amyotrophic lateral sclerosis / parkinsonism - dementia complex ( als / pdc ) is a rare disorder endemic to guam island and the kii peninsula of japan .
it shows a unique combination of parkinsonism , amyotrophy , and dementia , and the form of dementia , which shows a phenotype similar to alzheimer 's disease ( ad ) , is becoming predominant in the kii peninsula .
although kii als / pdc shows several unique clinical features , including severe atrophy of the frontal and temporal lobes on magnetic resonance imaging ( mri ) , decreased cerebral blood flow in the frontal and temporal lobes on single - photon emission computed tomography ( spect ) , pigmentary retinopathy , and decreased cardiac i - meta - iodobenzylguanidine uptake , a postmortem examination is required for a definitive diagnosis . since biomarkers for als
/ pdc have not yet been identified , we analyzed cerebrospinal fluid ( csf ) biomarkers for kii als / pdc to discriminate it from other neurodegenerative disorders .
we collected csf samples from 12 patients with kii als / pdc ( 6 men , 6 women , mean age 67.9  3.7 years , mean illness duration 5.63 years ) , nine patients with ad ( 2 men , 7 women , mean age 61.1  8.7 years , mean illness duration 1.92 years ) , 11 patients with als ( 8 men , 3 women , mean age 60.6  12.6 years , mean illness duration 1.1 years ) , nine patients with parkinson 's disease ( pd ; 7 men , 2 women , mean age 71.3  2.2 years , mean illness duration 4.42 years ) , and five disease control patients ( c ; 4 men , 1 woman , mean age 36.2  20.3 years ) .
all of the patients with kii als / pdc were natives of hohara village , which is an area of high als / pdc prevalence on the kii peninsula .
we collected csf samples over 10 years ; therefore , the period between csf collection and analysis was not standardized .
the diagnosis of kii als was made according to the airlie house criteria , since the clinical symptoms of kii als are essentially the same as those of classical als .
the diagnosis of kii pdc was made by a unique combination of levodopa - unresponsive parkinsonism and dementia , which are frequently accompanied by amyotrophy of the extremities and/or pyramidal tract signs .
mini - mental state examination ( mmse ) was used for the evaluation of dementia and cut - off point was 23 ( data not shown ) .
the frontal lobes and/or temporal lobes of als / pdc patients showed atrophy on mri and/or a decrease of cerebral blood flow on spect .
csf samples were immediately centrifuged at 1000  g for 15  min and stored at 80c with polypropylene tube .
the total tau ( t - tau ) , phosphorylated tau ( p - tau ) , and amyloid beta ( a ) concentrations were measured with an enzyme - linked immunosorbent assay ( elisa ) kit using a monoclonal antibody specific for t - tau , p - tau , and a142 ( innotest htau ag , phosphor tau(181p ) , and -amyloid ( 142 ) , innogenetics , ghent , belgium ) .
elisa assays were carried out using several samples from each group on the same plate in a randomized manner and were repeated using randomized samples in the same manner in plural times .
a factorial anova was performed with csf - t - tau , csf - p - tau , and csf - a42 , as dependent variables , with the diagnostic category ( ad , als , c , kii als / pdc , and pd ) using jmp 9.0 .
the ethics committee of mie university graduate school of medicine approved this study and the  declaration of helsinki  was followed .
csf - a42 , csf - t - tau , and csf - p - tau were compared between ad , als , c , kii als / pdc , and pd .
the concentrations of csf - t - tau and csf - p - tau were significantly higher in ad ( t - tau ; 378.0  41.76  pg / ml ; p < 0.001 , p - tau ; 42.4  6.78  pg / ml ; p < 0.028 ) than in the other groups .
however , the concentrations of csf - t - tau and csf - p - tau did not differ significantly between kii als / pdc , als , c , and pd ( figures 1(a ) and 1(b ) ) .
the concentration of csf - a42 was significantly reduced in ad ( 402.2  56.6  pg / ml ; p < 0.03 ) compared to als and c and relatively reduced in kii als / pdc ( 465.4  53.69  pg / ml ; p < 0.018 ) compared to als .
most of the als / pdc patients had csf concentration values that fell below the cutoff based on c ( figure 1(c ) ) .
the ratios of csf - p - tau to csf - a42 were significantly increased in ad ( 0.125  0.02 ) compared with kii als / pdc ( 0.043  0.02 ; p < 0.008 ) , als ( 0.035  0.019 ; p < 0.003 ) , pd ( 0.025  0.02 ; p < 0.002 ) , and c ( 0.027  0.09 ; p
the concentrations of csf - t - tau , csf - p - tau , or csf - a42 were not related to the clinical parameters ( age , sex , illness duration , or dementia ) in the kii als / pdc patients .
