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 Australian study of AD, DLB, and FTD (6/09) 
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Joined: Fri Aug 11, 2006 1:46 pm
Posts: 4811
Location: SF Bay Area (Northern CA)
Post Australian study of AD, DLB, and FTD (6/09)
This is an Australian study of 170 patients who were diagnosed during life with Alzheimer's Disease. Many of these patients also met the clinical diagnostic criteria for another dementia, usually DLB. One of the authors' conclusions is that the "clinical diagnostic criteria for the main dementia syndromes require refinement."

Of the 170 patients, 27 have died and donated their brain tissue. Of the 27, only 16 actually had AD. Eight had frontotemporal dementia (FTD). Four had DLB. (There must be a typo in these numbers, as reported in the abstract, because 16 plus 8 plus 4 is 28, not 27.) So the diagnostic accuracy is not very high.

Robin


International Psychogeriatrics. 2009 Jun 4:1-8. [Epub ahead of print]

Frontotemporal dementia and dementia with Lewy bodies in a case-control study of Alzheimer's disease.

Piguet O, Halliday GM, Creasey H, Broe GA, Kril JJ.
Prince of Wales Medical Research Institute and University of New South Wales, Sydney, Australia.

ABSTRACT
Background: The clinical presentations in dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) overlap considerably with that of Alzheimer's disease (AD) despite different pathological processes. Autopsy studies have also shown that multiple brain pathology occurs frequently, even in cases with a single clinical diagnosis. We aimed to determine the frequency of clinical diagnosis of FTD and DLB and the underlying pathology in a well-characterized cohort of patients with a clinical diagnosis of probable or possible AD.

Methods: We conducted a retrospective analysis of 170 AD patients (probable AD = 83; possible AD = 87) originally enrolled in a case-control study, 27 with postmortem examination, to establish the number of cases meeting probable diagnosis for FTD and DLB, using a checklist of features compiled from their consensus criteria.

Results: 23/83 probable AD cases and 32/87 possible AD cases met probable criteria for another dementia, more commonly DLB than FTD.

AD pathology was present in 8/15 probable AD and 8/12 possible AD cases coming to autopsy. DLB pathology was seen in four cases and FTD pathology in eight cases.

In the AD cases reaching clinical diagnosis for a second dementia syndrome and coming to autopsy, a minority showed non-AD pathology only.

Conclusions: Presence of core clinical features of non-AD dementia syndromes is common in AD. Concordance between clinical and pathological diagnoses of dementia remains variable. We propose that repeat clinical examinations and structural neuroimaging will improve diagnostic accuracy. In addition, clinical diagnostic criteria for the main dementia syndromes require refinement.

PubMed ID#: 19493380 (see pubmed.gov for this abstract only; it is available there for free)


Sat Jun 06, 2009 8:04 pm
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Joined: Sat Oct 06, 2007 4:28 pm
Posts: 770
Location: LA
Post my interest in this article
Robin, it was March/April 2008 when I sat like a little child listening to these learned medical people consisting of the attending nurse, head nurse, an assistant psychiatrist and the [all important] Dr Coe, geriactric psychiatrist as they discussed my husband, Mr B., who was being cared for in the psych ward of our local hospital. The language was foreign to me although I had been gradually becoming familiar with some of the terms and phrases because I had found this forum in November of 2007. I do remember Dr C. using the words "frontotemporal dementia" I think he said it did not show up on the MRI. That is also when he said we would treat the symtoms without a diagnosis. I was so unsure of mself at the time I only answered questions without asking about Lewy Body.

I came home and studied the treatment for LBD and on subsequent visits, I cornered the nurse [they were all so patient with me] to find the medicines being given to Mr B. Then I matched everything and found some to be unacceptable and reported my thoughts to the nurse who carried my concerns to [the mighty, in my eyes] Dr C. who immediately did an about face with the medicine regime and we found ourselves on the right path for help. But that term of FTD has lingered in my memory. If my request has been carried out by Dr C. to send the record of Mr B. to Mayo Clinic Jax, then pehaps someday this question will be answered.

In the meanwhile, I take care of Mr B. and wonder what illness is this that has stolen him from me, leaving only a shell of the husband and father of our family. After studying all the diseases which are discussed here, I always end up thinking this must be [has to be] LBD. But who knows.

I found this article to be very informative. Thanks for all your research and efforts. You are amazing!

