Article Text

Is it really Alzheimer's disease?
  1. C G BIEN,
  3. C E ELGER
  1. University of Bonn, Department of Epileptology, Sigmund-Freud-Str. 25, 53105 Bonn, Germany
  1. Dr C G Bien c.bien{at}
  1. G VILLA,
  2. A CAPPA,
  3. C MARRA,
  1. Servizio di Neuropsicologia, Istituto di Neurologia, Università Cattolica del Sacro Cuore, Policlinico A Gemelli, Largo Agostino Gemelli 8, I-00168 Roma, Italy
  1. Dr G Villa iclnp{at}

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We read the recent article of Cappa et alwith great interest.1Using HMPAO SPECT, the authors studied 24 patients diagnosed as having (probable) Alzheimer's disease (AD) on the basis of DSM-III-R and the NINCDS-ADRDA criteria. According to Butters et al, they distinguished, on the basis of neuropsychological tests, patients with a diffuse pattern of cognitive deficits (dAD) from those with focal temporal lobe dysfunction (FTLD).2Patients with FTLD are reported by both studies as having a better cognitive prognosis. Whereas the dAD group had diffuse perfusion deficits, the patients with FTLD showed a circumscribed reduction of tracer uptake in the left or right, or both temporal lobes.

We comment on the problem of suggesting AD in these patients with dementia. In the study of Butters et al, seven of the patients of the FTLD group underwent necropsy. Six had the typical histopathological signs of AD. One patient, however, showed the features of hippocampal sclerosis (HS) and not those of AD (Cappaet al wrongly state that all necropsied cases of Butters et al had AD). Two major groups of patients with the histopathological signs of HS have been described in the literature: (1) HS is the most common morphological substrate of medial temporal lobe epilepsy (MTLE). The affected patients are known to show characteristic memory impairment, which correlates well with the degree of pathological changes. Progress of memory impairment in MTLE is very slow and other cognitive functions are mostly preserved.3 Most (but not all) of them have an abnormal MRI signal and HMPAO SPECT usually shows temporal hypoperfusion.4 (2) Patients with HS have been described in necropsy series of patients with dementia.5 It is unknown whether these patients could have been identified by MRI, whether they had abnormal brain perfusion, and what the perfusion pattern would have been.

Cappa et al did not exclude patients with epilepsy, and it is not clear if their MRI procedure included high resolution T2/FLAIR sections angulated along or perpendicular to the hippocampus, which considerably increases the sensitivity for detection of MTLE-HS. They also had no histopathological evidence of AD. Thus, the authors may have included an unknown number of patients who actually did not have AD, but, for example, had temporal lobe epilepsy or dementia with the morphological substrate of HS. It is noteworthy that in a recent histopathological study on the causes of dementia (with further references)6 it was noted that fewer patients than clinically suspected fall into the histopathological category of AD but—among others—fall into the category of HS.


Cappa, et al reply:

We are grateful to Bien, Helmstaedter, and Elger as they allow us to clarify a point of our study that was not explicitely discussed in the paper recently published in thisJournal.1-1

We obviously agree with them that, in the absence of histopathological confirmation, the diagnosis of “probable” Alzheimer's disease (AD) can be questioned on methodological grounds, particularly in patients with focal temporal lobe dysfunction (FTLD).

However, we think it rather implausible that some of our patients with FTLD were in reality affected by other non-AD diseases, in particular by those suggested by Bien et al: medial temporal lobe epilepsy (MTLE) or dementia sustained by hippocampal sclerosis (HS).

As for MTLE, which Bien et al consider a relevant source of possible errors in the diagnosis of patients with AD and FTLD,1-2 we emphasise that none of our patients—with diffuse cognitive impairment (dAD) or with FTLD—was affected by epilepsy. In our paper, the exclusion of epileptic patients was implicit in the statement that all our patients met the NINCDS-ADRDA criteria for probable AD (according to these criteria, patients who have epilepsy could at the most attain a diagnosis of possible AD).

Apart from MTLE, we are certainly aware that HS is sometimes responsible for a dementia syndrome mimicking AD, as recently discussed in several neuropathological studies.1-3-1-8

On the other hand, a careful review of these studies leads to the following conclusions: (1) in a general demented population, pure HS (HS without Alzheimer-type or other well characterised degenerative or vascular pathological changes) seems to be a very rare cause of dementia. Ala et al 1-3 found only 0.4% of pure HS in a retrospective study of 1771 unselected demented patients and Jellinger1-7 1-8 obtained similar results (0.53%) in a consecutive necropsy series of 746 demented subjects older than 55 years! (2) HS significantly contributes to dementia only in old or very old (⩾80 years of age) demented patients with documented cardiovascular diseases (for example, ischaemic heart disease, arrhythmias, congestive heart failure in about 88% of cases) or with depression as another frequent (63%) clinical feature.1-4 1-6 (3) When HS is associated with other neuropathological changes, the precise boundaries with other forms of dementia are often less clear and the differential diagnosis may be controversial even at a pathological level. In the necropsy series of Corey-Bloom et al,1-4 for instance, more than 50% of patients with HS had enough amyloid plaques to meet NIA criteria1-9 for AD; and even using the more conservative criteria of CERAD,1-10 four patients out of eight could have been diagnosed as AD. (4) It is quite uncommon for demented patients with postmortem evidence of HS to have previously received a clinical diagnosis of probable AD (in most cases, patients with HS had been diagnosed as possible AD1-4).

Patients reported in our study as affected by AD with FTLD were clearly different from those described in studies claiming a significant contribution of HS to dementia.1-4-1-6 Their mean age was 67.3 (SD 8.1). All of them had received a diagnosis of probable AD according to the NINCDS-ADRDA criteria. None of them had a history of cardiovascular disease or depression. At MRI—performed with high resolution T2/FLAIR sections, using transverse and coronal planes to obtain a good visualisation of the mesial temporal cortex (hippocampal and parahippocampal gyri)—all of them exhibited atrophic changes consistently involving and yet exceeding the hippocampal structures, in the absence of focal lesions attributable to vascular or other diseases. With regard to this last point, it seems to us noteworthy that Helmstaedter and Elger,1-2 studying 63 patients with chronic pharmacoresistant MTLE sustained by HS, found significant difficulties with episodic memory tasks (learning, retrieval, and recognition of a word list), but not with semantic memory tasks (vocabulary). In our FTLD group, conversely, the presence of semantic memory impairment in association with episodic memory deficit was in agreement with the typical progression of AD pathological process, spreading from the mesial temporal areas to the adjacent temporal neocortex.1-11 Incidentally, in four patients with FTLD who completed a clinical and neuropsychological follow up of at least 3 years an evolution towards a more diffuse pattern of cognitive impairment has now been found. In two other patients with FTLD, who recently underwent neuropsychological retesting after a 12–15 month interval from the baseline assessment, a significant worsening of cognitive deficits, which nevertheless still remained relatively circumscribed to episodic and semantic memory, has been documented.

In conclusion—and also in the light of the above cited studies investigating the relations between HS and dementia—we think that the clinical characteristics of our patients with FTLD were hardly explainable in terms of an underlying HS and more consistent with the diagnosis of probable AD.


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