In the disorders considered here, selective neuronal populations are destroyed. We will review Alzheimer’s disease (AD), Pick’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s chorea. You should consider these to be representative of a larger group of diseases. For a discussion of Creutzfeldt-Jacob disease and the Prion disorders go to INFECTIONS.

Slide 66 & Slide 67 & Slide 68

Photographs 66, 67 and 68 depict cortical atrophy. These gross pictures are all taken from the brains of individuals who died with AD. On the external views note the generalized but predominantly frontal/parietal gyral thinning. This leads to widened sulci. In picture 66, we have removed the meninges to allow better visualization of atrophic gyri. In the coronal section, 68, taken at the level of the basal ganglia, you can appreciate widened frontal sulci and ex vacuo hydrocephalus (expansion of the lateral ventricle secondary to a loss of brain substance, not an obstructive hydrocephalus). The hippocampus and parahippocampal regions which are usually also involved are not shown in these photographs. In AD there is a significant loss of cortical neurons and synapses which accounts for much of the atrophy. In addition to cortex certain deep nuclear populations are involved. Can you name 2? Yes, the amygdala and nucleus basalis of Meynert are good answers. Which of these accounts for the loss of cortical acetylcholine which is typical of AD?

Now lets anticipate diagnostic microscopic findings. Without morphometric analysis the loss of neurons and synapses is not something we can adequately appreciate by routine microscopy. Photomicrographs 69 and 70 are of silver stained cerebral cortical sections at low and higher magnifications. What is the image shown in both? Is a specific finding for AD? If not, where else can it be seen? Senile plaque is the answer. Normal aged brains exhibit senile plaques. They are in lesser numbers than in AD. There are several morphological forms of senile plaques. The plaque shown in 70 is a good example of a compact neuritic plaque.

Slide 69 & Slide 70

Slide 71 & Slide 71a

For more information regarding the pathology of AD: plaques, neurofibrillary tangles and AD beta protein. Click on additional text

Look at the silver and Tau immuno stained cortical section in photographs 71 and 71a, neuronal neurofibrillary tangles are well illustrated in both photos. The Tau photo also reveals a senile plaque with Tau positive swollen neurites. These are briefly discussed in the above insert.

Now go back to photo 70, what is in the center of the plaque? How might you selectively visualize it? AD beta protein amyloid is the answer. With stains for amyloid like congo red or with antibodies to AD beta protein. If you use such antibodies, you will see many more positive areas than you would visualize with sensitive stains for amyloids, some rather diffuse in outline and shape. This is because not all immunoreactive protein is beta pleated sheet or fibrillar in nature. Plaques of this type are commonly seen in non-demented elderly individuals and in AD patients. What other structures might contain AD beta protein reactivity and congophilia? Yes, blood vessel walls. Where? Leptomeninges and cerebral cortex. Slide 70a below demonstrates senile plaque and vessel wall AD beta protein immunoreactivity.

Slide 70a

Are such vessels at risk of hemorrhage? Yes. Of intimal thickening, thrombosis and occlusion? Yes.

For a brief discussion of AD genetics. Click on additional text

Slide 72

On to picture 72 which shows exteme lobar atrophy of frontal and temporal lobe with sparing of the posterior third of the superior temporal gyrus. This is a classical picture of? Pick’s disease.

Slide 73a & 73b

The silver stained section at low magnification and the immuno stained section at higher magnification seen in 73a and b depict typical "ball shaped" Pick bodies, cytoplasmic argentophilic agreggates. Pick’s disease is a relatively rare form of dementia.

