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 Distinguishing LBDs from AD (Tarawneh/Galvin; Nov '07) 
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Post Distinguishing LBDs from AD (Tarawneh/Galvin; Nov '07)
Here's another great article! Thanks to fellow Forum member Patty for a scan of it....

This recently-published abstract compares LBD and AD. One of the
authors (Dr. Galvin) is on the LBDA SAC (Scientific Advisory
Council). Here's the abstract:

Expert Review of Neurotherapeutics. 2007 Nov;7(11):1499-1516.

Distinguishing Lewy body dementias from Alzheimer's disease.

Tarawneh R, Galvin JE.
Washington University School of Medicine, St Louis, MO.

Lewy body dementia (LBD) is the second most common dementia after
Alzheimer's disease (AD). LBD is characterized clinically by visual
hallucinations, extrapyramidal symptoms, cognitive fluctuations and
neuroleptic sensitivity. LBD and AD share many common features in
pathology, genetics and biochemical alterations; however, correct
clinical distinction between these disorders has prognostic and
therapeutic implications. There are currently no definitive
radiological or biological markers for LBD, but studies suggest that
premorbid differences in cognitive domains and personality traits,
differences in clinical presentation, and alterations in autonomic
function and sleep may improve diagnosis. Cholinergic dysfunction
plays a major role in both AD and LBD; however, dysfunction is
greater in LBD. This may account for the more prominent
hallucinations, and offers the possibility of a greater response to
cholinesterase inhibitors in LBD. The treatment of LBD is symptomatic
and is based on a limited number of clinical trials and extension of
results from trials in AD. Current research is focused on the role of
synuclein aggregation with possible roles for synuclein-derived
peptides as aggregation inhibitors. Other approaches target amyloid,
neuroinflammation, oxidative injury, proteolysis, lipid peroxidation
and immunotherapies with variable results. Improved understanding of
disease mechanisms may open new therapeutic avenues for LBD in the future.

PMID: 17997699 (see for abstract only)

This November '07 review article was very worthwhile reading. I wish
I could understand all of it! The section on "novel therapies for
LBD" was over my head.

Here are three of the many things I learned from the article:

* "In one large longitudinal study, DLB patients were shown to have
shorter survival times, either as overall mortality or from disease
onset, compared with AD. The DLB group also had shorter times to
nursing home placement, and AD patients survived a median of 10
months longer in nursing homes than DLB patients. Survival and
mortality was significantly impacted by gender (males died sooner),
the presence of EPS and depression. Tremor appears to offer a
protective effect, suggesting that rigid-predominant forms of DLB
have worse outcomes than the less common tremor-predominant
forms. These results were examined for both pure and mixed forms of DLB."

* "In the absence of the ability to reliably recognize LBD, it is
difficult to design and conduct clinical studies and treatment trials."

* Seborrhea is considered a symptom of autonomic dysfunction.

Here are all the excerpts from this article:

Lewy body dementia (LBD) "is not a single disorder but rather can be
thought of as a spectrum of disorders... LBD includes dementia with
LBs (DLB) and Parkinson's disease dementia (PDD). ...(Clinicians)
have come to realize that PDD occurs often and is among the most
debilitating symptoms associated with disease progression."

"[The] lack of recognition of the high prevalence, consequences and
costs of LBD to patients, caregivers and society has diminished
funding opportunities to promote research advances for diagnosis,
patient care and new therapeutics tailored specifically to address
the needs of LBD patients and families..."

"LBD can be readily diagnosed with recognition of the visuospatial,
executive and attentional components of dementia, in conjunction with
signs of parkinsonism, visual hallucinations and REM behavioral
disorder. Cognitive fluctuations, while quite specific for LBD, are
difficult to elicit even at expert centers owing to the absence of
standardized questionnaires that have been validated in large
populations. Additional suggestive features...include depression,
hallucinations in other modalities, syncope and frequent falls, and
there is now evidence that alterations in personality and behavior,
including growing apathy, loss of interest in hobbies and diminished
emotional responsiveness, may also aid diagnosis."

"The recently revised diagnostic criteria for DLB acknowledge that
many PD patients develop dementia, usually within 10 years of the
onset of motor symptoms, however, there are currently no specific
criteria to characterize PDD." (Robin's note: the authors note
later that a "consensus for the characterization of PDD...should be
available by the time this review is published." I don't think this
has been published yet.)

