Another characteristic that has guided understanding of degenerative disease is the possible contiguous “spread” of protein aggregation from one to another region by synaptic connections. In some cases, this results in adjacent regions being affected sequentially and in others, circuits that are functionally integrated but not necessarily contiguous are affected. This geographic mechanism, proposed by Braak and colleagues, conforms to certain pathologic observations such as the sequential appearance of synuclein in the olfactory system, thence in the Meissner-Auerbach plexus of the gut, followed by the vagus, to involvement of the vagal nuclei in the medulla, ascending trans- synaptically to the pons and midbrain nuclei. Whether this accounts for the selectivity of disease in areas such as the substantia nigra that is most affected in Parkinson disease, is not entirely known. In any case, the biologic and the physicochemical properties of these aggregated proteins have assumed great importance and the mechanisms by which they interfere with cellular function and potentially cause cell death are major areas of research in the degenerative diseases.
Because grouping of the degenerative diseases in terms of etiology is not entirely possible, except that a hereditary or genetic factor can be recognized in some. For this reason) we resort for practical purposes to a division based on the presenting clinical syndromes and their pathologic anatomy. Although this is the most elementary mode of classification of naturally occurring phenomena, it is a necessary prelude to diagnosis and scientific study and is more natural for the clinician than is a purely genetic or molecular classification. It is also an improvement on a haphazard listing of diseases by the names of the neurologists or neuropathologists who first described them. For reasons given in the introduction to this chapter, this approach remains effective in analyzing the problem presented by an individual patient. The main clinical categories are as follows:
I. Syndrome of progressive dementia, other neurologic signs absent or inconspicuous
A.	Alzheimer disease
B.	Some cases of Lewy body disease
C.	Frontotemporal dementias—Pick disease, including behavioral variant, primary progressive aphasias (several types)
D.	Posterior cortical atrophy (visuospatial dementia)
II. Syndrome of progressive dementia in combination with other neurologic abnormalities
A.	Huntington disease (chorea)
B.	Lewy-body disease (parkinsonian features)
C.	Corticobasal ganglionic degeneration (rigidity, dystonia)
D.	Cortical-striatal-spinal degeneration (spasticity)
E.	Frontotemporal dementia-amyotrophic lateral sclerosis complex
F.	Familial dementia with spastic paraparesis, amyotrophy, or myoclonus
G.	Polyglucosan body disease (neuropathy)
III. Syndrome of disordered posture and movement
A.	Parkinson disease
B.	Multiple system atrophy, MSA-P (striatonigral degeneration, autonomic failure)
C.	Progressive supranuclear palsy
D.	Dystonia musculorum deformans
E.	Huntington disease (chorea)
F.	Acanthocytosis with chorea
G.	Corticobasal ganglionic degeneration
H.	Lewy-body disease
I.	Restricted dystonias, including spasmodic torticollis and Meige syndrome
IV. Syndrome of progressive ataxia
A.	Spinocerebellar ataxias 1. Friedreich ataxia 2. Non-Friedreich ataxia (retained reflexes, tremor, hypogonadism, myoclonus, and other disorders)
B.	Cerebellar cortical ataxias 1. Holmes type of familial pure cerebellar-olivary atrophy 2. Late-onset cerebellar atrophy