Slide 85 & Slide 86

Slide 87 and Slide 87 enlarged

Now lets look at photograph 85 a gross section of the midbrain. Compare this section of midbrain with the normal in the next photograph, 86 which also includes the pons at the level of another pigmented nuclear area. What is it? By comparing 85 and 86 you may be able to see that there is gross depigmentation of the substancia nigra in Photo 85. With your handy microscope you now demonstrate that many pigmented neurons, in both pigmented structures, contain the finding in photograph 87. There will also be considerable loss of pigmented neurons. The finding is? A Lewy body. The diagnosis is---Idiopathic Parkinson’s disease. Lewy bodies can be seen not only in catecholaminergic neurons but also in other neuronal populations. They may be found in cerebral cortical neurons and in certain cholinergic regions, such as the nucleus basalis of Meynert. When their numbers in cortex are considerable and patients present with dementia, the diagnosis is Diffuse Lewy Body Disease.

Diffuse Lewy Body Disease is a relatively new concept which developed in response to the observation that amongst patients with dementia, there is a subgroup with cerebral cortical Lewy body formation which is more significant than plaques and tangles, which may also be present. Patients in this group may also have Lewy bodies in the pigmented brainstem populations, as is seen in Idiopathic Parkinson’s Disease (PD), however the brainstem involvement is not as impressive as the cortical involvement nor is it as intense as in PD.

Photomicrographs DLBD 1 and 2 below illustrate cortical Lewy bodies immunostained with antibodies to ubiquitin, red reaction product. In photograph 1 you will also see a positive senile plaque.

Slide 88 & Slide 89

What would you see in post encephalitic Parkinson’s disease. Slides 88 and 89 are typical. Note the depletion of the pigmented population in 88 and the slightly basophilic neuronal cytoplasmic inclusion, neurofibrillary degeneration, in 89. So neurofibrillary neuronal degeneration is not unique to AD!

The Spinal Muscular Atrophies (SMA) include genetically determined disorders which maybe grouped by age of onset, distribution of weakness, severity, clinical progression and pattern of inheritance. The largest category appears to be autosomal recessive SMA which, based upon age of onset and progression, is subdivided into 3 types. To date all three types are linked to abnormalities on chromosome 5.

For references

2. Identification of a Spinal Muscular Atrophy-Determining Gene by S. Lefebvre etal. Cell:80,155-165,1995.

The photomicrographs below illustrate findings in the ventral gray matter of the spinal cord of an infant who died from type I SMA, also referred as Werdnig Hoffmann disease. Note the paucity of motor neurons, the "empty cell beds" and the highly abnormal surviving neuronal morphology. The first picture is a low power image. The second and third are selected high power images.

Photographs: SMA 1,2,3

Slide 83

Now lets look at slide 83 which shows pallor in the cortical spinal pathways of spinal cord. This finding suggest the possibility of motor neuron disease. Where else would you expect to find pathology if this is a case of sporadic amyotrophic lateral sclerosis? Motor cortex, motor cranial nerve nuclei and ventral spinal motor neurons. What would you see? For the answer, compare slides 83b, normal spinal ventral grey matter, and c, ALS spinal ventral grey matter, below.

Slide 83b & Slide 83c

Slide 84

What would you expect in a skeletal muscle section from such a patient? This slide shows the typical picture of neurogenic atrophy. Note the big group of very small muscle fibers.

To learn more about ALS, Click on additional text

 

Slide 75 & Slide 76 & Slide 77

The last entity under neurodegenerative processes is shown in photographs 75,76 and 77. The 2 gross photographs depict atrophy of basal ganglia, best appreciated by the loss of the caudate contour within the lateral ventricle. In 76, you should also note some cerebral cortical atrophy. 77 is a section of caudate stained for astrocytes. Note the astrocytosis. In this neuronal destructive disease certain types of neurons are more resistant than others. What types of neurons are more resistant ? Very very recent reports suggest that the protein product of the abnormal gene, a long trinucleotide repeat-CAG repeat-forms a fibrillar, amloid-like, intranuclear deposit ( "Huntingtin-Encoded Polyglutamine Expansions Form amyloid-like Protein Aggregates in Vitro and In Vivo" in Cell, vol. 90,p 549-558,1997 by Scherzinger etal.). Yes, I have given away the diagnosis with the reference.