DrP


Sat Jun 06, 2009 10:43 pm
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Joined: Fri Aug 11, 2006 1:46 pm
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Location: SF Bay Area (Northern CA)
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I read the full article this morning. The main point of interest is that in only one of the 27 autopsy-confirmed cases of those clinically diagnosed with AD did DLB and AD co-occur. And in only three of the cases was DLB found, rather than AD.

Many patients in this study satisfied the clinical diagnostic criteria for both AD and DLB. The authors suggest: "when cases fulfill clinical criteria for AD, the diagnostic criteria for DLB need to be modified with reduced weight given to the core feature of parkinsonism." This is because really these people don't have DLB.

Finally, only a small percentage of patients agreed to be autopsied upon death. Of course the results would've been much stronger if there had been more than 27 autopsied cases.


Here are a few excerpts:

"Postmortem confirmation
...Postmortem data were available for 15 probable AD and 12 possible AD cases (16% of the sample)."

"Results
Mean symptom duration in this cohort of 170 AD cases was 4.4 years (SD=3.4). Importantly, 62% of cases exhibited clinical features for 4 years or less. ... No significant differences were observed between possible AD and probable AD cases with respect to MMSE, disease duration, or age (all p>0.05). Similarly, these variables did not differ significantly between cases with or without autopsy data. Age and disease duration in the AD cases who met clinical diagnostic criteria for a second dementia disorder did not differ from those who did not."

"Prevalence of core clinical signs for DLB in AD cases
The prevalence of the core clinical features for DLB was as follows: spontaneous parkinsonism: n=70 (41%), fluctuations in cognition: n=61 (36%), and recurrent visual hallucinations: n=29 (17%). Fluctuation in cognition was significantly more frequent in possible than in probable AD cases. In all instances, cases with or without a particular core feature did not differ in age or disease duration (all p>0.05). MMSE scores, however, were significantly lower in cases diagnosed with fluctuating cognition or visual hallucinations, but not with parkinsonism than in those without these features."

"Coexisting dementias in probable AD cases
Twenty-three of the 83 probable AD cases (28%) met probable criteria for another dementia. Among these cases, eight (10%) met clinical criteria for probable FTD, and a further 15 (18%) met clinical criteria for probable DLB. This included one case who met probable clinical diagnostic criteria for both FTD and DLB. The overlap between AD and FTD diagnoses was due primarily to the presence of impaired social and/or personal conduct, while overlap between AD and DLB diagnoses was due to the presence of parkinsonism early in the course of the disease."

"Of the 15 probable AD cases with autopsy data (Table 2), eight had pathologically confirmed AD. Six cases showed FTLD (five with Pick pathology and one with TDP-43 inclusions), two of these with coexisting AD pathology. Two cases exhibited cerebrovascular disease and one showed pathological DLB."

"Concordance between clinical and pathological diagnosis was variable. Of the nine cases diagnosed with probable AD only, only five cases exhibited AD pathology: two with co-existing Pick pathology and one with overlapping TDP-43 inclusions. Of the remaining four cases, three had Pick pathology and one had DLB pathology. Among the six cases fulfilling clinical diagnostic criteria for a second dementia syndrome, only three were found to have AD pathology and no case showed multiple pathologies (Table 2). Interestingly, the converse was also true: of the three cases meeting diagnosis for both probable AD and FTD, only one showed FTLD pathology only at autopsy, whereas none of the three cases meeting diagnostic criteria for both probable AD and DLB exhibited DLB pathology. Overall, this cohort with probable AD showed lower confirmation of pathological AD and pathological DLB than previous studies, and a high prevalence of pathological FTLD."


Table 2. Neuropathology according to clinical diagnostic criteria classification

CLINICAL NEUROPATHOLOGY
DIAGNOSIS (N) AD - FTLD - DLB - OTHER
....................................................................................................................................................
Probable AD (15)
AD only (9) --> 3* with AD neuropathology; 3 with FTLD neuropathology, 1* with DLB neuropathology
--> 2 with AD neuropathology (+ FTLD)
AD & FTD (3) --> 1 with AD neuropathology, 1 with FTLD neuropathology, and 1 with Other neuropathology (Right basal ganglia infarct)
AD & DLB (3) --> 2 with AD neuropathology; 1 with Other neuropathology (HS + SVD)

Possible AD (12)
AD only (3) --> 1* with AD neuropatholgy; 1 with DLB neuropathology
--> 1 with AD neuropathology (+ DLB)
AD and FTD (1) --> 1 with AD neuropathology
AD and DLB (eight) --> 5 with AD neuropathology; 2 with FTLD neuropathology; 1 with DLB neuropathology

FTLD=frontotemporal lobar degeneration; HS=hippocampal sclerosis; SVD=small vessel disease;
* =includes 1 case with TDP-43 positive inclusions.


