Daniel M. Keller, PhD

April 07, 2015

NICE, France — Early-onset and late-onset subcortical vascular cognitive impairment may have overlapping etiologies but varying contributions from vascular factors and age-related amyloid burden, a new study suggests.

"We found out that in the early-onset group, they had more vascular risk factors and more lacunes, and they were more likely to have 'pure' small vessel disease pathology," said Hee Jin Kim, MD, of the Sunkyunkwan University School of Medicine, in Seoul, Korea.

"On the contrary, the late-onset group had more amyloid burden, and they were more likely to have 'mixed' pathology," Dr Kim said.

Their findings were presented here at the AD/PD 2015: International Conference on Alzheimer's and Parkinson's Diseases.

Subcortical Vascular Dementias

Early-onset Alzheimer's disease and early-onset frontotemporal dementia have been studied extensively, but not so with the subcortical vascular dementias, the authors note.

To look more closely at these conditions, the researchers prospectively enrolled 142 patients from a single referral center. They defined early-onset subcortical vascular cognitive impairment (EOSVCI, n = 31) as onset before age 65 years and late-onset disease (LOSVCI, n = 111) as onset at 65 years or older.

All patients received brain MRI scans for brain structure volume evaluation, PiB-PET (Pittsburgh compound B positron emission tomography) imaging for amyloid, and neuropsychological testing.

The significantly different baseline characteristics between the EOSVCI and LOSVCI groups were age (65.3 vs 76.6 years, respectively; P < .001) and age at disease onset (58.7 vs 72.3 years, respectively; P < .001). There was also a difference in vascular risk factors.

The early-onset group had a higher history of stroke (38.7% vs 18.0%) and more obesity (61.3% vs 39.6%). The two groups were the same in terms of ApoE ε4 carriers (about 27%), educational level, and severity of cognitive impairment.

Dr Kim explained that subcortical vascular dementia is characterized by subjective cognitive complaints, objective cognitive decline by neuropsychological testing, focal neurological signs, and severe ischemia on MRI with lacunes, periventricular white matter hyperintensities of 10 mm or greater, and deep white matter hyperintensities of 25 mm or greater.

A standardized value uptake ratio (SUVR) on PiB-PET of less than 1.5 was considered negative for amyloid and therefore "pure" subcortical vascular cognitive impairment, and higher values were considered amyloid-positive, or "mixed" for amyloid with vascular impairment. Cerebellar gray matter was used as a reference.

The researchers hypothesized a spectrum, with pure EOSVCI having a high burden of small vessel disease and low amyloid burden, but decreasing vascular contribution and greater amyloid burden for LOSVCI.

EOSVCI: More Lacunes, Less Amyloid-Positive

Compared with LOSVCI, the group of EOSVCI patients had more lacunes and less amyloid accumulation, but they had the same volume of white matter hyperintensities. Cortical thickness and hippocampal volumes were also greater in the EOSVCI group (Table).

LOSVCI vs EOSVCI

Endpoint EOSVCI (n = 31) LOSVCI (n = 111) P-value
Small Vessel Disease Burden
White Matter Hyperintensities Volume, mL 37.6 ± 18.0 38.5 ± 18.33 .772
Lacunes, number 17.9 ± 20.0 9.8 ± 11.0 .005
Amyloid Burden
PiB SUVR* >1.5 5 (16.7%) 44 (39.6%) .015
Brain Structures*
Cortical Thickness, mm 2.9 2.8 .049
Hippocampal Volume, mm3 2900 2500 .047

*Adjusted for sex and intracranial volume.

 

The two groups did not differ with regard to results on memory tests.

In terms of structural changes, the EOSVCI group had more white matter network disruptions, whereas the late-onset group had more cortical and hippocampal atrophy. Both groups had cognitive impairment, particularly frontal-executive dysfunction among the early-onset patients.

Dr Kim concluded that more extensive small vessel disease burden was necessary to cause the same level of cognitive impairment in early-onset disease. In late-onset disease, age-related factors such as amyloid burden are partially responsible for the cognitive dysfunction.

Session moderator Reinhold Schmidt, MD, chairman of the Department of Neurology at the University of Graz, Austria, agreed that increasing amyloid burden becomes more important with age.

"What remains open is whether this amyloid deposition or coexisting vascular and primary degenerative pathology actually interacts or if it has only additive effects," he commented to Medscape Medical News.

He noted that Dr Kim said during the discussion period after her talk that she did not find much of an interaction. "This is actually in contrast to many other studies that rather focused [on] interactive effects between vascular factors and primary degenerative disease in old age," Dr Schmidt noted.

He said the study is "midsized," but was very thorough, "and maybe this is also a reason for the contrasting results with large epidemiological studies, where you see this interactive effect between Alzheimer-like findings, or at least cognitive patterns and vascular risk factors."

A clinical message that may be drawn is that if vascular factors contribute to the pathology, the treatment of vascular factors would also affect the evolution of Alzheimer's pathology, but Dr Schmidt says the lack of an interactive effect would argue against this notion.

Nonetheless, controlling common vascular risk factors early may lessen at least the vascular contribution to cognitive dysfunction later, he added.

There was no commercial funding for the study. Dr Kim and Dr Schmidt have disclosed no relevant financial relationships.

AD/PD 2015: International Conference on Alzheimer's and Parkinson's Diseases: Abstract 431. Presented March 21, 2015.

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