"No major differences between DLB and PDD have been found. ... If
motor symptoms precede dementia by more than 12 months, PDD is
diagnosed. If dementia precedes or is concurrent with parkinsonism,
then DLB is diagnosed."

"In a recent working group consensus, experts...agreed to endorse LBD
as the umbrella term for PD, PDD, and DLB..."

"The fact is that we really do not know how many people have
LBD. From postmortem studies, up to 40% of autopsied demented
patients have sufficient cortical LBs to be diagnosed with LBD,
although many cases are clinically diagnosed with AD. The Lewy Body
Dementia Association estimates that between 1 and 2 million Americans
have LBD, approximately half the prevalence rate of AD. The
contribution of LBD from PDD is unknown but we can begin to make
estimates. ... The prevalence rates [of PDD] range widely from less
than 10% to great than 80%..."

"Age, disease duration and severity, education, and gender are
important risk factors for PDD."

"In the absence of the ability to reliably recognize LBD, it is
difficult to design and conduct clinical studies and treatment
trials. ... Similarly, one could ask if medicine for AD work for LBD..."

The DLB criteria "allow for 83% sensitivity and 95% specificity for
the presence of neocortical LBs. However, these criteria are more
predictive of cases with pure or diffuse LB pathology than cases with
concomitant AD pathology, and cannot reliably differentiate between
pure DLB (which is rare) and the more common mixed forms of DLB and AD."

"(Detection) of pathology at an early preclinical stage has both
prognostic and therapeutic implications. ... This is further
supported by recent data suggesting that LBD patients might have
better responses to cholinesterase inhibitors than AD patients. In
addition, knowledge of LBD early in the course will allow physicians
to avoid certain medications such as classic neuroleptics. LBD
patients are very sensitive to neuroleptics and even very low doses
can have significant side effects. Up to 57% of LBD patients may
exhibit exaggerated EPS [extrapyramidal symptoms], sedation,
immobility or neuroleptic malignant syndrome with fever, generalized
rigidity and rhabdomyolysis, and neuroleptic sensitivity is one of
the suggestive features in the diagnosis of LBD. Neuroleptic
malignant syndrome is a life-threatening condition and the higher
prevalence in LBD suggests that 'classic' neuroleptics, such as
haloperidol, fluphenazine or thioridazine, should be avoided."

"Early diagnosis will also allow families and caregivers the time to
plan for the expected decline."

"Men are more likely to have LBD compared with AD, which exhibits a
female predominance. At the initial evaluation, LBD patients are
more likely to be impaired on tests of construction and visuospatial
skills. ... LBD cases are also more likely to exhibit psychiatric
symptoms and have greater functional impairment at the time of
diagnosis. In one analysis of autopsy-confirmed cases,
hallucinations and delusions were more frequent with LB pathology
(75%) than AD (21%) at the time of the initial clinical
evaluation. This was also true for mixed LBD and AD (53%) patients
who had a significantly higher frequency of psychotic features than
AD (21%). EPS...are more common in LBD. AD patients appear to have
a lower risk of developing EPS with the use of typical
neuroleptics. However, the results of several studies suggest that
LBD and AD cannot be reliably distinguished solely on the basis of
spontaneous EPS."

"(The) mean duration of [AD ranges] from 8 to 12 years. Despite
earlier reports suggesting that DLB might have a more rapid course
and a higher rate of cognitive decline with mean duration of less
than 6 years, those results have not bee reproduced by later studies.
... Using autopsy-confirmed diagnoses..., we found no significant
differences in the rate of dementia progression..."

"While LBD patients have significantly more psychiatric symptoms than
AD patients at the time of the initial evaluation, many of these
symptoms may remain stable or even decrease with time, whilst
psychosis and agitation may increase in frequency and severity with
disease progression in AD."

"(Both) groups reach end points of moderate-to-severe functional
impairment at roughly the same time."

"In one large longitudinal study, DLB patients were shown to have
shorter survival times, either as overall mortality or from disease
onset, compared with AD. The DLB group also had shorter times to
nursing home placement, and AD patients survived a median of 10
months longer in nursing homes than DLB patients. Survival and
mortality was significantly impacted by gender (males died sooner),
the presence of EPS and depression. Tremor appears to offer a
protective effect, suggesting that rigid-predominant forms of DLB
have worse outcomes than the less common tremor-predominant
forms. These results were examined for both pure and mixed forms of DLB."

