Neurodegenerative Diseases and Epilepsy

Indications for Imaging

The focus of imaging in suspected dementia has shifted from an exclusionary to an inclusionary approach. Exclusion of a (surgically) treatable cause of dementia (e.g. tumour or subdural haematoma) can be ascertained by using computed tomography (CT), but demonstration of positive disease markers (e.g. hippocampal atrophy for AD) becomes increasingly more relevant and magnetic resonance imaging (MRI) adds positive predictive value to the diagnosis in dementia. Catheter angiography (DSA) is hardly ever indicated, except perhaps for suspicion of vasculitis. While MRI is the investigation of choice for investigating dementia, multislice CT offers a reasonable alternative, with coronally reformatted images enabling examination of the medial temporal lobe. However, CT is still clearly inferior to MRI, for example, in subjects suspected of having some rare disorders causing dementia, such as encephalitis or Creutzfeldt–Jakob disease (CJD).

When structural imaging is equivocal or does not lead to the diagnosis, functional imaging may add diagnostic value. Second-line investigations include metabolic information obtained by using single-photon emission computed tomography (SPECT) or positron emission tomography (PET), or physiological information obtained by using diffusion or perfusion MRI. For example, in the early stages of frontotemporal lobar degeneration (FTLD) without discernible atrophy, fluorodeoxyglucose (FDG) PET (FDG-PET) or hexamethylpropyleneamine oxime SPECT (HMPAO-SPECT) may already demonstrate decreased metabolism or hypoperfusion. Molecular imaging provides even more early and specific information, for example, amyloid-PET in Alzheimer disease ( Fig. 59.1 ) and dopaminergic tracers in Lewy body dementia.

Protocol for Computed Tomography and Magnetic Resonance Imaging

Structured reporting is essential in dementia and should consider:

• Exclusion of mass lesion, haematoma or hydrocephalus.

• Vascular disease: territorial infarcts, lacunae, thalamic lesions, white matter lesions.

• Focal atrophy:

  • Medial temporal lobe and hippocampus or precuneus (AD)

  • Frontal lobe and temporal pole (FTLD)

  • Mesencephalon (progressive supranuclear palsy)

  • Pons (multisystem atrophy).

Alheimer Disease

The disease is named after Aloïs Alzheimer, who first described senile plaques and neurofibrillary tangles in a 51-year-old woman in 1906. Although the aetiology of AD is uncertain, the amyloid cascade predicts that abnormal aggregation of amyloid and abnormal tau protein leads to impaired nerve function, formation of extracellular amyloid (neuritic) plaques and subsequent formation of intracellular neurofibrillary tangles, leading to neuronal loss and atrophy. The process usually starts in the medial temporal lobe (entorhinal cortex and hippocampus) or the posterior cingulate, and then spreads to the tempoparietal cortex. In <1% of cases, a mutation in genes encoding for amyloid-processing enzymes is found; however, most cases are sporadic, with APOE4 genotype increasing the risk of AD moderately. Age and cardiovascular risk factors are important predictors as well.

The clinical manifestations of AD are episodic memory impairment, but in younger patients visuospatial disturbances may prevail, and even language problems can be seen. While a clinically probable AD diagnosis requires interference in at least two separate domains, biomarkers such as CSF amyloid, PET and MRI can be useful in the prodromal stage of mild cognitive impairment (MCI) by providing evidence of amyloid pathology and subsequent neurodegeneration. The conversion rate from MCI to AD is 10% to 15% per year and this risk increases markedly when MRI shows atrophy suggestive of AD (e.g. hippocampal atrophy).

MRI and CT are both useful for excluding surgically treatable disorders and demonstrate focal atrophy suggestive of AD. Coronal images perpendicular to the long axis of the temporal horn should be used to determine the amount of hippocampal and medial temporal lobe atrophy (MTA). As volumetric analysis of the hippocampus is quite time-consuming, MTA can best be analysed using a visual rating scale depicted in Fig. 59.2 .

A score of 2 is considered abnormal under the age of 75, and a score of 3 above that age. Strong asymmetry between left and right side should trigger a suspicion of FTD, which can be recognised by concomitant atrophy of the temporal poles and frontal lobes. In younger subjects with AD, the hippocampus may be spared, with pathology dominating in the precuneus (including posterior cingulate) and parietal cortex ( Fig. 59.3 ).

Vascular changes and AD are common coexisting problems in the elderly. The combination of infarcts and pathological features of Alzheimer disease is the strongest predictor of dementia in population-based autopsy studies. Atherosclerosis may lead to ischaemic brain damage and probably also accelerates the formation of Alzheimer pathology. In individual patients, it may be difficult to pinpoint their respective relevance, but vascular alterations, especially white matter lesions on MRI, provide an independent target for treatment. Treatment of vascular risk factors may not only prevent further vascular pathology but also benefit progress of AD.

Frontotemporal Lobar Degeneration

The term FTLD describes a group of disorders with tau pathology presenting with language and behavioural symptoms. FTLD is the third most common degenerative cause of dementia after AD and dementia with Lewy bodies, accounting for about 5% to 10% of all cases of dementia and, in younger patients, it is second in frequency after AD. Arnold Pick first described patients with focal atrophy of the frontal and temporal lobes in 1892, including patients with both personality change and language impairment.

The Lund–Manchester criteria recognise three main subtypes of FTLD:

• behavioural variant frontotemporal dementia (bvFTD);

• progressive non-fluent aphasia (PNFA); and

• semantic dementia (SD).