the number of c samples was small and the average age of control patients was low .
generally , csf tau level gradually increase according to age and csf a is not affected by age .
csf tau level of c samples was relatively low , but it was not significant .
thus , the csf values of c were not comparable to those of other groups .
nevertheless , the optimal cut - off values that discriminate c from ad were similar to those in previous reports [ 6 , 7 ] in which a larger number of control samples were analyzed .
csf tau level of kii als / pdc samples did not increase , although the average age of kii als / pdc group was older than that of ad group .
the present study showed that csf - t - tau and csf - p - tau concentrations from patients with kii als / pdc were not increased compared to those in the other disease groups , and a42 concentration in the csf was relatively decreased .
the ratio of csf - p - tau to csf - a42 segregates kii als / pdc from ad .
because als / pdc is associated with tau pathology in the absence of amyloid plaques , the expectation was that als / pdc patients would not show the alzheimer 's disease ( ad ) profile of decreased a42 but might show increased t - tau and/or p - tau in the csf .
in general , decreased csf - a42 indicates plaque pathology , and increased csf - t - tau and csf - p - tau indicate axonal degeneration and tangle pathology , respectively .
recently , the average age of onset of kii als / pdc is increasing and a deposition is conspicuous in autopsied patients . therefore , decreased csf - a42 may reflect a pathology in the most recent patients .
we analyzed the precise tau isoform of over 10 patients with autopsy - proven als / pdc recently and identified a 3r  +  4r type , 4r > 3r type , and a 4r predominant type .
the glial tau pathology is particularly related to the 4r isoform , and we consider kii als / pdc to be a 4r - dominant tauopathy ( unpublished data ) .
noguchi et al . examined the concentrations of csf - t - tau , csf - p - tau , and csf - a42 in patients with progressive supranuclear palsy ( psp ) and corticobasal degeneration ( cbd ) ; the concentrations of csf - t - tau and csf - p - tau did not significantly differ between psp , cbd , and controls , and the concentration of csf - a42 was significantly lower in psp and cbd than in controls .
the authors speculated that the absence of an increase of csf - t - tau and csf - p - tau concentrations might reflect 4r tau predominance and a reduction of csf - a42 might suggest deposition or mismetabolism of a . taken together , csf biomarkers of kii als / pdc might have similar properties to those of 4r tauopathy , psp , and cbd ; however the relationship between tau isoform and csf tau level remains to be resolved .
finally , the present findings , in which csf - t - tau and csf - p - tau concentrations were not increased and csf - a42 concentration was relatively decreased , suggest that csf analysis may be useful to differentiate als / pdc from ad , als , and pd . nevertheless there is a major limitation of the interpretation of the data .
the size of each group is small , the age of the control group is much younger , and there were two populations in the ad group regarding the levels tau , p - tau , and a/p - tau .
further study using groups with larger size of subjects is needed to confirm the proposed utility of the csf biomarkers .
 
 objective . 
 amyotrophic lateral sclerosis / parkinsonism - dementia complex is classified as one of the tauopathies . methods . 
 the total tau , phosphorylated tau , and amyloid 42 levels were assayed in cerebrospinal fluid from patients with kii amyotrophic lateral sclerosis / parkinsonism - dementia complex ( n = 12 ) , alzheimer 's disease ( n = 9 ) , parkinson 's disease ( n = 9 ) , amyotrophic lateral sclerosis ( n = 11 ) , and controls ( n = 5 ) using specific enzyme - linked immunosorbent assay methods . results . 
 total tau and phosphorylated tau did not increase and amyloid 42 was relatively reduced in kii amyotrophic lateral sclerosis / parkinsonism - dementia complex . 
 relatively reduced amyloid 42 might discriminate kii amyotrophic lateral sclerosis / parkinsonism - dementia complex from amyotrophic lateral sclerosis and parkinson 's disease , and the ratios of phosphorylated - tau to amyloid 42 could discriminate kii amyotrophic lateral sclerosis / parkinsonism - dementia complex from alzheimer 's disease 
 . conclusions . 
 cerebrospinal fluid analysis may be useful to differentiate amyotrophic lateral sclerosis / parkinsonism - dementia complex from alzheimer 's disease , amyotrophic lateral sclerosis , and parkinson 's disease . 