Neurodegenerative Disorders

Alzheimer's Disease

AD, the most common dementing disorder in older adults, has been recognized as one of the most significant health problems of the 20th and 21st centuries. AD is estimated to affect 10% of people older than 65 years and 50% of individuals older than 85 years. Two abnormal protein aggregates characterize AD pathology: neuritic plaques and neurofibrillary tangles (NFTs). Neuritic plaques are extracellular deposits and consist of a dense central core of amyloid β fibrils with inflammatory cells and dystrophic neurites in its periphery. The second major proteinopathy in AD is aggregated tau, which consists of intraneuronal polymers primarily composed of hyperphosphorylated tau in the form of NFTs.

In typical late-onset (arbitrarily defined as age at onset > 65 years) AD, the medial temporal lobes (MTL), especially the hippocampus and entorhinal cortex, are among the earliest sites of pathologic involvement ( Fig. 15-2 ). MTL atrophy in the presence of memory loss is now one of the supportive biomarkers to make a diagnosis of AD proposed by the new diagnostic criteria. Other severely affected regions include the posterior portion of the cingulate gyrus and the precuneus on the medial surface (see Fig. 15-2 ), and the parietal, posterior superior temporal, and frontal regions on the lateral cerebral surfaces.

Structural MRI studies in mild cognitive impairment (MCI) have produced mixed results, both in terms of hippocampal and posterior cingulate and parietal involvement (absent, unilateral, or bilateral). The reasons for this variability may consist of different subject selection (i.e., diverse diagnostic inclusion criteria), small sample size (i.e., studies are not adequately powered to pick up differences even at the group level), and methodological differences. It is also worth noting that the largest source of variance in MCI studies is likely to be the intrinsic heterogeneity of the MCI population, because a relevant proportion of these subjects will not progress to dementia. MCI patients with predominant memory impairment (amnestic MCI), who are at increased risk of developing AD, have atrophy in a consistent set of cortical regions (the “cortical signature of AD”), including the MTL and temporoparietal cortex. Conversely, nonamnestic MCI shows a different pattern of atrophy characterized by relative sparing of the MTL and a regional involvement that is typically highly consistent with the observed clinical deficits. It should be emphasized that MTL atrophy may occur in other diseases as well; thus MTL atrophy alone lacks the specificity to confidently exclude other dementias, in particular in patients at the MCI stage.

Early-onset AD patients (i.e., onset of symptoms before age 65) showed less prominent MTL atrophy and greater involvement of the parietal, lateral temporal, and frontal regions compared to late-onset AD cases. A specific visual rating scale has been designed, evaluating the posterior cingulate, precuneus, and superior parietal regions. The utility of such a scale has been assessed in pathologically proven (mostly early-onset) AD and frontotemporal lobar degeneration (FTLD) patients. Thirty percent of AD patients had posterior atrophy in the absence of abnormal MTL atrophy, whereas only 7% of the FTLD group had abnormal posterior atrophy scores and normal MTL. Adding the posterior atrophy to the MTL visual rating score improved discrimination of early-onset AD from normal controls and all AD from FTLD cases.

Cerebral blood flow (CBF) single-photon emission computed tomography (SPECT) and F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans of typical AD patients demonstrate predominant hypoperfusion or reduced glucose metabolism in the temporoparietal regions, including the precuneus and the posterior cingulate cortex ( Fig. 15-3 ). Functional frontal lobe involvement is also often reported in AD but usually in conjunction with and characteristically less severe than temporoparietal involvement. Overall hypoperfusion or hypometabolism in early-onset AD is much greater in magnitude and extent than that of late-onset AD, with similar dementia severity. The primary visual and sensorimotor cortices, cerebellum, thalamus, and basal ganglia are relatively spared in AD. FDG PET differentiates patients with MCI from healthy controls. Amnestic MCI typically shows regional hypometabolism consistent with AD, although the magnitude of reduction is milder than that in clinically probable AD cases. Longitudinal studies of patients with MCI found that if the baseline FDG PET scan suggests an AD-like pattern, the probability of clinical progression within several years is extremely high.

Frontotemporal Dementia

FTD is the umbrella term encompassing a group of progressive proteinopathies that are heterogeneous with regard to etiology and neuropathology but share (1) atrophy of the frontal and/or temporal cortex as a morphologic feature and (2) deposition of abnormal ubiquitinated protein inclusions in the cytoplasm and nucleus of neuronal and glial cells as major pathologic constituents. FTD includes three clinical syndromes and three major underlying neuropathologic subtypes. The clinical syndromes, which are distinguished by the early and predominant symptoms, are: a behavioral dysexecutive disorder (behavioral variant [bv]FTD); a language disorder (primary progressive aphasia [PPA] variants); and a motor disorder such as amyotrophic lateral sclerosis (ALS), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP) syndrome. The neuropathologic subtypes are characterized by an abnormal accumulation of proteins : microtubule-associated protein tau (MAPT), TAR DNA-binding protein (TDP) 43, and fused in sarcoma protein (FUS). FTLD-tau, FTLD-TDP, and FTLD-FUS represent 45%, 50%, and 5% of all FTLD cases, respectively, at postmortem examination.

The designation of probable bvFTD by the revised diagnostic criteria restricts diagnosis to patients with demonstrable functional decline and typical neuroimaging findings, including frontal and/or temporal atrophy, and hypoperfusion or hypometabolism on PET or SPECT.