"While some studies have suggested that LBD is marked by severe
impairment in frontal-subcortical tasks, such as executive function,
these findings have not been reproduced by other reports."

"A more consistent finding in LBD is prominent impairment in
visuospatial and visuoperceptual abilities. LBD patients often have
difficulty navigating in space... Brief cognitive tests such as the
(MMSE) or the Clock Draw may be able to detect deficits in
visuospatial or constructive abilities in moderate cases, but many
miss these deficits at the very mildest stage. Prominent
visuospatial dysfunction can be more readily detected by formal
psychometric testing..."

"Patients with AD with or without LB pathology have a more prominent
verbal memory deficit than that seen in pure DLB. Thus, individuals
with both AD and LBD are more severely affected in verbal and
visuospatial abilities than either pure AD or pure LBD."

"Autonomic dysfunction is a common clinical sign in LBD... It is a
less common finding in AD. Some of the supportive features included
in the consensus criteria, such as recurrent falls, syncope and
transient loss of consciousness, may be explained by underlying
autonomic dysfunction. Although these autonomic features tend to
occur later in the course, there have been cases with early and
prominent involvement. The most serious manifestation is
orthostasis, which can be either symptomatic or asymptomatic, the
former observed in approximately 15% of DLB patients. Other features
include decreased sweating, excess salivation (sialorrhea),
seborrhea, heat intolerance, urinary dysfunction, constipation or
diarrhea, and erectile dysfunction and impotence. These patients
have a higher frequency of carotid hypersensitivity than elderly
patients or patients with AD. This is also evidence of cardiac
denervation by...(MIBG) scintigraphic scanning, a finding not seen in AD."

"RBD is regarded as a supportive feature for the diagnosis of DLB,
although some now view RBD as a core diagnostic feature for DLB.
...[There is a] question of whether neuropsychological testing in rBD
is warranted to detect LBD at its earliest possible stages."

"Nondemented PD is misdiagnosed in 25% of cases, and DLB criteria has
a wide range of reported sensitivities (18-83%). ... In a recent
study, a review of 88 autopsy-confirmed cases suggested that
identification of clinical DLB is inversely proportional to Braak
staging of neurofibrillary pathology (although clinician sensitivity
was still poor regardless of classification scheme)."

"...(There) may be differences in how the pathology in DLB and PDD begins."

"LBD is also associated with cholinergic dysfunction and may in fact
be earlier in presentation and more severe than the cholinergic
dysfunction of AD. ... Severe losses of the basal forebrain ACh can
account for the hallucinations and fluctuations in arousal that
characterize LBD. On the other hand, postsynaptic muscarinic
receptors are better preserved and less functionally impaired in LBD
than in AD."

"Cortical cholinergic projections are severely reduced in LBD, thus
providing a rationale for developing therapies targeting the
alpha7-receptor subtype or drugs that can modulate the nicotinic
receptor activity such as galantamine." (galantamine = Razadyne)

"The occurrence of amyloid pathology is well documented for LBD."

"The Abeta1-40ox is reported to have a diagnostic sensitivity and
specificity of 88 and 73%...for the detection of LBD. ...[This has]
potential utility as a diagnostic marker..." (Robin's note: the
symbol won't work in email form. I believe this is a symbol for a
beta-amyloid peptide that is oxidized. I think this can be found in
cerebrospinal fluid.)

"...Beta-amyloid deposition may differentially promote tau
aggregation in AD and synuclein aggregation in LBD."

"APOE is also a risk factor for LBD..."

"To date, there is no compelling evidence that any one AChEI is
better than the other [in treating LBD]. Three independent clinical
studies of AChEI treatment using donepezil, galantamine or
rivastigmine is patients with LBD suggest that all AChEIs improve
cognitive and neuropsychiatric measures. There is no significant
increase in EPS with AChEI use." (donepezil = Aricept; galantamine =
Razadyne; rivastigmine = Exelon)

"There are no clinical trials on the best treatment of motor features
in LBD. ...(Some) improvement is seen in motor function with levodopa
therapy in most cases of LBD. This is a risk, however, of provoking
behavioral or psychotic symptoms."