"Coexisting dementias in possible AD cases
Of the 87 possible AD cases, 32 (37%) met probable criteria for another dementia. Probable FTD was uncommon (n=2) but probable DLB was very common in this setting (n=30, Table 1). The considerable overlap between AD and DLB diagnoses was again due primarily to the presence of parkinsonism early in the course of the disease."

"Eight of the 12 possible AD cases with autopsy data exhibited AD pathology. In six cases, AD was the sole pathology, one had additional TDP-43 inclusions and one had co-existing DLB pathology (Table 2). Of the four cases without AD pathology, two showed TDP-43 inclusions and two DLB pathology, consistent with these diseases’ clinical prevalence. Cerebral infarcts subsequent to recruitment occurred in six cases, contributing to early deaths. Among the possible AD cases meeting clinical criteria for a second dementia syndrome, concordance between clinical diagnosis and pathological findings was again variable. The single case that also met clinical criteria for FTD showed AD pathology. Of the eight cases meeting both possible AD and DLB clinical diagnosis, only one had DLB pathology, two cases had FTLD pathology and five cases showed AD pathology. No cases had multiple pathologies."

[Robin's note: So the answer to the "is there a typo because 27 is not the same as 28" question appears to be that a few people had multiple pathologies.]

Discussion ...
"Probable DLB in AD population
Over a quarter of AD cases met clinical diagnostic criteria for probable DLB. The considerable overlap between these clinical disorders was due to the high prevalence of parkinsonism. Importantly, the parkinsonian signs were not considered of sufficient severity to support a clinical diagnosis of Parkinson’s disease. While this finding may be surprising to clinicians, it is consistent with much of the literature which confirms that early signs of spontaneous parkinsonism are not uncommon in AD and can be observed with careful neurological examination. Previous studies involving patients from memory or movement disorder clinics have clearly shown that early spontaneous parkinsonism in AD is associated with the greatest rate of false-positive clinical diagnosis of DLB. Our data from a community population further highlight this problem and suggest that when cases fulfill clinical criteria for AD, the diagnostic criteria for DLB need to be modified with reduced weight given to the core feature of parkinsonism. Further, similar to AD cases also meeting clinical criteria for probable FTD, repeat assessment is again likely to improve diagnostic accuracy."

"Strengths and limitations of the study
...Arguably, because participants’ recruitment preceded the widespread acceptance of non-AD dementia syndromes, the quality of the clinical information available used to establish FTD and DLB diagnoses may have been affected. It is therefore possible that our results underestimate the clinical overlap between AD and FTD, and between AD and DLB when using existing clinical criteria, rather than the opposite. This, however, does not change the pathological overlap."

"Although the consent rate for autopsy was low, it is similar to other prospective studies of this type (e.g. 8% in DLB study; Lopez et al., 2002). The cases consenting to autopsy did not differ from the total sample in age, disease duration or MMSE score. The clear advantage of this study design is its close resemblance to a clinic population and its inclusion of cases with co-existing disease(s). In many autopsy studies, cases are selected with a single disease (e.g. AD, FTLD or DLB) and cases with multiple pathologies excluded. The presence of two or more diseases is an important yet undervalued consideration in clinical practice, especially in older individuals."

"Conclusions
This study confirms that a significant proportion of AD cases identified using strict clinical diagnostic criteria will also meet clinical criteria for another dementia syndrome and will show non-AD pathology. While overlap between AD and DLB clinically has been previously reported, our results demonstrate that overlap between AD and FTD is also common. The suggestion by Lopez and colleagues (2002) that the NINCDS-ADRDA criteria should be followed by the hierarchical use of other clinical criteria (DLB and/or FTD) for more accurate diagnosis has considerable merit.We suggest that improvement in diagnostic specificity will be achieved with repeated clinical examinations accompanied by MR T1-weighted brain images acquired in the coronal plane. These images will allow detailed examination of changes over time in regions of interest such as the medial temporal lobe and prefrontal cortex, which may be critical in differentiating AD from non-AD pathology. In recent years, attempts have been made to improve the clinical diagnosis of AD and FTD with mixed results. This evidence, along with our findings, demonstrates that the need to revisit clinical diagnostic criteria for the major dementia syndromes remains."


Sun Jun 07, 2009 12:43 pm
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