Structural MRI studies showed that classic bvFTD presents with a combination of medial frontal, orbital-insular and anterior temporal cortical atrophy ( Fig. 15-4 ). Such an atrophy pattern can be readily appreciated on coronal T1-weighted MRI scans (knife-edge atrophy) (see Fig. 15-4 ). The MTL is more affected anteriorly (i.e., the amygdala is more affected than the hippocampus and posterior hippocampus often appears normal). Nevertheless, the typical pattern is not necessarily present in all cases, particularly in patients with FTD and motor neuron disease, and the pattern of atrophy in bvFTD varies significantly across different cohorts. In some cases, bvFTD presents with remarkable atrophy of the right anterior temporal lobe and lesser involvement of the frontal regions.

BvFTD is identified on SPECT or PET scans by patterns of hypoperfusion or hypometabolism in frontal, insular, and anterior temporal regions that are typically quite asymmetrically centered into the frontolateral cortex (see Fig. 15-3 ). The regions mostly impaired are the medial frontal cortex, followed by the frontolateral and anterior temporal cortices. The regional pattern of predominantly frontal functional impairment in bvFTD, with relative sparing of posterior brain regions, usually allows a clear distinction between these patients and those with AD (see Fig. 15-3 ).

In patients clinically diagnosed with PPA, who are then divided into clinical variants based on specific speech and language features characteristic for each subtype, an “imaging-supported” diagnosis can be made if the expected pattern of focal atrophy on structural MRI scans or functional involvement on SPECT and FDG is found.

Semantic variant PPA is associated with left anterior temporal atrophy (temporal pole) affecting the lateral and ventral temporal surfaces (see Fig. 15-4 ) as well as particularly the anterior hippocampus, amygdala, and fusiform gyrus. Semantic patients may have left hippocampal atrophy that is at least as severe as that seen in AD patients. In these patients, the hippocampal atrophy is predominantly located anteriorly, with relative preservation of the posterior hippocampal regions. As the disease progresses, the right temporal lobe becomes more involved. The nonfluent PPA variant is associated with a characteristic pattern of left anterior perisylvian atrophy involving inferior, opercular, and insular portions of the frontal lobe (see Fig. 15-4 ). Motor and premotor regions and Broca's area are also involved. Compared with controls, nonfluent patients also have atrophy of the left hippocampus; however, it is less severe than that in AD patients. In the logopenic PPA variant, the pattern of atrophy primarily affects the left temporoparietal junction, including the left posterior superior and middle temporal gyri, as well as the inferior parietal lobule. Involvement of the left MTL is reported less consistently. Such a posterior temporoparietal pattern of atrophy chiefly discriminates this syndrome from the other subtypes of PPA.

In patients with semantic variant PPA, FDG PET studies showed asymmetric hypometabolism of the temporal lobes, more marked on the left side. A functional deficit of the left frontal opercular regions of the brain has been reported in nonfluent variant PPA patients. In these cases, functional involvement of bilateral caudate nuclei and thalami was also described. Logopenic PPA patients usually show a pattern of left posterior temporoparietal hypometabolism on FDG PET scans.

Dementia with Lewy Bodies

DLB is the second most common type of degenerative dementia, accounting for 10% to 15% of cases. The core clinical features of DLB include fluctuating attention, recurrent visual hallucinations, and spontaneous parkinsonism, as well as cognitive impairment characterized by deficits of attention, executive functions (e.g., planning deficits), and complex visual abilities. Memory deficits are not inevitably present, particularly in the early stages. Fluctuations of cognitive function over minutes, hours, or days are a core feature and affect mainly the level of arousal.

DLB is characterized by nigrostriatal dopaminergic neurodegeneration, making dopaminergic imaging a potentially useful diagnostic tool in the differential diagnosis with AD ( Fig. 15-5 ). Low dopamine transporter uptake in the basal ganglia demonstrated by SPECT or PET has been included as a suggestive feature in the diagnostic criteria for DLB. On the contrary, its negativity does not exclude a clinical diagnosis of probable DLB; about 20% of probable DLB cases have a normal or inconclusive scan.

Numerous studies reported predominant medial occipital cortex hypoperfusion or hypometabolism in DLB patients compared with AD, with a parietotemporal reduction common to both the diseases. Occipital lobe hypometabolism differentiated patients with DLB from AD in both clinically diagnosed and autopsy confirmed cohorts.

No clear signature pattern of cerebral atrophy associated with DLB has been established so far. Similar to AD, a diffuse pattern of global GM atrophy including temporal, parietal, frontal, and insular cortices may occur in DLB, but at the same time a pattern of cortical GM loss restricted to frontal and parietal lobes has also been reported. On the whole, several volumetric studies have not found significant or disproportionate occipital atrophy in DLB. A relatively robust MR finding in DLB is that of a relative preservation of the MTL when compared with AD of similar clinical severity. This finding is supported by a prospective MRI study with pathologic verification that found that MTL atrophy on MRI has a robust discriminatory power for distinguishing AD from DLB (sensitivity of 91% and specificity of 94%). Thus a relative preservation of MTL structures on CT or MRI supports a diagnosis of DLB in the consensus diagnostic criteria. Subcortical structural alterations in terms of putamen atrophy have been described in some cases of DLB relative to AD, whereas no significant atrophy was detected in the caudate nucleus. A pattern of relatively focused atrophy of the midbrain, hypothalamus, and substantia innominata, with relative sparing of the hippocampus and temporoparietal cortex, has been found in DLB compared to AD cases. Whether these findings can contribute to an early diagnosis remains unknown. Furthermore a substantial overlap between DLB and AD with regard to atrophy in these regions detracts from the usefulness of these markers in individual cases.