On characterisation and diagnosis of frontotemporal lobar degeneration syndromes : with special reference to the progressive aphasias

Abstract

Alzheimer's disease (AD) is the most common dementing brain disease, with episodic memory impairment as a characteristic early feature. However, not all primary degenerative brain syndromes include prominent deficits in day-to-day memorizing. Frontotemporal lobar degeneration (FTLD) syndromes are non-AD disorders affecting mainly the frontal and temporal cortical regions of the brain. Three major neurobehavioural syndromes can result from FTLD: a profound alteration in personality resulting in a frontotemporal dementia (FTD) and two other clinical syndromes in which impairment of language is the presenting symptom, semantic dementia (SD) and nonfluent progressive aphasia (PA). In 1892 the Austrian Arnold Pick presented the first case of progressive aphasia due to atrophy localized to the left temporal lobe, followed by Further cases in the early 20th century. The general purpose of this thesis was to call the attention of clinicians to the FTLD patients, and their specific impairments, which are now likely to be inappropriately diagnosed as having AD. The focus of this work was the progressive aphasias and the aim was to study which assessments that could be of value in identifying these conditions.

In study I we characterised patients with marked left temporal lobe atrophy, assessed by magnetic resonance imaging (MRI) referred to as "temporal lobe atrophy" patients TLA. The measurements confirmed that the TLA patients had significantly smaller left temporal lobes as compared to AD and FTD, whereas the volumes of the right temporal lobes did not differ between groups. Cerebral blood flow measured by Single Photon Emission Computed Tomography (SPECT) was significantly reduced in the left temporal region. Tests of visuospatial function clearly separated the TLA group from patients with AD. Four of the six TLA patients were followed longitudinally showing the mean annual bilateral decrease of temporal lobe volumes to be 9% for the left side and 8% for the right.

The possibility to use new biological and genetical markers resulted in study II and III. CSF amyloid beta protein (A-beta40) concentrations were found to be in linear relation (p<0.02) with the severity of frontal lobe atrophy in FTD. Detection of APOE allele frequencies in SD patients showed 31% for the epsilon-4 allele and 69% for epsilon-3. This overrepresentation of allele epsilon-4 was similar to what had been found in AD. Tau protein CSF concentrations in SD were found to be moderately elevated compared to healthy controls. No significant relation between tau protein CSF concentration and APOE genotype could be found, nor could any connection to disease duration be detected.

In study IV 32 patients referred for primary speech-language impairments were studied retrospectively. Twenty-one cases were classified as fluent progressive aphasia. At clinical presentation, most fluent aphasics had semantic anomia and word comprehension impairment. Wherever assessed for it, associative agnosia was also present save for one patient. These patients thus fulfilled criteria for SD. The rest displayed variants of nonfluent progressive aphasia.

In study V patients with SD and PA were characterised clinically. Typical age of onset of symptoms in progressive aphasia seems to be around 60 years of age regardless of aphasia type, The time span from debut to referral is 2-3 years. Both patients group showed atrophy and a reduction of cerebral blood flow in the temporal regions. The pathology was lateralised, commonly to the left side. However, the pathology in SD was focused to the temporal region while in PA the left hemisphere was affected more in general. On EEG the basal activity is typically unaffected. All except one, out of 34, patients were able to perform the figure-copying task in the Mini-Mental State Examination (MMSE), regardless of the great variety in total MMSE score. Furthermore even patients with as low MMSE score as 10 were relatively well functioning in daily life mirrored by low scores on the Global Deterioration Scale (GDS), typically GDS 2 or 3. Post-mortem examination ofone SD patient showed marked left temporal lobe atrophy (except the posterior half of the superior temporal gyros) with ubiquitin-positive neurites and intraneuronal inclusions but no signs of AD or vascular pathology.

The conclusion is that SD and PA are distinct neurodegenerative disorders. It is possible to diagnose and differentiate them from AD by using standard dementia investigation assessments. Progressive aphasia with relatively preserved visuospatial functions should lead to further investigations where detection of regional cerebral blood flow with SPECT appears to be of particular value. A use of "Pick's disease" or Pick complex for FTLD and related disorders would be historically justified and would perhaps be attractive for both caregivers and patients by making the disease more comprehensive clinically, in analogy with Alzheimer's disease.