Less commonly, patients with right-sided FTLD present with difficulty recognising faces. It should be noted that language and behavioural disturbances can also be seen in (atypical) AD cases and corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP).

In contrast to AD, a significant proportion of patients with FTLD have an autosomal dominant family history, sometimes linked to chromosome 17, which can be due to mutations in the microtubule-associated protein tau (MAPT) or progranulin. Other mutations can be found as well, especially in patients with increasingly recognised overlap syndromes with motor neuron disease and amyotrophic lateral sclerosis (ALS).

The hallmark imaging finding in FTLD is atrophy of the temporal and frontal lobes, often (initially) asymmetrical ( Fig. 59.4 ). The patients presenting with the language variant SD often have marked left temporal lobe atrophy (temporal pole more than hippocampus), but in patients with bvFTD, atrophy of the frontal lobes can be mild at the time of presentation. In particular, in these patients, FDG-PET and perfusion MRI can be useful to detect functional changes, although care should be taken to exclude depression, which may be similar clinically and on imaging.

Large-Vessel Vascular Dementia

Dementia may result from multiple or single cortical-subcortical or subcortical (e.g. borderzone) cerebrovascular lesions (infarcts) involving strategic regions of the brain, such as the hippocampus, paramedian thalamus and the thalamocortical networks, especially if they occur in the dominant hemisphere.

Small-Vessel Vascular Dementia

Also referred to as leukoaraïosis or subcortical arteriosclerotic encephalopathy, extensive small-vessel disease due to microangiopathy is the most common form of VaD. Most of these cases are idiopathic or sporadic; that is, there is no proven or specific/genetic cause that can be identified, although many patients will have a history of cardiovascular risk factors. Within the group of small-vessel VaD, the following subtypes exist:

• extensive white matter lesions—confluent hyperintensities involving >25% of white matter;

• multiple lacunes—at least two lacunes in basal ganglia and centrum semiovale each; and

• bilateral thalamic lesions—small infarcts in both medial thalami.

Fluid-attenuated inversion recovery (FLAIR) is best suited for detecting small-vessel disease and is able to differentiate (hyperintense) white matter lesions from (hypointense) lacunes. Thalamic lesions, however, are better seen on T ₂ than on FLAIR images. Recent white matter lesions can be bright on diffusion-weighted imaging (DWI), suggesting recent ‘lacunar’ infarction (i.e. involving a single perforating arteriolar territory). White matter lesions with more severe tissue destruction become T ₁ hypointense and are better appreciated on CT and tend to correlate better with clinical severity. The white matter lesions in small-vessel VaD involve most of the deep white matter of the frontal and parietal lobes but tend to spare the U-fibres (in contrast to multiple sclerosis) and the temporal lobes (in contrast to multiple sclerosis and CADASIL; see below). The basal ganglia and the central pons are also frequently affected.

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy, Fabry Disease and Cerebral Amyloid Angiopathy

While no specific cause can be identified in most cases of small-vessel VaD, there are few examples of inherited/genetic diseases that can be readily identified using MRI:

• cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL);

• Fabry disease; and

• cerebral amyloid angiopathy (CAA).

CADASIL is caused by a mutation in the gene notch-3 and may present with headache and presenile dementia. In presymptomatic mutation carriers, the white matter of the temporal poles is often affected in mid-life, and by the time patients become symptomatic, very extensive white matter changes extending into the U-fibres at the convexity are present ( Fig. 59.6 ). Lacunes and microbleeds are common.

Fabry disease is an X-linked recessive vasculopathy resulting from α-galactosidase A deficiency. As it accounts for ~1% of male strokes, there should be screening for it in young male patients. The imaging findings are mostly non-specific small- and large-vessel pathology on CT or MRI. A relatively specific MRI finding is hyperintensity of the pulvinar on T ₁ weighted images, with hypointensity on T ₂ * weighted images in the more severe cases, related to calcification on CT.

Several rare genetic causes of CAA exist in small genetic clusters. Most CAA cases, however, are sporadic and present with lobar haemorrhage and extensive white matter lesions and (silent) infarcts. Less advanced cases may present with multiple cerebral microbleeds (MBs) only, which can be visualised with T ₂ * gradient-echo images or susceptibility-weighted images ( Fig. 59.7 ). Such MBs are a risk factor for subsequent bleeding and stroke in CAA, but also in more typical cases of stroke. CAA is due to β-amyloid deposition in the media and adventitia of small to medium-sized cerebral arteries and is linked to Alzheimer pathology in a substantial number of cases.

Systemic Causes of Vascular Dementia

In addition to ischaemia caused by vascular wall changes, as discussed in the preceding sections, systemic disorders can also cause ischaemia and lead to cognitive dysfunction and ultimately dementia. Systemic causes of ischaemia include cellular dysfunction (mitochondrial disease), but also clotting disorders (e.g., sickle-cell disease) and anaemia/hypotension.

Differential Diagnosis of WM Disorders in Dementia

While most white matter lesions in ageing and dementia are of vascular origin, there is a long differential diagnosis that might be considered, especially in young-onset cases. For example, multiple sclerosis may first present with cognitive impairment, especially when juxtacortical lesions are abundant. Other autoimmune disorders that tend to impair cognition include systemic lupus erythematosus (SLE). Several metabolic disorders may first present in adulthood: for example, vanishing white matter disease and adult polyglucosan body disease. These typically present with symmetric confluent white matter abnormalities and should be differentiated from toxic disorders. Finally, several infections can manifest with dementia, such as HIV encephalitis and progressive multifocal leukoencephalopathy (PML), which will be discussed in the next section.

Infectious and Inflammatory Disease