"Dopamine agonists are associated with more side effects, especially
drug-induced psychosis, even at low doses. ... There are no direct
head-to-head trials comparing dopamine agonists with levodopa in
DLB. However, the best risk-benefit ratio in LBD with motor features
seems to be achieved with levodopa. Therefore, a trial of levodopa
is recommended in DLB with slow titration of the dose to produce
symptomatic benefit."

"Other PD medications such as amantidine,...and anti-cholinergics,
have the risk of exacerbating cognitive impairment and should
preferably be avoided."

"(The) cognitive impairment in DLB makes them poor candidates for DBS."

"AChEIs can potentially worsen parkinsonism. In a study on
rivastigmine in PD...the average Unified Parkinson Disease Rating
Scale score was not significantly different between the treatment and
placebo groups."

"The first-line measure in treating poor behaviors should be
nonpharmacologic, including evaluating for physical ailments that may
be provoking behavioral disturbances (eg, fecal impaction, pain or
decubitus ulcers)."

"Affective disorders (anxiety and depression) are common in LBD and,
anecdotally, LBD patients respond to selective serotonin transporter
inhibitors and anxiolytics, although they have not been rigorously
studied. A general rule is that when medications are needed to
modify behaviors, they should be used for the shortest duration
possible. Benzodiazepines are better avoided given their risk of
sedation and paradoxical agitation. Chloral hydrate should be given
on an as needed basis only." (chloral hydrate = Noctec)

"Visual hallucinations have been suggested as predictors of a good
response to AChEIs."

"(Therapies) directed at AD could potentially have deleterious
outcomes if administered to someone with LBD." (Robin's note: The
authors never gave specifics about this but perhaps they are
referring to antipsychotics.)

"Typical neuroleptics (such as haloperidol) and atypical neuroleptics
with D2 receptor antagonism (such as olanzapine and risperidone)
should be avoided for the risk of neuroleptic malignant syndrome,
parkinsonism, somnolence and orthostatic hypotension. ... Quetiapine
and clozapine are preferred when psychosis warrants treatment. ...
Aripiprazole has not been studied in LBD, but has been shown to be
effective in PD and AD and may be considered in the treatment of LBD
psychosis if needed. Quetiapine has become a popular treatment of
psychosis in LBD given the low incidence of motor deterioration and
its ability to control visual hallucinations with lose
doses. Efficacy and tolerability has been documented in both PD and DLB."

"A meta-analysis of six large trials in AD showed a small but
significant benefit for AChEIs in treating neuropsychiatric symptoms."

"Clonazepam has been the mainstay of medical therapy for RBD and is
usually effective at a dose of 0.25-0.5 mg/night, although doses
above 1 mg/night are necessary in some patients. Melatonin may also
offer some benefit either as a monotherapy or in conjunction with
clonazepam. Melatonin [may have] a more direct mode of action on REM
sleep pathophysiology."

"For insomnia, treatment can be attempted with low doses of
benzodiazepines, such as zolpidem or trazadone. These medications
have not been extensively studied in LBD and daytime sedation is a
potential side effect."

"If simple measures fail, medication such as midodrine or
fludrocortisone can be used" to manage orthostatic hypotension.

"Medications with anticholinergic activity...can be used to treat
urinary urgency... They should be used cautiously, however, given
their risk of exacerbating cognitive problems."

"Constipation can usually be treated by exercise and dietary
modifications. ... The prokinetic effect of cholinergic stimulation
by AChEIs might improve the symptoms in some patients."

"Memantine...was approved by the FDA for the treatment of
moderate-to-severe AD in 2003 but has not been studied in
LBD." (memantine = Namenda)

"(Statins) and other drugs that alter lipid homeostatis may have a
potential role in LBD."

"Clinical trials [of Vitamin E] in AD and PD had inconclusive results."

"A 16-month, randomized, placebo-controlled pilot trial in 80
subjects with mild PD found significant benefits for oral CoQ10 1200
mg/day to slow functional deterioration. However, to date, there are
no published clinical trials of CoQ10 in AD or LBD."

Fri Dec 28, 2007 5:21 pm

Joined: Sat Jan 27, 2007 8:38 pm
Posts: 712
Location: CA
Robin and Patty --
Thanks for making this article available to us -- it is one of the most understandable pieces on LBD that I've read, and I will be sharing it with Jerome's doctors and pharmacist.

Renata (and Jerome-in-Heaven)

Fri Dec 28, 2007 9:00 pm
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