN] or Alzheimer’s Disease Diagnostic and Treatment Centers [ADDTC]) were proposed to differentiate vascular dementias from AD.23,24

Previous studies

showed that by using these criteria it was possible to discriminate between these forms in 70–80% of cases. Current therapeutic strategies are based on an appropriate therapy in conjunction with secondary prophylaxis of vascular events, but there are currently no specific pharmaceutical therapies.

As cardiovascular risk factors are the major cause of vascular dementia, this form of dementia typically occurs in older age, at around 70 years of age, but vascular dementia has also been described in younger patients. Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL) is caused by mutation of Notch3 on chromosome 19. The clinical presentation is characterised in the early stages by migraine; during the clinical course psychiatric problems occur, followed later by dementia after repeated infarctions. Furthermore, various hereditary amyloid angiopathies have been described (familial British and Danish dementias associated with mutations in the BRI gene on chromosome 13) that produce complex neurological syndromes.

Frontotemporal Dementias

Unlike other neurodegenerative diseases, frontotemporal dementias occur earlier in life: at 57 years of age on average. In accordance with the clinical criteria,25

there are three clinical forms:

frontotemporal dementia, primary progressive aphasia and semantic dementia. The characteristic features of frontotemporal dementia early in the disease course are personality changes, impaired social contact and emotional indifference. Only later, when the disease has progressed to the point where memory deficits occur, is dementia, not a psychiatric cause, which is considered as a differential diagnosis. Primary progressive aphasia, by contrast, is characterised by slowed speech, impaired repetition of speech and grammatically incomplete sentences. Semantic aphasia, like primary progressive aphasia, is also essentially characterised by speech disorders, but although spontaneous speech is fluent, it is confused. On MRI, frontotemporal atrophy is seen in all three forms of frontotemporal dementia, but in the early stages of the diseases it may not be very pronounced.

There is a subform of frontotemporal dementia called Pick’s disease, which is characterised by deposition of Pick bodies. In about 40% of these cases there is an increased familial occurrence, even in the absence of pathogenic mutations. Depending on the disease entity, Pick bodies (visualisation of ballooned neurons with tau deposits by means of silver staining) are seen on neuropathological examination. Ubiquitin-positive cellular inclusions, which are typical of motor neuron diseases, are also found.

Pre-senile Dementia

The underlying cause of pre-senile dementia spans a wide range, with a higher frequency of familial, autoimmune and metabolic reasons. Furthermore, toxic exposure plays a more important role in the differential diagnosis than in older people. A list of mutations associated with dementia is given in Table 3. A typical pre-senile neurodegenerative disorder is Huntington’s disease, which is caused by autosomal-dominant expansion of CAG trinucleotide repeats in the

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