Involvement of the cholinergic basal forebrain nuclei in spinocerebellar ataxia type 2 (SCA2).
OBJECTIVE
Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG repeat or polyglutamine diseases. Along with a large variety of motor, behavioural and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of attention, impairments of memory, as well as frontal-executive and visuospatial dysfunctions. As the possible morphological correlates of these cognitive SCA2 deficits are unclear we examined the cholinergic basal forebrain nuclei, which are believed to be crucial for several aspects of normal cognition and may contribute to impairments of cognitive functions under pathological conditions.


METHODS
We studied pigment-Nissl-stained thick tissue sections through the cholinergic basal forebrain nuclei (that is, medial septal nucleus, nuclei of the diagonal band of Broca, basal nucleus of Meynert) of four clinically diagnosed and genetically confirmed SCA2 patients and of 13 control individuals according to the pathoanatomical approach. The pathoanatomical results were confirmed by additional quantitative investigations of these nuclei in the SCA2 patients and four age- and gender-matched controls.


RESULTS
Our study revealed a severe and consistent neuronal loss in all of the cholinergic basal forebrain nuclei (medial septal nucleus: 72%; vertical nucleus of the diagonal band of Broca: 74%; horizontal limb of the diagonal band of Broca: 72%; basal nucleus of Meynert: 86%) of the SCA2 patients studied. Damage to the basal forebrain nuclei was associated with everyday relevant cognitive deficits only in our SCA2 patient with an additional Braak and Braak stage V Alzheimer's disease (AD)-related tau pathology.


CONCLUSIONS
The findings of the present study: (1) indicate that the mutation and pathological process underlying SCA2 play a causative role for this severe degeneration of the cholinergic basal forebrain nuclei and (2) may suggest that degeneration of the cholinergic basal forebrain nuclei per se is not sufficient to cause profound and global dementia detrimental to everyday practice and activities of daily living.
Dr. Senckenberg Chronomedical Institute, Goethe-University, Frankfurt/Main, Germany.
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Rüb
K
K
Farrag
K
K
Seidel
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Brunt
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H
Heinsen
K
K
Bürk
B
B
Melegh
C
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von Gall
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Auburger
J
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Bohl
H W
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Korf
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Hoche
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den Dunnen
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology; D020532:Basal Nucleus of Meynert / Q000473:pathology*; D059329:Cholinergic Neurons / Q000473:pathology*; D020667:Diagonal Band of Broca / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012686:Septal Nuclei / Q000473:pathology*; D020754:Spinocerebellar Ataxias / Q000473:pathology*; D055815:Young Adult
ADCA; SCA2; basal forebrain; cholinergic system; dementia; pathoanatomy